IL-6 plays a critical role in the disease progression of rheumatoid arthritis (RA)1,2
IL-6 is one of the most abundant cytokines in the synovial fluid of patients with RA1,2
Elevated IL-6 in RA has widespread articular and systemic effects1,3,4
- IL-6, a multifunctional cytokine, works via a dual signaling mechanism (classical or cis-signaling and trans-signaling)
- When persistently elevated in RA, IL-6 can disrupt homeostasis in a wide variety of physiological processes
Persistently elevated IL-6 levels can contribute to structural damage, fatigue, morning stiffness, and other articular and systemic effects of RA2,5-10
Evidence shows IL-6 levels are 4x higher during the early morning hours in patients with RA7*
In a single-center controlled study, mean serum IL-6 levels were approximately 10x higher in patients with RA (n=66) than in control group (n=24)5†
Placement of systemic and articular labels on image is for illustrative purposes only.
*The study results demonstrated that the circulating levels of IL-6 were increased in the morning in patients with RA and declined from early in the afternoon to late in the evening.7
†Serum concentrations of IL-6 were measured in healthy subjects and adult patients with RA and the levels were correlated with disease activity.5
CRP=C-reactive protein; IL-6=interleukin-6.
Nearly 50% of patients with RA are uncontrolled on current treatment11
Patients with uncontrolled RA may be identified in different ways, such as showing inadequate clinical response or having to switch or discontinue current treatment.11
Up to 40% of patients with RA
are unable to achieve adequate clinical response (ACR20) despite treatment with a TNF inhibitor, leading them to experience some degree of limitation in their daily routines12,13
40% to 53%
of patients discontinue or switch to a new biologic at 1 year of initiating their first biologic14,15
Recent ACR and EULAR RA treatment guidelines conditionally recommend switching MOA as a treatment option for TNF-IR patients16,17‡
If treatment target of remission or low disease activity is not achieved in patients with moderate or high disease activity despite the use of MTX or a TNF inhibitor:
- Treat with a biologic agent with another MOA or a second TNF inhibitor
‡2021 American College of Rheumatology Guidelines and 2019 EULAR Recommendations.16,17
ACR20=American College of Rheumatology 20% improvement criteria; EULAR=European League Against Rheumatism; MOA=mechanism of action; MTX=methotrexate; TNF=tumor necrosis factor; TNF-IR=tumor necrosis factor inhibitor inadequate response or intolerant.
IMPORTANT SAFETY INFORMATION
WARNING: RISK OF SERIOUS INFECTIONS Patients treated with KEVZARA are at increased risk for developing serious infections that may lead to hospitalization or death. 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:
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. |
CONTRAINDICATION
Do not use KEVZARA in patients with known hypersensitivity to sarilumab or any of the inactive ingredients.
WARNINGS AND PRECAUTIONS
- 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, TB, candidiasis, and pneumocystis were reported with KEVZARA. The most frequently observed serious infections with KEVZARA in RA patients included pneumonia and cellulitis.
- Hold treatment with KEVZARA if a patient develops a serious infection or an opportunistic infection.
- Patients with latent TB should be treated 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.
- 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 TB, or lived in or traveled to areas of endemic TB or endemic mycoses.
- Viral reactivation has been reported with immunosuppressive biologic therapies. Cases of herpes zoster were observed in clinical studies with KEVZARA.
- Laboratory Abnormalities. Treatment with KEVZARA was associated with decreases in absolute neutrophil counts (including neutropenia), and platelet counts; and increases in transaminase levels and lipid parameters (LDL, HDL cholesterol, and/or triglycerides). Increased frequency and magnitude of these elevations were observed when potentially hepatotoxic drugs (e.g., MTX) were used in combination with KEVZARA. Assess neutrophil count, platelet count, and ALT/AST levels prior to initiation with KEVZARA. Monitor these parameters 4 to 8 weeks after start of therapy and every 3 months thereafter. Assess lipid parameters 4 to 8 weeks after start of therapy, then at 6 month intervals.
- Gastrointestinal Perforation. GI perforation risk may be increased with concurrent diverticulitis or concomitant use of NSAIDs or corticosteroids. Gastrointestinal perforations have been reported in clinical studies, primarily as complications of diverticulitis. Promptly evaluate patients presenting with new onset abdominal symptoms.
- 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 have been reported in clinical studies.
- Hypersensitivity Reactions. Hypersensitivity reactions have been reported in association with KEVZARA. 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.
- 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.
- Live Vaccines. Avoid concurrent use of live vaccines during treatment with KEVZARA due to potentially increased risk of infections. 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.
ADVERSE REACTIONS
- For Rheumatoid Arthritis: The most common serious adverse reactions were infections. The most frequently observed serious infections included pneumonia and cellulitis. The most common adverse reactions (occurred in at least 3% of patients treated with KEVZARA + DMARDs) are neutropenia, increased ALT, injection site erythema, upper respiratory infections, and urinary tract infections.
- For Polymyalgia Rheumatica: Serious adverse reactions of neutropenia occurred in 2 patients (3.4%) in the KEVZARA group compared to none in the placebo group. The proportion of patients with serious infections was similar in the KEVZARA group (5.1%) compared to the placebo group (5.2%). The common adverse reactions occurring in ≥5% of patients treated with KEVZARA were neutropenia, leukopenia, constipation, rash pruritic, myalgia, fatigue, and injection site pruritus.
- For Polyarticular Juvenile Idiopathic Arthritis: 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%). The most common adverse drug reactions were nasopharyngitis, neutropenia, upper respiratory tract infection, and injection site erythema.
DRUG INTERACTIONS
- Exercise caution when KEVZARA is co-administered with CYP substrates with a narrow therapeutic index (e.g. warfarin or theophylline), or with CYP3A4 substrates (e.g. oral contraceptives or statins) as there may be a reduction in exposure which may reduce the activity of the CYP3A4 substrate.
- Elevated interleukin-6 (IL-6) concentration may down-regulate CYP activity such as in patients with RA and hence increase drug levels compared to subjects without RA. Blockade of IL-6 signaling by IL-6Rα antagonists such as KEVZARA might reverse the inhibitory effect of IL-6 and restore CYP activity, leading to altered drug concentrations.
USE IN SPECIFIC POPULATIONS
- KEVZARA should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. Because monoclonal antibodies could be excreted in small amounts in human milk, the benefits of breastfeeding and the potential adverse effects on the breastfed child should be considered along with the mother’s clinical need for KEVZARA.
- Use caution when treating the elderly.
Advise patients to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).
Please see full Prescribing Information, including Boxed WARNING.
INDICATIONS
KEVZARA® (sarilumab) is 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).
- adult patients with polymyalgia rheumatica (PMR) who have had an inadequate response to corticosteroids or who cannot tolerate corticosteroid taper.
- patients who weigh 63 kg or greater with active polyarticular juvenile idiopathic arthritis (pJIA).
IMPORTANT SAFETY INFORMATION
WARNING: RISK OF SERIOUS INFECTIONS Patients treated with KEVZARA are at increased risk for developing serious infections that may lead to hospitalization or death. 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:
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. |
CONTRAINDICATION
Do not use KEVZARA in patients with known hypersensitivity to sarilumab or any of the inactive ingredients.
WARNINGS AND PRECAUTIONS
- 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, TB, candidiasis, and pneumocystis were reported with KEVZARA. The most frequently observed serious infections with KEVZARA in RA patients included pneumonia and cellulitis.
- Hold treatment with KEVZARA if a patient develops a serious infection or an opportunistic infection.
- Patients with latent TB should be treated 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.
- 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 TB, or lived in or traveled to areas of endemic TB or endemic mycoses.
- Viral reactivation has been reported with immunosuppressive biologic therapies. Cases of herpes zoster were observed in clinical studies with KEVZARA.
- Laboratory Abnormalities. Treatment with KEVZARA was associated with decreases in absolute neutrophil counts (including neutropenia), and platelet counts; and increases in transaminase levels and lipid parameters (LDL, HDL cholesterol, and/or triglycerides). Increased frequency and magnitude of these elevations were observed when potentially hepatotoxic drugs (e.g., MTX) were used in combination with KEVZARA. Assess neutrophil count, platelet count, and ALT/AST levels prior to initiation with KEVZARA. Monitor these parameters 4 to 8 weeks after start of therapy and every 3 months thereafter. Assess lipid parameters 4 to 8 weeks after start of therapy, then at 6 month intervals.
- Gastrointestinal Perforation. GI perforation risk may be increased with concurrent diverticulitis or concomitant use of NSAIDs or corticosteroids. Gastrointestinal perforations have been reported in clinical studies, primarily as complications of diverticulitis. Promptly evaluate patients presenting with new onset abdominal symptoms.
- 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 have been reported in clinical studies.
- Hypersensitivity Reactions. Hypersensitivity reactions have been reported in association with KEVZARA. 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.
- 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.
- Live Vaccines. Avoid concurrent use of live vaccines during treatment with KEVZARA due to potentially increased risk of infections. 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.
ADVERSE REACTIONS
- For Rheumatoid Arthritis: The most common serious adverse reactions were infections. The most frequently observed serious infections included pneumonia and cellulitis. The most common adverse reactions (occurred in at least 3% of patients treated with KEVZARA + DMARDs) are neutropenia, increased ALT, injection site erythema, upper respiratory infections, and urinary tract infections.
- For Polymyalgia Rheumatica: Serious adverse reactions of neutropenia occurred in 2 patients (3.4%) in the KEVZARA group compared to none in the placebo group. The proportion of patients with serious infections was similar in the KEVZARA group (5.1%) compared to the placebo group (5.2%). The common adverse reactions occurring in ≥5% of patients treated with KEVZARA were neutropenia, leukopenia, constipation, rash pruritic, myalgia, fatigue, and injection site pruritus.
- For Polyarticular Juvenile Idiopathic Arthritis: 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%). The most common adverse drug reactions were nasopharyngitis, neutropenia, upper respiratory tract infection, and injection site erythema.
DRUG INTERACTIONS
- Exercise caution when KEVZARA is co-administered with CYP substrates with a narrow therapeutic index (e.g. warfarin or theophylline), or with CYP3A4 substrates (e.g. oral contraceptives or statins) as there may be a reduction in exposure which may reduce the activity of the CYP3A4 substrate.
- Elevated interleukin-6 (IL-6) concentration may down-regulate CYP activity such as in patients with RA and hence increase drug levels compared to subjects without RA. Blockade of IL-6 signaling by IL-6Rα antagonists such as KEVZARA might reverse the inhibitory effect of IL-6 and restore CYP activity, leading to altered drug concentrations.
USE IN SPECIFIC POPULATIONS
- KEVZARA should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. Because monoclonal antibodies could be excreted in small amounts in human milk, the benefits of breastfeeding and the potential adverse effects on the breastfed child should be considered along with the mother’s clinical need for KEVZARA.
- Use caution when treating the elderly.
Advise patients to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).
Please see full Prescribing Information, including Boxed WARNING.
INDICATIONS
KEVZARA® (sarilumab) is 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).
- adult patients with polymyalgia rheumatica (PMR) who have had an inadequate response to corticosteroids or who cannot tolerate corticosteroid taper.
- patients who weigh 63 kg or greater with active polyarticular juvenile idiopathic arthritis (pJIA).
References: 1. Kevzara [prescribing information]. Bridgewater, NJ: Sanofi/Regeneron Pharmaceuticals, Inc. 2. Dayer J-M, Choy E. Therapeutic targets in rheumatoid arthritis: the interleukin-6 receptor. Rheumatology (Oxford). 2010;49(1):15-24 3. Genovese MC, Fleischmann R, Kivitiz AJ, et al. Sarilumab plus methotrexate in patients with active rheumatoid arthritis and inadequate response to methotrexate. Arthritis Rheumatol. 2015;67(6):1424-1437. 4. Tanaka T, Narazaki M, Kishimoto T. Interleukin-6 (IL-6) immunotherapy. Cold Spring Harb Perspect Biol. 2018;10(8):a028456. doi:10.1101/cshperspect.a028456. 5. Robak T, Gladalska A, Stephen H, Robak E. Serum levels of interleukin-6 type cytokines and soluble interleukin-6 receptor in patients with rheumatoid arthritis. Mediators Inflamm. 1998;7(5):347-353. 6. Favalli EG. Understanding the role of interleukin-6 (IL-6) in the joint and beyond: a comprehensive review of IL-6 inhibition for the management of rheumatoid arthritis: correlations with clinical and laboratory indices of disease activity. Ann Rheum Dis. 1994;53(8):521-524. 7. Arvidson NG, Gudbjörnsson B, Elfman L, Rydén A-C, Tötterman TH, Hällgren R. Circadian rhythm of serum interleukin-6 in rheumatoid arthritis. Ann Rheum Dis. 1994;53(8):521-524. 8. Madhok R, Crilly A, Watson J, Capell HA. Serum interleukin-6 levels in rheumatoid arthritis: correlations with clinical and laboratory indices of disease activity. Ann Rheum Dis. 1993;52(3):232-234. 9. Chernoff D, Eastman PS, Hwang CC, et al. Determination of the minimally important difference (MID) in multi-biomarker disease activity (MBDA) test scores: impact of diurnal and daily biomarker variation patterns on MBDA scores. Clin Rheumatol. 2019;38(2):437-445. 10. Sebba A. Pain: a review of interleukin-6 and its roles in the pain of rheumatoid arthritis. Open Access Rheumatol. 2021;13:31-43. 11. Chaiamnuay A, Jiemjit S, Songdechaphipat W, Narongroeknawin P, Pakchotanon R, Asavatanabodee P. Predictors of flare in rheumatoid arthritis patients with persistent clinical remission/low disease activity. Medicine (Baltimore). 2022;101(32):e29974. doi:10.1097/MD.0000000000029974. 12. Rubbert-Roth A, Finckh A. Treatment options in patients with rheumatoid arthritis failing initial TNF inhibitor therapy: a critical review. Arthritis Res Ther. 2009;11(suppl1):S1-S12. 13. Kukar M, Petryna O, Efthimiou P. Biological targest in the treatment of rheumatoid arthritis: a comprehensive review of current and in-development biological disease modifying anti-rheumatic drugs. Biologics. 2009;3:443-457. 14. Gu T, Mutebi A, Stolshek BS, Tan H. Cost of biologic treatment persistence or switching in rheumatoid arthritis. Am J Manag Care. 2018;24(8):SP338-SP345. 15. Bonafede M, Johnson BH. Compliance and cost of biologic therapies for rheumatoid arthritis. Pharmacy Times. 2017;9(5):1-16. 16. Fraenkel L, Bathon JM, England BR, et al. 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol. 2021;73(7):1108-1123. 17. Smolen JS, Landewé RBM, Bijlsma JWJ, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic aqnd biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis. 2019;79(6):685-699.