Sarilumab, a recombinant human immunoglobulin G1 (IgG1) kappa monoclonal antibody specific for the interleukin-6 (IL-6) receptor, is a biologic response modifier and a disease-modifying antirheumatic drug (DMARD).1, 2, 3, 7, 13, 14, 15, 16, 17
Sarilumab is used for the management of moderately to severely active rheumatoid arthritis in adults who have had an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs).1, 2, 3 Sarilumab may be used alone or in combination with methotrexate or other nonbiologic DMARDs (e.g., hydroxychloroquine, leflunomide, sulfasalazine).1, 2, 3 Sarilumab has been shown to induce clinical responses, improve physical function, and inhibit progression of structural damage in adults with rheumatoid arthritis.1, 2, 3
Efficacy of sarilumab in patients with rheumatoid arthritis has been evaluated primarily in 2 randomized, double-blind, placebo-controlled, multicenter studies in adults (18 years of age or older) with moderately to severely active rheumatoid arthritis (as defined by the American College of Rheumatology [ACR]).1, 2, 3 In these studies, sarilumab was administered in combination with methotrexate in patients with an inadequate response to this drug (MOBILITY study) or in combination with methotrexate and/or other nonbiologic DMARDs (hydroxychloroquine, leflunomide, and/or sulfasalazine) in patients who had an inadequate response to, or had not tolerated, one or more TNF blocking agents (TARGET study).1, 2, 3 Patients included in these studies had 8 or more tender joints and 6 or more swollen joints.1, 2, 3 Those receiving low stable dosages of corticosteroids (equivalent to 10 mg or less of prednisone daily) could continue such therapy.2, 3 Sarilumab was administered subcutaneously at a dosage of 150 or 200 mg once every 2 weeks.1, 2, 3
The ACR criteria for improvement (ACR response) in measures of disease activity were used as the principal measure of clinical response in studies evaluating the efficacy of sarilumab.1, 2, 3 An ACR 20 response is achieved if the patient experiences a 20% or greater improvement in tender and swollen joint count and a 20% or greater improvement in at least 3 of the following criteria: patient pain assessment, patient global assessment, physician global assessment, patient self-assessed disability, or laboratory measures of disease activity (i.e., erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP] level).4 An ACR 70 response is defined using the same criteria but with a level of improvement of 70%.4, 11, 12 The proportion of patients who achieved an ACR 20 response at week 24 was the primary end point in the studies of sarilumab.1, 2, 3 In addition, the total van der Heijde-modified Sharp score (a composite score of erosions and joint space narrowing in hands and feet) was used as the principal measure of joint damage and the Health Assessment Questionnaire Disability Index (HAQ-DI) was used to assess physical function and disability.1, 2, 3
In the MOBILITY study, 1197 patients who had active rheumatoid arthritis for at least 3 months despite receiving a stable dosage of methotrexate (10-25 mg/week) were randomized to receive 1 of 3 regimens: sarilumab 150 mg every 2 weeks, sarilumab 200 mg every 2 weeks, or placebo, each given in combination with methotrexate for 52 weeks.1, 2 At week 16, patients previously randomized to receive sarilumab 150 mg every 2 weeks or placebo who achieved less than 20% improvement from baseline in the number of tender or swollen joints were permitted to cross over to open-label therapy with sarilumab 200 mg every 2 weeks.1, 2 Approximately 20% of patients in the study had previously received a biologic DMARD; patients with a history of nonresponse to prior biologic DMARD therapy were excluded from the study.2
In the MOBILITY study, ACR 20 responses were achieved at 24 weeks in 58, 66.4, or 33.4% of patients receiving sarilumab 150 mg and methotrexate, sarilumab 200 mg and methotrexate, or placebo and methotrexate, respectively, while ACR 70 responses were achieved at 24 weeks in 19.8, 24.8, or 7.3% of patients receiving these respective treatment regimens.1, 2 ACR responses observed at 24 weeks were maintained through 1 year.1, 2 At 1 year, 12.8, 14.8, or 3% of patients receiving sarilumab 150 mg and methotrexate, sarilumab 200 mg and methotrexate, or placebo and methotrexate, respectively, had achieved major clinical responses (defined as ACR 70 responses for a continuous 24-week period).1 At 24 weeks, a greater proportion of patients receiving sarilumab 150 or 200 mg (27.8 or 34.1%, respectively) had a low level of disease activity, as defined by a 28-joint Disease Activity Score using CRP (DAS 28 [CRP]) of less than 2.6, compared with patients who received placebo (10.1%).1, 2 However, this criterion does not preclude residual disease activity, and 33.1, 37.8, or 20% of patients in these respective treatment groups who achieved a DAS 28 (CRP) of less than 2.6 still had 3 or more active joints.1, 5 Findings at 1 year indicated that treatment with sarilumab 150 or 200 mg inhibited progression of structural damage compared with placebo.1, 2, 5 At 1 year, 47.8 or 55.6% of patients receiving sarilumab 150 or 200 mg, respectively, exhibited no radiographic progression, as determined by change in the total van der Heijde-modified Sharp score, compared with 38.7% of patients receiving placebo.1, 2 Patients receiving sarilumab 150 or 200 mg also experienced greater improvements in physical function and disability, as assessed using HAQ-DI scores, at 16 weeks compared with those who received placebo.1, 2 An open-label extension study (EXTEND) enrolling patients who completed the MOBILITY study found that treatment with sarilumab maintained clinical efficacy for up to 5 years.14
In the TARGET study, 546 patients who had active rheumatoid arthritis for at least 6 months and who had an inadequate response to, or had not tolerated, one or more TNF blocking agents were randomized to receive 1 of 3 regimens: sarilumab 150 mg every 2 weeks, sarilumab 200 mg every 2 weeks, or placebo, each given in combination with methotrexate and/or other nonbiologic DMARDs for 24 weeks.1, 3 At week 12, patients with less than 20% improvement from baseline in the number of both tender or swollen joints were permitted to cross over to open-label therapy with sarilumab 200 mg every 2 weeks.1, 3 ACR 20 responses were achieved at 24 weeks in 55.8, 60.9, or 33.7% of patients receiving sarilumab 150 mg, sarilumab 200 mg, or placebo, respectively, while ACR 70 responses were achieved at 24 weeks in 19.9, 16.3, or 7.2% of patients receiving these respective treatment regimens.1, 3 At 24 weeks, a greater proportion of patients receiving sarilumab 150 or 200 mg (24.9 or 28.8%, respectively) had a low level of disease activity, as defined by a DAS 28 (CRP) of less than 2.6, compared with patients who received placebo (7.2%).1, 3 Patients receiving sarilumab 150 or 200 mg also experienced greater improvements in physical function and disability, as assessed using HAQ-DI scores, at 12 weeks compared with those who received placebo.1, 3 An open-label extension study (EXTEND) enrolling patients who completed the TARGET study found that treatment with sarilumab maintained clinical efficacy for up to 5 years.15
In a randomized, double-blind, double-dummy, multicenter trial (MONARCH study), 369 adults who had active rheumatoid arthritis for at least 3 months and were not candidates for methotrexate or had an inadequate response or intolerance to methotrexate were randomized to receive subcutaneous administration of sarilumab 200 mg every 2 weeks or adalimumab 40 mg every 2 weeks.16 After week 16, dose escalation to weekly administration of adalimumab or matching placebo in the sarilumab group was permitted for patients who did not achieve a 20% or greater improvement in tender and swollen joint count.16 The primary measure of efficacy was change in the 28-joint Disease Activity Score using ESR (DAS28 [ESR]) from baseline to week 24.16 At 24 weeks, patients receiving sarilumab 200 mg had significantly greater reductions in DAS28 (ESR) compared to patients treated with adalimumab 40 mg.16 Secondary endpoints, including remission of DAS28 (ESR), ACR20, ACR50, and ACR 70 responses, and HAQ-DI scores, were also significantly improved at 24 weeks in patients treated with sarilumab compared with those treated with adalimumab.16
Subgroup analysis of the MOBILITY, TARGET, and MONARCH studies found that improvements in clinical, radiographic, and physical function seen in patients treated with sarilumab were generally consistent across a variety of subgroups (e.g., based on age, sex, duration of rheumatoid arthritis, and prior treatment).17
The American College of Rheumatology issued guidelines for the treatment of rheumatoid arthritis in 2021.2003 Disease-modifying treatments for rheumatoid arthritis include conventional DMARDs (e.g., methotrexate, hydroxychloroquine, sulfasalazine), biologic DMARDs (e.g., TNF blocking agents, abatacept, tocilizumab, sarilumab, rituximab), and/or targeted synthetic DMARDs (e.g., Janus kinase inhibitors).2003 Specific agents for rheumatoid arthritis treatment are selected according to current disease activity, prior therapies used, and the presence of comorbidities.2003 A “treat-to-target” approach is typically employed, with the goal of achieving low disease activity or remission.2003
The IL-6 inhibitors used in the treatment of rheumatoid arthritis are tocilizumab and sarilumab.2003 Methotrexate monotherapy is strongly recommended over biologic DMARD monotherapy for DMARD-naïve patients with moderate to high disease activity, because it is less costly and has established safety and efficacy.2003 Add-on therapy with biologic DMARDs (including IL-6 inhibitors) and targeted synthetic DMARDs is conditionally recommended over triple therapy (i.e., addition of sulfasalazine and hydroxychloroquine) for patients who are taking maximally tolerated doses of methotrexate and are not at target.2003 Recommendations for the use and selection of biologic DMARDs in rheumatoid arthritis vary based on the presence of certain comorbidities (e.g., heart failure, previous serious infection, nontuberculous mycobacterial lung disease).2003 Consult the American College of Rheumatology guidelines for additional details.2003
Sarilumab is used for the management of polymyalgia rheumatica in adult patients who have had an inadequate response to corticosteroids or who cannot tolerate tapering of corticosteroids.1 Sarilumab is used in combination with corticosteroids during the taper and and then as monotherapy following discontinuation of the corticosteroids.1 Sarilumab has been shown to achieve sustained remission and reduce the cumulative glucocorticoid dose in patients with a relapse of polymyalgia rheumatica during glucocorticoid tapering.1, 2004
The efficacy of sarilumab in patients with polymyalgia rheumatica has been evaluated in a randomized, double-blind, placebo-controlled, 52-week, multicenter study in adults with polymyalgia rheumatica as defined by the American College of Rheumatology/European Union League against Rheumatism (ACR/EULAR) classification criteria.1 Patients selected for this study, had at least one episode of unequivocal polymyalgia rheumatica flare while attempting to taper corticosteroids.1, 2004 In this study, patients with active polymyalgia rheumatica were randomized to receive sarilumab 200 mg every 2 weeks with a pre-established 14-week taper of prednisone or placebo every 2 weeks with an established 52-week taper of prednisone.1 Patients experiencing a disease flare or unable to adhere to the assigned prednisone tapering schedule could receive corticosteroids as rescue therapy.1
The primary endpoint of this study was the proportion of patients with sustained remission at week 52.1 Sustained remission was defined as achievement of disease remission no later than week 12, absence of disease flare from week 12 through week 52, sustained reduction of C-reactive protein (to <10 mg/L) from week 12 through week 52, and successful adherence to prednisone taper from week 12 through week 52.1 An additional endpoint was total cumulative corticosteroid dose over 52 weeks.1
Sarilumab exhibited improvement in achieving sustained remission and reducing the cumulative corticosteroid dose in patients with a relapse of polymyalgia rheumatica during corticosteroid tapering.1 At 52 weeks, a higher proportion of patients receiving sarilumab achieved each component of the sustained remission endpoint (28.3%) compared to those patients receiving placebo (10.3%).1, 2004 Additionally, the total actual cumulative corticosteroid dose including all corticosteroids taken during the study (i.e., prednisone taper regimen per protocol, add-on prednisone prior to week 12, corticosteroid use due to rescue, or corticosteroid used during the treatment period to manage an adverse reaction not related to polymyalgia rheumatica) was 777 mg in those patients receiving sarilumab compared with 2044 mg in those receiving placebo.1, 2004
Polyarticular Juvenile Idiopathic Arthritis
Sarilumab is used for the treatment of active polyarticular juvenile idiopathic arthritis in patients weighing ≥63 kg.1 The use of sarilumab in pediatric patients with polyarticular juvenile idiopathic arthritis is supported by data from adequate and well-controlled studies of the drug in adult patients with rheumatoid arthritis, pharmacokinetic data from adult patients with rheumatoid arthritis, and pharmacokinetic comparability in 101 pediatric patients 2-17 years of age treated with sarilumab.1
The American College of Rheumatology and the Arthritis Foundation issued a joint guideline for the treatment of juvenile idiopathic arthritis manifesting as nonsystemic polyarthritis (including polyarticular disease), sacroiliitis, or enthesitis in 2019.2005 Several drug classes are used to treat juvenile idiopathic arthritis, including NSAIAs, systemic and intra-articular corticosteroids, conventional DMARDs (e.g., methotrexate, sulfasalazine, hydroxychloroquine, leflunomide), and biologic DMARDs (e.g., TNF blocking agents, abatacept, tocilizumab, rituximab).2005 Specific agents for juvenile idiopathic arthritis treatment are selected according to the presence of certain risk factors (e.g., positive anti-cyclic citrullinated peptide antibodies, positive rheumatoid factor, joint damage), level of disease activity, involvement of specific joints, presence of certain comorbidities (e.g., uveitis), and prior therapies used.2005, 2006 An individualized “treat-to-target” approach is typically employed, with the goal of achieving remission or minimal/low disease activity.2006
Sarilumab is administered by subcutaneous injection only.1 Sarilumab is intended for use under the guidance and supervision of a clinician; however, the drug may be self-administered if the clinician determines that the patient and/or their caregiver is competent to safely administer the drug after appropriate training.1 The ability of pediatric patients to self-inject the prefilled pen has not been evaluated.1
Sarilumab is commercially available in single-use prefilled syringes and single-use prefilled pens.1 Each syringe or pen delivers 150 or 200 mg of sarilumab in 1.14 mL.1 The entire contents of the prefilled syringe or pen should be administered as a single dose.1
Sarilumab injection is a clear and colorless to pale yellow solution.1 Prior to administration, sarilumab solution should be inspected visually for particulate matter or discoloration; if the syringe or pen appears to be damaged or the solution contains particulates or is cloudy or discolored, the solution should be discarded.1 Sarilumab prefilled syringes and pens should be stored at 2-8°C in the original carton until administration and protected from light.1 The injection should not be frozen or shaken.1 If refrigeration is not available, the prefilled syringes and pens may be stored at room temperature up to 25°C in the original carton for a period of up to 14 days.1 At least 30 minutes prior to administration, the prefilled syringe should be removed from the refrigerator and allowed to reach room temperature; the prefilled pen should be removed from refrigeration at least 60 minutes prior to administration.1 The syringe or pen should not be warmed in any other way (e.g., microwave, hot water).1
Sarilumab is administered subcutaneously into the anterior thigh or abdomen (except for the 2-inch area around the umbilicus).1 Sarilumab may be administered subcutaneously into the upper arm by a caregiver or clinician.1 Injection sites should be rotated.1 Injections should not be made into areas where the skin is tender, bruised, or damaged or into scars.1
For the management of moderately to severely active rheumatoid arthritis in adults who have had an inadequate response or intolerance to one or more DMARDs, the recommended dosage of sarilumab is 200 mg by subcutaneous injection once every 2 weeks.1 Sarilumab may be used as monotherapy or in combination with methotrexate or other conventional DMARDs.1
For the management of polymyalgia rheumatica in adults who have had an inadequate response to corticosteroids or who cannot tolerate corticosteroid taper, the recommended dosage of sarilumab is 200 mg by subcutaneous injection once every 2 weeks, in combination with a tapering course of systemic corticosteroids.1 Sarilumab can be used as monotherapy following discontinuation of corticosteroids.1
Polyarticular Juvenile Idiopathic Arthritis
For the management of polyarticular juvenile idiopathic arthritis in patients weighing ≥63 kg, the recommended dosage of sarilumab is 200 mg by subcutaneous injection once every 2 weeks.1 The maximum dose of sarilumab for this indication is 200 mg.1 Sarilumab can be used as monotherapy or in combination with conventional DMARDs.1
Dosage Modifications or Discontinuance due to Toxicity in Patients with Rheumatoid Arthritis
If a serious infection or an opportunistic infection develops, sarilumab should be interrupted until the infection is controlled.1
If certain dose-related laboratory changes (i.e., neutropenia, thrombocytopenia, elevated liver enzyme concentrations) occur, reduction in sarilumab dosage to 150 mg every 2 weeks or temporary interruption or discontinuance of sarilumab therapy is recommended (see Tables 1-3).1
ANC (cells/mm3) | Recommendation |
|---|---|
>1000 | Maintain current dosage |
500-1000 | Interrupt sarilumab therapy until ANC is >1000; resume sarilumab at 150 mg every 2 weeks and increase to 200 mg every 2 weeks as clinically indicated |
<500 | Discontinue sarilumab |
Platelet Count (cells/mm3) | Recommendation |
|---|---|
50,0000-100,000 | Interrupt sarilumab therapy until platelet count is >100,000; resume sarilumab at 150 mg every 2 weeks and increase to 200 mg every 2 weeks as clinically indicated |
<50,000 | Repeat platelet count; discontinue sarilumab if results are confirmed |
ALT or AST Value | Recommendation |
|---|---|
>1 to 3 times ULN | Modify dosage of concomitant DMARDs if appropriate |
>3 to 5 times ULN | Interrupt sarilumab therapy until ALT or AST values are <3 times ULN; resume sarilumab at 150 mg every 2 weeks and increase to 200 mg every 2 weeks as clinically indicated |
>5 times ULN | Discontinue sarilumab |
Dosage Modification or Discontinuance for Toxicity in Patients with Polymyalgia Rheumatica
If a serious infection or an opportunistic infection develops, sarilumab should be interrupted until the infection is controlled.1
If certain dose-related laboratory changes (i.e., neutropenia, thrombocytopenia, elevated liver enzyme concentrations) occur, discontinuance of sarilumab therapy is recommended.1 (See Tables 4-6.) Dosage modifications have not been studied in patients with polymyalgia rheumatica with these conditions.1
ANC (cells/mm3) | Recommendation |
|---|---|
<1000 at the end of the dosing interval | Discontinue sarilumab |
Platelet Count (cells/mm3) | Recommendation |
|---|---|
<100,000 | Discontinue sarilumab |
AST or ALT | Recommendation |
|---|---|
>3 times ULN | Discontinue sarilumab |
Dosage Modification or Discontinuance for Toxicity in Patients with Polyarticular Juvenile Idiopathic Arthritis
In patients with polyarticular juvenile idiopathic arthritis, dose reduction of sarilumab has not been evaluated.1 Sarilumab should be discontinued in these patients if ALT >5 times ULN, platelet count ≤50,000 cells/mm3, or neutrophil count <500 cells/mm3 associated with infection.1 Sarilumab should be withheld if ALT >3 to ≤5 times ULN, platelet count >50,000 to ≤100,000 cells/mm3, and neutrophil count ≥500 to <1000 cells/mm3, and until the clinical condition has been evaluated.1 Discontinuation of sarilumab therapy should be based upon a medical evaluation of the individual patient.1 Dosing of concomitant medications should be modified or discontinued as well, if appropriate.1
Sarilumab is not recommended in patients with hepatic impairment.1
Dosage adjustment is not necessary in patients with mild or moderate renal impairment.1
Sarilumab has not been studied in patients with severe renal impairment.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
A boxed warning about the risk of serious infections is included in the prescribing information for sarilumab.1 Serious and sometimes fatal infections, including bacterial, mycobacterial, invasive fungal, viral, or other opportunistic infections, have been reported in patients receiving immunosuppressive agents including sarilumab.1, 2, 3 The most common serious infections reported in patients with rheumatoid arthritis receiving sarilumab have included pneumonia and cellulitis.1 Opportunistic infections (e.g., tuberculosis, candidiasis, pneumocystosis) also have been reported in patients receiving sarilumab.1 Other serious infections (e.g., aspergillosis, cryptococcal infection, histoplasmosis) may occur.1 Patients have presented with disseminated rather than local disease; patients often were receiving concomitant therapy with immunosuppressive agents (e.g., methotrexate, corticosteroids) that, in addition to their underlying condition, could have predisposed them to infections.1
Closely monitor patients during treatment with sarilumab for the development of signs or symptoms of infection.1
Sarilumab therapy should not be initiated in patients with active infections, including localized infections.1 Clinicians should consider potential risks and benefits of the drug prior to initiating therapy in patients with a history of chronic, recurring, serious, or opportunistic infections; patients with underlying conditions that may predispose them to infections; and patients who have been exposed to tuberculosis or who reside or have traveled in regions where tuberculosis or mycoses are endemic.1 Any patient who develops a new infection while receiving sarilumab should undergo a thorough diagnostic evaluation (appropriate for an immunocompromised patient), appropriate anti-infective therapy should be initiated, and the patient should be closely monitored.1 If a serious or opportunistic infection develops, sarilumab should be interrupted until the infection is controlled.1
All patients should be evaluated for latent tuberculosis and for the presence of risk factors for tuberculosis prior to and periodically during therapy with sarilumab.1 When indicated, an appropriate antimycobacterial regimen for the treatment of latent tuberculosis infection should be initiated prior to sarilumab therapy.1 Antimycobacterial therapy should be considered prior to initiation of sarilumab in individuals with a history of latent or active tuberculosis in whom an adequate course of antimycobacterial treatment cannot be confirmed and in individuals with a negative test for latent tuberculosis who have risk factors for tuberculosis.1 Consultation with a tuberculosis specialist is recommended when deciding whether antimycobacterial therapy should be initiated.1 Patients receiving sarilumab, including individuals with a negative test for latent tuberculosis, should be monitored for signs and symptoms of active tuberculosis.1
Viral reactivation can occur in patients receiving immunosuppressive therapies.1 Herpes zoster exacerbation has been reported in patients receiving sarilumab.1 The risk of reactivation of hepatitis B virus (HBV) infection in patients receiving sarilumab is not known.1
Other Warnings and Precautions
Hypersensitivity reactions (e.g., injection site rash, rash, urticaria) have been reported in patients receiving sarilumab.1 During clinical trials of sarilumab, hypersensitivity reactions requiring treatment discontinuance have been reported.1
Patients receiving sarilumab should be advised to seek medical attention if they experience symptoms of a hypersensitivity reaction.1 If a hypersensitivity reaction occurs, administration of the drug should be stopped immediately.1 Sarilumab is contraindicated in patients with known hypersensitivity to the drug.1
Neutropenia and thrombocytopenia have been reported during clinical trials in patients receiving sarilumab, but decreases in neutrophil counts were not associated with infection, including serious infection, and decreases in platelet counts were not associated with bleeding.1
Neutrophil and platelet counts should be evaluated prior to initiation of sarilumab therapy, 4-8 weeks after initiation of therapy, and every 3 months thereafter.1 In patients with neutropenia or thrombocytopenia, dosage adjustment, treatment interruption, or discontinuance of the drug may be necessary.1
Sarilumab has been associated with elevated aminotransferase concentrations.1 In clinical trials, these changes were transient and were not associated with clinical evidence of hepatic injury.1 The incidence and magnitude of aminotransferase elevations were increased when sarilumab was used in conjunction with a hepatotoxic drug (e.g., methotrexate).1
Serum ALT and AST concentrations should be evaluated prior to initiation of sarilumab therapy, 4-8 weeks after initiation of therapy, and every 3 months thereafter.1 Other liver function tests (e.g., bilirubin) should be monitored when clinically indicated.1 In patients with elevated aminotransferase concentrations, dosage adjustment, treatment interruption, or discontinuance of sarilumab or concomitantly administered disease-modifying antirheumatic drugs (DMARDs) may be necessary.1 Sarilumab is not recommended in patients with active hepatic disease or hepatic impairment.1
Increased serum concentrations of total cholesterol, triglycerides, low-density lipoprotein (LDL)-cholesterol, and/or high-density lipoprotein (HDL)-cholesterol have been reported in patients receiving sarilumab.1, 2, 3
Evaluate lipoprotein concentrations (total cholesterol, LDL cholesterol, HDL cholesterol and/or triglycerides) prior to initiation of sarilumab.1 Lipoprotein concentrations should be monitored 4-8 weeks after initiation of sarilumab therapy and approximately every 6 months thereafter.1 Lipid disorders should be managed according to clinical guidelines.1
GI perforation has been reported in patients receiving sarilumab, usually as a complication of diverticulitis.1 Risk may be increased with concurrent diverticulitus or in patients receiving concomitant therapy with nonsteroidal anti-inflammatory agents (NSAIAs) or corticosteroids.1
Patients who experience new-onset abdominal symptoms should be promptly evaluated.1
Immunosuppressive therapy may increase the risk of malignancies.1 Whether treatment with sarilumab affects development of malignancies remains to be determined.1 Malignancies were reported in clinical trials of the drug.1
Live vaccines should be avoided during therapy with sarilumab.1
As with all therapeutic proteins, there is potential for immunogenicity in patients who receive sarilumab.1 In clinical studies in patients with rheumatoid arthritis, antibodies to sarilumab were detected in approximately 4, 5.7, or 1.9% of patients receiving sarilumab 200 mg every 2 weeks, 150 mg every 2 weeks, or placebo, respectively, in combination with a DMARD.1 Neutralizing antibodies were detected in 1% of patients receiving sarilumab 200 mg, 1.6% of patients receiving sarilumab 150 mg, and 0.2% of patients receiving placebo in combination with a DMARD.1 Antibodies to sarilumab were detected in approximately 9.2% of patients receiving sarilumab alone; neutralizing antibodies developed in about 6.9% of such patients.1 Prior to administration of sarilumab monotherapy, 2.3% of patients had neutralizing antibodies.1 In clinical studies in patients with polymyalgia rheumatica, antibodies to sarilumab were detected in one patient receiving sarilumab 200 mg every 2 weeks in combination with a corticosteroid taper; this patient did not exhibit a clinical response.1 In clinical studies in patients with polyarticular juvenile idiopathic arthritis, antibodies to sarilumab were detected in 3 patients treated with the recommended dose; neutralizing antibodies were detected in one patient.1 Due to the low occurrence of anti-sarilumab antibodies, the effect of these antibodies on safety and effectiveness in polymyalgia rheumatica or polyarticular juvenile idiopathic arthritis is unknown.1
The limited data with sarilumab in pregnant women are insufficient to inform drug-associated risk for major birth defects and miscarriage.1 As pregnancy progresses, monoclonal antibodies are increasingly transported across the placenta, with the largest amount transferred during the third trimester.1 However, there was no evidence of embryotoxicity or fetal malformations in cynomolgus monkeys following administration of sarilumab during organogenesis at dosages producing exposures up to 84 times the exposure at the maximum recommended human dosage.1 Because interleukin-6 (IL-6) is increased in cervical and myometrial tissues during parturition, sarilumab may delay parturition by interfering with cervical ripening and myometrial contractions.1 Sarilumab should be used during pregnancy only when the potential benefits to the woman justify the potential risk to the fetus.1
Infants exposed to sarilumab in utero may have impaired immune responses.1 Consider the risks and benefits of administering live vaccines to such infants.1
It is not known whether sarilumab is distributed into milk or is absorbed from the GI tract in breast-fed infants.1 Because immunoglobulin G (IgG) is distributed into human milk, it is possible that sarilumab is distributed into milk.1 Potential effects of the drug on milk production or on breast-fed infants are unknown.1 Consider the benefits of breast-feeding and the importance of sarilumab to the woman along with potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.1
The efficacy and safety of sarilumab for active polyarticular juvenile idiopathic arthritis in pediatric patients weighing ≥63 kg are supported by data from adequate and well-controlled studies of sarilumab in adults with rheumatoid arthritis, pharmacokinetic data in adults with rheumatoid arthritis, and a pharmacokinetic, pharmacodynamic, dose-finding, and safety study in pediatric patients with polyarticular juvenile idiopathic arthritis ≥2 years of age.1 The efficacy and safety of sarilumab have not been established in pediatric patients with polyarticular juvenile idiopathic arthritis <2 years of age.1 In addition, sarilumab is not approved in pediatric patients weighing <63 kg due to lack of an appropriate dosage form.1
Neonates and infants who were exposed to sarilumab in utero may have impaired immune responses; consider the risks and benefits of administering live vaccines to such infants.1
Of the total number of patients with rheumatoid arthritis studied in clinical trials of sarilumab, 15% were ≥65 years of age while 1.6% were ≥75 years of age.1 Of the total number of patients with polymyalgia rheumatica studied in the clinical trials, 55.9% were 65 to 75 years of age and 17% were ≥75 years of age.1 Although no overall differences in safety and efficacy were observed between geriatric and younger patients, serious infections occurred more frequently in those ≥65 years of age.1 Because the geriatric population in general may have a higher incidence of infections than younger adults, use sarilumab with caution in this age group.1
Safety and efficacy of sarilumab have not been established in patients with hepatic impairment, including those with serologic evidence of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.1 Use of the drug in patients with active hepatic disease or hepatic impairment is not recommended.1
The effect of renal impairment on the pharmacokinetics of sarilumab has not been specifically studied to date.1 Although population pharmacokinetic data suggest an increase in exposure to sarilumab in patients with mild to moderate renal impairment (creatinine clearance of 30 to <90 mL/minute), sarilumab is not expected to undergo substantial renal elimination and dosage adjustment is not necessary.1, 10 Sarilumab has not been evaluated in patients with severe renal impairment.1
Adverse effects reported in 3% or more of patients with rheumatoid arthritis receiving sarilumab include neutropenia, increased ALT concentrations, injection site erythema, upper respiratory tract infection, and urinary tract infection.1, 2, 3
Adverse effects reported in 5% or more of patients with polymyalgia rheumatica receiving sarilumab include neutropenia, leukopenia, and injection site pruritus.1
Adverse effects reported in patients with polyarticular juvenile idiopathic arthritis receiving sarilumab include nasopharyngitis, neutropenia, upper respiratory tract infection, and injection site erythema.1
Drugs Metabolized by Hepatic Microsomal Enzymes
Because increased levels of cytokines including interleukin-6 (IL-6) in inflammatory conditions such as rheumatoid arthritis may suppress the formation of cytochrome P-450 (CYP) enzymes, inhibition of IL-6 activity by sarilumab may restore CYP enzyme activity to higher levels.1, 6 Effects of sarilumab on CYP enzyme activity may persist for several weeks after the drug is discontinued.1 Following initiation or discontinuance of sarilumab therapy, patients receiving certain drugs metabolized by CYP isoenzymes (i.e., those with a low therapeutic index that require individualized dosing [e.g., theophylline, warfarin]) should be monitored for therapeutic effect and/or changes in serum concentrations, and dosages of these drugs should be adjusted as needed.1 Caution also is advised when sarilumab is used concomitantly with CYP3A4 substrates (e.g., oral contraceptives, atorvastatin, lovastatin) for which a reduction in efficacy would be undesirable.1
Subcutaneous administration of a single 200-mg dose of sarilumab one week prior to oral administration of a single 40-mg dose of simvastatin (a substrate of CYP3A4 and organic anion transport protein [OATP] 1B1) in patients with rheumatoid arthritis reduced systemic exposures to simvastatin and simvastatin acid by 45 and 36%, respectively, compared with administration of simvastatin alone.1, 6
Concomitant use of methotrexate does not appear to affect clearance of sarilumab.1 Sarilumab has not been studied in conjunction with biologic disease-modifying antirheumatic drugs (DMARDs), including tumor necrosis factor (TNF; TNF-α) blocking agents, or with Janus kinase (JAK) inhibitors (e.g., tofacitinib).1 Concomitant use of sarilumab with biologic DMARDs should be avoided.1
Safety of live vaccines in patients receiving sarilumab has not been established and there is a possibility of increased risk of infection with concomitant use.1 Live vaccines should be avoided during therapy with sarilumab.1 The interval between administration of live vaccines and initiation of sarilumab therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.1 Information is not available regarding secondary transmission of infection from individuals receiving live vaccines to patients receiving sarilumab.1
Sarilumab, a recombinant human monoclonal antibody specific for the interleukin-6 (IL-6) receptor, is a biologic response modifier and a disease-modifying antirheumatic drug (DMARD).1, 2, 3, 7 Sarilumab is an IgG1 kappa immunoglobulin that binds specifically to both soluble and membrane-bound IL-6 receptors and inhibits IL-6-mediated signaling through these receptors, thereby resulting in a reduction in inflammatory mediator production.1, 2, 3, 7, 13
IL-6, a pleiotropic proinflammatory cytokine, is produced by various cell types, including T cells, B lymphocytes, monocytes, fibroblasts, synoviocytes, and endothelial cells, and has a broad spectrum of biologic activities.1, 2, 3, 9 IL-6 is involved in T-cell activation, induction of immunoglobulin secretion, initiation of hepatic acute phase protein synthesis, stimulation of hematopoietic precursor cell proliferation and differentiation, and induction of osteoclast differentiation and activation.1, 2, 3, 7, 8, 9 While the causes of rheumatoid arthritis have not been fully elucidated, proinflammatory cytokines, including IL-6, appear to play critical roles in the disease process.1, 2, 3, 7, 9 IL-6 is overexpressed in synovial tissue in patients with rheumatoid arthritis and is thought to contribute to synovial proliferation and joint destruction in patients with the disease.1, 2, 3, 7, 8, 9 Elevated levels of IL-6 in serum and synovial fluid have been shown to correlate with clinical and laboratory measures of disease activity in patients with rheumatoid arthritis.2, 3, 7, 8, 9
The absolute bioavailability of sarilumab following subcutaneous injection is approximately 80%.5 Following repeated subcutaneous administration of sarilumab 150 or 200 mg every 2 weeks in patients with rheumatoid arthritis, peak serum concentrations of the drug are attained in approximately 2-4 days and steady-state concentrations of the drug are attained within 14-16 weeks; systemic accumulation of the drug is 2- to 3-fold.1 With an increase in dosage from 150 mg every 2 weeks to 200 mg every 2 weeks in patients with rheumatoid arthritis, steady-state concentrations of the drug increase by approximately 2-fold.1 The median time to steady state in patients with polymyalgia rheumatica is estimated to be 28 weeks and there was accumulation following subcutaneous administration of sarilumab 200 mg, with an accumulation ratio of approximately 6-fold.1 In general, pharmacokinetic exposures were higher in patients with polymyalgia rheumatica when compared to patients with rheumatoid arthritis.1 In patients with polyarticular juvenile idiopathic arthritis, steady state was reached in 12 to 28 weeks; steady state concentrations were within the range of exposures in adults with rheumatoid arthritis following 150 mg/200 mg every 2 weeks.1 The metabolic pathway of sarilumab has not been characterized; as with other therapeutic proteins, the drug is expected to be catabolized into peptides and amino acids in the same manner as endogenous IgG.1 Sarilumab exhibits concentration-dependent clearance.1 At low sarilumab concentrations, target-mediated nonlinear clearance plays a major role in determining total drug clearance; at higher concentrations, the nonlinear pathway is saturated and clearance is determined mainly by linear clearance.1 The apparent steady-state half-life of sarilumab in adults with rheumatoid arthritis is up to 8 or 10 days following subcutaneous administration of sarilumab 150 or 200 mg, respectively, every 2 weeks.1 Patients who developed anti-sarilumab antibodies generally had increased clearance of the drug.1 The pharmacokinetics of sarilumab are not affected by age, gender, or race.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection, for subcutaneous use | 150 mg/1.14 mL | Kevzara® (available as single-use prefilled syringes and prefilled injection pens) | |
200 mg/1.14 mL | Kevzara® (available as single-use prefilled syringes and prefilled injection pens) | Sanofi-Aventis and Regeneron |
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions January 10, 2025. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Sanofi-Aventis. Kevzara® (sarilumab) injection prescribing information. Bridgewater, NJ; 2024 Jun.
2. Genovese MC, Fleischmann R, Kivitz AJ et al. Sarilumab plus methotrexate in patients with active rheumatoid arthritis and inadequate response to methotrexate: Results of a phase III study. Arthritis Rheum . 2015; 67:(6):1424-37.
3. Fleischmann R, van Adelsberg J, Lin Y et al. Sarilumab and nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis and inadequate response or intolerance to tumor necrosis factor inhibitors. Arthritis Rheum . 2017; 69:(2):277-90.
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5. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 761037Orig1s000: Clinical review(s). From FDA website. [Web]
6. Lee EB, Daskalakis N, Xu C et al. Disease-Drug Interaction of Sarilumab and Simvastatin in Patients with Rheumatoid Arthritis. Clin Pharmacokinet . 2017; 56:607-615. [PubMed 27722854]
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8. Boyapati A, Msihid J, Fiore S et al. Sarilumab plus methotrexate suppresses circulating biomarkers of bone resorption and synovial damage in patients with rheumatoid arthritis and inadequate response to methotrexate: a biomarker study of MOBILITY. Arthritis Res Ther . 2016; 18:225. [PubMed 27716324]
9. Park JY, Pillinger MH. Interleukin-6 in the pathogenesis of rheumatoid arthritis. Bull NYU Hosp Jt Dis . 2007; 65 Suppl 1:S4-10. [PubMed 17708744]
10. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 761037Orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website. [Web]
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13. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 761037Orig1s000: Product quality review(s). From FDA website. [Web]
14. Genovese MC, van der Heijde D, Lin Y et al. Long-term safety and efficacy of sarilumab plus methotrexate on disease activity, physical function and radiographic progression: 5 years of sarilumab plus methotrexate treatment. RMD Open . 2019; 5:e000887. [PubMed 31452928]
15. Fleischmann R, Genovese MC, Maslova K et al. Long-term safety and efficacy of sarilumab over 5 years in patients with rheumatoid arthritis refractory to TNF inhibitors. Rheumatology (Oxford) . 2021; 60:4991-5001. [PubMed 33871596]
16. Burmester GR, Lin Y, Patel R et al. Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-group phase III trial. Ann Rheum Dis . 2017; 76:840-847. [PubMed 27856432]
17. Genovese MC, Fleischmann R, Kivitz A et al. Efficacy and safety of sarilumab in combination with csDMARDs or as monotherapy in subpopulations of patients with moderately to severely active rheumatoid arthritis in three phase III randomized, controlled studies. Arthritis Res Ther . 2020; 22:139. [PubMed 32522251]
2003. Fraenkel L, Bathon JM, England BR et al. 2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Care Res (Hoboken) . 2021; 73:924-939. [PubMed 34101387]
2004. Spiera RF, Unizony S, Warrington KJ, et al. Sarilumab for Relapse of Polymyalgia Rheumatica during Glucocorticoid Taper. N Engl J Med. 2023; 389:1263-72.
2005. Ringold S, Angeles-Han ST, Beukelman T, et al. 2019 American College of Rheumatology/Arthritis Foundation guideline for the treatment of juvenile idiopathic arthritis: therapeutic approaches for non-systemic polyarthritis, sacroilitis, and enthesitis. Arthritis Rheumatol. 2019;71(6):846-63.
2006. Ravelli A, Consolaro A, Horneff G. Treating juvenile idiopathic arthritis to target: recommendations of an international task force. Ann Rheum Dis. 2018;77:819-828.