Sarilumab

Introduction Overview

Generic Name

sarilumab

Brand Name

Kevzara

Dosage Form

pre-filled syringe injection (150 mg/1.14 mL, 200 mg/1.14 mL), pre-filled pen injection (150 mg/1.14 mL, 200 mg/1.14 mL)

Drug Class

Antirheumatics, Interleukin inhibitors

Pharmacokinetics

Absorption: Sarilumab, administered subcutaneously as Kevzara, demonstrates relatively slow absorption with peak plasma concentrations typically achieved within 2 to 4 days post-dose. Bioavailability following subcutaneous injection is approximately 80%. The absorption process is influenced by the injection site and the patient’s subcutaneous tissue characteristics. Distribution: Sarilumab has a moderate volume of distribution, estimated around several liters, consistent with monoclonal antibodies confined largely to the vascular and interstitial spaces. It binds specifically to the interleukin-6 receptor (IL-6R), which influences its pharmacodynamics and tissue distribution. No significant binding to plasma proteins other than IL-6R has been reported. Metabolism: As a human monoclonal antibody, sarilumab is catabolized by standard proteolytic pathways into small peptides and amino acids. It is not metabolized by cytochrome P450 enzymes; however, IL-6 blockade may modulate CYP450 activity indirectly by reducing inflammation-mediated suppression of these enzymes. This modulation can alter the metabolism of concomitant drugs metabolized by CYP450. Elimination: The elimination half-life of sarilumab ranges between approximately 21 to 28 days, typical for IgG1 monoclonal antibodies. Clearance involves target-mediated drug disposition through binding to IL-6R and subsequent internalization and degradation, as well as nonspecific proteolytic catabolism within the reticuloendothelial system. The elimination is dose-dependent at lower concentrations due to receptor-mediated clearance but approximates linear kinetics at therapeutic doses.

Dosage Forms

Available Dosage Forms: Kevzara is supplied as single-dose pre-filled syringes and pre-filled autoinjector pens for subcutaneous injection. The available strengths are 150 mg/1.14 mL and 200 mg/1.14 mL for both delivery systems. Dosages for Adults and Adolescents: For adult patients with moderate to severe active rheumatoid arthritis and polymyalgia rheumatica, the recommended dose is 200 mg injected subcutaneously every 2 weeks. This regimen may be used as monotherapy or in combination with conventional disease-modifying antirheumatic drugs (DMARDs), such as methotrexate. In active polyarticular juvenile idiopathic arthritis (pJIA), Kevzara is approved for patients weighing 63 kg or greater with the same dosing of 200 mg subcutaneously every 2 weeks. Specific Patient Populations: Dosage modifications are recommended based on clinical parameters such as cytopenias, abnormal liver enzymes, or infectious complications. Patients with latent tuberculosis require appropriate treatment prior to initiation. Concomitant use of other biologic DMARDs is generally avoided due to increased risk of immunosuppression and infections. Considerations during pregnancy, lactation, hepatic or renal impairment, and patients with a history of malignancy should involve careful risk-benefit assessment. Monitoring is advised for infections and laboratory parameters during treatment.

Mechanism Of Action

Sarilumab is a fully-human monoclonal antibody that selectively binds to both soluble and membrane-bound forms of the interleukin-6 receptor (IL-6R), competitively inhibiting IL-6 from binding to its receptor. IL-6 is a pro-inflammatory cytokine implicated in the pathogenesis of inflammatory disorders such as rheumatoid arthritis and polymyalgia rheumatica. By blocking IL-6 signaling, sarilumab attenuates downstream activation of the JAK-STAT and MAPK signaling pathways, which reduces expression of inflammatory mediators and acute phase proteins. At the cellular level, this blockade results in decreased recruitment and activation of immune effector cells, reduction in synovial inflammation, and suppression of joint damage progression. Clinically, inhibition of IL-6 mitigates pain, swelling, and stiffness, improving functional outcomes in inflammatory arthritis and related conditions. Compared to other IL-6 receptor antagonists like tocilizumab, sarilumab exhibits comparable binding affinity and mechanisms of receptor blockade but differs in molecular structure and pharmacokinetic profile. Clinical trials have demonstrated significant and sustained improvements in disease activity scores and reduction of structural joint damage with sarilumab, validating its mechanism of action as a targeted biologic therapy. Research into the broader immunomodulatory effects of IL-6 blockade continues to provide insights into the management of systemic inflammatory diseases.

Pharmacological Actions

Selective blockade of the interleukin-6 receptor (IL-6R), inhibiting IL-6 signaling.
Attenuation of pro-inflammatory cytokine-mediated pathways involved in immune response.
Reduction of acute phase reactant synthesis in the liver, lowering systemic inflammation.
Suppression of inflammatory cell recruitment to affected joints and tissues.
Improvement of clinical symptoms in autoimmune and inflammatory disorders.
Modulation of immune effector pathways, balancing pro- and anti-inflammatory signals.
Potential reduction of joint destruction by inhibiting osteoclastogenesis driven by IL-6.
Demonstrates dose-dependent pharmacodynamic effects correlating with clinical efficacy.
Indirect modulation of cytochrome P450 enzymes through decreased inflammatory cytokines.

Therapeutic Or Clinical Uses

Treatment of moderate to severe active rheumatoid arthritis in adults with inadequate response or intolerance to one or more DMARDs.
Management of polymyalgia rheumatica in adults unresponsive or intolerant to corticosteroid tapering.
Therapy for active polyarticular juvenile idiopathic arthritis in patients weighing 63 kg or greater.
Used as monotherapy or in combination with conventional DMARDs such as methotrexate.
Reduction of pain, swelling, and morning stiffness associated with inflammatory arthritis.
Improvement of physical function and quality of life in autoimmune inflammatory conditions.
Alternative biologic therapy for patients failing or intolerant to other disease-modifying agents.
Clinical use guided by disease activity scores and regular monitoring of laboratory parameters.
Treatment aimed at preventing structural joint damage and disease progression.

Side Or Adverse Effects

Injection site reactions, including redness, pain, or swelling at the injection site.
Common upper respiratory tract infections such as runny or stuffy nose and sinus pain.
Sore throat and symptoms of nasopharyngitis.
Abnormal liver function tests indicating potential hepatotoxicity.
Urinary tract infections with painful urination.
Increased risk of serious infections including bacterial, fungal, and viral infections.
Rare but serious gastrointestinal perforations, especially in patients with diverticulitis or concomitant corticosteroid/NSAID use.
Hypersensitivity reactions including anaphylaxis, urticaria, and angioedema.
Laboratory abnormalities such as neutropenia, thrombocytopenia, and elevated liver enzymes.
Potential lipid profile alterations including elevated cholesterol levels.
Fatigue and malaise reported in some patients.
Rare reports of malignancies associated with immunomodulation.
Possible gastrointestinal symptoms including diarrhea and abdominal pain.
Elevated risk of infections requiring monitoring, especially tuberculosis reactivation.
Potential transient decreases in blood counts necessitating regular hematologic monitoring.

Precautions

Screen and treat latent tuberculosis infection prior to initiation of Kevzara therapy.
Avoid use in patients with active infections until infection resolution.
Regular monitoring of complete blood count and liver function tests recommended during treatment.
Caution in patients with history of gastrointestinal ulcers, diverticulitis, or gastrointestinal perforation.
Monitor for signs and symptoms of serious infections and malignancies due to immune suppression.
Use with caution in patients with pre-existing liver disease or elevated transaminases.
Avoid concomitant use with other biologic DMARDs to minimize risk of immunosuppression.
Assess patient vaccination status; delay live vaccines until therapy cessation.
Careful consideration before use in pregnant or breastfeeding women due to limited safety data.
Educate patients on proper injection technique and management of injection site reactions.
Inform patients about risk of increased cholesterol and need for lipid monitoring.
Monitor for neutropenia and other hematologic abnormalities during treatment.
Consider dose adjustments or discontinuation in case of severe infections or laboratory abnormalities.
Advise patients to avoid close contact with individuals with communicable infections.
Ensure adherence to storage guidelines to maintain drug stability and efficacy.

Warnings

Kevzara increases susceptibility to serious and potentially fatal infections, including bacterial, fungal, and viral pathogens.
Risk of gastrointestinal perforation, especially in patients with diverticulitis, ulcers, or concurrent corticosteroid/NSAID/methotrexate use.
Immune system suppression may increase the risk of certain malignancies; monitor patients accordingly.
Concomitant use with other biologic immunosuppressants is not recommended due to heightened infection risk.
Live vaccines are contraindicated during therapy due to danger of vaccine-associated infection.
Frequent laboratory monitoring is required; treatment may be delayed or discontinued based on results.
Patient should immediately report signs of infection such as fever, chills, cough, or unusual fatigue.
Use caution in patients with history of tuberculosis or exposure to endemic fungal infections.
Potential for hypersensitivity reactions including anaphylaxis; appropriate medical support should be available.
Pregnancy safety has not been established; the drug should be used only if clearly needed.
Risk of neutropenia and thrombocytopenia mandates periodic hematologic assessment.
May cause elevation of liver enzymes; hepatic function should be monitored closely.
Discontinue use if severe infections or malignancies develop during treatment.
Patients should be informed of signs and symptoms of gastrointestinal perforation including abdominal pain and fever.
Store the drug properly to maintain stability; improper storage may reduce efficacy and safety.

Contraindication

Known hypersensitivity to sarilumab or any component of Kevzara formulation.
Active, severe infections including sepsis or tuberculosis.
Use in patients with concurrent administration of other biologic immunomodulators.
Pregnancy unless the potential benefit justifies the potential risk to the fetus.
Patients with a history of severe allergic reactions to monoclonal antibodies.
Known hypersensitivity to excipients such as polysorbate 20 or sucrose in the formulation.
Use immediately following live vaccine administration or concurrent live vaccines.
Patients with uncontrolled systemic infections or immunodeficiency disorders.
Severe hepatic impairment due to lack of data on safety and pharmacokinetics.
Any clinical situation where immunosuppression may pose a significant risk to the patient.

Drug Interactions

Concomitant administration with other biologic DMARDs such as abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, rituximab, tocilizumab, or tofacitinib increases risk of immunosuppression and infections.
IL-6 blockade can normalize cytochrome P450 enzyme activity, potentially reducing serum concentrations of drugs metabolized by CYP450 enzymes like warfarin, cyclosporine, and some statins.
Avoid live vaccines during treatment to prevent vaccine-related infections.
Close monitoring of concomitant immunosuppressant drugs is advised to reduce infection risk.
Potential pharmacodynamic interactions with NSAIDs and corticosteroids that may increase gastrointestinal perforation risk.
May alter metabolism of drugs processed via CYP1A2, CYP2C9, CYP2C19, and CYP3A4 pathways indirectly due to IL-6 inhibition.
Immunosuppressive effects can potentiate adverse effects of other immunomodulatory agents.
No direct pharmacokinetic drug-drug interaction identified with common medications; interaction primarily through IL-6 modulation.
Possible interaction with methotrexate when used in combination; clinical monitoring warranted.
Herbal supplements or vitamins with immunomodulatory properties may alter therapeutic outcomes.
Interactions with therapies for infectious diseases such as antitubercular agents require careful management.
Careful evaluation needed when co-administered with agents affecting hematopoietic function.
Concomitant use with live vaccines is contraindicated.
No significant interactions reported with common over-the-counter analgesics, but pharmacodynamics may vary.
Regular review of all medications is necessary to minimize overlapping toxicities and interactions.

Preparations Of The Drug

Kevzara is available as a single-dose pre-filled syringe containing either 150 mg or 200 mg sarilumab in 1.14 mL solution.
Also available as a single-dose pre-filled autoinjector pen with the same dose options (150 mg/1.14 mL and 200 mg/1.14 mL).
Each preparation contains inactive ingredients including arginine, histidine, polysorbate 20, sucrose, and water for injection, USP.
The product is supplied refrigerated and protected from light in its original carton to maintain stability.
Prefilled syringes and pens are for single use only and come with clear instructions for subcutaneous injection.
The liquid formulation is clear to opalescent, colorless to pale yellow, and must not be shaken or frozen.
Storage instructions include refrigeration at 2°C to 8°C (36°F to 46°F) and allowance for up to 14 days at room temperature (up to 25°C) once removed from refrigeration.
The preparation is designed for subcutaneous administration, suitable for self-injection after proper training.
Each injectable unit includes a fixed volume and concentration to ensure dosing accuracy.
No preservatives are present in the formulation, emphasizing the single-use format to avoid contamination.
The package includes safety mechanisms to prevent needle-stick injuries during use and disposal.
Disposal of used syringes or pens should be done in puncture-proof sharps containers according to local regulations.
Preparations are designed for stability and efficacy under recommended storage conditions but should be discarded if used beyond recommended time frames or if compromised.
Manufactured under strict quality control by sanofi-aventis U.S. LLC and Regeneron Pharmaceuticals, Inc.
The formulation is patented and trademarked under the Sanofi Biotechnology and Regeneron collaboration.