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Dupilumab

Class: Skin and Mucous Membrane Agents, Miscellaneous
Chemical Name: Immunoglobulin, anti-(human interleukin 4 receptor a) (human REGN668 heavy chain), disulfide with human REGN668 k-chain, dimer
Molecular Formula: CH10066N1730O2052S466512H10066N1730O205S46
CAS Number: 1190264-60-8
Brands: Dupixent

Medically reviewed on Mar 5, 2018

Introduction

See also: Dupixent

Recombinant human IgG4 monoclonal antibody that binds specifically to the interleukin-4 receptor alpha subunit (IL-4Rα) of interleukin-4 (IL-4) and interleukin-13 (IL-13).1 2 3 6 7 8

Uses for Dupilumab

Atopic Dermatitis

Treatment of moderate to severe atopic dermatitis in adults who have had an inadequate response to topical therapy (e.g., topical corticosteroids) or in whom such therapy is inadvisable because of potential risks.1 2 3

Dupilumab Dosage and Administration

General

  • May be used with or without concomitant topical corticosteroids.1 Topical calcineurin inhibitors also may be used concomitantly, but reserve for use only on the face, neck, and intertriginous and genital areas.1

Administration

Administer by sub-Q injection.1

Intended for use under supervision of a clinician, but may be self-administered if clinician determines that the patient and/or their caregiver is competent to safely administer the drug sub-Q after appropriate training and with medical follow-up as necessary.1

Available as single-use, prefilled syringes containing 300 mg of the drug.1

Remove appropriate number of prefilled syringes from refrigerator and allow to sit at room temperature for 45 minutes prior to injection.1 Do not warm or expose syringe to direct sunlight.1 Do not remove needle cap while prefilled syringe is warming to room temperature.1 Do not shake.1

Solution should appear clear to slightly opalescent and colorless to pale yellow;1 discard if cloudy, discolored, or contains particulates.1

Sub-Q Administration

Make sub-Q injection into upper arm, thigh, or abdomen (except within 2 inches of the navel).1 Only a clinician or caregiver should make sub-Q injections into upper arm.1

Do not make sub-Q injections into areas where skin is tender, damaged, bruised, or scarred.1

Rotate injection sites for each subsequent dose.1

If a dose is missed and remembered ≤7 days after originally scheduled, administer missed dose as soon as possible and resume original schedule.1 If missed dose is remembered >7 days after originally scheduled, skip and give next dose at usual time.1

Consult manufacturer's instructions for additional information about preparation and administration of dupilumab.1

Dosage

Adults

Moderate to Severe Atopic Dermatitis
Sub-Q

Initial dose of 600 mg (given as two 300-mg doses administered at different injection sites), then 300 mg once every other week.1

Special Populations

Hepatic Impairment

Manufacturer makes no specific dosage recommendations.1

Renal Impairment

Manufacturer makes no specific dosage recommendations.1

Geriatric Patients

Dosage adjustments not needed.1

Cautions for Dupilumab

Contraindications

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

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity reactions, including generalized urticaria, serum sickness, and serum sickness-like reactions, reported.1

If an allergic reaction occurs, discontinue dupilumab immediately and initiate appropriate therapy.1

Ocular Effects

Conjunctivitis (e.g., allergic conjunctivitis, bacterial conjunctivitis, viral conjunctivitis, giant papillary conjunctivitis, eye irritation, eye inflammation) and keratitis (e.g., ulcerative keratitis, allergic keratitis, atopic keratoconjunctivitis, ophthalmic herpes simplex) reported.1 2 3 Blepharitis, eye pruritus, and dry eye also reported.1

In clinical studies, conjunctivitis generally resolved or improved in most patients despite continued dupilumab treatment.1

Patients with Asthma

Safety and efficacy for treatment of asthma not established.1

Patients with asthma who are receiving dupilumab for treatment of atopic dermatitis should not discontinue or adjust their asthma therapy without consulting a clinician.1

Patients with Parasitic Infections

Patients with helminth infections were excluded from dupilumab clinical trials;1 manufacturer states that it is not known whether the drug affects immune responses to such infections.1

Dupilumab inhibits signaling through IL-4 and IL-13 receptors;1 2 3 4 IL-4 and IL-13 may be involved in type 2 immune responses to parasitic helminth infections.5

Immunogenicity

Like other therapeutic proteins, potential for immunogenicity exists.1

Approximately 7% of patients in clinical trials who received dupilumab alone or in conjunction with topical corticosteroids developed antibodies to the drug;1 30 or 14% of these individuals, respectively, had antibodies that were classified as neutralizing.1

Although antibody titers generally are low, high antibody titers reported in 2 patients who developed serum sickness or serum sickness-like reactions to the drug.1

Decreased serum concentrations of dupilumab reported in patients with antibodies to the drug;1 serum concentrations of the drug undetectable in a few patients with high antibody titers.1

Specific Populations

Pregnancy

Data not available regarding use in pregnant women.1

Potential for fetal exposure since human IgG crosses the placenta.1

In animal studies, no evidence of adverse embryofetal toxicity or malformations and no adverse effects on morphologic, functional, or immunologic development.1

Lactation

Not known whether dupilumab is distributed into human milk, affects human milk production, or affects breast-fed infants.1

Human IgG is known to be distributed into human milk.1

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

Pediatric Use

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

Geriatric Use

No overall differences in safety and efficacy relative to younger adults; however, insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.1

Hepatic Impairment

No formal pharmacokinetic studies to date.1

Renal Impairment

No formal pharmacokinetic studies to date.1

Common Adverse Effects

Injection site reactions (e.g., erythema, swelling, warmth),1 2 3 4 ocular effects (e.g., conjunctivitis, blepharitis, keratitis, pruritus, dry eye),1 2 3 herpes simplex virus infection.1 2 3

Interactions for Dupilumab

No formal drug interaction studies to date.1

Drugs Metabolized by Hepatic Microsomal Enzymes

Because elevated levels of certain cytokines during chronic inflammation may alter formation of CYP isoenzymes, antagonism of IL-4- and IL-13 activity by dupilumab could affect formation of CYP enzymes.1

CYP substrates: When dupilumab is initiated or discontinued, consider monitoring for therapeutic effects or drug concentrations and consider adjusting dosage of the CYP substrate, especially if substrate has narrow therapeutic index.1

Specific Drugs

Drug

Interaction

Comments

Cyclosporine

Possible effect on cyclosporine metabolism;1 cyclosporine is a CYP substrate and dupilumab may affect formation of CYP isoenzymes1

Consider monitoring cyclosporine concentrations when dupilumab initiated or discontinued;1 consider adjusting cyclosporine dosage1

Meningococcal Vaccines

MPSV4 (Menomune): Dupilumab did not alter immune response to meningococcal group C antigen;1 immune responses to meningococcal groups A, Y, and W-135 antigens not assessed1

Tetanus toxoid and reduced diphtheria toxoid and acellular pertussis vaccine adsorbed (Tdap)

Tdap (Adacel): Dupilumab did not alter immune response to tetanus antigen;1 immune responses to diphtheria and pertussis antigens not assessed1

Vaccines, live

Do not use in patients receiving dupilumab1

Warfarin

Possible effect on warfarin metabolism;1 warfarin is a CYP substrate and dupilumab may affect formation of CYP isoenzymes1

Consider monitoring therapeutic effect of warfarin when dupilumab initiated or discontinued;1 consider adjusting warfarin dosage1

Dupilumab Pharmacokinetics

Absorption

Bioavailability

Estimated bioavailability is 64% following sub-Q administration.1

Nonlinear pharmacokinetics over sub-Q dose range of 75–600 mg;1 systemic exposure increases in a greater than dose-proportional manner.1

Plasma Concentrations

Following single 600-mg sub-Q dose, peak plasma concentrations attained by approximately 7 days.1

In patients who receive initial 600-mg sub-Q dose followed by 300-mg sub-Q doses once every other week, steady-state concentrations attained by week 16.1

Following last 300-mg steady-state dose given 2 weeks after previous dose, median time to undetectable serum concentrations (<78 ng/mL) is 10 weeks.1

Special Populations

Steady-state trough concentrations decrease as body weight increases.1

Age does not substantially alter steady-state trough concentrations in adults with atopic dermatitis.1

Distribution

Extent

Not known whether distributed into human 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

Special Populations

Pharmacokinetics not formally studied in renal or hepatic impairment.1

Stability

Storage

Parenteral

Injection

2–8°C; keep in original carton to protect from light.1

If necessary, may be kept at room temperature (≤25°C) for maximum of 14 days;1 after removal from refrigerator, must be used within 14 days or discarded.1

Do not expose to heat or sunlight;1 do not freeze.1

Actions

  • Recombinant fully human IgG monoclonal antibody that binds specifically to IL-4Rα, a shared cell-surface subunit of IL-4 and IL-13.1 2 3 6 7 8

  • Disrupts signaling through IL-4- and IL-13 receptors, thereby inhibiting release of proinflammatory cytokines, chemokines, and IgE.1 2 3 4 6 7 8

  • IL-4 and IL-13 are key cytokines involved in inflammatory skin response in patients with atopic dermatitis.2 3 4 6 7

Advice to Patients

  • Provide all patients with a copy of the manufacturer's patient information and instructions for use of dupilumab with each prescription of the drug.1 Importance of patients reading the patient information and instructions for use prior to initiation of therapy and each time the prescription is refilled.1

  • Instruct patient and/or caregiver regarding proper storage, dosage, and administration of dupilumab, including use of aseptic technique and proper disposal of needles and syringes, if it is determined that the patient and/or caregiver is competent to safely administer the drug.1

  • Advise patients to immediately discontinue dupilumab and contact a clinician if symptoms of hypersensitivity (e.g., hives, itching, fever, swollen lymph nodes, joint pain, rash) occur.1

  • Inform patients that dupilumab may cause eye problems (e.g., conjunctivitis, keratitis).1 Importance of promptly contacting a clinician if new-onset or worsening eye symptoms occur, including eye pain or changes in vision.1

  • Advise patients with asthma that they should not discontinue or adjust their asthma therapy during dupilumab treatment without consulting a clinician.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., parasitic infections, asthma, eye problems).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.

Dupilumab

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for subcutaneous use

300 mg/2 mL

Dupixent

Sanofi-Aventis

AHFS DI Essentials. © Copyright 2018, Selected Revisions March 5, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Sanofi-Aventis. Dupixent (dupilumab) injection for subcutaneous use prescribing information. Bridgewater, NJ. 2017 Mar

2. Simpson EL, Bieber T, Guttman-Yassky E et al. Two Phase 3 Trials of Dupilumab versus Placebo in Atopic Dermatitis. N Engl J Med. 2016; 375:2335-2348. http://www.ncbi.nlm.nih.gov/pubmed/27690741?dopt=AbstractPlus

3. Blauvelt A, de Bruin-Weller M, Gooderham M et al. Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomised, double-blinded, placebo-controlled, phase 3 trial. Lancet. 2017; 389:2287-2303. http://www.ncbi.nlm.nih.gov/pubmed/28478972?dopt=AbstractPlus

4. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 761055Orig1s000: Medical Review(s). From FDA website

5. Oliphant CJ, Barlow JL, McKenzie AN. Insights into the initiation of type 2 immune responses. Immunology. 2011; 134:378-85. http://www.ncbi.nlm.nih.gov/pubmed/22044021?dopt=AbstractPlus

6. D'Erme AM, Romanelli M, Chiricozzi A. Spotlight on dupilumab in the treatment of atopic dermatitis: design, development, and potential place in therapy. Drug Des Devel Ther. 2017; 11:1473-1480. http://www.ncbi.nlm.nih.gov/pubmed/28553077?dopt=AbstractPlus

7. Mansouri Y, Guttman-Yassky E. Immune Pathways in Atopic Dermatitis, and Definition of Biomarkers through Broad and Targeted Therapeutics. J Clin Med. 2015; 4:858-73. http://www.ncbi.nlm.nih.gov/pubmed/26239452?dopt=AbstractPlus

8. Boguniewicz M, Alexis AF, Beck LA et al. Expert Perspectives on Management of Moderate-to-Severe Atopic Dermatitis: A Multidisciplinary Consensus Addressing Current and Emerging Therapies. J Allergy Clin Immunol Pract. 2017; http://www.ncbi.nlm.nih.gov/pubmed/28970084?dopt=AbstractPlus

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