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Kevzara

Generic Name: Sarilumab
Class: Disease-modifying Antirheumatic Drugs
Chemical Name: Immunoglobulin G1, anti-(human interleukin 6 receptorα) (human REGN88 heavy chain), disulfide with human REGN88 light chain, dimer
Molecular Formula: C6388H9918N1718O1998S44
CAS Number: 1189541-98-7

Medically reviewed on Jul 16, 2018

Warning

    Serious Infections
  • Serious, sometimes fatal infections including tuberculosis (pulmonary or extrapulmonary disease), bacterial and viral infections, invasive fungal infections (may be disseminated), and other opportunistic infections reported.1 (See Infectious Complications under Cautions.)

  • Carefully consider risks and benefits prior to initiating sarilumab therapy in patients with chronic or recurring infections.1 Avoid use in patients with active infection.1

  • Evaluate patients for latent tuberculosis infection prior to and periodically during sarilumab therapy; if indicated, initiate appropriate antimycobacterial regimen prior to initiating therapy.1

  • Closely monitor patients for infection, including active tuberculosis in those with a negative tuberculin skin test, during treatment.1 If serious infection develops, interrupt sarilumab until infection is controlled.1

Introduction

See also: Orencia

Biologic response modifier and a disease-modifying antirheumatic drug (DMARD); a recombinant human IgG1 kappa monoclonal antibody specific for interleukin-6 (IL-6) receptor.1 2 3 7 13

Uses for Kevzara

Rheumatoid Arthritis in Adults

Management of moderately to severely active rheumatoid arthritis in adults who have had an inadequate response or intolerance to one or more DMARDs.1 2 3

Can be used alone or in combination with methotrexate or other nonbiologic DMARDs (e.g., hydroxychloroquine, leflunomide, sulfasalazine).1 2 3

Do not use concomitantly with other biologic DMARDs, such as tumor necrosis factor (TNF; TNF-α) blocking agents (e.g., adalimumab, certolizumab, etanercept, golimumab, infliximab), interleukin-1 (IL-1) receptor antagonists (e.g., anakinra), anti-CD20 monoclonal antibodies (e.g., rituximab), and selective costimulation modulators (e.g., abatacept); concomitant use has not been studied and there is a possibility of increased immunosuppression and increased risk of infection.1

Kevzara Dosage and Administration

General

  • Do not initiate sarilumab therapy in patients with ANC <2000 cells/mm3, platelet count <150,000 cells/mm3, or ALT or AST concentration >1.5 times the ULN.1

  • Prior to initiating sarilumab, evaluate patients for tuberculosis infection and initiate antimycobacterial therapy if indicated.1 (See Infectious Complications under Cautions.)

Concomitant Therapy

  • Methotrexate, other nonbiologic DMARDs, and corticosteroids may be continued in patients with rheumatoid arthritis.1 2 3

  • Do not use concomitantly with other biologic DMARDs.1 (See Rheumatoid Arthritis in Adults under Uses.)

Administration

Sub-Q Administration

Administer by sub-Q injection using single-dose prefilled syringe.1

Intended for use under the guidance and supervision of a clinician, but may be self-administered if the clinician determines that the patient and/or their caregiver is competent to safely administer the drug after appropriate training.1 (See Advice to Patients.)

Administer sub-Q injections into anterior thigh or abdomen (except for the 2-inch area around the umbilicus); may be administered into the upper arm by a caregiver or clinician.1 Rotate injection sites.1 Do not make injections into areas where the skin is tender, bruised, or damaged or into scars.1

Allow prefilled syringe to sit at room temperature for at least 30 minutes prior to administration; do not warm sarilumab any other way (e.g., microwave, hot water).1 Do not shake syringe.1

Administer entire contents of prefilled syringe as a single dose.1

Dosage

Adults

Rheumatoid Arthritis
Sub-Q

200 mg once every 2 weeks.1

Dosage Modification or Discontinuance for Toxicity
Sub-Q

If a serious infection or opportunistic infection develops, interrupt sarilumab until the infection is controlled.1

If certain dose-related laboratory changes (i.e., neutropenia, thrombocytopenia, elevated liver enzyme concentrations) occur, reduce sarilumab dosage to 150 mg every 2 weeks or temporarily interrupt or discontinue therapy (see tables).1

Table 1. Recommended Dosage Adjustment Based on ANC.1

ANC (cells/mm3)

Recommendation

>1000

Maintain current dosage

500–1000

Interrupt sarilumab therapy until ANC is >1000; resume sarilumab at 150 mg every 2 weeks and increase to 200 mg every 2 weeks as clinically indicated

<500

Discontinue sarilumab

Table 2. Recommended Dosage Adjustment Based on Platelet Count.1

Platelet Count (cells/mm3)

Recommendation

50,0000–100,000

Interrupt sarilumab therapy until platelet count is >100,000; resume sarilumab at 150 mg every 2 weeks and increase to 200 mg every 2 weeks as clinically indicated

<50,000

Repeat platelet count; discontinue sarilumab if results are confirmed

Table 3. Recommended Dosage Adjustment Based on Changes in Liver Enzyme Laboratory Value.1

ALT Value

Recommendation

>1 to 3 times ULN

Modify dosage of concomitant DMARDs if appropriate

>3 to 5 times ULN

Interrupt sarilumab therapy until ALT values are <3 times ULN; resume sarilumab at 150 mg every 2 weeks and increase to 200 mg every 2 weeks as clinically indicated

>5 times ULN

Discontinue sarilumab

Special Populations

Hepatic Impairment

Use is not recommended.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Dosage adjustment not necessary in patients with mild or moderate renal impairment; not evaluated in severe renal impairment.1

Geriatric Patients

Manufacturer makes no specific dosage recommendations.1

Cautions for Kevzara

Contraindications

  • Known hypersensitivity to sarilumab or any ingredient in the formulation.1 (See Hypersensitivity Reactions under Cautions.)

Warnings/Precautions

Warnings

Infectious Complications

Serious, sometimes fatal infections (including bacterial, mycobacterial, invasive fungal, viral, or other opportunistic infections) reported in patients with rheumatoid arthritis, particularly in those receiving concomitant therapy with other immunosuppressive agents (e.g., methotrexate, corticosteroids).1 Opportunistic infections may include tuberculosis, cryptococcal infection, aspergillosis, candidiasis, and pneumocystosis.1 Infections may be disseminated.1

Do not initiate sarilumab in patients with active infections, including localized infections.1 Consider potential risks and benefits of the drug prior to initiating therapy in patients with a history of chronic, recurring, serious, or opportunistic infections; patients with underlying conditions that may predispose them to infections; and patients who have been exposed to tuberculosis or who have resided or traveled in regions where tuberculosis or mycoses are endemic.1

Closely monitor patients during treatment with sarilumab for the development of signs or symptoms of infection.1

If new infection occurs during therapy, perform thorough diagnostic evaluation (appropriate for immunocompromised patient), initiate appropriate anti-infective therapy, and closely monitor patient.1 If serious or opportunistic infection develops, interrupt sarilumab until the infection is controlled.1

Evaluate all patients for latent tuberculosis and for risk factors for tuberculosis prior to and periodically during therapy.1 When indicated, initiate an appropriate antimycobacterial regimen for the treatment of latent tuberculosis infection prior to sarilumab therapy.1 Consider initiation of antimycobacterial therapy prior to initiation of sarilumab in individuals with a history of latent or active tuberculosis in whom an adequate course of antimycobacterial treatment cannot be confirmed and in individuals with a negative test for latent tuberculosis who have risk factors for tuberculosis.1 Consultation with a tuberculosis specialist is recommended when deciding whether to initiate antimycobacterial therapy.1

Monitor all patients, including those with a negative test for latent tuberculosis, for active tuberculosis.1

Viral reactivation can occur in patients receiving immunosuppressive therapies.1 Herpes zoster exacerbation reported in patients receiving sarilumab.1 Risk of reactivation of HBV infection not known.1

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., injection site rash or erythema, rash, pruritus, urticaria), including hypersensitivity reactions requiring treatment discontinuance, reported.1 Sarilumab is contraindicated in patients with known hypersensitivity to the drug.1

If a hypersensitivity reaction occurs, immediately stop administration of the drug.1

Other Warnings and Precautions

Hematologic Effects

Possible neutropenia or thrombocytopenia.1

In clinical trials, decreases in neutrophil counts were not associated with infection, including serious infection, and decreases in platelet counts were not associated with bleeding.1

Monitor neutrophil and platelet counts prior to and 4–8 weeks after initiation of therapy, then every 3 months thereafter.1

Dosage adjustment, treatment interruption, or discontinuance of the drug may be necessary.1 (See General and also Dosage Modification or Discontinuance for Toxicity under Dosage and Administration.)

Evaluate neutrophil count at the end of the 2-week dosing interval; nadir generally occurs 3–4 days following sarilumab administration and neutrophil count then recovers toward baseline.1

Hepatic Effects

Elevated aminotransferase concentrations may occur.1 In clinical trials, changes were reversible following reduction of sarilumab dosage or interruption of sarilumab therapy and were not associated with clinical evidence of hepatic injury.1

Incidence and magnitude of aminotransferase elevations were increased with concomitant use of hepatotoxic drugs (e.g., methotrexate).1

Monitor serum ALT and AST prior to and 4–8 weeks after initiation of therapy, then every 3 months thereafter.1 Monitor other liver function tests when clinically indicated.1

Dosage adjustment, treatment interruption, or discontinuance of sarilumab or concomitantly administered DMARDs may be necessary.1 (See General and also Dosage Modification or Discontinuance for Toxicity under Dosage and Administration.)

Effects on Serum Lipid

Increased serum concentrations of total cholesterol, triglycerides, LDL-cholesterol, and/or HDL-cholesterol reported.1 2 3

Monitor lipoprotein concentrations 4–8 weeks after initiation of sarilumab therapy and approximately every 6 months thereafter.1

Manage lipid disorders as clinically appropriate.1

GI Perforation

GI perforation reported, usually as a complication of diverticulitis and most commonly in patients receiving concomitant therapy with NSAIAs or corticosteroids.1 The relative contribution of these agents versus sarilumab to the occurrence of GI perforation remains to be determined.1

Promptly evaluate patients with new-onset abdominal symptoms.1

Malignancies

Immunosuppressive therapy may increase the risk of malignancies.1 Whether treatment with sarilumab affects development of malignancies remains to be determined.1 Malignancies reported in clinical trials.1

Immunization

Do not administer live vaccines to patients receiving sarilumab.1 (See Vaccines under Interactions and see Pediatric Use under Cautions.)

Immunogenicity

Antibodies to sarilumab, including neutralizing antibodies, reported.1 Increased drug clearance reported in patients with neutralizing antibodies; however, effects of antibody development on clinical response or adverse reactions not observed.1 2 3

Specific Populations

Pregnancy

No adequate data in pregnant women.1 No evidence of embryotoxicity or fetal malformations in animal studies.1

As pregnancy progresses, monoclonal antibodies are increasingly transported across the placenta; largest amount transferred during the third trimester.1 Infants exposed to sarilumab in utero may have impaired immune responses.1 (See Vaccines under Interactions.)

IL-6 is increased in cervical and myometrial tissues during parturition; sarilumab may delay parturition by interfering with cervical ripening and myometrial contractions.1

Use during pregnancy only when potential benefits to the woman justify potential fetal risks.1

Pregnancy registry at 877-311-8972.1

Lactation

Not known whether sarilumab is distributed into milk or absorbed systemically following ingestion.1 Because IgG is distributed into human milk, sarilumab may distribute into milk.1 Potential effects on milk production or on breast-fed infants are unknown.1

Consider benefits of breast-feeding and the importance of sarilumab to the woman as well as potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.1

Pediatric Use

Safety and efficacy not established in children <18 years of age.1

Neonates and infants exposed to sarilumab in utero may have impaired immune responses; consider risks and benefits of administering live vaccines to such infants.1

Geriatric Use

Geriatric patients in general may have a higher incidence of infections than younger adults.1 In clinical trials of sarilumab, no overall differences in safety and efficacy between geriatric and younger patients, but incidence of serious infections was increased in geriatric patients ≥65 years of age.1 Use sarilumab with caution in this age group.1

Hepatic Impairment

Safety and efficacy not established in patients with hepatic impairment, including those with serologic evidence of HBV or HCV infection.1 Use in patients with active hepatic disease or hepatic impairment is not recommended.1

Renal Impairment

In patients with mild to moderate renal impairment (Clcr 30 to <90 mL/minute), population pharmacokinetic data suggest increased exposure, but sarilumab is not expected to undergo substantial renal elimination and dosage adjustment is not necessary.1 10

Not evaluated in patients with severe renal impairment.1

Common Adverse Effects

Neutropenia,1 2 3 increased ALT concentrations,1 2 3 injection site reactions (e.g., erythema, pruritus),1 2 3 upper respiratory tract infection,1 2 3 urinary tract infection.1 2 3

Interactions for Kevzara

May alter expression of CYP isoenzymes.1 6

Drugs Metabolized by Hepatic Microsomal Enzymes

Possible increased metabolism of drugs metabolized by CYP isoenzymes.1 6 Because IL-6 may down-regulate CYP isoenzymes, inhibition of IL-6 by sarilumab in patients with rheumatoid arthritis may restore CYP enzyme activity to higher levels.1 6 Effects on CYP enzyme activity may persist for several weeks after drug discontinuance.1

Drugs metabolized by CYP isoenzymes that have a low therapeutic index and require individualized dosing: Carefully monitor therapeutic effect and serum concentrations following initiation or discontinuance of sarilumab; adjust dosage as needed.1

Other CYP3A4 substrates: Caution advised when a reduction in efficacy would be undesirable.1

Vaccines

Avoid live vaccines.1 Safety not established.1 Possible increased risk of infections.1 (See Pediatric Use under Cautions.)

Information not available regarding secondary transmission of infection from individuals receiving live vaccines to patients receiving sarilumab.1

Consult current vaccination guidelines regarding interval between administration of live vaccines and initiation of immunosuppressive (e.g., sarilumab) therapy.1

Specific Drugs

Drug

Interaction

Comments

Contraceptives, oral

Possible increased metabolism of oral contraceptive1

Caution advised1

DMARDs, biologic (e.g., TNF blocking agents)

Possible increased immunosuppression and increased risk of infection; concomitant use not studied1

Concomitant use not recommended1

HMG CoA reductase inhibitors (statins)

Statins metabolized by CYP isoenzymes (e.g., atorvastatin, lovastatin): Possible increased metabolism of the statin1

Simvastatin: Decreased AUC of simvastatin and simvastatin acid1 6

Caution advised1

Methotrexate

Concomitant use does not appear to affect clearance of sarilumab1

Theophylline

Possible increased metabolism of theophylline1

Carefully monitor therapeutic effect and serum concentrations of theophylline following initiation or discontinuance of sarilumab; adjust dosage as needed1

Warfarin

Possible increased metabolism of warfarin1

Carefully monitor therapeutic effect of warfarin following initiation or discontinuance of sarilumab; adjust dosage as needed1

Kevzara Pharmacokinetics

Absorption

Bioavailability

Following sub-Q injection, bioavailability is approximately 80%.5

Following sub-Q injection every 2 weeks, peak serum concentrations are attained in approximately 2–4 days, steady-state concentrations are attained within 14–16 weeks, and systemic accumulation is twofold to threefold.1 5

Plasma Concentrations

With increase in dosage from 150 mg every 2 weeks to 200 mg every 2 weeks, steady-state concentrations increase by approximately twofold.1

Special Populations

Systemic exposure tends to decrease as body weight increases, but differences in exposure do not affect efficacy or safety in patients with rheumatoid arthritis.10

Distribution

Extent

Not known whether distributed into milk.1

Elimination

Metabolism

Metabolic pathway not characterized.1

Expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.1

Half-life

Up to 8 days at dosage of 150 mg every 2 weeks; up to 10 days at dosage of 200 mg every 2 weeks.1

Exhibits concentration-dependent clearance.1 At low sarilumab concentrations, target-mediated nonlinear clearance plays a major role in determining total drug clearance; at higher concentrations, nonlinear pathway is saturated and clearance is determined mainly by linear clearance.1

Special Populations

Pharmacokinetics not formally studied in renal or hepatic impairment.1

Population pharmacokinetic data indicate that age, gender, and race do not alter pharmacokinetics.1

Increased clearance in patients who develop antisarilumab antibodies.1

Stability

Storage

Parenteral

Injection

2–8°C.1 Keep in original carton and protect from light.1 Do not freeze.1

May store at room temperatures up to 25°C in the original carton for up to 14 days if refrigeration unavailable; do not return to refrigerator after allowing drug to warm to room temperature.1

Actions

  • Binds specifically to both soluble and membrane-bound IL-6 receptors and inhibits IL-6-mediated signaling through these receptors, thereby resulting in a reduction in inflammatory mediator production.1 2 3 7 13

  • IL-6, a pleiotropic proinflammatory cytokine, is produced by various cell types (e.g., T cells, B lymphocytes, monocytes, fibroblasts, synoviocytes, endothelial cells) and has a broad spectrum of biologic activities,1 2 3 9 including involvement in T-cell activation, induction of immunoglobulin secretion, initiation of hepatic acute phase protein synthesis, stimulation of hematopoietic precursor cell proliferation and differentiation, and induction of osteoclast differentiation and activation.1 2 3 7 8 9

  • IL-6 is overexpressed in synovial tissue in patients with rheumatoid arthritis and is thought to contribute to synovial proliferation and joint destruction in patients with the disease.1 2 3 7 8 9 Elevated levels of IL-6 in serum and synovial fluid correlate with clinical and laboratory measures of disease activity in patients with rheumatoid arthritis.2 3 7 8 9

Advice to Patients

  • Provide a copy of the manufacturer’s patient information (medication guide and instructions for use) for sarilumab to all patients.1 Importance of patients and/or caregivers reading the patient information prior to initiation of therapy and each time the prescription is refilled.1

  • Importance of instructing patient regarding proper dosage and administration of sarilumab, including the use of aseptic technique, and proper disposal of the prefilled syringes if it is determined that the patient is competent to safely administer the drug.1

  • Risk of increased susceptibility to infection.1 Importance of informing clinicians immediately if any signs or symptoms suggestive of infection (e.g., fever, sweating, or chills; cough, dyspnea, or blood in phlegm; diarrhea; weight loss; burning upon urination or frequent urination; warm, red, or painful skin) develop.1

  • Risk of GI perforation, usually as a complication of diverticulitis and in those receiving NSAIAs or corticosteroids concomitantly.1 Importance of informing clinician immediately if severe, persistent abdominal pain occurs.1

  • Risk of hypersensitivity reactions.1 Importance of contacting a clinician prior to administering the next dose if manifestations of an allergic reaction (e.g., urticaria, rash, flushing) occur; importance of seeking immediate medical attention if manifestations of a serious allergic reaction (e.g., difficulty breathing, chest pain, feelings of faintness or dizziness, abdominal pain or vomiting, swelling of the lips, tongue, or face) occur.1

  • Importance of patients informing clinicians that they are receiving sarilumab therapy before scheduling any surgery or medical procedures.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (e.g., biologic DMARDs, immunizations) and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., active infection, liver disease, diverticulitis, stomach ulcers) or any history of tuberculosis or other chronic or recurring infections.1

  • Importance of periodic laboratory monitoring.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

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, for subcutaneous use

150 mg/1.14 mL

Kevzara (available as single-use prefilled syringes)

Sanofi-Aventis and Regeneron

200 mg/1.14 mL

Kevzara (available as single-use prefilled syringes)

Sanofi-Aventis and Regeneron

AHFS DI Essentials™. © Copyright 2018, Selected Revisions July 16, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Sanofi-Aventis. Kevzara (sarilumab) injection prescribing information. Bridgewater, NJ; 2017 May.

2. 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 Rheum. 2015; 67:(6):1424-37.

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 Rheum. 2017; 69:(2):277-90.

4. Felson DT, Anderson JJ, Boers M et al. American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum. 1995; 38::727-35.

5. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 761037Orig1s000: Clinical review(s). From FDA website.

6. Lee EB, Daskalakis N, Xu C et al. Disease-Drug Interaction of Sarilumab and Simvastatin in Patients with Rheumatoid Arthritis. Clin Pharmacokinet. 2017; 56:607-615. http://www.ncbi.nlm.nih.gov/pubmed/27722854?dopt=AbstractPlus

7. Raimondo MG, Biggioggero M, Crotti C et al. Profile of sarilumab and its potential in the treatment of rheumatoid arthritis. Drug Des Devel Ther. 2017; 11:1593-1603. http://www.ncbi.nlm.nih.gov/pubmed/28579757?dopt=AbstractPlus

8. Boyapati A, Msihid J, Fiore S et al. Sarilumab plus methotrexate suppresses circulating biomarkers of bone resorption and synovial damage in patients with rheumatoid arthritis and inadequate response to methotrexate: a biomarker study of MOBILITY. Arthritis Res Ther. 2016; 18:225. http://www.ncbi.nlm.nih.gov/pubmed/27716324?dopt=AbstractPlus

9. Park JY, Pillinger MH. Interleukin-6 in the pathogenesis of rheumatoid arthritis. Bull NYU Hosp Jt Dis. 2007; 65 Suppl 1:S4-10. http://www.ncbi.nlm.nih.gov/pubmed/17708744?dopt=AbstractPlus

10. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 761037Orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/761037Orig1s000ClinPharmR.pdf

11. Felson DT, Anderson JJ, Boers M et al. The American College of Rheumatology preliminary core set of disease activity measures for rheumatoid arthritis clinical trials. Arthritis Rheum. 1993; 36:729-40. http://www.ncbi.nlm.nih.gov/pubmed/8507213?dopt=AbstractPlus

12. Felson DT, Anderson JJ, Lange MLM et al. Should improvement in rheumatoid arthritis clinical trials be defined as fifty percent or seventy percent improvement in core set measures, rather than twenty percent. Arthritis Rheum. 1998; 41:1564-70. http://www.ncbi.nlm.nih.gov/pubmed/9751088?dopt=AbstractPlus

13. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 761037Orig1s000: Product quality review(s). From FDA website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/761037Orig1s000ChemR.pdf

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