KEVZARA

WARNING: RISK OF SERIOUS INFECTIONS Patients treated with KEVZARA are at increased risk for developing serious infections that may lead to hospitalization or death [see Warnings and Precautions (5.1) , Adverse Reactions (6.1) ]. Opportunistic infections have also been reported in patients receiving KEVZARA. Most patients who developed infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Avoid use of KEVZARA in patients with an active infection. Reported infections include: Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before KEVZARA use and during therapy. Treatment for latent infection should be initiated prior to KEVZARA use. Invasive fungal infections, such as candidiasis, and pneumocystis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease. Bacterial, viral and other infections due to opportunistic pathogens. Closely monitor patients for signs and symptoms of infection during treatment with KEVZARA. If a serious infection develops, interrupt KEVZARA until the infection is controlled. Consider the risks and benefits of treatment with KEVZARA prior to initiating therapy in patients with chronic or recurrent infection. WARNING: RISK OF SERIOUS INFECTIONS See full prescribing information for complete boxed warning . Serious infections leading to hospitalization or death including bacterial, viral, invasive fungal, and other opportunistic infections have occurred in patients receiving KEVZARA. ( 5.1 ) If a serious infection develops, interrupt KEVZARA until the infection is controlled. ( 5.1 ) Cases of tuberculosis (TB) have been reported. Prior to starting KEVZARA, test for latent TB; if positive, start treatment for TB. ( 5.1 ) Closely monitor patients for signs and symptoms of infection during treatment with KEVZARA. ( 5.1 )

5 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 date with all immunizations in agreement with current immunization guidelines. The interval between live vaccinations and initiation of KEVZARA therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents [see Drug Interactions (7.3) ] .

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.

<table width="85%" ID="t2"><caption>Table 2: Incidence of Liver Enzyme Elevations in Adults with Moderately to Severely Active Rheumatoid Arthritis<footnote>Phase 3 placebo-controlled safety population through the pre-rescue period</footnote></caption><col width="25%" align="left" valign="top"/><col width="25%" align="center" valign="top"/><col width="25%" align="center" valign="top"/><col width="25%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule"/><th styleCode="Rrule">Placebo + DMARD N=579</th><th styleCode="Rrule">KEVZARA 150 mg + DMARD N=579</th><th styleCode="Rrule">KEVZARA 200 mg + DMARD N=582</th></tr></thead><tfoot><tr><td colspan="4" align="left" valign="top">ULN = Upper Limit of Normal</td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">AST </content></td><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Greater than ULN to 3 times ULN or less</td><td styleCode="Rrule">15%</td><td styleCode="Rrule">27%</td><td styleCode="Rrule">30%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Greater than 3 times ULN to 5 times ULN</td><td styleCode="Rrule">0%</td><td styleCode="Rrule">1%</td><td styleCode="Rrule">1%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Greater than 5 times ULN</td><td styleCode="Rrule">0%</td><td styleCode="Rrule">0.7%</td><td styleCode="Rrule">0.2%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">ALT </content></td><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Greater than ULN to 3 times ULN or less</td><td styleCode="Rrule">25%</td><td styleCode="Rrule">38%</td><td styleCode="Rrule">43%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Greater than 3 times ULN to 5 times ULN</td><td styleCode="Rrule">1%</td><td styleCode="Rrule">4%</td><td styleCode="Rrule">3%</td></tr><tr><td styleCode="Lrule Rrule">Greater than 5 times ULN</td><td styleCode="Rrule">0%</td><td styleCode="Rrule">1%</td><td styleCode="Rrule">0.7%</td></tr></tbody></table>

<table width="85%" ID="t3"><caption>Table 3: Common Adverse Reactions<footnote>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</footnote> in Adults with Moderately to Severely Active Rheumatoid Arthritis <footnote>Pre-rescue, placebo-controlled population</footnote></caption><col width="35%" align="left" valign="top"/><col width="15%" align="center" valign="top"/><col width="25%" align="center" valign="top"/><col width="25%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule" valign="middle">Adverse Reactions</th><th styleCode="Rrule">Placebo + DMARD (N=579)</th><th styleCode="Rrule">KEVZARA 150 mg + DMARD (N=579)</th><th styleCode="Rrule">KEVZARA 200 mg + DMARD (N=582)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Neutropenia</td><td styleCode="Rrule">0.2%</td><td styleCode="Rrule">7%</td><td styleCode="Rrule">10%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Alanine aminotransferase increased</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">5%</td><td styleCode="Rrule">5%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Injection site erythema</td><td styleCode="Rrule">0.9%</td><td styleCode="Rrule">5%</td><td styleCode="Rrule">4%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Injection site pruritus</td><td styleCode="Rrule">0.2%</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">2%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Upper respiratory tract infection</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">4%</td><td styleCode="Rrule">3%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Urinary tract infection</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">3%</td><td styleCode="Rrule">3%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypertriglyceridemia</td><td styleCode="Rrule">0.5%</td><td styleCode="Rrule">3%</td><td styleCode="Rrule">1%</td></tr><tr><td styleCode="Lrule Rrule">Leukopenia</td><td styleCode="Rrule">0%</td><td styleCode="Rrule">0.9%</td><td styleCode="Rrule">2%</td></tr></tbody></table>