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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 (SOLO 1, SOLO 2, and CHRONOS) and one dose-ranging trial (AD-1021) 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.
SOLO 1, SOLO 2, and AD-1021 compared the safety of DUPIXENT monotherapy to placebo through Week 16. CHRONOS compared the safety of DUPIXENT + TCS to placebo + TCS through Week 52.
AD-1225 is a multicenter, open-label extension (OLE) trial which assessed the long-term safety of repeat doses of DUPIXENT through 260 weeks of treatment in adults with moderate-to-severe AD who had previously participated in controlled trials of DUPIXENT or had been screened for SOLO 1 or SOLO 2. The safety data in AD-1225 reflect exposure to DUPIXENT 200 mg QW, 300 mg QW and 300 mg Q2W in 2677 subjects, including 2254 exposed for at least 52 weeks, 1224 exposed for at least 100 weeks, 561 exposed for at least 148 weeks and 179 exposed for at least 260 weeks.
Weeks 0 to 16 (SOLO 1, SOLO 2, CHRONOS, and AD-1021): In DUPIXENT monotherapy trials (SOLO 1, SOLO 2, and AD-1021) 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 24 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 24.)
Click on icon to see table/diagram/imageSafety through Week 52 (CHRONOS): In the DUPIXENT with concomitant TCS trial (CHRONOS) 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.
Safety through 260 Weeks (AD-1225): The long-term safety profile observed in this trial through 260 weeks was generally consistent with the safety profile of DUPIXENT observed in controlled studies.
Pediatric Subjects 12 to 17 Years of Age with Atopic Dermatitis: The safety of DUPIXENT was assessed in a trial of 250 pediatric subjects 12 to 17 years of age with moderate-to-severe atopic dermatitis (AD-1526). The safety profile of DUPIXENT in these subjects through Week 16 was similar to the safety profile seen in adults with atopic dermatitis.
The long-term safety of DUPIXENT was assessed in an open-label extension study in pediatric subjects 12 to 17 years of age with moderate-to-severe atopic dermatitis (AD-1434). The safety profile of DUPIXENT in subjects followed through Week 52 was similar to the safety profile observed at Week 16 in AD-1526. The long-term safety profile of DUPIXENT observed in pediatric subjects 12 to 17 years of age was consistent with that seen in adults with atopic dermatitis.
Pediatric Subjects 6 to 11 Years of Age with Atopic Dermatitis: The safety of DUPIXENT with concomitant TCS was assessed in a trial of 367 pediatric subjects 6 to 11 years of age with severe atopic dermatitis (AD-1652). The safety profile of DUPIXENT + TCS in these subjects through Week 16 was similar to the safety profile from trials in adults and pediatric subjects 12 to 17 years of age with atopic dermatitis.
The long-term safety of DUPIXENT ± TCS was assessed in an open-label extension study of 368 pediatric subjects 6 to 11 years of age with atopic dermatitis (AD-1434). Among subjects who entered this study, 110 (30%) had moderate and 72 (20%) had severe atopic dermatitis at the time of enrollment in AD-1434. The safety profile of DUPIXENT ± TCS in subjects followed through Week 52 was similar to the safety profile observed through Week 16 in AD-1652. The long-term safety profile of DUPIXENT + TCS observed in pediatric subjects 6 to 11 years of age was consistent with that seen in adults and pediatric subjects 12 to 17 years of age with atopic dermatitis [see Use in Children under Precautions].
Pediatric Subjects 6 Months to 5 Years of Age with Atopic Dermatitis: The safety of DUPIXENT with concomitant TCS was assessed in a trial of 161 pediatric subjects 6 months to 5 years of age with moderate-to-severe atopic dermatitis (AD-1539). The safety profile of DUPIXENT + TCS in these subjects through Week 16 was similar to the safety profile from trials in adults and pediatric subjects 6 to 17 years of age with atopic dermatitis.
The long-term safety of DUPIXENT ± TCS was assessed in an open-label extension study of 180 pediatric subjects 6 months to 5 years of age with atopic dermatitis (AD-1434). The majority of subjects were treated with DUPIXENT 300 mg every 4 weeks. The safety profile of DUPIXENT ± TCS in subjects followed through Week 52 was similar to the safety profile observed through Week 16 in AD-1539. The long-term safety profile of DUPIXENT ± TCS observed in pediatric subjects 6 months to 5 years of age was consistent with that seen in adults and pediatric subjects 6 to 17 years old with atopic dermatitis. In addition, hand-foot-and-mouth disease was reported in 9 (5%) pediatric subjects and skin papilloma was reported in 4 (2%) pediatric subjects treated with DUPIXENT ± TCS. These cases did not lead to study drug discontinuation [see Use in Children under Precautions].
Atopic Dermatitis with Hand and/or Foot Involvement: The safety of DUPIXENT was assessed in a 16-week, multicenter, randomized, double-blind, parallel-group, placebo-controlled trial (Liberty-AD-HAFT) in 133 adult and pediatric subjects 12 to 17 years of age with atopic dermatitis with moderate-to-severe hand and/or foot involvement [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions]. In this trial 67 subjects received DUPIXENT, and 66 subjects received placebo. DUPIXENT-treated subjects received the recommended dosage based on their age and body weight [see Recommended Dosage for Atopic Dermatitis under Dosage & Administration]. The safety profile of DUPIXENT in these subjects through Week 16 was consistent with the safety profile from studies in adult and pediatric subjects 6 months of age and older with moderate-to-severe AD.
Asthma: Adults and Pediatric Subjects 12 Years of Age and Older with Asthma: A total of 2888 adult and pediatric subjects 12 to 17 years of age with asthma (AS) were evaluated in 3 randomized, placebo-controlled, multicenter trials of 24 to 52 weeks duration (DRI12544, QUEST, and VENTURE). Of these, 2678 had a history of 1 or more severe exacerbations in the year prior to enrollment despite regular use of medium to high-dose inhaled corticosteroids plus an additional controller(s) (DRI12544 and QUEST). A total of 210 subjects with oral corticosteroid-dependent asthma receiving high-dose inhaled corticosteroids plus up to two additional controllers were enrolled (VENTURE). The safety population (DRI12544 and QUEST) was 12-87 years of age, of which 63% were female, and 82% were white. DUPIXENT 200 mg or 300 mg was administered subcutaneously Q2W, following an initial dose of 400 mg or 600 mg, respectively.
In DRI12544 and QUEST, the proportion of subjects who discontinued treatment due to adverse events was 4% of the placebo group, 3% of the DUPIXENT 200 mg Q2W group, and 6% of the DUPIXENT 300 mg Q2W group.
Table 25 summarizes the adverse reactions that occurred at a rate of at least 1% in subjects treated with DUPIXENT and at a higher rate than in their respective comparator groups in DRI12544 and QUEST. (See Table 25.)
Click on icon to see table/diagram/imageInjection site reactions were most common with the loading (initial) dose.
The safety profile of DUPIXENT through Week 52 was generally consistent with the safety profile observed at Week 24.
Pediatric Subjects 6 to 11 years of age with Asthma: The safety of DUPIXENT was assessed in 270 patients 6 to 11 years of age with asthma (VOYAGE). The safety profile of DUPIXENT in these patients through Week 52 was similar to the safety profile from studies in adults and pediatric subjects 12 years of age and older with asthma, with the additional adverse reactions of enterobiasis and eosinophilia. Enterobiasis was reported in 1.8% (5 patients) in the DUPIXENT groups and none in the placebo group. All enterobiasis cases were mild to moderate and patients recovered with anti-helminth treatment without DUPIXENT treatment discontinuation. Eosinophilia (blood eosinophils ≥3,000 cells/mcL or deemed by the investigator to be an adverse event) was reported in 6.6% of the DUPIXENT groups and 0.7% in the placebo group.
Chronic Rhinosinusitis with Nasal Polyposis: A total of 722 adult subjects with chronic rhinosinusitis with nasal polyposis (CRSwNP) were evaluated in 2 randomized, placebo-controlled, multicenter trials of 24 to 52 weeks duration (SINUS-24 and SINUS-52). The safety pool consisted of data from the first 24 weeks of treatment from both studies.
In the safety pool, the proportion of subjects who discontinued treatment due to adverse events was 5% of the placebo group and 2% of the DUPIXENT 300 mg Q2W group.
Table 26 summarizes the adverse reactions that occurred at a rate of at least 1% in subjects treated with DUPIXENT and at a higher rate than in their respective comparator group in SINUS-24 and SINUS-52. (See Table 26.)
Click on icon to see table/diagram/imageThe safety profile of DUPIXENT through Week 52 was generally consistent with the safety profile observed at Week 24.
Prurigo Nodularis: A total of 309 adult subjects with prurigo nodularis (PN) were evaluated in two 24-week randomized, double-blind, placebo-controlled, multicenter trials (PRIME and PRIME2). The safety pool included data from the 24 week treatment and 12 week follow-up periods from both trials.
In the safety pool, the proportion of subjects who discontinued treatment due to adverse events was 3% of the placebo group and 0% of the DUPIXENT 300 mg Q2W group.
Table 27 summarizes the adverse reactions that occurred at a rate of at least 1% in subjects treated with DUPIXENT and at a higher rate than in their respective comparator group in PRIME and PRIME2. (See Table 27.)
Click on icon to see table/diagram/imageChronic Obstructive Pulmonary Disease: A total of 1874 adult subjects with inadequately controlled chronic obstructive pulmonary disease (COPD) and an eosinophilic phenotype were evaluated in two randomized, double-blind, multicenter, parallel group, placebo-controlled trials with a 52-week treatment period (BOREAS and NOTUS) [see Pharmacodynamics: Clinical Studies: Chronic Obstructive Pulmonary Disease under Actions]. Of those randomized, 1872 subjects received at least one dose of DUPIXENT 300 mg or placebo subcutaneously every 2 weeks (Q2W). The safety of DUPIXENT was assessed in the pooled safety population from BOREAS and NOTUS, which consisted of 938 adult subjects treated with DUPIXENT. Of the subjects treated with DUPIXENT, 98% utilized inhaled triple therapy at baseline (comprising of an inhaled corticosteroid, long-acting beta-agonist, and long-acting muscarinic antagonist), and 97% had chronic bronchitis.
Table 28 summarizes the adverse reactions that occurred in at least 2% of subjects treated with DUPIXENT and at a higher rate than placebo in BOREAS and NOTUS trials. (See Table 28.)
Click on icon to see table/diagram/imageLess Common Adverse Reaction in Subjects with COPD: Cholecystitis: In adult subjects with COPD, cholecystitis was reported in 6 subjects (0.6%) in the DUPIXENT group compared to 1 subject (0.1%) in the placebo group. Among these subjects, serious cholecystitis was reported in 4 (0.4%) of the DUPIXENT group compared with 0% of the placebo group.
Specific Adverse Reactions: Conjunctivitis and Keratitis: In adult subjects with atopic dermatitis, conjunctivitis was reported in 10% (34 per 100 subject-years) in the 300 mg Q2W dose group and in 2% of the placebo group (8 per 100 subject-years) during the 16-week treatment period of the monotherapy trials (SOLO 1, SOLO 2, and AD-1021). During the 52-week treatment period of concomitant therapy atopic dermatitis trial (CHRONOS), 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). During the long-term OLE trial with data through 260 weeks (AD-1225), conjunctivitis was reported in 21% of the DUPIXENT group (12 per 100 subject-years).
In DUPIXENT atopic dermatitis monotherapy trials (SOLO 1, SOLO 2, and AD-1021) through Week 16, keratitis was reported in <1% of the DUPIXENT group (1 per 100 subject-years) and in 0% of the placebo group (0 per 100 subject-years). In the 52-week atopic dermatitis DUPIXENT + topical corticosteroids (TCS) atopic dermatitis trial (CHRONOS), keratitis was reported in 4% of the DUPIXENT + TCS group (4 per 100 subject-years) and in 2% of the placebo + TCS group (2 per 100 subject-years). Conjunctivitis and keratitis occurred more frequently in atopic dermatitis subjects who received DUPIXENT. Conjunctivitis was the most frequently reported eye disorder. During the long-term OLE trial with data through 260 weeks (AD-1225), keratitis was reported in 3% of the DUPIXENT group (1 per 100 subject-years). Most subjects with conjunctivitis or keratitis recovered or were recovering during the treatment period.
Among asthma and COPD subjects, the frequency of conjunctivitis and keratitis was low and similar between DUPIXENT and placebo.
In subjects with CRSwNP, the frequency of conjunctivitis was 2% in the DUPIXENT group compared to 1% in the placebo group in the 24-week safety pool; these subjects recovered.
In the 52-week CRSwNP study (SINUS-52), the frequency of conjunctivitis was 3% in the DUPIXENT subjects and 1% in the placebo subjects; all of these subjects recovered. There were no cases of keratitis reported in the CRSwNP development program [see Conjunctivitis and Keratitis under Precautions].
In patients with Prurigo Nodularis, the frequency of conjunctivitis was low, although the frequency in the DUPIXENT group was higher than in the placebo group. There was no cases of keratitis reported in the PN development program.
Eczema Herpeticum and Herpes Zoster: The rate of eczema herpeticum was similar in the placebo and DUPIXENT groups in the atopic dermatitis trials. The rates remained stable through 260 weeks in the long-term OLE trial (AD-1225).
Herpes zoster was reported in <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). During the long-term OLE trial with data through 260 weeks (AD-1225), 2.0% of DUPIXENT-treated subjects reported herpes zoster (0.94 per 100 subject-years of follow up). Among asthma subjects the frequency of herpes zoster was similar between DUPIXENT and placebo. Among CRSwNP subjects there were no reported cases of herpes zoster or eczema herpeticum.
Hypersensitivity Reactions: Hypersensitivity reactions were reported in <1% of DUPIXENT-treated subjects. These included anaphylaxis, serum sickness or serum sickness-like reaction, generalized urticaria, rash, erythema nodosum and erythema multiforme [see Contraindications, Hypersensitivity under Precautions, and Immunogenicity as follows].
Eosinophils: DUPIXENT-treated subjects with atopic dermatitis, asthma, CRSwNP and COPD had a greater initial increase from baseline in blood eosinophil count compared to subjects treated with placebo. In adult subjects with atopic dermatitis (SOLO 1, SOLO 2 and AD-1021), the mean and median increases in blood eosinophils from baseline to Week 4 were 100 and 0 cells/mcL respectively. In pediatric subjects <6 years old with atopic dermatitis, the mean and median increases from baseline to Week 4 were 478 and 90 cells/mcL, respectively.
In adult and pediatric subjects 12 years of age and older with asthma (DRI12544 and QUEST), the mean and median increases in blood eosinophils from baseline to Week 4 were 130 and 10 cells/mcL, respectively. In subjects 6 to 11 years of age with asthma (VOYAGE), the mean and median increases in blood eosinophils from baseline to Week 12 were 124 and 0 cells/mcL, respectively.
In adult subjects with CRSwNP (SINUS-24 and SINUS-52), the mean and median increases in blood eosinophils from baseline to Week 16 were 150 and 50 cells/mcL, respectively.
Compared to placebo, no increase in mean blood eosinophil counts was observed in PN (PRIME and PRIME2).
In COPD, the incidence of treatment-emergent eosinophilia (≥500 cells/mcL) was higher in the DUPIXENT group than in the placebo; none of the cases were associated with clinical symptoms.
Across the trials for atopic dermatitis, asthma, and CRSwNP indications, the incidence of treatment-emergent eosinophilia (≥500 cells/mcL) was similar in DUPIXENT and placebo groups. In the trials for the Prurigo Nodularis indication, the incidence of treatment-emergent eosinophilia (≥500 cells/mcL) was lower in DUPIXENT than in the placebo group.
Treatment-emergent eosinophilia (≥5,000 cells/mcL) was reported in <3% of DUPIXENT-treated subjects and <0.5% in placebo-treated subjects (SOLO 1, SOLO 2 and AD-1021; DRI12544, QUEST, and VOYAGE; SINUS-24 and SINUS-52; PRIME and PRIME2; BOREAS and NOTUS). Blood eosinophil counts declined to near baseline levels during study treatment. In study AD-1539, treatment-emergent eosinophilia (≥5,000 cells/mcL) was reported in 8% of DUPIXENT-treated subjects and 0% in placebo-treated subjects [see Eosinophilic Conditions under Precautions].
Cardiovascular: In the 1-year placebo controlled trial in adult and pediatric subjects 12 years of age and older with asthma (QUEST), cardiovascular thromboembolic events (cardiovascular deaths, non-fatal myocardial infarctions, and non-fatal strokes) were reported in 1 (0.2%) of the DUPIXENT 200 mg Q2W group, 4 (0.6%) of the DUPIXENT 300 mg Q2W group, and 2 (0.3%) of the placebo group.
In the 1-year placebo controlled trial in subjects with atopic dermatitis (CHRONOS), 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.
In the 24-week placebo controlled trial in subjects with CRSwNP (SINUS-24), cardiovascular thromboembolic events (cardiovascular deaths, non-fatal myocardial infarctions, and non-fatal strokes) were reported in 1 (0.7%) of the DUPIXENT group and 0 (0.0%) of the placebo group. In the 1-year placebo controlled trial in subjects with CRSwNP (SINUS-52), there were no cases of cardiovascular thromboembolic events (cardiovascular deaths, non-fatal myocardial infarctions, and non-fatal strokes) reported in any treatment arm.
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.
Atopic Dermatitis: Approximately 5% of subjects with atopic dermatitis or asthma or CRSwNP 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. Similar results were observed in adult patients with Prurigo Nodularis who received DUPIXENT 300mg Q2W for 24 weeks, pediatric subjects 6 months to 11 years of age with atopic dermatitis who received either DUPIXENT 200mg Q2W, 200mg Q4W or 300mg Q4W and pediatric subjects 6 to 11 years of age with asthma who received DUPIXENT 100 mg Q2W or 200 mg Q2W up to 52 weeks.
Approximately 16% of pediatric subjects 12 to 17 years of age 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.
Asthma: Approximately 9% of subjects with asthma who received DUPIXENT 200 mg Q2W for 52 weeks developed antibodies to dupilumab; approximately 4% exhibited persistent ADA responses, and approximately 4% had neutralizing antibodies.
COPD: Approximately 8% of patients with COPD who received DUPIXENT 300 mg Q2W for 52 weeks developed antibodies to dupilumab; approximately 3% exhibited persistent ADA responses and approximately 3% had neutralizing antibodies.
Regardless of age or population, up to 4% of subjects in placebo groups were positive for antibodies to DUPIXENT; approximately 2% 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 adult subjects who experienced high titer antibody responses developed serum sickness or serum sickness-like reactions during DUPIXENT therapy [see Hypersensitivity under Precautions].
Post Marketing Experience: The following adverse reactions have been identified during post-approval use of DUPIXENT. Because these adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Immune system disorders: Angioedema [see Hypersensitivity under Precautions].
Skin and subcutaneous tissue disorders: Facial skin reactions, including erythema, rash, scaling, edema, papules, pruritus, burning, and pain.
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