Introduction
Kevzara (sarilumab) is a human monoclonal antibody developed by Sanofi and Regeneron Pharmaceuticals for the treatment of moderate-to-severe rheumatoid arthritis. It represents a targeted biologic therapy that specifically inhibits interleukin-6 (IL-6) mediated inflammation, offering an important treatment option for patients who have had inadequate response to conventional disease-modifying antirheumatic drugs (DMARDs).
Mechanism of Action
Sarilumab binds specifically to both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R), inhibiting IL-6-mediated signaling through these receptors. IL-6 is a pleiotropic pro-inflammatory cytokine produced by various cell types including T-cells, B-cells, monocytes, fibroblasts, and synovial cells. Elevated IL-6 levels are found in the synovial fluid of rheumatoid arthritis patients and contribute to the inflammatory process that leads to joint destruction. By blocking IL-6 binding to its receptors, sarilumab reduces the production of acute phase reactants such as C-reactive protein (CRP), serum amyloid A, fibrinogen, and hepcidin, while also decreasing lymphocyte counts and platelet production.
Indications
Kevzara is FDA-approved for the treatment of:
- Moderate to severe rheumatoid arthritis in adults who have had an inadequate response or intolerance to one or more DMARDs
- May be used as monotherapy or in combination with conventional DMARDs such as methotrexate
Dosage and Administration
Standard dosing: 200 mg subcutaneous injection every 2 weeks Alternative dosing: 150 mg subcutaneous injection every 2 weeks (may be considered for patients with neutropenia, thrombocytopenia, or hepatic enzyme abnormalities) Administration:- Administer subcutaneously in the thigh, abdomen, or upper arm
- Rotate injection sites
- Allow prefilled syringe to reach room temperature (30 minutes) before injection
- Do not shake the product
- Renal impairment: No dosage adjustment necessary
- Hepatic impairment: Not recommended in patients with hepatic impairment
- Elderly: No dosage adjustment required
- Pediatric: Safety and effectiveness not established
Pharmacokinetics
Absorption: Following subcutaneous administration, sarilumab has an absolute bioavailability of 80%. Maximum serum concentrations are achieved in 2-4 days after administration. Distribution: Steady-state volume of distribution is approximately 7.3 L. Sarilumab is expected to be distributed in the circulatory system and to tissues where IL-6 receptors are expressed. Metabolism: Sarilumab is metabolized via proteolytic enzymes throughout the body, similar to endogenous IgG antibodies. It is not metabolized by cytochrome P450 enzymes. Elimination: The elimination half-life is approximately 8-10 days. Clearance increases with body weight and decreases with increasing age.Contraindications
- Known hypersensitivity to sarilumab or any component of the formulation
- Active, serious infections
- Neutrophil count < 500 cells/mm³
- Platelet count < 50,000 cells/mm³
- ALT or AST > 1.5 times upper limit of normal
Warnings and Precautions
Serious Infections: Increased risk of serious infections leading to hospitalization or death, including tuberculosis, bacterial, invasive fungal, viral, and other opportunistic infections. Gastrointestinal Perforation: Use with caution in patients who may be at increased risk for gastrointestinal perforation. Laboratory Abnormalities: May cause neutropenia, thrombocytopenia, and elevated liver enzymes. Monitor accordingly. Hypersensitivity Reactions: Anaphylaxis and other hypersensitivity reactions have been reported. Vaccinations: Avoid live vaccines during treatment. Update vaccinations prior to initiation. Malignancy: The impact of IL-6 inhibition on the development of malignancies is not fully understood.Drug Interactions
CYP450 Substrates: IL-6 inhibition may reduce CYP450 activity, potentially increasing concentrations of drugs metabolized by CYP450 enzymes (e.g., warfarin, cyclosporine, theophylline). Other Biologics: Avoid concurrent use with other biologic DMARDs due to increased risk of infection. Tocilizumab: Similar mechanism of action; concomitant use not recommended.Adverse Effects
Most common adverse reactions (≥5%):- Neutropenia (6-15%)
- Increased ALT (5-10%)
- Injection site reactions (7-10%)
- Upper respiratory tract infections (7%)
- Urinary tract infections (5%)
- Serious infections (3%)
- Gastrointestinal perforation (<1%)
- Anaphylaxis (<1%)
- Significant hepatic transaminase elevations
Monitoring Parameters
Baseline:- Complete blood count with differential
- Liver function tests
- Lipid profile
- Tuberculosis screening
- Vaccination status assessment
- CBC with differential (every 2-4 weeks for first 3 months, then every 8-12 weeks)
- Liver function tests (every 4-8 weeks for first 6 months, then every 12 weeks)
- Lipid panel (at 4-8 weeks and then every 6 months)
- Signs and symptoms of infection
- Clinical response assessment
Patient Education
- Instruct patients on proper injection technique and rotation of injection sites
- Educate about signs and symptoms of infection and when to seek medical attention
- Advise patients to report any abdominal pain promptly
- Inform about increased risk of gastrointestinal perforation
- Discuss importance of avoiding live vaccines during treatment
- Counsel about potential side effects and when to contact healthcare provider
- Emphasize importance of regular laboratory monitoring
References
1. 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 Rheumatol. 2015;67(6):1424-1437.
2. Kevzara [package insert]. Bridgewater, NJ: Sanofi-Aventis U.S. LLC; 2023.
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 Rheumatol. 2017;69(2):277-290.
4. Smolen JS, Behrens F, Nash P, et al. Maintenance, reduction, or withdrawal of etanercept after treatment with etanercept and methotrexate in patients with moderate rheumatoid arthritis (PRESERVE): a randomised controlled trial. Lancet. 2013;381(9870):918-929.
5. 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(5):840-847.
6. FDA Center for Drug Evaluation and Research. Kevzara approval documents. Accessed January 2023.
