Sarilumab

1 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.

2 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 a patient with RA develops a serious infection or an opportunistic infection, hold treatment with KEVZARA until the infection is controlled [see Warnings and Precautions (5.1) ]. Dosage Modifications for Patients with Polymyalgia Rheumatica Laboratory Abnormalities : Discontinue KEVZARA in patients with PMR who develop the following laboratory abnormalities [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2) ] : neutropenia (ANC below 1,000 per mm 3 at the end of the dosing interval) thrombocytopenia (platelet count below 100,000 per mm 3 ) AST or ALT elevations 3 times above the ULN Dosage modifications have not been studied in patients with PMR with these conditions. For treatment initiation criteria, refer to the dosage recommendations for PMR [see Dosage and Administration (2.1 , 2.3) ] . Infections : If a patient with PMR develops a serious infection or an opportunistic infection, hold treatment with KEVZARA until the infection is controlled [see Warnings and Precautions (5.1) ]. Dosage Modification for Patients with Polyarticular Juvenile Idiopathic Arthritis Dose reduction of KEVZARA has not been studied in the pJIA population. Discontinue KEVZARA if ALT >5 ULN, platelet count ≤50,000 cells/mm 3 , neutrophil count <500 cells/mm 3 associated with infection. Hold KEVZARA dosing for ALT >3 to ≤5 ULN, platelet count >50,000 to ≤100,000 cells/mm 3 , and neutrophil count ≥500 to <1000 cells/mm 3 , and until the clinical condition has been evaluated. The decision to discontinue KEVZARA should be based upon the medical assessment of the individual patient. If appropriate, the dose of concomitant methotrexate and/or other medications should be modified or discontinued.

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in labeling: Serious infections [see Warnings and Precautions (5.1) ] Neutropenia, thrombocytopenia, elevated liver enzymes, lipid abnormalities [see Warnings and Precautions (5.2) ] Gastrointestinal perforation [see Warnings and Precautions (5.3) ] Immunosuppression [see Warnings and Precautions (5.4) ] Hypersensitivity reactions [see Warnings and Precautions (5.5) ] Most common adverse reactions are: Rheumatoid Arthritis (incidence ≥3 %): neutropenia, increased ALT, injection site erythema, upper respiratory infections and urinary tract infections. ( 6.1 ) Polymyalgia Rheumatica (incidence ≥ 5%): neutropenia, leukopenia and injection site pruritus. ( 6.1 ) Polyarticular Juvenile Idiopathic Arthritis: nasopharyngitis, neutropenia, upper respiratory tract infection and injection site erythema. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis at 1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience 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 reflect the rates observed in practice. Rheumatoid Arthritis All patients in the safety data described below had moderately to severely active rheumatoid arthritis. The safety of KEVZARA in combination with conventional DMARDs was evaluated based on data from seven studies, of which two were placebo-controlled, consisting of 2887 patients (long-term safety population). Of these, 2170 patients received KEVZARA for at least 24 weeks, 1546 for at least 48 weeks, 1020 for at least 96 weeks, and 624 for at least 144 weeks. The pre-rescue placebo-controlled population includes patients from the two Phase 3 efficacy studies (Studies 1 and 2) from weeks 0 to 16 for Study 1 and weeks 0 to 12 for Study 2, and was used to assess common adverse reactions and laboratory abnormalities prior to patients being permitted to switch from placebo to KEVZARA. In this population, 582 patients, 579 patients, and 579 patients received KEVZARA 200 mg, KEVZARA 150 mg, or placebo once every two weeks, respectively, in combination with conventional DMARDs. The 52-week placebo-controlled population includes patients from one Phase 2 study of 12-week duration and two Phase 3 efficacy studies (one of 24-week duration and the other of 52-week duration). This placebo-controlled population includes all subjects from the double-blind, placebo-controlled periods from each study and was analyzed under their original randomization assignment. In this population, 661 patients, 660 patients, and 661 patients received KEVZARA 200 mg, KEVZARA 150 mg, or placebo once every two weeks, respectively, in combination with conventional DMARDs. Most safety data are described for the pre-rescue population. For rarer events, the 52-week placebo-controlled population is used. The most common serious adverse reactions were infections . The most frequent adverse reactions (occurring in at least 3% of patients treated with KEVZARA in combination with DMARDs) observed with KEVZARA in the clinical studies were neutropenia, increased ALT, injection site erythema, upper respiratory infections, and urinary tract infections. In the pre-rescue placebo-controlled population, premature discontinuation due to adverse reactions occurred in 8%, 6% and 3% of patients treated with KEVZARA 200 mg, KEVZARA 150 mg, and placebo, respectively. The most common adverse reaction (greater than 1%) that resulted in discontinuation of therapy with KEVZARA was neutropenia. The use of KEVZARA as monotherapy was assessed in 132 patients, of which 67 received KEVZARA 200 mg and 65 patients received KEVZARA 150 mg without concomitant DMARDs. The safety profile was generally consistent with that in the population receiving concomitant DMARDs. Overall Infections In the pre-rescue placebo-controlled population, the rate of infections in the 200 mg and 150 mg KEVZARA + DMARD group was 110 and 105 events per 100 patient-years, respectively, compared to 81 events per 100 patient-years in the placebo + DMARD group. The most commonly reported infections (2% to 4% of patients) were upper respiratory tract infections, urinary tract infections, and nasopharyngitis. In the 52-week placebo-controlled population, 0.8% of patients (5 patients) treated with KEVZARA 200 mg + DMARD, 0.6% (4 patients) treated with KEVZARA 150 mg + DMARD and 0.5% (3 patients) treated with placebo + DMARD had an event of herpes zoster [see Warnings and Precautions (5.1) ] . The overall rate of infections with KEVZARA + DMARD in the long-term safety population was consistent with rates in the controlled periods of the studies. Serious Infections In the pre-rescue population, the rate of serious infections in the 200 mg and 150 mg KEVZARA + DMARD group was 3.8 and 4.4 events per 100 patient-years, respectively, compared to 2.5 events per 100 patient-years in the placebo + DMARD group. In the 52-week placebo-controlled population, the rate of serious infections in the 200 mg and 150 mg KEVZARA + DMARD group was 4.3 and 3.0 events per 100 patient-years, respectively, compared to 3.1 events per 100 patient-years in the placebo + DMARD group. In the long-term safety population, the overall rate of serious infections was consistent with rates in the controlled periods of the studies. The most frequently observed serious infections included pneumonia and cellulitis. Cases of opportunistic infection have been reported [see Warnings and Precautions (5.1) ] . Gastrointestinal Perforation In the 52-week placebo-controlled population, one patient on KEVZARA therapy experienced a gastrointestinal (GI) perforation (0.11 events per 100 patient-years). In the long-term safety population, the overall rate of GI perforation was consistent with rates in the controlled periods of the studies. Reports of GI perforation were primarily reported as complications of diverticulitis including lower GI perforation and abscess. Most patients who developed GI perforations were taking concomitant nonsteroidal anti-inflammatory medications (NSAIDs) or corticosteroids. The contribution of these concomitant medications relative to KEVZARA in the development of GI perforations is not known [see Warnings and Precautions (5.3) ] . Hypersensitivity Reactions In the pre-rescue placebo-controlled population, the proportion of patients who discontinued treatment due to hypersensitivity reactions was higher among those treated with KEVZARA (0.3% in 200 mg, 0.2% in 150 mg) than placebo (0%). The rate of discontinuations due to hypersensitivity in the long-term safety population was consistent with the placebo-controlled period. Injection Site Reactions In the pre-rescue placebo-controlled population, injection site reactions were reported in 7% of patients receiving KEVZARA 200 mg, 6% receiving KEVZARA 150 mg, and 1% receiving placebo. These injection site reactions (including erythema and pruritus) were mild in severity for the majority of patients and necessitated drug discontinuation in 2 (0.2%) patients receiving KEVZARA. Laboratory Abnormalities Decreased neutrophil count In the pre-rescue placebo-controlled population, decreases in neutrophil counts less than 1000 per mm 3 occurred in 6% and 4% of patients in the 200 mg KEVZARA + DMARD and 150 mg KEVZARA + DMARD group, respectively, compared to no patients in the placebo + DMARD groups. Decreases in neutrophil counts less than 500 per mm 3 occurred in 0.7% of patients in both the 200 mg KEVZARA + DMARD and 150 mg KEVZARA + DMARD groups. Decrease in ANC was not associated with the occurrence of infections, including seriou s infections. In the long-term safety population, the observations on neutrophil counts were consistent with what was seen in the placebo-controlled clinical studies [see Warnings and Precautions (5.2) ] . Decreased platelet count In the pre-rescue placebo-controlled population, decreases in platelet counts less than 100,000 per mm 3 occurred in 1% and 0.7% of patients on 200 mg and 150 mg KEVZARA + DMARD, respectively, compared to no patients on placebo + DMARD, without associated bleeding events. In the long-term safety population, the observations on platelet counts were consistent with what was seen in the placebo-controlled clinical studies [see Warnings and Precautions (5.2) ] . Elevated liver enzymes Liver enzyme elevations in the pre-rescue placebo-controlled population (KEVZARA + DMARD or placebo + DMARD) are summarized in Table 2. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as interruption of KEVZARA or reduction in dose, resulted in decrease or normalization of liver enzymes [see Dosage and Administration (2.6) ] . These elevations were not associated with clinically relevant increases in direct bilirubin, nor were they associated with clinical evidence of hepatitis or hepatic impairment [see Warnings and Precautions (5.2) ] . Table 2: Incidence of Liver Enzyme Elevations in Adults with Moderately to Severely Active Rheumatoid Arthritis Phase 3 placebo-controlled safety population through the pre-rescue period Placebo + DMARD N=579 KEVZARA 150 mg + DMARD N=579 KEVZARA 200 mg + DMARD N=582 ULN = Upper Limit of Normal AST Greater than ULN to 3 times ULN or less 15% 27% 30% Greater than 3 times ULN to 5 times ULN 0% 1% 1% Greater than 5 times ULN 0% 0.7% 0.2% ALT Greater than ULN to 3 times ULN or less 25% 38% 43% Greater than 3 times ULN to 5 times ULN 1% 4% 3% Greater than 5 times ULN 0% 1% 0.7% Lipid Abnormalities Lipid parameters (LDL, HDL, and triglycerides) were first assessed at 4 weeks following initiation of KEVZARA + DMARDs in the placebo-controlled population. Increases were observed at this time point with no additional increases observed thereafter. Changes in lipid parameters from baseline to Week 4 are summarized below: Mean LDL increased by 12 mg/dL in the KEVZARA 150 mg every two weeks + DMARD group and 16 mg/dL in the KEVZARA 200 mg every two weeks + DMARD group. Mean triglycerides increased by 20 mg/dL in the KEVZARA 150 mg every two weeks + DMARD group and 27 mg/dL in the KEVZARA 200 mg every two weeks + DMARD group. Mean HDL increased by 3 mg/dL in both the KEVZARA 150 mg every two weeks + DMARD and KEVZARA 200 mg every two weeks + DMARD groups. In the long-term safety population, the observations in lipid parameters were consistent with what was observed in the placebo-controlled clinical studies. Malignancies In the 52-week placebo-controlled population, 9 malignancies (exposure-adjusted event rate of 1.0 event per 100 patient-years) were diagnosed in patients receiving KEVZARA + DMARD compared to 4 malignancies in patients in the control group (exposure-adjusted event rate of 1.0 event per 100 patient-years). In the long-term safety population, the rate of malignancies was consistent with the rate observed in the placebo-controlled period [see Warnings and Precautions (5.4) ] . Other Adverse Reactions Adverse reactions occurring in 2% or more of patients on KEVZARA + DMARD and greater than those observed in patients on placebo + DMARD are summarized in Table 3. Table 3: Common Adverse Reactions Adverse reactions occurring in 2% or more in the 150 mg KEVZARA + DMARD or 200 mg KEVZARA + DMARD groups and greater than observed in Placebo + DMARD in Adults with Moderately to Severely Active Rheumatoid Arthritis Pre-rescue, placebo-controlled population Adverse Reactions Placebo + DMARD (N=579) KEVZARA 150 mg + DMARD (N=579) KEVZARA 200 mg + DMARD (N=582) Neutropenia 0.2% 7% 10% Alanine aminotransferase increased 2% 5% 5% Injection site erythema 0.9% 5% 4% Injection site pruritus 0.2% 2% 2% Upper respiratory tract infection 2% 4% 3% Urinary tract infection 2% 3% 3% Hypertriglyceridemia 0.5% 3% 1% Leukopenia 0% 0.9% 2% Medically relevant adverse reactions occurring at an incidence less than 2% in patients with rheumatoid arthritis treated with KEVZARA in controlled studies was oral herpes. Polymyalgia Rheumatica Safety has been studied in one Phase 3 study (Study 3) in 117 PMR patients of whom 59 received subcutaneous KEVZARA 200 mg [see Clinical Studies (14.2) ] . Of these, 45 patients received KEVZARA for at least 24 weeks, 44 patients for at least 40 weeks, and 10 patients for at least 52 weeks. The total patient years duration in the KEVZARA PMR population was 47.37 patient years during the 12-month double blind, placebo-controlled study. The common adverse reactions occurring in ≥5% of patients treated with KEVZARA were neutropenia (15.3%), leukopenia (6.8%), constipation (6.8%), rash pruritic (5.1%), myalgia (6.8%), fatigue (5.1%), and injection site pruritus (5.1%). Serious adverse reactions of neutropenia occurred in 2 patients (3.4%) in the KEVZARA group compared to none in the placebo group. In both cases of neutropenia, the participants had a neutrophil count less than 500 per mm 3 without any infections and resolved following permanent discontinuation of study drug. The most common adverse reactions that resulted in permanent discontinuation of therapy with KEVZARA were neutropenia in 3 patients (5.1%) and infection in 3 separate patients (5.1%), including COVID-19 (n=1), intervertebral discitis (n=1), and pneumonia (n=1). Overall Infections In Study 3, the proportion of patients with infections was lower in the KEVZARA group (37.3%) compared to the placebo group (50.0%). Two patients (3.2%) in the KEVZARA group and 1 patient (1.7%) in the placebo group had an event of herpes zoster. Serious infections In Study 3, the proportion of patients with serious infections was similar in the KEVZARA group (5.1%) compared to the placebo group (5.2%). Injection Site Reactions In Study 3, three patients (5.1%) in the KEVZARA group experienced injection site reactions of pruritus which were mild in severity. No patient in the placebo group experienced injection site reactions. Laboratory Abnormalities Decreased neutrophil count In Study 3, decreases in neutrophil counts less than 1,000 per mm 3 occurred in 12% of the KEVZARA treated group and no patient in the placebo treated group. Decreases in neutrophil counts less than 500 per mm 3 occurred in 3.4% of patients in KEVZARA treated group compared to no patient in the placebo treated group. Decreased platelet count In Study 3, decreases in platelet counts between 75,000 to 100,000 per mm 3 occurred in two patients (3.4%) in the KEVZARA group, compared to no patient in the placebo treated group. These platelet count decreases were transient and not associated with bleeding events. Elevated liver enzymes In Study 3, no KEVZARA treated patients had an ALT or AST greater than 3 times the upper limit of normal (ULN). In the placebo treated group, 2 patients had ALT elevations greater than 3 times the ULN. Lipid Abnormalities In Study 3, cholesterol levels ≥299.27 mg/dL were observed in 8/58 (13.8%) patients in the KEVZARA group compared to 4/58 (6.9%) patients in the placebo group. Triglycerides ≥407.4 mg/dL were observed in 3/58 (5.2%) patients in the KEVZARA group compared to 1/58 (1.7%) in the placebo group. No significant differences in mean HDL between KEVZARA group and placebo group were observed. At Week 52, mean increase from baseline for LDL and triglycerides levels were observed in the KEVZARA group though both remained within the normal range. Polyarticular Juvenile Idiopathic Arthritis (pJIA) The safety of KEVZARA was studied in patients 2 to 17 years of age with pJIA who have had an inadequate response to current therapy (Study 4) [see Clinical Studies (14.3) ] . A total of 93 patients received at least one administration of the recommended dose: 79 (84.9%) patients received the recommended dose for 52 weeks, 53 (57%) patients received it for 96 weeks and 30 (32.2%) patients received it for 156 weeks. The overall median duration of study treatment for the recommended dose was 672 days. The cumulative exposure to treatment for patients who received the recommended dose at any time during the study was 184.1 patient-years. The most common adverse drug reactions were nasopharyngitis, neutropenia, upper respiratory tract infection, and injection site erythema. The most common adverse drug reaction that resulted in permanent discontinuation of therapy with KEVZARA was neutropenia (5.4%). No new adverse reactions and safety concerns were identified in the pJIA population compared to the RA population. Infections In Study 4, the rate of infections was 146.6 events per 100 patient-years. The most common infections observed were nasopharyngitis (36.6%) and upper respiratory tract infections (URTI) (14.0%). Injection Site Reactions In Study 4, injection site reactions (ISRs) occurred in 13 (14.0%) patients and the most commonly reported ISR was injection site erythema (9.7%). The majority of these events were mild and none of the ISRs required patient withdrawal from treatment or dose interruption. Laboratory Abnormalities Decrease neutrophil count In Study 4, decreases in neutrophil counts less than 1000 per mm 3 occurred in 10/52 (19.2%) patients weighing in ≥30 kg and 20/41 (48.8%) patients weighing 10 to <30 kg. The frequency of decreased neutrophil count was higher until Week 12. Decrease in ANC was not associated with an occurrence of infections, including serious infections. Decrease monocyte count In Study 4, decrease in monocyte counts occurred in 4 (4.3%) patients and were mild in severity and non-serious. Elevated liver enzymes In Study 4, nine (9.7%) patients had ALT increases, including one (1.1%) patient who had ALT >3 times upper limit of normal (ULN) and up to ≤5 times ULN, and two (2.2%) patients who had ALT increases >5 times ULN and up to ≤10 times ULN that resulted in permanent discontinuation. All patients recovered. Lipid Abnormalities In Study 4, triglyceride levels of ≥150 mg/dL (1 × ULN) were observed in one (1.1%) patient. Three (3.2%) patients overall had elevation in triglycerides, and all were mild in severity and non-serious. No significant changes in mean LDL, HDL or total cholesterol were observed during the entire 156-week treatment period.

12.3 Pharmacokinetics Rheumatoid Arthritis Absorption The pharmacokinetics of sarilumab were characterized in 1770 adult patients with rheumatoid arthritis (RA) treated with sarilumab which included 631 patients treated with 150 mg and 682 patients treated with 200 mg doses by subcutaneous injection every two weeks for up to 52 weeks. The median t max was observed in 2 to 4 days. At steady state, exposure over the dosing interval measured by area under curve (AUC) increased 2-fold with an increase in dose from 150 to 200 mg every two weeks. Steady state was reached in 14 to 16 weeks with a 2- to 3-fold accumulation compared to single dose exposure. For the 150 mg every two weeks dose regimen, the estimated mean (± SD) steady-state AUC, C min and C max of sarilumab were 202 ± 120 mg.day/L, 6.35 ± 7.54 mg/L, and 20.0 ± 9.20 mg/L, respectively. For the 200 mg every two weeks dose regimen, the estimated mean (± SD) steady-state AUC, C min and C max of sarilumab were 395 ± 207 mg.day/L, 16.5 ± 14.1 mg/L, and 35.6 ± 15.2 mg/L, respectively. Distribution In patients with RA, the apparent volume of distribution at steady state was 7.3 L. Elimination Sarilumab is eliminated by parallel linear and non-linear pathways. At higher concentrations, the elimination is predominantly through the linear, non-saturable proteolytic pathway, while at lower concentrations, non-linear saturable target-mediated elimination predominates. The half-life of sarilumab is concentration-dependent. At 200 mg every 2 weeks, the concentration-dependent half-life is up to 10 days in patients with RA at steady state. At 150 mg every 2 weeks, the concentration-dependent half-life is up to 8 days in patients with RA at steady state. After the last steady state dose of 150 mg and 200 mg sarilumab, the median times to non-detectable concentration are 28 and 43 days, respectively. Population pharmacokinetic analyses in patients with RA revealed that there was a trend toward higher apparent clearance of sarilumab in the presence of anti-sarilumab antibodies. Metabolism The metabolic pathway of sarilumab has not been characterized. As a monoclonal antibody sarilumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG. Excretion Monoclonal antibodies, including sarilumab, are not eliminated via renal or hepatic pathways. Polymyalgia Rheumatica The pharmacokinetic profile of subcutaneous sarilumab in PMR patients was determined using a population pharmacokinetic analysis on a data set including 58 PMR patients treated with repeated subcutaneous administration of sarilumab 200 mg every two weeks. In general, pharmacokinetic exposures were higher in patients with PMR when compared to patients with RA. For this dose regimen, the estimated mean (± SD) steady-state AUC, C min and C max of sarilumab were 551 ± 321 mg.day/L, 27.0 ± 21.5 mg/L, and 46.5 ± 23.0 mg/L, respectively. The median time to steady state in PMR patients was estimated to be 28 weeks. There was accumulation following subcutaneous administration of sarilumab 200 mg, with an accumulation ratio of approximately 6-fold based on the mean trough concentrations. Polyarticular juvenile idiopathic arthritis (pJIA) The pharmacokinetics of sarilumab in pJIA patients was characterized by a population pharmacokinetic analysis which included 101 pediatric patients 2 to 17 years of age who were treated with repeated subcutaneous doses of sarilumab. For 3 mg/kg sarilumab (patients with a body weight ≥30 kg) given every 2 weeks, the estimated mean (±SD) steady-state AUC, Cmin, and Cmax of sarilumab were 276 ± 121 mg.day/L, 9.57 ± 5.84 mg/L, and 27.1 ± 11.6 mg/L, respectively. For 4 mg/kg sarilumab (patients with a body weight 10 to <30 kg) given every 2 weeks, the estimated mean (± SD) steady-state AUC, Cmin, and Cmax of sarilumab were 395 ± 101 mg.day/L, 14.4 ± 9.81 mg/L, and 40.4 ± 7.77 mg/L, respectively. Steady state was reached in 12 to 28 weeks with a 2- to 4-fold accumulation compared to single dose exposure for 3 and 4 mg/kg q2w. Steady state concentrations were within the range of exposures in adult RA patients following 150 mg/200 mg every 2 weeks. Specific Populations Population pharmacokinetic analyses in adult patients showed that age, gender and race did not meaningfully influence the pharmacokinetics of sarilumab. Although body weight influenced the pharmacokinetics of sarilumab, no dose adjustments are recommended for any of these demographics in adult patients. Hepatic Impairment No formal study of the effect of hepatic impairment on the pharmacokinetics of sarilumab was conducted. Renal Impairment No formal study of the effect of renal impairment on the pharmacokinetics of sarilumab was conducted. Based on population pharmacokinetic analysis of data from 1770 patients with RA, including patients with mild (creatinine clearance (CL cr ): 60 to 90 mL/min; N=471 at baseline) or moderate (CL cr : 30 to 60 mL/min; N=74 at baseline) renal impairment, CL cr was correlated with sarilumab exposure. However, the effect of CL cr on exposure is not sufficient to warrant a dose adjustment [see Use in Specific Populations (8.7) ] . Patients with severe renal impairment were not studied. Drug-Drug Interactions CYP450 Substrates Simvastatin is a CYP3A4 and OATP1B1 substrate. In 17 patients with RA, one week following a single 200-mg subcutaneous administration of sarilumab, exposure of simvastatin and simvastatin acid decreased by 45% and 36%, respectively [see Drug Interactions (7.2) ] .