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Mepolizumab

Class: Anti-inflammatory Agents
Chemical Name: Disulfide with human-mouse monoclonal SB-240563 κ-chain, anti-(human interleukin 5) (human-mouse monoclonal SB-240563 γ1-chain) immunoglobulin G1, dimer
Molecular Formula: C6476H10084N1732O2028S46
CAS Number: 196078-29-2
Brands: Nucala

Introduction

Antiasthmatic agent; a recombinant DNA-derived humanized interleukin-5 (IL-5) receptor antagonist monoclonal antibody and IgG1 kappa immunoglobulin.1 6 7

Uses for Mepolizumab

Asthma

Adjunctive maintenance therapy in patients with severe eosinophilic asthma.1 2 3 4

Reduces asthma exacerbation rate and decreases oral corticosteroid dosage requirements.1 2 3 4 No effect on lung function as measured by change in baseline FEV1.1

Eosinophilic phenotype (i.e., eosinophilic asthma) is generally characterized by blood and sputum eosinophilia, eosinophilic inflammation, recurrent asthma exacerbations, and frequently, responsiveness to corticosteroids.6 8 9 11

Not indicated for treatment of other eosinophilic conditions.1

Not indicated for relief of acute bronchospasm or status asthmaticus.1

Mepolizumab Dosage and Administration

Administration

Sub-Q Administration

Administer by sub-Q injection into the upper arm, thigh, or abdomen every 4 weeks by a clinician.1

Reconstitution

Reconstitute vial containing 100 mg of mepolizumab lyophilized powder with 1.2 mL of sterile water for injection (using a 2- or 3-mL syringe with 21-gauge needle) to provide a solution containing 100 mg/mL.1

Direct the stream of sterile water diluent onto the lyophilized powder.1 Swirl vial gently for 10 seconds approximately every 15 seconds until completely dissolved (typically ≤5 minutes).1 Do not shake.1

Mechanical reconstitution device may be used to swirl the vial at 450 rpm for ≤10 minutes or at 1000 rpm for ≤5 minutes.1

Reconstituted solution is clear to opalescent, colorless to pale yellow or pale brown, and essentially free from particulates (small air bubbles acceptable).1

Dosage

Pediatric Patients

Asthma
Sub-Q

Adolescents ≥12 years of age: 100 mg every 4 weeks.1

Adults

Asthma
Sub-Q

100 mg every 4 weeks.1

Special Populations

No special population dosage recommendations at this time.1

Cautions for Mepolizumab

Contraindications

  • History of hypersensitivity to the drug or any ingredient in the formulation.1

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity

Hypersensitivity reactions (e.g., angioedema, bronchospasm, hypotension, urticaria, rash) reported, generally occurring within hours or possibly days following administration.1 If hypersensitivity reaction occurs, discontinue mepolizumab.1 (See Contraindications under Cautions.)

Deterioration of Disease and Acute Episodes

Not indicated for treatment of acute asthma symptoms or exacerbations, acute bronchospasm, or status asthmaticus.1 (See Advice to Patients.)

Infectious Complications

Herpes Zoster Infection

Herpes zoster infection (sometimes serious) reported.1 Consider varicella (zoster) vaccination before starting therapy, if medically appropriate.1 13

Parasitic Infection

Immune response against some parasitic (helminth) infections may be altered.1 Not studied in patients with known parasitic infections.1 Treat patients with preexisting parasitic (helminth) infections before initiating mepolizumab.1 If parasitic infection occurs and does not respond to anthelmintic treatment, interrupt mepolizumab therapy until infection resolves.1

Reduction of Corticosteroid Dosage

Do not abruptly discontinue systemic or inhaled corticosteroid therapy upon initiation of mepolizumab therapy.1 If appropriate, reduce corticosteroid dosage gradually and supervise such reduction carefully.1

Immunogenicity

Antibodies to mepolizumab detected in 6% of patients and associated with approximately 20% increased drug clearance.1 No apparent correlation between anti-mepolizumab antibody titers and change in eosinophil concentrations.1 Clinical importance of such antibodies not known.1

Specific Populations

Pregnancy

No evidence of fetal harm in monkeys following IV mepolizumab during pregnancy.1 Potential effects of monoclonal antibodies (e.g., mepolizumab) more likely to occur in second and third trimesters.1

Encourage patients to enroll in pregnancy registry at 877-311-8972 or .1

Lactation

Distributed into milk in monkeys.1 Not known whether distributed into human milk.1 Since IgG distributes into milk in humans, mepolizumab is expected to distribute into human milk.1

Weigh potential risks to infants against clinical need and known benefits of breast-feeding.1

Pediatric Use

Safety and efficacy not established in children <12 years of age.1

Evaluated in 19 adolescent patients 12–17 years of age with asthma; adverse effect profile generally similar to that observed in adults.1 Mean apparent clearance was 35% less than that of adults.1

Geriatric Use

Insufficient experience in patients ≥65 years of age.1 No overall differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1

Hepatic Impairment

Pharmacokinetics not studied in patients with hepatic impairment.1

Renal Impairment

Pharmacokinetics not studied in patients with renal impairment.1

Common Adverse Effects

Headache,1 injection site reaction,1 back pain,1 fatigue,1 influenza,1 urinary tract infection,1 upper abdominal pain,1 pruritus,1 eczema,1 muscle spasm.1

Interactions for Mepolizumab

No formal drug interaction studies to date.1

Mepolizumab Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability following sub-Q injection approximately 80%.1

Maximum plasma concentrations occurred from 4–8 days following sub-Q administration.12

Steady-state concentrations reached by approximately 16 weeks.12 Twofold accumulation of drug observed at steady state.1 12

Dose-proportional pharmacokinetics over a sub-Q dosage range of 12.5–250 mg.1

Onset

Decreases in blood eosinophil count observed on the third day following sub-Q administration.1 7

Duration

Following drug discontinuance, blood and sputum eosinophil counts increase within 3 months, blood eosinophil counts return to baseline over 6 months, and rate of severe asthma exacerbations increases over 3–6 months.10 Exacerbation rate no different than that with placebo after 12 months.10

Distribution

Extent

Distributed into milk in monkeys.1 Not known whether distributed into human milk.1 (See Lactation under Cautions.)

Elimination

Metabolism

Metabolized by widely distributed proteolytic enzymes.1 12

Half-life

16–22 days.1 12

Special Populations

Adolescents 12–17 years of age: Mean apparent clearance 35% less than that of adults.1

Stability

Storage

Parenteral

Powder for Injection

<25°C.1 Keep in original package and protect from light.1 Do not freeze.1

Reconstituted solution: Use immediately or store at <30°C for up to 8 hours.1 Do not freeze.1

Actions

  • Recombinant DNA-derived humanized interleukin-5 (IL-5) receptor antagonist monoclonal antibody and IgG1 kappa immunoglobulin.1

  • Inhibits IL-5 binding to the alpha chain of the IL-5 receptor complex expressed on the eosinophil cell surface.1 6 7 11

  • Blocks IL-5 signaling that interferes with growth, differentiation, recruitment, activation, and survival of eosinophils and decreases eosinophil-mediated inflammation.1 6 7 8 11

Advice to Patients

  • Risk of hypersensitivity reactions.1 Importance of patients informing clinicians if hypersensitivity reactions (e.g., angioedema, bronchospasm, hypotension, urticaria, rash) occur.1 (See Sensitivity Reactions under Cautions.)

  • Importance of informing patients that mepolizumab does not relieve acute asthma symptoms or exacerbations.1 Advise patients to contact their clinician if asthma remains uncontrolled or worsens after treatment initiation.1

  • Possible increased risk of herpes zoster infections.1 Importance of patients informing clinicians if they do not have a history of varicella infection or vaccination.1

  • Importance of informing patients with asthma receiving inhaled or systemic corticosteroids not to discontinue or reduce corticosteroid dosage since withdrawal symptoms or worsening of asthma may occur; change corticosteroid dosage only under direct supervision of a clinician.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Importance of clinicians informing women about the manufacturer's pregnancy registry and encouraging patient enrollment.1 (See Pregnancy under Cautions.)

  • 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.

Mepolizumab

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for subcutaneous use only

100 mg

Nucala

GlaxoSmithKline

AHFS DI Essentials. © Copyright 2016, Selected Revisions September 30, 2016. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. GlaxoSmithKline. Nucala (mepolizumab) for injection, for subcutaneous use prescribing information. Research Triangle Park, NC; 2015 Nov.

2. Pavord ID, Korn S, Howarth P et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. 2012; 380:651-9. [PubMed 22901886]

3. Ortega HG, Liu MC, Pavord ID et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014; 371:1198-207. [PubMed 25199059]

4. Bel EH, Wenzel SE, Thompson PJ et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014; 371:1189-97. [PubMed 25199060]

5. Katz LE, Gleich GJ, Hartley BF et al. Blood eosinophil count is a useful biomarker to identify patients with severe eosinophilic asthma. Ann Am Thorac Soc. 2014; 11:531-6. [PubMed 24606022]

6. Walford HH, Doherty TA. Diagnosis and management of eosinophilic asthma: a US perspective. J Asthma Allergy. 2014; 7:53-65. [PubMed 24748808]

7. Pouliquen IJ, Kornmann O, Barton SV et al. Characterization of the relationship between dose and blood eosinophil response following subcutaneous administration of mepolizumab. Int J Clin Pharmacol Ther. 2015; 53:1015-27. [PubMed 26445140]

8. George L, Brightling CE. Eosinophilic airway inflammation: role in asthma and chronic obstructive pulmonary disease. Ther Adv Chronic Dis. 2016; 7:34-51. [PubMed 26770668]

9. Chung KF, Wenzel SE, Brozek JL et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014; 43:343-73. [PubMed 24337046]

10. Haldar P, Brightling CE, Singapuri A et al. Outcomes after cessation of mepolizumab therapy in severe eosinophilic asthma: a 12-month follow-up analysis. J Allergy Clin Immunol. 2014; 133:921-3. [PubMed 24418480]

11. Menzella F, Lusuardi M, Galeone C et al. Profile of anti-IL-5 mAb mepolizumab in the treatment of severe refractory asthma and hypereosinophilic diseases. J Asthma Allergy. 2015; 8:105-14. [PubMed 26504401]

12. GlaxoSmithKline. Nucala (mepolizumab) for injection, for subcutaneous use product monograph. Research Triangle Park, NC; 2015 Dec.

13. GlaxoSmithKline. Research Triangle Park, NC: Personal communication.

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