1.14 ML sarilumab 132 MG/ML Prefilled Syringe

INDICATIONS AND USAGE KEVZARA ® is an interleukin-6 (IL-6) receptor antagonist indicated for treatment of: adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs). ( 1.1 ) adult patients with polymyalgia rheumatica (PMR) who have had an inadequate response to corticosteroids or who cannot tolerate corticosteroid taper. ( 1.2 ) patients who weigh 63 kg or greater with active polyarticular juvenile idiopathic arthritis (pJIA). ( 1.3 ) 1.1 Rheumatoid Arthritis (RA) KEVZARA ® is indicated for treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs). 1.2 Polymyalgia Rheumatica (PMR) KEVZARA is indicated for treatment of adult patients with polymyalgia rheumatica who have had an inadequate response to corticosteroids or who cannot tolerate corticosteroid taper. 1.3 Polyarticular Juvenile Idiopathic Arthritis (pJIA) KEVZARA is indicated for treatment of active polyarticular juvenile idiopathic arthritis (pJIA) in patients who weigh 63 kg or greater.

DOSAGE AND ADMINISTRATION General Considerations for Administration KEVZARA initiation is not recommended in patients with ANC less than 2,000/mm 3 , platelets less than 150,000/mm 3 or liver transaminases above 1.5 times ULN. See Full Prescribing Information (FPI) for complete information. ( 2.1 ) Recommended Dosage in RA The recommended dosage is 200 mg subcutaneously, once every 2 weeks. ( 2.2 ) For RA, KEVZARA may be used as monotherapy or in combination with methotrexate (MTX) or other conventional DMARDs. ( 2.2 ) Recommended Dosage in PMR The recommended dosage is 200 mg subcutaneously, once every two weeks in combination with a tapering course of corticosteroids. ( 2.3 ) For PMR, KEVZARA can be used as monotherapy following discontinuation of corticosteroids. ( 2.3 ) Recommended Dosage in pJIA The recommended dosage is 200 mg given subcutaneously once every 2 weeks for pJIA patients who weigh 63 kg or greater using the 200 mg/1.14 mL pre-filled syringe. ( 2.4 ) For pJIA, KEVZARA can be used as monotherapy or in combination with conventional DMARDs. ( 2.4 ) Dosage Modifications for Cytopenias, Abnormal Liver Enzymes, Infections See FPI for complete information. ( 2.6 ) 2.1 General Considerations Prior to Administration Not Recommended for Concomitant Use with Biological DMARDS The concurrent use of KEVZARA with biological DMARDs such as tumor necrosis factor (TNF) antagonists, IL-1R antagonists, anti-CD20 monoclonal antibodies and selective co-stimulation modulators has not been studied. Avoid using KEVZARA with biological DMARDs because of the possibility of increased immunosuppression and increased risk of infection. Recommended Evaluations Prior to Treatment Complete blood count (CBC): Treatment initiation with KEVZARA is not recommended in patients with an absolute neutrophil count (ANC) below 2000 per mm 3 , or platelet count below 150,000 per mm 3 . Monitor laboratory parameters [see Warnings and Precautions (5.2) ]. Liver function tests (LFT): Treatment initiation with KEVZARA is not recommended in patients with or who have alanine transaminase (ALT) or aspartate aminotransferase (AST) above 1.5 times the upper limit of normal (ULN). Monitor laboratory parameters [see Dosage and Administration (2.6) and Warnings and Precautions (5.2) ] . Lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol and/or triglycerides): Assess lipid parameters at baseline. Monitor laboratory parameters [see Warnings and Precautions (5.2) ]. Active and latent tuberculosis infection evaluation: Prior to initiating KEVZARA, test patients for active and latent tuberculosis (TB). KEVZARA should not be administered to patients with active TB. If positive for latent infection, consider treating for TB prior to KEVZARA use [see Warnings and Precautions (5.1) ]. Evaluate for infections: Avoid KEVZARA use in patients with active infections [see Warnings and Precautions (5.1) ] . 2.2 Recommended Dosage for Rheumatoid Arthritis The recommended dosage of KEVZARA is 200 mg once every two weeks given as a subcutaneous injection [see Dosage and Administration (2.1) ]. KEVZARA may be used as monotherapy or in combination with methotrexate (MTX) or other conventional DMARDs. Modify the dosage as recommended in Table 1 if the patient develops neutropenia, thrombocytopenia, or liver enzyme abnormalities [see Dosage and Administration (2.6) , Warnings and Precautions (5.2) and Adverse Reactions (6.1) ]. 2.3 Recommended Dosage for Polymyalgia Rheumatica The recommended dosage of KEVZARA is 200 mg once every two weeks given as a subcutaneous injection, in combination with a tapering course of systemic corticosteroids [see Dosage and Administration (2.1) ] . KEVZARA can be used as monotherapy following discontinuation of corticosteroids. Discontinue KEVZARA if the patient develops neutropenia (using ANC results obtained at the end of the dosing interval), thrombocytopenia, or liver enzyme abnormalities [see Dosage and Administration (2.6) , Warnings and Precautions (5.2) and Adverse Reactions (6.1) ]. 2.4 Recommended Dosage for Polyarticular Juvenile Idiopathic Arthritis The recommended dosage of KEVZARA for patients who weigh 63 kg and greater is 200 mg once every two weeks given as a subcutaneous injection (maximum dose 200 mg). Dosage in this patient population can be achieved by administering the 200 mg/1.14 mL pre-filled syringe. The pre-filled pen is not intended for use in pediatric patients [see Dosage and Administration (2.6) , Warnings and Precautions (5.2) and Adverse Reactions (6.1) ]. KEVZARA is not approved in pediatric patients weighing less than 63 kg because of the lack of an appropriate dosage form. In patients with pJIA, KEVZARA can be used alone or in combination with conventional DMARDs. 2.5 Preparation and Administration Instructions Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. KEVZARA solution should be clear and colorless to pale yellow. Do not use if the solution is cloudy, discolored or contains particles, or if any part of the pre-filled syringe or pre-filled pen appears to be damaged. Rotate injection sites with each injection. Do not inject into skin that is tender, damaged, or has bruises or scars. Pre-filled Pen and Pre-filled Syringe KEVZARA is intended for use under the guidance of a healthcare professional. A patient may self-inject KEVZARA or the patient's caregiver may administer KEVZARA. Provide proper training to patients and/or caregivers on the preparation and administration of KEVZARA prior to use according to the Instructions for Use (IFU). Allow the pre-filled syringe to sit at room temperature for 30 minutes prior to subcutaneous injection. Do not warm KEVZARA in any other way. If using a pre-filled pen, allow the pre-filled pen to sit at room temperature for 60 minutes prior to subcutaneous injection. Do not warm KEVZARA in any other way. Instruct patients to inject the full amount in the syringe or pen (1.14 mL), which provides 200 mg or 150 mg of KEVZARA, according to the directions provided in the IFU. The ability of pediatric patients to self-inject with the pre-filled pen has not been tested. 2.6 Dosage Modifications for Cytopenias, Abnormal Liver Enzymes, or Infections Dosage Modifications for Patients with Rheumatoid Arthritis Laboratory Abnormalities : Modify dosage in case of neutropenia, thrombocytopenia, or liver enzyme elevations as shown in Table 1 [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2) ] . For treatment initiation criteria, refer to the dosage recommendations for RA [see Dosage and Administration (2.1 , 2.2) ] . Table 1: Dosage Modifications due to Neutropenia, Thrombocytopenia, or Elevated Liver Enzymes in Patients with Rheumatoid Arthritis Low Absolute Neutrophil Count (ANC) Lab Value (cells/mm 3 ) Recommendation ANC greater than 1,000 Maintain current dosage of KEVZARA. ANC 500 to 1,000 Hold treatment with KEVZARA until ANC greater than 1,000. KEVZARA can then be resumed at 150 mg every two weeks and increased to 200 mg every two weeks as clinically appropriate. ANC less than 500 Discontinue KEVZARA. Low Platelet Count Lab Value (cells/mm 3 ) Recommendation 50,000 to 100,000 Hold treatment with KEVZARA until platelets greater than 100,000. KEVZARA can then be resumed at 150 mg every two weeks and increased to 200 mg every two weeks as clinically appropriate. Less than 50,000 If confirmed by repeat testing, discontinue KEVZARA. Liver Enzyme Abnormalities Lab Value Recommendation ALT or AST greater than ULN to 3 times ULN Consider dosage modification of concomitant DMARDs as clinically appropriate. ALT or AST greater than 3 times ULN to 5 times ULN Hold treatment with KEVZARA until ALT or AST less than 3 times ULN. KEVZARA can then be resumed at 150 mg every two weeks and increased to 200 mg every two weeks as clinically appropriate. ALT or AST greater than 5 times ULN Discontinue KEVZARA. Infections: If

WARNINGS AND PRECAUTIONS Serious Infections: Avoid KEVZARA use during an active infection. ( 5.1 ) Neutropenia, Thrombocytopenia, Elevated Liver Enzymes, Lipid Abnormalities: Monitor laboratory parameters. ( 5.2 ) Gastrointestinal (GI) Perforation: Risk may be increased with concurrent diverticulitis or concomitant use of NSAIDs or corticosteroids. Promptly evaluate acute abdominal signs or symptoms. ( 5.3 ) Hypersensitivity reactions. ( 5.5 ) Live vaccines: Avoid use with KEVZARA. ( 5.7 , 7.3 ) 5.1 Serious Infections Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving immunosuppressive agents including KEVZARA. Among opportunistic infections, tuberculosis, candidiasis, and pneumocystis were reported with KEVZARA. Some patients presented with disseminated rather than localized disease and were often taking concomitant immunosuppressants such as methotrexate or corticosteroids. The most frequently observed serious infections with KEVZARA in RA patients included pneumonia and cellulitis [see Adverse Reactions (6.1) ] . While not reported in KEVZARA clinical studies, other serious infections (e.g., histoplasmosis, cryptococcus, aspergillosis) have been reported in patients receiving other immunosuppressive agents for the treatment of RA. Avoid use of KEVZARA in patients with an active infection, including localized infections. Consider the risks and benefits of treatment prior to initiating KEVZARA in patients who have: chronic or recurrent infection; a history of serious or opportunistic infections; underlying conditions that may predispose them to infection; been exposed to tuberculosis; or lived in or traveled to areas of endemic tuberculosis or endemic mycoses. Closely monitor patients for the development of signs and symptoms of infection during treatment with KEVZARA, as signs and symptoms of acute inflammation may be lessened due to suppression of the acute phase reactants [see Dosage and Administration (2.6) , Adverse Reactions (6.1) ] . Hold treatment with KEVZARA if a patient develops a serious infection or an opportunistic infection. Perform prompt and complete diagnostic testing appropriate for an immunocompromised patient who develops a new infection during treatment with KEVZARA; initiate appropriate antimicrobial therapy, and closely monitor the patient. Tuberculosis Evaluate patients for tuberculosis (TB) risk factors and test for latent infection prior to initiating treatment with KEVZARA. Treat patients with latent TB with standard antimycobacterial therapy before initiating KEVZARA. Consider anti-TB therapy prior to initiation of KEVZARA in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent TB but having risk factors for TB infection. When considering anti-TB therapy, consultation with a physician with expertise in TB may be appropriate. Closely monitor patients for the development of signs and symptoms of TB including patients who tested negative for latent TB infection prior to initiating therapy. Viral Reactivation Viral reactivation has been reported with immunosuppressive biologic therapies. Cases of herpes zoster were observed in clinical studies with KEVZARA [see Adverse Reactions (6.1) ] . The risk of Hepatitis B reactivation with KEVZARA is unknown since patients who were at risk for reactivation were excluded. 5.2 Laboratory Abnormalities Neutropenia Treatment with KEVZARA was associated with a higher incidence of decrease in absolute neutrophil count (ANC), including neutropenia [see Adverse Reactions (6.1) ] . Assess neutrophil count prior to initiation of KEVZARA and monitor neutrophil count 4 to 8 weeks after start of therapy and every 3 months thereafter [see Clinical Pharmacology (12.2) ] . For recommendations regarding initiating KEVZARA therapy and dosage modifications based on ANC results see Dosage and Administration (2.1 and 2.6) . Based on the pharmacodynamics of the changes in ANC [see Clinical Pharmacology (12.2) ] , use results obtained at the end of the dosing interval when considering dosage modification. Thrombocytopenia Treatment with KEVZARA was associated with a reduction in platelet counts in clinical studies [see Adverse Reactions (6.1) ] . Assess platelet count prior to initiation of KEVZARA and monitor platelets 4 to 8 weeks after start of therapy and every 3 months thereafter. For recommendations regarding initiating KEVZARA therapy and dosage modifications based on platelet counts see Dosage and Administration (2.1 and 2.6) . Elevated Liver Enzymes Treatment with KEVZARA was associated with a higher incidence of transaminase elevations. These elevations were transient and did not result in any clinically evident hepatic injury in clinical studies [see Adverse Reactions (6.1) ] . Increased frequency and magnitude of these elevations were observed when potentially hepatotoxic drugs (e.g., MTX) were used in combination with KEVZARA. Assess ALT/AST levels prior to initiation of KEVZARA and monitor ALT and AST levels 4 to 8 weeks after start of therapy and every 3 months thereafter. When clinically indicated, consider other liver function tests such as bilirubin. For recommendations regarding initiating KEVZARA therapy and dosage modifications based on transaminase elevations see Dosage and Administration (2.1 and 2.6) . Lipid Abnormalities Treatment with KEVZARA was associated with increases in lipid parameters such as LDL cholesterol, HDL cholesterol and/or triglycerides [see Adverse Reactions (6.1) ] . Assess lipid parameters approximately 4 to 8 weeks following initiation of treatment with KEVZARA, then at approximately 6-month intervals. Manage patients according to clinical guidelines for the management of hyperlipidemia. 5.3 Gastrointestinal Perforation Gastrointestinal perforations have been reported in clinical studies, primarily as complications of diverticulitis. GI perforation risk may be increased with concurrent diverticulitis or concomitant use of NSAIDs or corticosteroids. Promptly evaluate patients presenting with new onset abdominal symptoms [see Adverse Reactions (6.1) ] . 5.4 Immunosuppression Treatment with immunosuppressants may result in an increased risk of malignancies. The impact of treatment with KEVZARA on the development of malignancies is not known but malignancies were reported in clinical studies [see Adverse Reactions (6.1) ] . 5.5 Hypersensitivity Reactions Hypersensitivity reactions have been reported in association with KEVZARA [see Adverse Reactions (6.1) ]. Hypersensitivity reactions that required treatment discontinuation were reported in 0.3% of patients in controlled RA trials. Injection site rash, rash, and urticaria were the most frequent hypersensitivity reactions. Advise patients to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction. If anaphylaxis or other hypersensitivity reaction occurs, stop administration of KEVZARA immediately. Do not administer KEVZARA to patients with known hypersensitivity to sarilumab [see Contraindications (4) and Adverse Reactions (6.1) ] . 5.6 Active Hepatic Disease and Hepatic Impairment Treatment with KEVZARA is not recommended in patients with active hepatic disease or hepatic impairment, as treatment with KEVZARA was associated with transaminase elevations [see Adverse Reactions (6.1) , Use in Specific Populations (8.6) ] . 5.7 Live Vaccines Avoid concurrent use of live vaccines during treatment with KEVZARA due to potentially increased risk of infections; clinical safety of live vaccines during KEVZARA treatment has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving KEVZARA. Prior to initiating treatment, it is recommended that all patients be brought up to dat

CONTRAINDICATIONS KEVZARA is contraindicated in patients with known hypersensitivity to sarilumab or any of the inactive ingredients [see Warnings and Precautions (5.5) and Adverse Reactions (6.1) ] . KEVZARA is contraindicated in patients with known hypersensitivity to sarilumab or any of the inactive ingredients. ( 4 )

Mechanism of Action Sarilumab binds to both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R), and has 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.