Is Kevzara (sarilumab) a safe drug?

Is Kevzara (Sarilumab) Safe?

Kevzara (sarilumab) is generally safe and well-tolerated when used appropriately, with a safety profile consistent with IL-6 receptor inhibition and similar to other immunomodulatory agents used in rheumatoid arthritis, though it requires specific monitoring for infections, neutropenia, liver enzyme elevations, and lipid abnormalities. 1, 2

Overall Safety Profile

The safety profile of sarilumab has been extensively evaluated across multiple populations and is consistent with the anticipated effects of IL-6 receptor blockade 1, 3. According to the 2020 EULAR systematic literature review on DMARD safety, no unexpected safety outcomes were found with IL-6 receptor inhibitors like sarilumab, confirming the known safety profile of biological DMARDs 1.

Common Adverse Reactions

The most frequently reported adverse reactions in clinical trials include:

• Neutropenia (15.3%) - the most common adverse reaction 2
• Injection site reactions - occurring in 5.1-14% of patients, typically mild pruritus or erythema 2
• Upper respiratory tract infections and nasopharyngitis 2
• Laboratory abnormalities including leukopenia (6.8%), elevated liver enzymes, and lipid changes 2

These adverse events are generally manageable and consistent with the mechanism of action 3, 4.

Serious Infections

The risk of serious infections with sarilumab is low but requires vigilance. In the polymyalgia rheumatica study, serious infections occurred in 5.1% of sarilumab-treated patients compared to 5.2% in placebo 2. The overall infection rate was actually lower in the sarilumab group (37.3%) compared to placebo (50.0%) 2.

• Herpes zoster infections occurred in 3.2% of sarilumab patients versus 1.7% in placebo 2
• The EULAR systematic review found no increased risk of serious infections across biological DMARDs when properly monitored 1
• Infections occurred at a rate of 59.9 per 100 patient-years in long-term extension studies 5

Patients should be screened for tuberculosis and hepatitis B/C before initiating therapy, as recommended for all immunomodulatory agents 1, 2.

Neutropenia

Neutropenia is a class effect of IL-6 receptor inhibitors and requires monitoring:

• Decreases in neutrophil counts <1,000/mm³ occurred in 12% of adult patients 2
• Severe neutropenia (<500/mm³) occurred in 3.4% of patients 2
• Importantly, decreased neutrophil counts were not associated with increased infections, including serious infections 2
• In pediatric patients with pJIA, neutropenia was more common (19.2-48.8% depending on weight) but similarly not associated with infections 2

The FDA label recommends monitoring absolute neutrophil count before, 4-8 weeks after starting treatment, and every 3 months thereafter 2.

Liver Enzyme Elevations

Transaminase elevations are expected with IL-6 receptor blockade:

• ALT elevations >3× upper limit of normal occurred in 8-9.5% of patients 2, 4
• In the pivotal MOBILITY trial, 24 patients discontinued due to elevated transaminases 4
• All patients who discontinued due to liver enzyme elevations recovered 2
• No cases of drug-induced liver injury or hepatic failure have been reported 2

Monitor ALT/AST before treatment, 4-8 weeks after starting, and every 3 months during therapy 2.

Lipid Abnormalities

Increases in cholesterol and triglycerides are common:

• Total cholesterol ≥299 mg/dL occurred in 13.8% of sarilumab patients versus 6.9% placebo 2
• Triglycerides ≥407 mg/dL occurred in 5.2% versus 1.7% placebo 2
• HDL levels remained stable, and LDL/triglycerides stayed within normal range despite increases 2

Lipid monitoring should occur 4-8 weeks after starting treatment and approximately every 6 months thereafter 2.

Gastrointestinal Perforation

Unlike tocilizumab (another IL-6 receptor inhibitor), sarilumab has not shown an increased risk of lower intestinal perforation. The EULAR systematic review found that tocilizumab had an increased risk of lower intestinal perforation compared to conventional DMARDs (adjusted HR 4.5) and TNF inhibitors (adjusted HR 2.6-4.0) 1. This specific risk has not been identified with sarilumab in clinical trials 2, 3.

Cardiovascular Safety

No increased risk of major cardiovascular events has been identified with sarilumab 1. The EULAR systematic review found no differences in cardiovascular risk between biological DMARDs and conventional synthetic DMARDs 1.

Importantly, unlike JAK inhibitors, sarilumab has not shown an increased risk of venous thromboembolism (VTE). The EULAR review identified VTE as a specific concern with JAK inhibitors but not with IL-6 receptor inhibitors 1.

Malignancy Risk

No increased risk of malignancy has been identified with sarilumab or other biological DMARDs 1. The EULAR systematic review found no increased cancer risk with biological DMARDs compared to conventional synthetic DMARDs across five studies 1.

Long-Term Safety

Long-term safety data extending to 96 weeks and beyond demonstrate:

• No new safety signals emerged with extended treatment 5, 3
• Efficacy was sustained over ≤3 years of therapy 3
• Cumulative exposure data of 273.7 patient-years showed consistent safety profile 5
• No cases of grade 4 neutropenia occurred in long-term follow-up 5

Comparison to Other Biologics

Sarilumab's safety profile is comparable to other IL-6 receptor inhibitors and biological DMARDs 1. The 2019 EULAR recommendations place sarilumab alongside other biological and targeted synthetic DMARDs without preference based on safety, as efficacy and safety are considered similar across these agents 1.

Sarilumab demonstrated superior efficacy to adalimumab in head-to-head comparison (ACR20 response 71.1% vs 58.4%) without increased safety concerns 1.

Special Populations

Pediatric Patients (pJIA)

• No new adverse reactions or safety concerns were identified in pediatric patients aged 2-17 years compared to adults 2
• Neutropenia was more common but not associated with infections 2

Pregnancy and Lactation

• Sarilumab is not adequately studied in pregnancy 2
• Unknown if sarilumab passes into breast milk 2

Key Monitoring Requirements

To ensure safe use of sarilumab:

1. Before starting: Screen for tuberculosis, hepatitis B/C, obtain baseline CBC, liver enzymes, lipid panel 2
2. 4-8 weeks after starting: Monitor ANC, ALT/AST, lipids 2
3. Every 3 months during treatment: Monitor ANC, liver enzymes 2
4. Every 6 months: Monitor lipid panel 2

Clinical Pitfalls to Avoid

• Do not combine with other biologics (TNF inhibitors, rituximab, tocilizumab, abatacept) or JAK inhibitors due to increased infection risk 2
• Do not use in patients with active infections 2
• Do not ignore neutropenia - while not associated with infections in trials, severe neutropenia (<500/mm³) requires dose modification or discontinuation 2
• Ensure adequate interval before/after surgery - allow healing before initiating or resuming therapy 2

Bottom Line

Sarilumab is a safe and effective option for rheumatoid arthritis, polymyalgia rheumatica, and polyarticular juvenile idiopathic arthritis when used with appropriate patient selection and monitoring. The safety profile is well-characterized, predictable, and manageable with routine laboratory monitoring 1, 2, 3.