Avtozma Drug Information

General Considerations for Administration Not Recommended for Concomitant Use with Biological DMARDs Tocilizumab products have not been studied in combination with biological DMARDs such as TNF antagonists, IL-1R antagonists, anti-CD20 monoclonal antibodies and selective co-stimulation modulators because of the possibility of increased immunosuppression and increased risk of infection. Avoid using 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 – It is recommended that AVTOZMA not be initiated in patients with an absolute neutrophil count (ANC) below 2000 per mm 3, platelet count below 100,000 per mm 3, or ALT or AST above 1.5 times the upper limit of normal (ULN). CRS - Patients with severe or life-threatening CRS frequently have cytopenias or elevated ALT or AST due to the lymphodepleting chemotherapy or the CRS. The decision to administer AVTOZMA should take in to account the potential benefit of treating the CRS versus the risks of short-term treatment with AVTOZMA.

COVID-19 – It is recommended that AVTOZMA not be initiated in patients with an absolute neutrophil count (ANC) below 1000 per mm 3, platelet count below 50,000 mm 3, or ALT or AST above 10 times ULN.

Recommended Dosage for Rheumatoid Arthritis 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.

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

• Recommended Dosage for Giant Cell Arteritis 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. AVTOZMA can be used alone following discontinuation of glucocorticoids. Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia. Doses exceeding 600 mg per infusion are not recommended in GCA patients.
• 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.

Recommended Dosage for Polyarticular Juvenile Idiopathic Arthritis 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: When transitioning from AVTOZMA intravenous therapy to subcutaneous administration, administer the first subcutaneous dose instead of the next scheduled intravenous dose.

Recommended Dosage for Cytokine Release Syndrome (CRS)

Use only the intravenous route for treatment of CRS. The recommended dose of AVTOZMA for treatment of CRS given as a 60-minute intravenous infusion is: • If no clinical improvement in the signs and symptoms of CRS occurs after the first dose, up to 3 additional does of AVTOZMA may be administered.

Coronavirus Disease 2019 (COVID-19) 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.

Subcutaneous administration is not approved for COVID-19.

Preparation and Administration Instructions for Intravenous Infusion 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. Step 1. Withdraw a volume of 0.9% or 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.

Step 2. Withdraw the amount of AVTOZMA for intravenous infusion from the vial(s) and add slowly into the 0.9% or 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. 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.

Preparation and Administration Instructions for Subcutaneous Injection AVTOZMA for subcutaneous injection is not intended for intravenous drip infusion. Assess suitability of patient for subcutaneous home use and instruct patients to inform a healthcare professional before administering the next dose if they experience any symptoms of allergic reaction. Patients should seek immediate medical attention if they develop symptoms of serious allergic reactions.

AVTOZMA subcutaneous injection is intended for use under the guidance of a healthcare practitioner. After proper training in subcutaneous injection technique, a patient may self-inject AVTOZMA or the patient's caregiver may administer AVTOZMA if a healthcare practitioner determines that it is appropriate. PJIA and SJIA patients may self-inject with the AVTOZMA prefilled syringe or prefilled autoinjector, or the patient's caregiver may administer AVTOZMA if both the healthcare practitioner and the parent/legal guardian determines it is appropriate.

Patients, or patient caregivers, should be instructed to follow the directions provided in the Instructions for Use (IFU) for additional details on medication 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.

Dosage

Modifications due to Serious Infections or Laboratory Abnormalities 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 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.

Clinical Trials Experience in Rheumatoid Arthritis Patients Treated with Intravenous Tocilizumab (Tocilizumab-IV) The tocilizumab-IV data in rheumatoid arthritis (RA) includes 5 double-blind, controlled, multicenter studies. The all exposure population includes all patients in registration studies who received at least one dose of tocilizumab-IV. All patients in these studies had moderately to severely active rheumatoid arthritis.

The study population had a mean age of 52 years, 82% were female and 74% were Caucasian. The most common serious adverse reactions were serious infections. The most commonly reported adverse reactions in controlled studies up to 24 weeks (occurring in at least 5% of patients treated with tocilizumab-IV monotherapy or in combination with DMARDs) were upper respiratory tract infections, nasopharyngitis, headache, hypertension and increased ALT.

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

The relative contribution of these concomitant medications versus tocilizumab-IV to the development of GI perforations is not known. Infusion Reactions In the 24 week, controlled clinical studies, adverse events associated with the infusion (occurring during or within 24 hours of the start of infusion) were reported in 8% and 7% of patients in the 4 mg per kg and 8 mg per kg tocilizumab-IV plus DMARD group, respectively, compared to 5% of patients in the placebo plus DMARD group. The most frequently reported event on the 4 mg per kg and 8 mg per kg dose during the infusion was hypertension (1% for both doses), while the most frequently reported event occurring within 24 hours of finishing an infusion were headache (1% for both doses) and skin reactions (1% for both doses), including rash, pruritus and urticaria.

These events were not treatment limiting. 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.

Approximately half of the instances of ANC below 1000 per mm 3 occurred within 8 weeks of starting therapy. There was no clear relationship between decreases in neutrophils below 1000 per mm 3 and the occurrence of serious infections. In the all-exposure population, the pattern and incidence of decreases in neutrophil counts remained consistent with what was seen in the 24 week controlled clinical studies.

Elevated Liver Enzymes Liver enzyme abnormalities are summarized in Table 1. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of tocilizumab-IV, or reduction in tocilizumab-IV dose, resulted in decrease or normalization of liver enzymes. These elevations were not associated with clinically relevant increases in direct bilirubin, nor were they associated with clinical evidence of hepatitis or hepatic insufficiency.

Table 1 Incidence of Liver Enzyme Abnormalities in the 24 Week Controlled Period of Studies I to V For a description of these studies, see Section 14, Clinical Studies. In the all-exposure population, the elevations in ALT and AST remained consistent with what was seen in the 24 week, controlled clinical trials. One serious event of drug induced hepatitis with hyperbilirubinemia was reported in association with tocilizumab.

Lipids Elevations in lipid parameters (total cholesterol, LDL, HDL, triglycerides) were first assessed at 6 weeks following initiation of tocilizumab-IV in the controlled 24 week clinical trials. Increases were observed at this time point and remained stable thereafter. Increases in triglycerides to levels above 500 mg per dL were rarely observed.

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. In the all-exposure population, the rate of malignancies remained consistent with the rate observed in the 24 week, controlled period.

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 Other infrequent and medically relevant adverse reactions occurring at an incidence less than 2% in rheumatoid arthritis patients treated with tocilizumab-IV in controlled trials were: Infections and Infestations: oral herpes simplex Gastrointestinal disorders: stomatitis, gastric ulcer Investigations: weight increased, total bilirubin increased Blood and lymphatic system disorders: leukopenia General disorders and administration site conditions: edema peripheral Respiratory, thoracic, and mediastinal disorders: dyspnea, cough Eye disorders: conjunctivitis Renal disorders: nephrolithiasis Endocrine disorders: hypothyroidism

Clinical Trials Experience in Rheumatoid Arthritis Patients Treated with Subcutaneous Tocilizumab (Tocilizumab-SC) The tocilizumab-SC data in rheumatoid arthritis (RA) includes 2 double-blind, controlled, multicenter studies. Study SC-I was a non-inferiority study that compared the efficacy and safety of tocilizumab 162 mg administered every week subcutaneously and 8 mg/kg intravenously every four weeks in 1262 adult subjects with rheumatoid arthritis. Study SC-II was a placebo controlled superiority study that evaluated the safety and efficacy of tocilizumab 162 mg administered every other week subcutaneously or placebo in 656 patients.

All patients in both studies received background non-biologic DMARDs. The safety observed for tocilizumab-SC administered subcutaneously was consistent with the known safety profile of intravenous tocilizumab, with the exception of injection site reactions (ISRs), which were more common with tocilizumab-SC compared with placebo SC injections (IV arm). Injection Site Reactions In the 6-month control period, in SC-I, the frequency of ISRs was for the weekly tocilizumab-SC and placebo SC (IV-arm) groups, respectively.

In SC-II, the frequency of ISRs was 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.

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. There was no clear relationship between decreases in neutrophils below 1 × 10 9 /L and the occurrence of serious infections. Thrombocytopenia During routine laboratory monitoring in the tocilizumab-SC 6-month controlled clinical trials, none of the patients had a decrease in platelet count to ≤50,000/mm 3.

The total patient years duration in the tocilizumab-SC GCA all exposure population was 138.5 patient years during the 12-month double blind, placebo-controlled phase of the study. The overall safety profile observed in the tocilizumab-SC treatment groups was generally consistent with the known safety profile of tocilizumab. There was an overall higher incidence of infections in GCA patients relative to RA patients.

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

Clinical Trials Experience in Giant Cell Arteritis Patients Treated with Intravenous Tocilizumab (Tocilizumab-IV) The safety of tocilizumab-IV was studied in an open label PK-PD and safety study in 24 patients with GCA who were in remission on tocilizumab-IV at time of enrollment. The total patient years exposure to treatment was 17.5 years. The overall safety profile observed for tocilizumab administered intravenously in GCA patients was consistent with the known safety profile of tocilizumab.

Clinical Trials Experience in Polyarticular Juvenile Idiopathic Arthritis Patients Treated with Intravenous Tocilizumab (Tocilizumab-IV) The safety of tocilizumab-IV was studied in 188 pediatric patients 2 to 17 years of age with PJIA who had an inadequate clinical response or were intolerant to methotrexate. The total patient exposure in the tocilizumab-IV all exposure population (defined as patients who received at least one dose of tocilizumab-IV) was 184.4 patient years. At baseline, approximately half of the patients were taking oral corticosteroids and almost 80% were taking methotrexate.

In general, the types of adverse drug reactions in patients with PJIA were consistent with those seen in RA and SJIA patients. 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.

Infusion Reactions In PJIA patients, infusion-related reactions are defined as all events occurring during or 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.

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

Elevated Liver Enzymes During routine laboratory monitoring in the tocilizumab-IV all exposure population, elevation in ALT or AST at or greater than 3 × ULN occurred in 4% and less than 1% of patients, respectively. Lipids During routine laboratory monitoring in the tocilizumab all exposure population, elevation in total cholesterol greater than 1.5-2 × ULN occurred in one patient (0.5%) and elevation in LDL greater than 1.5-2 × ULN occurred in one patient (0.5%).

Clinical Trials Experience in Polyarticular Juvenile Idiopathic Arthritis Patients Treated with Subcutaneous Tocilizumab (Tocilizumab-SC) The safety of tocilizumab-SC was studied in 52 pediatric patients 1 to 17 years of age with PJIA who had an inadequate clinical response or were intolerant to methotrexate. The total patient exposure in the PJIA tocilizumab-SC population (defined as patients who received at least one dose of tocilizumab-SC and accounting for treatment discontinuation) was 49.5 patient years. In general, the safety observed for tocilizumab administered subcutaneously was consistent with the known safety profile of intravenous tocilizumab, with the exception of injection site reactions (ISRs), and neutropenia.

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

One patient subsequently withdrew from the study.

Clinical Trials Experience in Systemic Juvenile Idiopathic Arthritis Patients Treated with Intravenous Tocilizumab (Tocilizumab-IV) The data described below reflect exposure to tocilizumab-IV in one randomized, double-blind, placebo- controlled trial of 112 pediatric patients with SJIA 2 to 17 years of age who had an inadequate clinical response to nonsteroidal anti-inflammatory drugs (NSAIDs) or corticosteroids due to toxicity or lack of efficacy. At baseline, approximately half of the patients were taking 0.3 mg/kg/day corticosteroids or more, and almost 70% were taking methotrexate. The trial included a 12 week controlled phase followed by an open-label extension.

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. 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. 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.

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

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. 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. 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.

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

Clinical Trials Experience in Patients with Cytokine Release Syndrome Treated with Intravenous Tocilizumab (Tocilizumab-IV) In a retrospective analysis of pooled outcome data from multiple clinical trials 45 patients were treated with tocilizumab 8 mg/kg (12 mg/kg for patients less than 30 kg) with or without additional high-dose corticosteroids for severe or life-threatening CAR T cell-induced CRS. A median of 1 dose of tocilizumab (range, 1-4 doses) was administered. No adverse reactions related to tocilizumab were reported.

Clinical Trials Experience in COVID-19 Patients Treated with Intravenous Tocilizumab (Tocilizumab-IV) The safety of tocilizumab in hospitalized COVID-19 patients was evaluated in a pooled safety population that includes patients enrolled in EMPACTA, COVACTA, AND REMDACTA. The analysis of adverse reactions included a total of 974 patients exposed to tocilizumab. Patients received a single, 60-minute infusion of intravenous tocilizumab 8 mg/kg (maximum dose of 800 mg).

If clinical signs or symptoms worsened or did not improve, one additional dose of tocilizumab 8 mg/kg could be administered between 8- 24 hours after the initial dose. Adverse reactions summarized in Table 3 occurred in at least 3% of tocilizumab-treated patients and more commonly than in patients on placebo in the pooled safety population. Table 3 Adverse Reactions Patients are counted once for each category regardless of the number of reactions Identified From the Pooled COVID-19 Safety Population In the pooled safety population, the rates of infection/serious infection events were 30%/19% in patients receiving tocilizumab versus 32%/23% receiving placebo.

Laboratory Abnormalities In the pooled safety population of EMPACTA, COVACTA, and REMDACTA, neutrophil counts <1000 cells/mcl occurred in 3.4% of patients who received tocilizumab and 0.5% of patients who received placebo. Platelet counts <50,000 cells/mcl occurred in 3.2% of patients who received tocilizumab and 1.5% of patients who received placebo. ALT or AST at or above 5× ULN occurred in 11.7% of patients who received tocilizumab and 9.9% of patients who received placebo.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of tocilizumab products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hypersensitivity Reactions: Fatal anaphylaxis, Stevens-Johnson Syndrome, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Pancreatitis Drug-induced liver injury, Hepatitis, Hepatic failure, Jaundice Hypofibrinogenemia

Concomitant Drugs for Treatment of Adult Indications 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.

In GCA patients, no effect of concomitant corticosteroid on tocilizumab exposure was observed.

Interactions with CYP450 Substrates 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.g., warfarin) or drug concentration (e.g., 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.g., oral contraceptives, lovastatin, atorvastatin, etc. The effect of tocilizumab products on CYP450 enzyme activity may persist for several weeks after stopping therapy.

Live Vaccines

Avoid use of live vaccines concurrently with AVTOZMA.

Pregnancy 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 exposed infant.

In animal reproduction studies, intravenous administration of tocilizumab to Cynomolgus monkeys during organogenesis caused abortion/embryo-fetal death at doses 1.25 times and higher than the maximum recommended human dose by the intravenous route of 8 mg per kg every 2 to 4 weeks. The literature in animals suggests that inhibition of IL-6 signaling may interfere with cervical ripening and dilatation and myometrial contractile activity leading to potential delays of parturition. Based on the animal data, there may be a potential risk to the fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 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. 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.

For mice deficient in IL-6 (ll6 -/- null mice), parturition was delayed relative to wild-type (ll6 +/+ ) mice. Administration of recombinant IL-6 to ll6 -/- null mice restored the normal timing of delivery.

Pediatric Use 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 Severe or life-threatening CAR T cell-induced cytokine release syndrome (CRS) in patients with 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, SJIA or CRS have not been established. Systemic Juvenile Idiopathic Arthritis – Intravenous Use A multicenter, open-label, single arm study to evaluate the PK, safety and exploratory PD and efficacy of tocilizumab over 12-weeks in SJIA patients (N=11) under 2 years of age was conducted.

Patients received intravenous tocilizumab 12 mg/kg every two weeks. Concurrent use of stable background treatment with corticosteroids, MTX, and/or non-steroidal anti-inflammatory drugs was permitted. Patients who completed the 12-week period could continue to the optional extension period (a total of 52-weeks or until the age of 2 years, whichever was longer).

The primary PK endpoints (C max, C trough and AUC 2weeks ) of tocilizumab at steady-state in this study were within the ranges of these parameters observed in patients with SJIA aged 2 to 17 years. The safety and immunogenicity of tocilizumab for patients with SJIA under 2 years of age was assessed descriptively. SAEs, AEs leading to discontinuation, and infectious AEs were reported by 27.3%, 36.4%, and 81.8% of patients.

Six patients (54.5%) experienced hypersensitivity reactions, defined as all adverse events occurring during or within 24 hours after an infusion considered related to tocilizumab. Three of these patients experienced serious hypersensitivity reactions and were withdrawn from the study. Three patients with hypersensitivity reactions (two with serious hypersensitivity reactions) developed treatment induced anti- tocilizumab antibodies after the event.

There were no cases of MAS based on the protocol-specified criteria, but 2 cases of suspected MAS based on Ravelli criteria Ravelli A, Minoia F, Davì S on behalf of the Paediatric Rheumatology International Trials Organisation, the Childhood Arthritis and Rheumatology Research Alliance, the Pediatric Rheumatology Collaborative Study Group, and the Histiocyte Society, et al. 2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis. Annals of the Rheumatic Diseases 2016;75:481-489. There were no differences between the pediatric patients and the adults for safety or efficacy.

AVTOZMA is contraindicated in patients with known hypersensitivity to tocilizumab products. Known hypersensitivity to tocilizumab products.

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.