The following adverse reactions are discussed in greater detail as follows: Hypersensitivity [see Hypersensitivity under Precautions], Conjunctivitis and Keratitis [see Conjunctivitis and Keratitis under Precautions].
Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Adults with Atopic Dermatitis: Three randomized, double-blind, placebo-controlled, multicenter trials (Trials 1, 2, and 3) and one dose-ranging trial (Trial 4) evaluated the safety of DUPIXENT in subjects with moderate-to-severe atopic dermatitis. The safety population had a mean age of 38 years; 41% of subjects were female, 67% were white, 24% were Asian, and 6% were black; in terms of comorbid conditions, 48% of the subjects had asthma, 49% had allergic rhinitis, 37% had food allergy, and 27% had allergic conjunctivitis. In these 4 trials, 1472 subjects were treated with subcutaneous injections of DUPIXENT, with or without concomitant topical corticosteroids (TCS).
A total of 739 subjects were treated with DUPIXENT for at least 1 year in the development program for moderate-to-severe atopic dermatitis.
Trials 1, 2, and 4 compared the safety of DUPIXENT monotherapy to placebo through Week 16. Trial 3 compared the safety of DUPIXENT + TCS to placebo + TCS through Week 52.
Weeks 0 to 16 (Trials 1 to 4): In DUPIXENT monotherapy trials (Trials 1, 2, and 4) through Week 16, the proportion of subjects who discontinued treatment because of adverse events was 1.9% in both the DUPIXENT 300 mg Q2W and placebo groups.
Table 5 summarizes the adverse reactions that occurred at a rate of at least 1% in the DUPIXENT 300 mg Q2W monotherapy groups, and in the DUPIXENT + TCS group, all at a higher rate than in their respective comparator groups during the first 16 weeks of treatment. (See Table 5.)
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Safety through Week 52 (Trial 3): In the DUPIXENT with concomitant TCS trial (Trial 3) through Week 52, the proportion of subjects who discontinued treatment because of adverse events was 1.8% in DUPIXENT 300 mg Q2W + TCS group and 7.6% in the placebo + TCS group. Two subjects discontinued DUPIXENT because of adverse reactions: atopic dermatitis (1 subject) and exfoliative dermatitis (1 subject).
The safety profile of DUPIXENT + TCS through Week 52 was generally consistent with the safety profile observed at Week 16.
Adolescents with Atopic Dermatitis: The safety of DUPIXENT was assessed in a trial of 250 subjects 12 to 17 years of age with moderate-to-severe atopic dermatitis (Trial 6). The safety profile of DUPIXENT in these subjects through Week 16 was similar to the safety profile from studies in adults with atopic dermatitis.
The long-term safety of DUPIXENT was assessed in an open-label extension study in subjects 12 to 17 years of age with moderate-to-severe atopic dermatitis (Trial 7). The safety profile of DUPIXENT in subjects followed through Week 52 was similar to the safety profile observed at Week 16 in Trial 6. The long-term safety profile of DUPIXENT observed in adolescents was consistent with that seen in adults with atopic dermatitis.
Specific Adverse Reactions: Conjunctivitis: During the 52-week treatment period of concomitant therapy atopic dermatitis trial (Trial 3), conjunctivitis was reported in 16% of the DUPIXENT 300 mg Q2W + TCS group (20 per 100 subject-years) and in 9% of the placebo + TCS group (10 per 100 subject-years) [see Conjunctivitis and Keratitis under Precautions].
Eczema Herpeticum and Herpes Zoster: The rate of eczema herpeticum was similar in the placebo and DUPIXENT groups in the atopic dermatitis trial.
Herpes zoster was reported in <0.1% of the DUPIXENT groups (<1 per 100 subject-years) and in <1% of the placebo group (1 per 100 subject-years) in the 16-week atopic dermatitis monotherapy trials. In the 52-week DUPIXENT + TCS atopic dermatitis trial, herpes zoster was reported in 1% of the DUPIXENT + TCS group (1 per 100 subject-years) and 2% of the placebo + TCS group (2 per 100 subject-years).
Hypersensitivity Reactions: Hypersensitivity reactions were reported in <1% of DUPIXENT-treated subjects. These included serum sickness reaction, serum sickness-like reaction, and generalized urticaria, rash, erythema nodosum, and anaphylaxis[see Contraindications, Hypersensitivity under Precautions, and Immunogenicity under Adverse Reactions].
Eosinophils: DUPIXENT-treated subjects had a greater mean initial increase from baseline in eosinophil count compared to subjects treated with placebo. In subjects with atopic dermatitis, the mean and median increases in blood eosinophils from baseline to Week 4 were 100 and 0 cells/mcL respectively.
The incidence of treatment-emergent eosinophilia (≥500 cells/mcL) was similar in DUPIXENT and placebo groups. Treatment-emergent eosinophilia (≥5,000 cells/mcL) was reported in <2% of DUPIXENT-treated patients and <0.5% in placebo-treated patients. Blood eosinophil counts declined to near baseline levels during study treatment [see Reduction of Corticosteroid Dosage under Precautions].
Cardiovascular: In the 1-year placebo controlled trial in subjects with atopic dermatitis (Trial 3), cardiovascular thromboembolic events (cardiovascular deaths, non-fatal myocardial infarctions, and non-fatal strokes) were reported in 1 (0.9%) of the DUPIXENT + TCS 300 mg Q2W group, 0 (0.0%) of the DUPIXENT + TCS 300 mg QW group, and 1 (0.3%) of the placebo + TCS group.
Immunogenicity: As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to dupilumab in the studies described as follows with the incidence of antibodies in other studies or to other products may be misleading.
Approximately 6% of subjects with atopic dermatitis who received DUPIXENT 300 mg Q2W for 52 weeks developed antibodies to dupilumab; approximately 2% exhibited persistent ADA responses, and approximately 2% had neutralizing antibodies.
Approximately 16% of adolescent subjects with atopic dermatitis who received DUPIXENT 300 mg or 200 mg Q2W for 16 weeks developed antibodies to dupilumab; approximately 3% exhibited persistent ADA responses, and approximately 5% had neutralizing antibodies.
Approximately 4% of adolescent subjects with atopic dermatitis in the placebo group were positive for antibodies to DUPIXENT; approximately 1% exhibited persistent ADA responses, and approximately 1% had neutralizing antibodies.
The antibody titers detected in both DUPIXENT and placebo subjects were mostly low. In subjects who received DUPIXENT, development of high titer antibodies to dupilumab was associated with lower serum dupilumab concentrations [see Pharmacology: Pharmacokinetics under Actions].
Two subjects who experienced high titer antibody responses developed serum sickness or serum sickness-like reactions during DUPIXENT therapy [see Hypersensitivity under Precautions].