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Sarilumab

Class: Disease-modifying Antirheumatic Drugs
Brands: Kevzara

Warning

Warning: Risk of Serious Infections

See full prescribing information for complete boxed warning.1

  • Serious infections leading to hospitalization or death including bacterial, viral, invasive fungal, and other opportunistic infections have occurred in patients receiving sarilumab.1

  • If a serious infection develops, interrupt sarilumab therapy until the infection is controlled.1

  • Cases of tuberculosis (TB) have been reported. Prior to starting sarilumab, test for latent TB; if positive, start treatment for TB.1

  • Closely monitor patients for signs and symptoms of infection during treatment with sarilumab.1

Introduction

Sarilumab, a recombinant human immunoglobulin G1 (IgG1) monoclonal antibody specific for interleukin-6 (IL-6) receptor, is a disease-modifying antirheumatic drug (DMARD).1

Uses for Sarilumab

Sarilumab has the following uses:

Sarilumab is an interleukin-6 (IL-6) receptor antagonist indicated for treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs).1

Sarilumab Dosage and Administration

General

Sarilumab is available in the following dosage form(s) and strength(s):

Injection: 150 mg/1.14 mL or 200 mg/1.14 mL solution in a single-dose pre-filled syringe.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

  • Sarilumab may be used as monotherapy or in combination with methotrexate (MTX) or other conventional DMARDs.1

  • The recommended dosage of sarilumab is 200 mg once every two weeks, administered as a subcutaneous injection.1

  • Sarilumab initiation is not recommended in patients with ANC less than 2000/mm3, platelets less than 150,000/mm3 or liver transaminases above 1.5 times ULN.1

  • Modify dosage to manage neutropenia, thrombocytopenia, and/or elevated liver transaminases.1

Cautions for Sarilumab

Contraindications

Sarilumab is contraindicated in patients with known hypersensitivity to sarilumab or any of the inactive ingredients.1

Warnings/Precautions

Serious Infections

Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving immunosuppressive agents including sarilumab for rheumatoid arthritis (RA). The most frequently observed serious infections with sarilumab included pneumonia and cellulitis. Among opportunistic infections, tuberculosis, candidiasis, and pneumocystis were reported with sarilumab. Some patients presented with disseminated rather than localized disease and were often taking concomitant immunosuppressants such as methotrexate or corticosteroids, which in addition to RA may predispose them to infections. While not reported in sarilumab clinical studies, other serious infections (e.g., histoplasmosis, cryptococcus, aspergillosis) have been reported in patients receiving other immunosuppressive agents for the treatment of RA.1

Avoid use of sarilumab in patients with an active infection, including localized infections. Consider the risks and benefits of treatment prior to initiating sarilumab in patients who have: 1

  • chronic or recurrent infection;1

  • a history of serious or opportunistic infections;1

  • underlying conditions, in addition to RA, that may predispose them to infection;1

  • been exposed to tuberculosis; or1

  • lived in or traveled to areas of endemic tuberculosis or endemic mycoses.1

Closely monitor patients for the development of signs and symptoms of infection during treatment with sarilumab, as signs and symptoms of acute inflammation may be lessened due to suppression of the acute phase reactants.1

Hold treatment with sarilumab if a patient develops a serious infection or an opportunistic infection.1

Perform prompt and complete diagnostic testing appropriate for an immunocompromised patient who develops a new infection during treatment with sarilumab; initiate appropriate antimicrobial therapy, and closely monitor the patient.1

Tuberculosis

Evaluate patients for tuberculosis (TB) risk factors and test for latent infection prior to initiating treatment with sarilumab. Treat patients with latent TB with standard antimycobacterial therapy before initiating sarilumab. Consider anti-TB therapy prior to initiation of sarilumab in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent TB but having risk factors for TB infection. When considering anti-TB therapy, consultation with a physician with expertise in TB may be appropriate.1

Closely monitor patients for the development of signs and symptoms of TB including patients who tested negative for latent TB infection prior to initiating therapy.1

Viral Reactivation

Viral reactivation has been reported with immunosuppressive biologic therapies. Cases of herpes zoster were observed in clinical studies with sarilumab. The risk of hepatitis B reactivation with sarilumab is unknown since patients who were at risk for reactivation were excluded.1

Laboratory Abnormalities

Neutropenia

Treatment with sarilumab was associated with a higher incidence of decrease in absolute neutrophil count (ANC), including neutropenia.1

  • Assess neutrophil count prior to initiation of sarilumab and monitor neutrophil count 4 to 8 weeks after start of therapy and every 3 months thereafter.1

  • Based on the pharmacodynamics of the changes in ANC, use results obtained at the end of the dosing interval when considering dose modification.1

Thrombocytopenia

Treatment with sarilumab was associated with a reduction in platelet counts in clinical studies.1

  • Assess platelet count prior to initiation of sarilumab and monitor platelets 4 to 8 weeks after start of therapy and every 3 months thereafter.1

Elevated Liver Enzymes

Treatment with sarilumab was associated with a higher incidence of transaminase elevations. These elevations were transient and did not result in any clinically evident hepatic injury in clinical studies. Increased frequency and magnitude of these elevations were observed when potentially hepatotoxic drugs (e.g., MTX) were used in combination with sarilumab.1

  • Assess ALT/AST levels prior to initiation of sarilumab and monitor ALT/AST levels 4 to 8 weeks after start of therapy and every 3 months thereafter. When clinically indicated, consider other liver function tests such as bilirubin.1

Lipid Abnormalities

Treatment with sarilumab was associated with increases in lipid parameters such as LDL cholesterol, HDL cholesterol and/or triglycerides.1

  • Assess lipid parameters approximately 4 to 8 weeks following initiation of treatment with sarilumab, then at approximately 6 month intervals.1

  • Manage patients according to clinical guidelines for the management of hyperlipidemia.1

Gastrointestinal Perforation

Gastrointestinal perforations have been reported in clinical studies, primarily as complications of diverticulitis. GI perforation risk may be increased with concurrent diverticulitis or concomitant use of NSAIDs or corticosteroids. Promptly evaluate patients presenting with new onset abdominal symptoms.1

Immunosuppression

Treatment with immunosuppressants may result in an increased risk of malignancies. The impact of treatment with sarilumab on the development of malignancies is not known but malignancies were reported in clinical studies.1

Hypersensitivity Reactions

Hypersensitivity reactions have been reported in association with sarilumab. Hypersensitivity reactions that required treatment discontinuation were reported in 0.3% of patients in controlled RA trials. Injection site rash, rash, and urticaria were the most frequent hypersensitivity reactions. Advise patients to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction. If anaphylaxis or other hypersensitivity reaction occurs, stop administration of sarilumab immediately. Do not administer sarilumab to patients with known hypersensitivity to sarilumab.1

Active Hepatic Disease and Hepatic Impairment

Treatment with sarilumab is not recommended in patients with active hepatic disease or hepatic impairment, as treatment with sarilumab was associated with transaminase elevations.1

Live Vaccines

Avoid concurrent use of live vaccines during treatment with sarilumab due to potentially increased risk of infections; clinical safety of live vaccines during sarilumab treatment has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving sarilumab. The interval between live vaccinations and initiation of sarilumab therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.1

Specific Populations

Pregnancy

Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to sarilumab during pregnancy. Physicians are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-877-311-8972.1

Risk Summary: The limited human data with sarilumab in pregnant women are not sufficient to inform drug-associated risk for major birth defects and miscarriage. Monoclonal antibodies, such as sarilumab, are actively transported across the placenta during the third trimester of pregnancy and may affect immune response in the in utero exposed infant. From animal data, and consistent with the mechanism of action, levels of IgG, in response to antigen challenge, may be reduced in the fetus/infant of treated mothers. In an animal reproduction study, consisting of a combined embryo-fetal and pre- and postnatal development study with monkeys that received intravenous administration of sarilumab, there was no evidence of embryotoxicity or fetal malformations with exposures up to approximately 84 times the maximum recommended human dose (MRHD). The literature suggests that inhibition of IL-6 signaling may interfere with cervical ripening and dilatation and myometrial contractile activity leading to potential delays of parturition. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Sarilumab should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.1

Fetal/Neonatal Adverse Reactions: Monoclonal antibodies are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester. Risks and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed to sarilumab in utero From the animal data, and consistent with the mechanism of action, levels of IgG, in response to antigen challenge, may be reduced in the fetus/infant of treated mothers.1

Animal Data

In a combined embryo-fetal and pre- and postnatal development study, pregnant cynomolgus monkeys received sarilumab at intravenous doses of 0, 5, 15, or 50 mg/kg/week from confirmation of pregnancy at gestation day (GD) 20, throughout the period of organogenesis (up to approximately GD 50), and continuing to natural birth of infants at around GD 165. Maintenance of pregnancy was not affected at any doses. Sarilumab was not embryotoxic or teratogenic with exposures up to approximately 84 times the MRHD (based on AUC with maternal intravenous doses up to 50 mg/kg/week). Sarilumab had no effect on neonatal growth and development evaluated up to one month after birth. Sarilumab was detected in the serum of neonates up to one month after birth, suggesting that the antibody had crossed the placenta.1

Following antigen challenge, decreased IgG titers attributed to the immunosuppressive action of sarilumab were evident in studies with older monkeys, with exposures up to approximately 80 times the MRHD (based on AUC with intravenous doses up to 50 mg/kg/week) and juvenile mice treated with an analogous antibody, which binds to murine IL-6Rα to inhibit IL-6 mediated signaling, at subcutaneous doses up to 200 mg/kg/week. These findings suggest the potential for decreased IgG titers, following antigen challenge, in infants of mothers treated with sarilumab.1

Parturition is associated with significant increases of IL-6 in the cervix and myometrium. The literature suggests that inhibition of IL-6 signaling may interfere with cervical ripening and dilatation and myometrial contractile activity leading to potential delays of parturition. For mice deficient in IL-6 (ll6-/- null mice), parturition was delayed relative to wild-type (ll6+/+) mice. Administration of recombinant IL-6 to ll6-/- null mice restored the normal timing of delivery.1

Lactation

No information is available on the presence of sarilumab in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Maternal IgG is present in human milk. If sarilumab is transferred into human milk, the effects of local exposure in the gastrointestinal tract and potential limited systemic exposure in the infant to sarilumab are unknown. The lack of clinical data during lactation precludes clear determination of the risk of sarilumab to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for sarilumab and the potential adverse effects on the breastfed child from sarilumab or from the underlying maternal condition.1

Pediatric Use

Safety and efficacy of sarilumab in pediatric patients have not been established.1

Geriatric Use

Of the total number of patients in clinical studies of sarilumab, 15% were 65 years of age and over, while 1.6% were 75 years and over. In clinical studies, no overall differences in safety and efficacy were observed between older and younger patients. The frequency of serious infection among sarilumab and placebo-treated patients 65 years of age and older was higher than those under the age of 65. As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly.1

Hepatic Impairment

The safety and efficacy of sarilumab have not been studied in patients with hepatic impairment, including patients with positive HBV or HCV serology.1

Renal Impairment

No dose adjustment is required in patients with mild to moderate renal impairment. Sarilumab has not been studied in patients with severe renal impairment.1

Common Adverse Effects

Most common adverse reactions (incidence at least 3%) are neutropenia, increased ALT, injection site erythema, upper respiratory infections and urinary tract infections.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Please see product labeling for drug interaction information.

Actions

Mechanism of Action

Sarilumab binds to both soluble and membrane-bound interleukin-6 (IL-6) receptors (sIL-6R and mIL-6R), and has been shown to inhibit IL-6-mediated signaling through these receptors. IL-6 is a pleiotropic pro-inflammatory cytokine produced by a variety of cell types including T- and B-cells, lymphocytes, monocytes, and fibroblasts. IL-6 has been shown to be involved in diverse physiological processes such as T-cell activation, induction of immunoglobulin secretion, initiation of hepatic acute phase protein synthesis, and stimulation of hematopoietic precursor cell proliferation and differentiation. IL-6 is also produced by synovial and endothelial cells leading to local production of IL-6 in joints affected by inflammatory processes such as rheumatoid arthritis. 1

Advice to Patients

Advise the patients to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).1

Infections

Inform patients that sarilumab may lower their resistance to infections. Instruct patients to contact their physician immediately when symptoms suggesting infection appear, to ensure rapid evaluation and appropriate treatment.1

Gastrointestinal Perforation

Inform patients that some patients, particularly those also taking NSAIDS, and/or steroids, have had tears (perforations) of the stomach or intestines. Inform patients that gastrointestinal perforations have been reported in sarilumab-treated patients in clinical studies, primarily as a complication of diverticulitis. Instruct patients to contact their physician immediately when symptoms of severe, persistent abdominal pain appear to ensure rapid evaluation and appropriate treatment.1

Hypersensitivity and Serious Allergic Reaction

Inform patients that some patients who have been treated with sarilumab have developed serious allergic reactions. Advise patients to seek immediate medical attention if they experience any symptom of serious allergic reactions.1

Pregnancy Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to sarilumab during pregnancy. Encourage participation in the registry.1

Instruction on Injection Technique

Instruct patients and caregivers to read the Instructions for Use before the patient starts using sarilumab, and each time the patient gets a refill as there may be new information they need to know.1

Assess patient suitability for home use of subcutaneous injection. Provide guidance to patients and caregivers on proper subcutaneous injection technique, including aseptic technique, and how to use the pre-filled syringe correctly.1

The pre-filled syringe should be left at room temperature for 30 minutes prior to use. The syringe should be used within 14 days after being taken out of the refrigerator. A puncture-resistant container for disposal of syringes should be used and should be kept out of the reach of children. Instruct patients or caregivers in the technique as well as proper pre-filled syringe disposal, and caution against reuse of these items.1

Additional Information

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

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.

Sarilumab

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, Solution

150 mg /1.14 mL

Kevzara

Sanofi-Aventis U.S. LLC

200 mg /1.14 mL

Kevzara

Sanofi-Aventis U.S. LLC

AHFS Drug Information. © Copyright 2017, Selected Revisions June 5, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Sanofi-Aventis U.S. LLC. KEVZARA (sarilumab) injection for subcutaneous use prescribing information. 2017 May.

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