6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail elsewhere in the labeling: Hypersensitivity [see Warnings and Precautions (5.1)] Conjunctivitis and Keratitis [see Warnings and Precautions (5.2)] Most common adverse reactions (incidence ≥1%) are injection site reactions, conjunctivitis, blepharitis, oral herpes, keratitis, eye pruritus, other herpes simplex virus infection, and dry eye. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Regeneron at 1-855-395-3248 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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. 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 1 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. Table 1: Adverse Reactions Occurring in ≥1% of the DUPIXENT Monotherapy Group or the DUPIXENT + TCS Group in the Atopic Dermatitis Trials through Week 16 DUPIXENT Monotherapypooled analysis of Trials 1, 2, and 4 DUPIXENT + TCSanalysis of Trial 3 where subjects were on background TCS therapy Adverse Reaction DUPIXENT 300 mg Q2WDUPIXENT 600 mg at Week 0, followed by 300 mg every two weeks Placebo DUPIXENT 300 mg Q2W + TCS Placebo + TCS N=529 n (%) N=517 n (%) N=110 n (%) N=315 n (%) Injection site reactions 51 (10) 28 (5) 11 (10) 18 (6) ConjunctivitisConjunctivitis cluster includes conjunctivitis, allergic conjunctivitis, bacterial conjunctivitis, viral conjunctivitis, giant papillary conjunctivitis, eye irritation, and eye inflammation. 51 (10) 12 (2) 10 (9) 15 (5) Blepharitis 2 (<1) 1 (<1) 5 (5) 2 (1) Oral herpes 20 (4) 8 (2) 3 (3) 5 (2) KeratitisKeratitis cluster includes keratitis, ulcerative keratitis, allergic keratitis, atopic keratoconjunctivitis, and ophthalmic herpes simplex. 1 (<1) 0 4 (4) 0 Eye pruritus 3 (1) 1 (<1) 2 (2) 2 (1) Other herpes simplex virus infectionOther herpes simplex virus infection cluster includes herpes simplex, genital herpes, herpes simplex otitis externa, and herpes virus infection, but excludes eczema herpeticum. 10 (2) 6 (1) 1 (1) 1 (<1) Dry eye 1 (<1) 0 2 (2) 1 (<1) 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. Specific Adverse Reactions Conjunctivitis During the 52-week treatment period of concomitant therapy 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 Warnings and Precautions (5.2)]. Eczema Herpeticum and Herpes Zoster The rate of eczema herpeticum was similar in the placebo and DUPIXENT groups. 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 monotherapy trials. In the 52-week DUPIXENT + TCS 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 [see Contraindications (4), Warnings and Precautions (5.1), and Adverse Reactions (6.2)]. Eosinophils DUPIXENT-treated subjects had a greater mean initial increase from baseline in eosinophil count compared to subjects treated with placebo in the monotherapy trials. Eosinophil counts declined to near baseline levels by Week 16. The initial increase in eosinophils was not observed in the 52-week DUPIXENT + TCS trial. In Trials 1, 2, and 3, the incidence of treatment-emergent eosinophilia (≥500 cells/mcL) was similar in DUPIXENT and placebo groups. In Trials 1, 2, and 3, treatment-emergent eosinophilia (≥5,000 cells/mcL) was reported in <1% of DUPIXENT-treated patients and none in placebo-treated patients. In most cases, eosinophil counts declined to near baseline during study treatment. 6.2 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 below with the incidence of antibodies in other studies or to other products may be misleading. Approximately 7% of subjects with atopic dermatitis who received DUPIXENT 300 mg Q2W for 16 weeks developed antibodies to dupilumab. Of the subjects who developed antibodies to dupilumab, approximately 30% (2% of all subjects receiving DUPIXENT) had antibodies that were classified as neutralizing. Of the subjects with atopic dermatitis who received DUPIXENT 300 mg Q2W + TCS for 52 weeks, approximately 7% developed antibodies to dupilumab and approximately 2% had persistent antibody responses, defined as having at least 2 consecutive positive post-baseline samples. Of the subjects who developed antibodies to dupilumab, approximately 14% (1% of all subjects receiving DUPIXENT + TCS) had antibodies that were classified as neutralizing. In subjects who received DUPIXENT, development of antibodies to dupilumab was associated with lower serum dupilumab concentrations [see Clinical Pharmacology (12.3)]. Antibodies to dupilumab were detected in approximately 2% and 8% of subjects with atopic dermatitis in the placebo or the placebo + TCS groups, respectively. The antibody titers detected in both DUPIXENT and placebo subjects were generally low. Two subjects developed serum sickness or serum sickness-like reactions and high titers of antibodies to dupilumab during DUPIXENT therapy [see Warnings and Precautions (5.1)].