FDA Approves DUPIXENT (Dupilumab) for the Treatment of Adult Patients with Moderate-To-Severe Atopic Dermatitis Whose Disease is Not Adequately Controlled with Topical Prescription Therapies or when Those Therapies are Not Advisable
On March 28, 2017, the U.S. Food and Drug Administration (FDA) approved DUPIXENT (dupilumab), a human monoclonal IgG4 antibody, for the treatment of adult patients with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. The approved recommended dosage of DUPIXENT is an initial dose of 600 mg (two 300 mg subcutaneous (SC) injections in different injection sites), followed by 300 mg given every other week. DUPIXENT can be used with or without topical corticosteroids. Topical calcineurin inhibitors may be used, but should be reserved for problem areas only, such as the face, neck, intertriginous and genital areas. Avoid use of live vaccines in patients treated with DUPIXENT.
Mechanism of Action (MOA), General Pharmacokinetics (PK), and Pharmacodynamics (PD)
- MOA: DUPIXENT is an interleukin-4 receptor alpha antagonist.
- Dose Proportionality: Dupilumab exhibited nonlinear target-mediated pharmacokinetics with exposures increasing in a greater than dose-proportional manner. The systemic exposure increased by 30-fold when the dose increased 8-fold following a single dose of dupilumab from 75 mg to 600 mg (i.e., 0.25 to 2 times the approved recommended dosage).
- Time to Steady State: Steady-state concentrations were achieved by Week 16 following administration of the approved recommended dosage.
- Absorption: Dupilumab reached peak mean ± SD concentrations (Cmax) of 70.1 ± 24.1 mcg/mL by approximately 1 week following the initial SC dose of 600 mg. The bioavailability of dupilumab following a SC dose is estimated to be 64%.
- Distribution: The mean ± SD estimated total volume of distribution was approximately 4.8 ± 1.3 L.
- Elimination: After the last steady-state dose of dupilumab 300 mg every two weeks or 300 mg every week, the median times to non-detectable concentration (< 78 ng/mL) are 10 and 13 weeks, respectively.
- Metabolism: The metabolic pathway of dupilumab has not been characterized. As a human monoclonal IgG4 antibody, dupilumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.
- Immunogenicity: Development of antibodies to dupilumab was associated with lower serum dupilumab concentrations. A few subjects who had high antibody titers also had no detectable serum dupilumab concentrations.
- PD: Consistent with receptor blockade, serum levels of IL-4 and IL-13 were increased following dupilumab treatment. The relationship between the pharmacodynamic activity and the mechanism(s) by which dupilumab exerts its clinical effects is unknown.
Drug interaction studies have not been conducted with DUPIXENT.
DUPIXENT, an antagonist of IL-4 receptor alpha, could modulate the formation of CYP450 enzymes. Therefore, upon initiation or discontinuation of DUPIXENT in patients who are receiving concomitant drugs which are CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for effect (e.g., for warfarin) or drug concentration (e.g., for cyclosporine) and consider dosage modification of the CYP450 substrate.
Use in Specific Populations
No dose adjustment in geriatric patients who are 65 years and older is recommended. Dupilumab trough concentrations were lower in subjects with higher body weight. The effect of hepatic or renal impairment on the pharmacokinetics of dupilumab is unknown.
Efficacy and Safety
Three randomized, double-blind, placebo-controlled trials enrolled a total of 2119 subjects 18 years of age and older with moderate-to-severe atopic dermatitis not adequately controlled by topical medication(s). Subjects received the approved recommended dosage for 16 weeks in the monotherapy trials (Trials 1 and 2) and for 52 weeks in the concomitant therapy trial (Trial 3). In Trial 3, subjects received DUPIXENT or placebo with concomitant topical corticosteroids and as-needed topical calcineurin inhibitors for problem areas only, such as the face, neck, intertriginous and genital areas. In all three trials, responders were defined as subjects with an Investigator’s Global Assessment (IGA) score of 0 (clear) or 1 (almost clear) with a reduction of at least 2 points on a 0-4 IGA scale. At Week 16, the proportion of responders in the DUPIXENT group was 38%, 36%, and 39% vs. 10%, 9%, and 12% in the placebo group in Trials 1, 2, and 3, respectively.
Hypersensitivity reactions, including generalized urticaria and serum sickness or serum sickness-like reactions, were reported in less than 1% of subjects who received DUPIXENT in clinical trials. Two subjects experienced serum sickness or serum sickness-like reactions that were associated with high titers of antibodies to dupilumab. Most common adverse reactions (incidence ≥ 1%) are injection site reactions, conjunctivitis, blepharitis, oral herpes, keratitis, eye pruritus, other herpes simplex virus infections, and dry eye.
Full prescribing information is available at https://go.usa.gov/xXQnx.
Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval.
A non-comprehensive list of examples of clinical substrates, inhibitors and inducers for metabolic and transporter system related interactions may be found at https://go.usa.gov/xXY9C.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/
report.htm, by faxing (1-800-FDA-0178), or by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).
We always welcome your thoughts regarding the format, content, and utility of the communication. Comments may be sent via email to email@example.com.
This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.
FDA/Center for Drug Evaluation and Research (CDER)
Office of Translational Sciences
Office of Clinical Pharmacology
Office of Translational Sciences
Office of Clinical Pharmacology