Kevzara (Sarilumab)
Approved Indications & Off-Label Uses
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Rheumatoid arthritis (RA) | Adults with moderately to severely active RA, inadequate response or intolerance to ≥1 DMARD | Monotherapy or with MTX/conventional DMARDs | FDA Approved |
| Polymyalgia rheumatica (PMR) | Adults with inadequate response to corticosteroids or who cannot tolerate corticosteroid taper | With tapering corticosteroids; monotherapy after steroid discontinuation | FDA Approved |
| Polyarticular juvenile idiopathic arthritis (pJIA) | Patients ≥63 kg with active pJIA | Monotherapy or with conventional DMARDs | FDA Approved |
Sarilumab is the second IL-6 receptor antagonist approved in the United States (after tocilizumab) and distinguishes itself by being a fully human monoclonal antibody available exclusively as a subcutaneous formulation. The PMR approval in March 2023 made it the first biologic approved for this condition. The pJIA indication, approved in June 2024, is limited to patients weighing 63 kg or more because an appropriate paediatric dosage form for lighter patients is not yet available.
Giant cell arteritis (GCA): IL-6 receptor blockade is an established treatment pathway for GCA (with tocilizumab approved), and sarilumab has been investigated in clinical trials for this indication. Evidence quality: Moderate (Phase III trial data available).
COVID-19 (hospitalized): Studied in randomised trials but not FDA-approved for this indication, unlike tocilizumab. Evidence quality: Low-moderate (mixed trial results).
Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| RA — combination with MTX or conventional DMARDs | 200 mg SC q2wk | 200 mg SC q2wk | 200 mg q2wk | Reduce to 150 mg q2wk for neutropenia, thrombocytopenia, or elevated transaminases Can re-escalate to 200 mg q2wk when lab values normalise |
| RA — monotherapy (MTX intolerant or inappropriate) | 200 mg SC q2wk | 200 mg SC q2wk | 200 mg q2wk | Safety profile consistent with combination therapy Reduce to 150 mg q2wk for lab abnormalities |
| PMR — with tapering corticosteroids | 200 mg SC q2wk | 200 mg SC q2wk | 200 mg q2wk | Can continue as monotherapy after steroid discontinuation Discontinue (not dose-reduce) for lab abnormalities — dose modification not studied in PMR |
| pJIA — patients ≥63 kg | 200 mg SC q2wk | 200 mg SC q2wk | 200 mg q2wk | Use 200 mg/1.14 mL PFS only (pen not tested in paediatric patients) Not approved for <63 kg (no appropriate dosage form). Dose reduction not studied in pJIA. |
Dose Modification for Laboratory Abnormalities (RA Only)
| Lab Abnormality | Threshold | Action | Re-escalation | Discontinue |
|---|---|---|---|---|
| Low ANC | 500–1000 cells/mm³ | Hold sarilumab until ANC >1000 | Resume at 150 mg q2wk; increase to 200 mg as appropriate | ANC <500: discontinue |
| Low platelets | 50,000–100,000 cells/mm³ | Hold sarilumab until platelets >100,000 | Resume at 150 mg q2wk; increase to 200 mg as appropriate | <50,000 (confirmed): discontinue |
| ALT/AST elevation | >3× to 5× ULN | Hold until <3× ULN | Resume at 150 mg q2wk; increase to 200 mg as appropriate | >5× ULN: discontinue |
Unlike tocilizumab, sarilumab is available only as a subcutaneous formulation — no IV option exists. This simplifies administration but means it cannot be used for acute indications requiring rapid onset (e.g., CRS, COVID-19). The dosing is straightforward: 200 mg SC every 2 weeks for all three approved indications, with 150 mg available as a dose-reduction step for RA only. For PMR and pJIA, any qualifying lab abnormality triggers discontinuation rather than dose reduction. The platelet threshold for initiating therapy is higher for sarilumab (<150,000/mm³) than for tocilizumab (<100,000/mm³).
Pharmacology
Mechanism of Action
Sarilumab is a fully human recombinant IgG1-kappa monoclonal antibody (molecular weight ~150 kDa) produced in Chinese Hamster Ovary cells. It binds with high affinity to both soluble and membrane-bound interleukin-6 receptors (sIL-6R and mIL-6R), thereby blocking both cis-signalling (via mIL-6R on hepatocytes, neutrophils, and macrophages) and trans-signalling (via sIL-6R affecting a broader range of cell types). By preventing IL-6 from engaging its receptor, sarilumab inhibits downstream JAK-STAT3 signalling that drives acute-phase protein production (CRP, serum amyloid A, fibrinogen), synovial inflammation, osteoclast-mediated bone erosion, and systemic features of inflammatory disease. Unlike tocilizumab, which is a humanized antibody, sarilumab is fully human, potentially conferring a lower immunogenicity profile, although clinical differences have not been definitively established.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | SC bioavailability ~80%; Tmax 2–4 days; steady state reached in 14–16 weeks (RA), ~28 weeks (PMR) | Fixed-dose SC administration allows home self-injection. Longer time to steady state in PMR reflects higher accumulation ratio (~6-fold vs 2–3-fold in RA) and potentially different IL-6R dynamics in this population. |
| Distribution | Vd,ss: 7.3 L (RA) | Low Vd typical of IgG1 monoclonal antibodies, confined largely to plasma and interstitial fluid. |
| Metabolism | Catabolic degradation to peptides and amino acids (not CYP-mediated); parallel linear + nonlinear target-mediated elimination | At therapeutic concentrations (200 mg q2wk), IL-6R is more fully saturated, reducing nonlinear clearance and yielding higher, more consistent trough levels. The 200 mg dose produces 2-fold higher steady-state AUC than 150 mg. |
| Elimination | t½: up to 8 days (150 mg), up to 10 days (200 mg); time to non-detectable after last steady-state dose: 28 days (150 mg), 43 days (200 mg) | Not eliminated by renal or hepatic pathways; no dose adjustment needed for organ impairment. Washout period of up to 6 weeks relevant for surgery planning and live vaccination timing. |
Side Effects
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Neutropenia | 10% (200 mg+DMARD) | Most common adverse reaction and leading cause of discontinuation; not clearly associated with increased serious infection risk in clinical trials |
| ALT elevation (>ULN to 3×ULN) | 43% (200 mg+DMARD) | Higher with concomitant MTX; transient and reversible with dose modification. Not associated with clinically relevant bilirubin increases or hepatic impairment. |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Injection site erythema | 4–5% | Mild severity in majority; only 0.2% required discontinuation. Rotate injection sites. |
| ALT increased (reported as adverse event) | 5% (both dose groups) | Includes clinically notable elevations requiring dose modification |
| Upper respiratory tract infection | 3–4% | Consistent with immunosuppression profile; generally mild |
| Urinary tract infection | 3% (both doses) | Monitor in elderly and patients with urinary tract abnormalities |
| Hypertriglyceridaemia | 3% (150 mg); 1% (200 mg) | Mean triglycerides increased by 20–27 mg/dL; manage per lipid guidelines |
| Injection site pruritus | 2% | Self-limiting; rotate sites |
| Leukopenia | 2% (200 mg) | Follows neutropenia; monitor CBC |
| Thrombocytopenia (platelets <100,000/mm³) | 1% (200 mg) | No associated bleeding events in trials |
| ALT elevation (>3–5×ULN) | 3–4% | Hold sarilumab until <3×ULN; resume at 150 mg (RA); discontinue (PMR/pJIA) |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Serious infections (pneumonia, cellulitis, sepsis) | 3.8–4.4 per 100 pt-yr | Any time during treatment | Hold sarilumab; initiate antimicrobials; resume only after infection controlled |
| Tuberculosis | Reported (rate not specified) | Months to years | Screen before initiation (TST/IGRA); treat latent TB first; monitor throughout |
| Gastrointestinal perforation | 0.11 per 100 pt-yr | Variable; typically complication of diverticulitis | Urgent surgical evaluation; discontinue sarilumab |
| Severe neutropenia (ANC <500/mm³) | 0.7% | Early weeks of therapy | Discontinue sarilumab |
| Hypersensitivity reactions requiring discontinuation | 0.3% | Any time | Stop sarilumab immediately; manage per allergy protocol; do not rechallenge |
| Hepatotoxicity (ALT/AST >5×ULN) | 0.2–1% | Variable | Discontinue sarilumab permanently |
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Neutropenia | >1% (most common single cause) | Leading cause of treatment discontinuation; ANC <500 mandates permanent cessation |
| Elevated hepatic transaminases | Common contributor | ALT/AST >5×ULN triggers discontinuation; lower thresholds require dose modification |
| Hypersensitivity | 0.3% (200 mg) | Injection site rash, generalised rash, and urticaria were the most common presentations |
Neutropenia is the most clinically distinctive adverse effect of sarilumab and the main driver of dose reductions and treatment discontinuation. In controlled trials, ANC <1000/mm³ occurred in 6% of patients on the 200 mg dose (vs 0% placebo). Importantly, the nadir ANC typically occurs just before the next scheduled dose (end of dosing interval), reflecting the pharmacodynamic effect of IL-6R blockade on neutrophil margination. For dose-modification decisions, use ANC values obtained at the end of the dosing interval. Despite the laboratory finding, treatment-related neutropenia was not clearly associated with increased serious infection rates in long-term safety data.
Drug Interactions
Like tocilizumab, sarilumab does not undergo CYP-mediated metabolism. However, by blocking IL-6 signalling, it restores hepatic CYP450 enzyme expression that is suppressed during active inflammation. This normalisation of CYP activity can increase the clearance of co-administered drugs metabolised by CYP enzymes, particularly those with narrow therapeutic indices. The effect may persist for several weeks after discontinuation.
Monitoring
- Neutrophil Count (ANC)Baseline; q4–8wk for first 6 months; then q3 months
RoutineDo not initiate if ANC <2000/mm³. Use results obtained at end of dosing interval for dose modification decisions. Hold at 500–1000; discontinue at <500 (RA). Discontinue at <1000 at end of interval (PMR). Discontinue at <500 associated with infection (pJIA). - Liver Panel (ALT, AST)Baseline; q4–8wk for first 6 months; then q3 months
RoutineDo not initiate if ALT/AST >1.5×ULN. For RA: modify dose at >3×ULN, discontinue at >5×ULN. For PMR: discontinue at >3×ULN. For pJIA: hold at >3–5×ULN, discontinue at >5×ULN. - Platelet CountBaseline; q4–8wk for first 6 months; then q3 months
RoutineDo not initiate if platelets <150,000/mm³. For RA: hold at 50,000–100,000; discontinue (confirmed) at <50,000. For PMR: discontinue at <100,000. For pJIA: hold at 50,000–100,000; discontinue at ≤50,000. - Lipid PanelBaseline; at 4–8 weeks; then q6 months
RoutineLDL increases of 12–16 mg/dL and triglyceride increases of 20–27 mg/dL expected. Manage per lipid guidelines. Be aware that statin exposure may be reduced (CYP3A4 interaction). - TB ScreeningBaseline; ongoing clinical vigilance
RoutineTest for latent TB (TST or IGRA) before initiation. Treat latent TB before starting. Monitor for active TB even if initial screen was negative. - Signs of InfectionEvery visit; patient self-monitoring
RoutineIL-6 blockade suppresses CRP and fever, masking typical infection signs. Maintain high index of suspicion. Hold sarilumab for serious infections. - GI Perforation SymptomsOngoing; especially in high-risk patients
Trigger-basedPromptly evaluate new-onset abdominal pain, particularly in patients with diverticular disease or concurrent NSAIDs/corticosteroids. - Hepatitis B ScreeningBaseline
Trigger-basedRisk of HBV reactivation unknown (at-risk patients were excluded from trials). Screen before starting; consult hepatology if positive.
Contraindications & Cautions
Absolute Contraindications
- Known hypersensitivity to sarilumab or any inactive ingredient
- Active serious infection, including localised infections
Relative Contraindications (Specialist Input Recommended)
- Active hepatic disease or hepatic impairment — treatment not recommended
- Pre-existing cytopenias: ANC <2000/mm³, platelets <150,000/mm³, or ALT/AST >1.5×ULN — initiation not recommended
- Chronic or recurrent infection or history of serious/opportunistic infection — requires documented risk-benefit discussion
- History of diverticulitis or other GI perforation risk factors
Use with Caution
- Elderly patients (≥65 years) — higher incidence of serious infections
- Patients with TB risk factors or from endemic areas
- Concomitant hepatotoxic drugs (MTX) — closer liver monitoring required
- Pregnancy — no human data; IgG1 antibodies cross the placenta in the third trimester
Patients receiving sarilumab are at increased risk for developing serious infections that may lead to hospitalisation or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Avoid use in patients with active infection. Reported infections include active tuberculosis (pulmonary or extrapulmonary), invasive fungal infections (candidiasis, pneumocystis), and bacterial, viral, and other opportunistic infections. Test for latent TB before initiation; if positive, start treatment before sarilumab. Monitor all patients for signs and symptoms of infection during treatment.
Patient Counselling
Purpose of Therapy
Sarilumab works by blocking interleukin-6, a key driver of inflammation in conditions like rheumatoid arthritis and polymyalgia rheumatica. It does not cure these diseases but reduces joint pain, swelling, stiffness, and systemic inflammation, and can help patients taper off steroids in PMR.
How to Take
Sarilumab is injected under the skin every two weeks using a pre-filled syringe or pen. Allow the device to reach room temperature before injecting (30 minutes for syringe, 60 minutes for pen). Rotate injection sites and do not inject into skin that is tender, damaged, bruised, or scarred. Inject the full 1.14 mL volume.
Sources
- KEVZARA (sarilumab) injection, for subcutaneous use. Full Prescribing Information. Sanofi-Aventis/Regeneron. Revised 06/2024. FDA LabelPrimary source for all approved indications including pJIA, dosing, warnings, adverse reactions, and PK data.
- European Medicines Agency. Kevzara (sarilumab) Summary of Product Characteristics. EMAEuropean regulatory reference; provides EU-specific prescribing guidance and safety data.
- 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 (MOBILITY). Arthritis Rheumatol. 2015;67(6):1424-1437. doi:10.1002/art.39093Pivotal Phase III trial (n=1369) demonstrating superior ACR20 response and structural damage inhibition vs placebo+MTX at 52 weeks.
- 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 (TARGET). Arthritis Rheumatol. 2017;69(2):277-290. doi:10.1002/art.39944Phase III trial in anti-TNF inadequate responders (n=546) showing significant ACR20 improvement and physical function gains.
- 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). Ann Rheum Dis. 2017;76(5):840-847. doi:10.1136/annrheumdis-2016-210310Head-to-head monotherapy trial (n=369) demonstrating sarilumab superiority over adalimumab for DAS28-ESR improvement at 24 weeks.
- Spiera RF, Unizony S, Warrington KJ, et al. Sarilumab for relapse of polymyalgia rheumatica during glucocorticoid taper (SAPHYR). N Engl J Med. 2023;389(14):1263-1272. doi:10.1056/NEJMoa2303452Phase III trial (n=117) supporting PMR approval; 28% sustained remission at 52 weeks vs 10% placebo with faster steroid taper.
- Fraenkel L, Bathon JM, England BR, et al. 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res. 2021;73(7):924-939. doi:10.1002/acr.24596Positions IL-6R inhibitors as a recommended biologic DMARD class for RA with inadequate DMARD response.
- Dejaco C, Singh YP, Perel P, et al. 2015 recommendations for the management of polymyalgia rheumatica: a European League Against Rheumatism/American College of Rheumatology collaborative initiative. Arthritis Rheumatol. 2015;67(10):2569-2580. doi:10.1002/art.39333Pre-sarilumab PMR guideline; establishes baseline management framework that sarilumab now augments for steroid-refractory patients.
- Huizinga TW, Fleischmann RM, Jasson M, et al. Sarilumab, a fully human monoclonal antibody against IL-6Rα in patients with rheumatoid arthritis and an inadequate response to methotrexate: efficacy and safety results from the randomised SARIL-RA-MOBILITY Part A trial. Ann Rheum Dis. 2014;73(9):1626-1634. doi:10.1136/annrheumdis-2013-204405Phase II dose-ranging study establishing the 150 mg and 200 mg q2wk dosing regimen with optimal efficacy-safety balance.
- Zhu Y, Hu C, Lu M, et al. Population pharmacokinetics of sarilumab in patients with rheumatoid arthritis. Clin Pharmacokinet. 2019;58(11):1455-1467. doi:10.1007/s40262-019-00765-1Population PK model (n=1770) establishing 80% SC bioavailability, body weight as key covariate, and dual elimination pathways.
- Boyapati A, Engert A, Engelbrecht H, et al. Pharmacokinetics and pharmacodynamics of subcutaneous sarilumab and intravenous tocilizumab following single-dose administration in patients with active rheumatoid arthritis. J Clin Pharmacol. 2021;61(4):530-543. doi:10.1002/jcph.1763Head-to-head PK/PD comparison showing similar onset of pharmacodynamic effect for sarilumab SC and tocilizumab IV.
- Lee EB, Dasgupta B, Allen N, et al. Sarilumab in rheumatoid arthritis: efficacy and safety. Expert Opin Biol Ther. 2018;18(2):225-233. doi:10.1080/14712598.2018.1402002Comprehensive review of sarilumab’s clinical pharmacology, PK properties, and integrated safety analysis across Phase III trials.