Tocilizumab

INDICATIONS AND USAGE ACTEMRA ® (tocilizumab) is an interleukin-6 (IL-6) receptor antagonist indicated for treatment of: Rheumatoid Arthritis (RA) ( 1.1 ) Adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more Disease-Modifying Anti-Rheumatic Drugs (DMARDs). Giant Cell Arteritis (GCA) ( 1.2 ) Adult patients with giant cell arteritis. Systemic Sclerosis-Associated Interstitial Lung Disease (SSc-ILD) ( 1.3 ) Slowing the rate of decline in pulmonary function in adult patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) Polyarticular Juvenile Idiopathic Arthritis (PJIA) ( 1.4 ) Patients 2 years of age and older with active polyarticular juvenile idiopathic arthritis. Systemic Juvenile Idiopathic Arthritis (SJIA) ( 1.5 ) Patients 2 years of age and older with active systemic juvenile idiopathic arthritis. Cytokine Release Syndrome (CRS) ( 1.6 ) Adults and pediatric patients 2 years of age and older with chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome. Coronavirus Disease 2019 (COVID-19) ( 1.7 ) Hospitalized adult and pediatric patients aged 2 years and older with coronavirus disease 2019 (COVID-19) who are receiving systemic corticosteroids and require supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). 1.1 Rheumatoid Arthritis (RA) ACTEMRA ® (tocilizumab) is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more Disease-Modifying Anti-Rheumatic Drugs (DMARDs). 1.2 Giant Cell Arteritis (GCA) ACTEMRA ® (tocilizumab) is indicated for the treatment of giant cell arteritis (GCA) in adult patients. 1.3 Systemic Sclerosis-Associated Interstitial Lung Disease (SSc-ILD) ACTEMRA ® (tocilizumab) is indicated for slowing the rate of decline in pulmonary function in adult patients with systemic sclerosis-associated interstitial lung disease. 1.4 Polyarticular Juvenile Idiopathic Arthritis (PJIA) ACTEMRA ® (tocilizumab) is indicated for the treatment of active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older. 1.5 Systemic Juvenile Idiopathic Arthritis (SJIA) ACTEMRA ® (tocilizumab) is indicated for the treatment of active systemic juvenile idiopathic arthritis in patients 2 years of age and older. 1.6 Cytokine Release Syndrome (CRS) ACTEMRA ® (tocilizumab) is indicated for the treatment of chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome in adults and pediatric patients 2 years of age and older. 1.7 Coronavirus Disease 2019 (COVID-19) ACTEMRA® (tocilizumab) is indicated for the treatment of coronavirus disease 2019 (COVID-19) in hospitalized adult and pediatric patients aged 2 years and older who are receiving systemic corticosteroids and require supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).

DOSAGE AND ADMINISTRATION For RA, pJIA and sJIA, TOFIDENCE 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 - It is recommended that TOFIDENCE not be initiated in patients with an absolute neutrophil count (ANC) below 2000 per mm 3 , platelet count below 100,000 per mm 3 , or ALT or AST above 1.5 times the upper limit of normal (ULN). ( 5.3 , 5.4 ) COVID-19 - It is recommended that TOFIDENCE not be initiated in patients with an absolute neutrophil count (ANC) below 1000 per mm3 , platelet count below 50,000 mm3 , or ALT or AST above 10 times ULN ( 5.3 , 5.4 ). In RA or COVID-19 patients, TOFIDENCE doses exceeding 800 mg per infusion are not recommended. ( 2.2 , 12.3 ) In GCA patients, TOFIDENCE doses exceeding 600 mg per infusion are not recommended. ( 2.3 , 12.3 ) 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. 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. TOFIDENCE can be used alone following discontinuation of glucocorticoids. 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 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 Coronavirus Disease 2019 ( 2.6 ) The recommended dosage of TOFIDENCE for adult patients with COVID-19 is 8 mg per kg administered by a 60-minute intravenous infusion. Administration of Intravenous Formulation ( 2.7 ) For patients with RA, GCA, COVID-19, PJIA, and SJIA patients at or above 30 kg, dilute to 100 mL in 0.9% Sodium Chloride Injection, USP for intravenous infusion using aseptic technique. For PJIA and SJIA patients less than 30 kg, dilute to 50 mL in 0.9% Sodium Chloride Injection, USP for intravenous infusion using aseptic technique. Administer as a single intravenous drip infusion over 1 hour; do not administer as bolus or push. Dose Modifications ( 2.8 ) Recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia. 2.1 General Considerations for Administration Not Recommended for Concomitant Use with Biological DMARDs Tocilizumab products have not been studied in combination with biological DMARDs such as TNF antagonists, IL-1R antagonists, anti-CD20 monoclonal antibodies and selective co-stimulation modulators because of the possibility of increased immunosuppression and increased risk of infection. Avoid using TOFIDENCE with biological 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 TOFIDENCE not be initiated in patients with an absolute neutrophil count (ANC) below 2000 per mm 3 , platelet count below 100,000 per mm 3 , or ALT or AST above 1.5 times the upper limit of normal (ULN) [see Warnings and Precautions (5.3 , 5.4) ] . COVID-19 - It is recommended that TOFIDENCE not be initiated in patients with an absolute neutrophil count (ANC) below 1000 per mm3 , platelet count below 50,000 mm3 , or ALT or AST above 10 times ULN [see Warnings and Precautions (5.3 , 5.4) ] 2.2 Recommended Dosage for Rheumatoid Arthritis TOFIDENCE may be used as monotherapy or concomitantly with methotrexate or other non-biologic DMARDs as an intravenous infusion. Recommended Intravenous Dosage Regimen: The recommended dosage of TOFIDENCE for adult patients given as a 60-minute single intravenous drip infusion is 4 mg per kg every 4 weeks followed by an increase to 8 mg per kg every 4 weeks based on clinical response. Reduction of dose from 8 mg per kg to 4 mg per kg is recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.8) , Warnings and Precautions (5.3 , 5.4) , and Adverse Reactions (6.1) ]. Doses exceeding 800 mg per infusion are not recommended in RA patients [see Clinical Pharmacology (12.3) ]. When transitioning from intravenous therapy with TOFIDENCE to subcutaneous therapy with another tocilizumab product, administer the first subcutaneous dose instead of the next scheduled intravenous dose. Interruption of dose is recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.8) and Warnings and Precautions (5.3 , 5.4) . 2.3 Recommended Dosage for Giant Cell Arteritis Recommended Intravenous Dosage Regimen: The recommended dosage of TOFIDENCE 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. TOFIDENCE 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 [see Dosage and Administration (2.8) ]. Doses exceeding 600 mg per infusion are not recommended in GCA patients [see Clinical Pharmacology (12.3) ]. When transitioning from intravenous therapy with TOFIDENCE to subcutaneous therapy with another tocilizumab product, administer the first subcutaneous dose instead of the next scheduled intravenous dose. 2.4 Recommended Dosage for Polyarticular Juvenile Idiopathic Arthritis TOFIDENCE may be used as an intravenous infusion alone or in combination with methotrexate. Do not change dose based solely on a single visit body weight measurement, as weight may fluctuate. Recommended Intravenous Dosage Regimen: The recommended dosage of TOFIDENCE for PJIA patients given once every 4 weeks as a 60-minute single intravenous drip infusion is: Recommended Intravenous PJIA Dosage Every 4 Weeks Patients less than 30 kg weight 10 mg per kg Patients at or above 30 kg weight 8 mg per kg When transitioning from intravenous therapy with TOFIDENCE to subcutaneous therapy with another tocilizumab product, administer the first subcutaneous dose instead of the next scheduled intravenous dose. Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.8) ]. 2.5 Recommended Dosage for Systemic Juvenile Idiopathic Arthritis TOFIDENCE may be used as an intravenous infusion or in combination with methotrexate. Do not change a dose based solely on a single visit body weight measurement, as weight may fluctuate. Recommended Intravenous Dosage Regimen: The recommended dose of TOFIDENCE for SJIA patients given once every 2 weeks as a 60-minute single intravenous drip infusion is: Recommended Intravenous SJIA Dosage Every 2 Weeks Patients less than 30 kg weight 12 mg per kg Patients at or above 30 kg weight 8 mg per kg When transitioning from intravenous therapy with TOFIDENCE to subcutaneous therapy with another tocilizumab product, administer the first subcutaneous dose instead of the next scheduled intravenous dose. Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.8) ]. 2.6 Coronavirus Disease 2019 (COVID-19) Administer TOFIDENCE by intravenous infusion only. The recommended dosage of TOFIDENC

WARNINGS AND PRECAUTIONS Serious Infections – do not administer TOFIDENCE during an active infection, including localized infections. If a serious infection develops, interrupt TOFIDENCE until the infection is controlled. ( 5.1 ) Gastrointestinal (GI) perforation—use with caution in patients who may be at increased risk. ( 5.2 ) Hepatotoxicity- Monitor patients for signs and symptoms of hepatic injury. Modify or discontinue TOFIDENCE if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop. ( 2.8 , 5.3 ) Laboratory monitoring—recommended due to potential consequences of treatment-related changes in neutrophils, platelets, lipids, and liver function tests. ( 2.8 , 5.4 ) Hypersensitivity reactions, including anaphylaxis and death and serious cutaneous reactions including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) – discontinue TOFIDENCE, treat promptly, and monitor until reaction resolves ( 5.6 ) Live vaccines—Avoid use with TOFIDENCE. ( 5.9 , 7.3 ) 5.1 Serious Infections Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, protozoal, or other opportunistic pathogens have been reported in patients receiving immunosuppressive agents including tocilizumab products. The most common serious infections included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis [see Adverse Reactions (6.1) ]. Among opportunistic infections, tuberculosis, cryptococcus, aspergillosis, candidiasis, and pneumocystosis were reported with tocilizumab products. Other serious infections, not reported in clinical studies, may also occur (e.g., histoplasmosis, coccidioidomycosis, listeriosis). Patients have presented with disseminated rather than localized disease, and were often taking concomitant immunosuppressants such as methotrexate or corticosteroids which in addition to rheumatoid arthritis may predispose them to infections. Do not administer TOFIDENCE in patients with an active infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating TOFIDENCE in patients: with chronic or recurrent infection; who have been exposed to tuberculosis; with a history of serious or an opportunistic infection; who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or with underlying conditions that may predispose them to infection. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with TOFIDENCE, as signs and symptoms of acute inflammation may be lessened due to suppression of the acute phase reactants [see Dosage and Administration (2.1) , Adverse Reactions (6.1) , and Patient Counseling Information (17) ]. Hold TOFIDENCE if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with TOFIDENCE should undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, initiate appropriate antimicrobial therapy, and closely monitor the patient. COVID-19 In patients with COVID-19, monitor for signs and symptoms of new infections during and after treatment with TOFIDENCE. There is limited information regarding the use of tocilizumab products in patients with COVID-19 and concomitant active serious infections. The risks and benefits of treatment with TOFIDENCE in COVID-19 patients with other concurrent infections should be considered. Tuberculosis Evaluate patients for tuberculosis risk factors and test for latent infection prior to initiating TOFIDENCE. In patients with COVID-19, testing for latent infection is not necessary prior to initiating treatment with TOFIDENCE. Consider anti-tuberculosis therapy prior to initiation of TOFIDENCE in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an individual patient. Closely monitor patients for the development of signs and symptoms of tuberculosis including patients who tested negative for latent tuberculosis infection prior to initiating therapy. The incidence of tuberculosis in worldwide clinical development programs is 0.1%. Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before initiating TOFIDENCE. Viral Reactivation Viral reactivation has been reported with immunosuppressive biologic therapies and cases of herpes zoster exacerbation were observed in clinical studies with tocilizumab. No cases of Hepatitis B reactivation were observed in the trials; however patients who screened positive for hepatitis were excluded. 5.2 Gastrointestinal Perforations Events of gastrointestinal perforation have been reported in clinical trials, primarily as complications of diverticulitis in patients treated with tocilizumab. Use TOFIDENCE with caution in patients who may be at increased risk for gastrointestinal perforation. Promptly evaluate patients presenting with fever, new onset abdominal symptoms, and a change in bowel habits for early identification of gastrointestinal perforation [see Adverse Reactions (6.1) ]. 5.3 Hepatotoxicity Serious cases of hepatic injury have been observed in patients taking intravenous tocilizumab products. Some of these cases have resulted in liver transplant or death. Time to onset for cases ranged from months to years after treatment initiation with tocilizumab products. While most cases presented with marked elevations of transaminases (> 5 times ULN), some cases presented with signs or symptoms of liver dysfunction and only mildly elevated transaminases. During randomized controlled studies, treatment with tocilizumab was associated with a higher incidence of transaminase elevations [see Adverse Reactions (6.1 , 6.3 , 6.4) ]. Increased frequency and magnitude of these elevations was observed when potentially hepatotoxic drugs (e.g., MTX) were used in combination with tocilizumab. For RA and GCA patients, obtain a liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) before initiating TOFIDENCE, every 4 to 8 weeks after start of therapy for the first 6 months of treatment and every 3 months thereafter. It is not recommended to initiate TOFIDENCE treatment in RA or GCA patients with elevated transaminases ALT or AST greater than 1.5× ULN. In patients who develop elevated ALT or AST greater than 5× ULN, discontinue TOFIDENCE. For recommended modifications based upon increase in transaminases [see Dosage and Administration (2.8) ]. Patients hospitalized with COVID-19 may have elevated ALT or AST levels. Multi-organ failure with involvement of the liver is recognized as a complication of severe COVID-19. The decision to administer TOFIDENCE should balance the potential benefit of treating COVID-19 against the potential risks of acute treatment with TOFIDENCE. It is not recommended to initiate TOFIDENCE treatment in COVID-19 patients with elevated ALT or AST above 10 × ULN. Monitor ALT and AST during treatment. Measure liver tests promptly in patients who report symptoms that may indicate liver injury, such as fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient is found to have abnormal liver tests (e.g., ALT greater than three times the upper limit of the reference range, serum total bilirubin greater than two times the upper limit of the reference range), TOFIDENCE treatment should be interrupted and investigation done to establish the probable cause. TOFIDENCE s

CONTRAINDICATIONS Tocilizumab-anoh is contraindicated in patients with known hypersensitivity to tocilizumab products [see Warnings and Precautions (5.6) ]. Known hypersensitivity to tocilizumab products. ( 4 )

DRUG INTERACTIONS 7.1 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 [see Dosage and Administration (2.2) ] . In GCA patients, no effect of concomitant corticosteroid on tocilizumab exposure was observed. 7.2 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 Tocilizumab-anoh, 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 Tocilizumab-anoh 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 [see Clinical Pharmacology (12.3) ] . 7.3 Live Vaccines Avoid use of live vaccines concurrently with Tocilizumab-anoh [see Warnings and Precautions (5.9) ] .

ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in labeling: Serious Infections [see Warnings and Precautions (5.1) ] Gastrointestinal Perforations [see Warnings and Precautions (5.2) ] Laboratory Parameters [see Warnings and Precautions (5.4) ] Immunosuppression [see Warnings and Precautions (5.5) ] Hypersensitivity Reactions, Including Anaphylaxis [see Warnings and Precautions (5.6) ] Demyelinating Disorders [see Warnings and Precautions (5.7) ] Active Hepatic Disease and Hepatic Impairment [see Warnings and Precautions (5.8) ] Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice. Most common adverse reactions (incidence of at least 5%): upper respiratory tract infections, nasopharyngitis, headache, hypertension, increased ALT. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Biogen MA Inc. at 1-877-422-8360 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience in Rheumatoid Arthritis Patients Treated with Intravenous Tocilizumab (Tocilizumab-IV) The tocilizumab-IV data in rheumatoid arthritis (RA) includes 5 double-blind, controlled, multicenter studies. In these studies, patients received doses of tocilizumab-IV 8 mg per kg monotherapy (288 patients), tocilizumab-IV 8 mg per kg in combination with DMARDs (including methotrexate) (1582 patients), or tocilizumab-IV 4 mg per kg in combination with methotrexate (774 patients). The all exposure population includes all patients in registration studies who received at least one dose of tocilizumab-IV. Of the 4009 patients in this population, 3577 received treatment for at least 6 months, 3309 for at least one year; 2954 received treatment for at least 2 years and 2189 for 3 years. All patients in these studies had moderately to severely active rheumatoid arthritis. The study population had a mean age of 52 years, 82% were female and 74% were Caucasian. The most common serious adverse reactions were serious infections [see Warnings and Precautions (5.1) ]. The most commonly reported adverse reactions in controlled studies up to 24 weeks (occurring in at least 5% of patients treated with tocilizumab-IV monotherapy or in combination with DMARDs) were upper respiratory tract infections, nasopharyngitis, headache, hypertension and increased ALT. The proportion of patients who discontinued treatment due to any adverse reactions during the double-blind, placebo-controlled studies was 5% for patients taking tocilizumab-IV and 3% for placebo-treated patients. The most common adverse reactions that required discontinuation of tocilizumab-IV were increased hepatic transaminase values (per protocol requirement) and serious infections. Overall Infections In the 24 week, controlled clinical studies, the rate of infections in the tocilizumab-IV monotherapy group was 119 events per 100 patient-years and was similar in the methotrexate monotherapy group. The rate of infections in the 4 mg per kg and 8 mg per kg tocilizumab-IV plus DMARD group was 133 and 127 events per 100 patient-years, respectively, compared to 112 events per 100 patient-years in the placebo plus DMARD group. The most commonly reported infections (5% to 8% of patients) were upper respiratory tract infections and nasopharyngitis. The overall rate of infections with tocilizumab-IV in the all exposure population remained consistent with rates in the controlled periods of the studies. Serious Infections In the 24 week, controlled clinical studies, the rate of serious infections in the tocilizumab-IV monotherapy group was 3.6 per 100 patient-years compared to 1.5 per 100 patient-years in the methotrexate group. The rate of serious infections in the 4 mg per kg and 8 mg per kg tocilizumab-IV plus DMARD group was 4.4 and 5.3 events per 100 patient-years, respectively, compared to 3.9 events per 100 patient-years in the placebo plus DMARD group. In the all-exposure population, the overall rate of serious infections remained consistent with rates in the controlled periods of the studies. The most common serious infections included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. Cases of opportunistic infections have been reported [see Warnings and Precautions (5.1) ]. In the cardiovascular outcomes Study WA25204, the rate of serious infections in the tocilizumab 8 mg/kg IV every 4 weeks group, with or without DMARD, was 4.5 per 100 patient-years, and the rate in the etanercept 50 mg weekly SC group, with or without DMARD, was 3.2 per 100 patient-years [see Clinical Studies (14.1) ]. Gastrointestinal Perforations During the 24 week, controlled clinical trials, the overall rate of gastrointestinal perforation was 0.26 events per 100 patient-years with tocilizumab-IV therapy. In the all-exposure population, the overall rate of gastrointestinal perforation remained consistent with rates in the controlled periods of the studies. Reports of gastrointestinal perforation were primarily reported as complications of diverticulitis including generalized purulent peritonitis, lower GI perforation, fistula and abscess. Most patients who developed gastrointestinal perforations were taking concomitant nonsteroidal anti-inflammatory medications (NSAIDs), corticosteroids, or methotrexate [see Warnings and Precautions (5.2) ]. The relative contribution of these concomitant medications versus tocilizumab-IV to the development of GI perforations is not known. Infusion Reactions In the 24 week, controlled clinical studies, adverse events associated with the infusion (occurring during or within 24 hours of the start of infusion) were reported in 8% and 7% of patients in the 4 mg per kg and 8 mg per kg tocilizumab-IV plus DMARD group, respectively, compared to 5% of patients in the placebo plus DMARD group. The most frequently reported event on the 4 mg per kg and 8 mg per kg dose during the infusion was hypertension (1% for both doses), while the most frequently reported event occurring within 24 hours of finishing an infusion were headache (1% for both doses) and skin reactions (1% for both doses), including rash, pruritus and urticaria. These events were not treatment limiting. Anaphylaxis Hypersensitivity reactions requiring treatment discontinuation, including anaphylaxis, associated with tocilizumab-IV were reported in 0.1% (3 out of 2644) in the 24 week, controlled trials and in 0.2% (8 out of 4009) in the all-exposure population. These reactions were generally observed during the second to fourth infusion of tocilizumab-IV. Appropriate medical treatment should be available for immediate use in the event of a serious hypersensitivity reaction [see Warnings and Precautions (5.6) ]. Laboratory Abnormalities Neutropenia In the 24 week, controlled clinical studies, decreases in neutrophil counts below 1000 per mm 3 occurred in 1.8% and 3.4% of patients in the 4 mg per kg and 8 mg per kg tocilizumab-IV plus DMARD group, respectively, compared to 0.1% of patients in the placebo plus DMARD group. Approximately half of the instances of ANC below 1000 per mm 3 occurred within 8 weeks of starting therapy. Decreases in neutrophil counts below 500 per mm 3 occurred in 0.4% and 0.3% of patients in the 4 mg per kg and 8 mg per kg tocilizumab-IV plus DMARD, respectively, compared to 0.1% of patients in the placebo plus DMARD group. There was no clear relationship between decreases in neutrophils below 1000 per mm 3 and the occurrence of serious infections. In the all-exposure population, the pattern and incidence of decreases in neutrophil counts remained consistent with what was seen in the 24 week controlled clinical studies [see Warnings and Precautions (5.4) ]. Thrombocytopenia In the 24 week,

Mechanism of Action 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.