DUPILUMAB SIDE EFFECTS

SIDE EFFECTS

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Hypersensitivity.
• Conjunctivitis and Keratitis.
• Arthralgia.

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 co-morbid 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) study which assessed the long-term safety of repeat doses of DUPIXENT (through 148 weeks of treatment) in adults with moderate-tosevere AD who had previously participated in controlled studies of DUPIXENT or had been screened for SOLO 1 or SOLO 2. The safety data in AD-1225 reflect exposure to DUPIXENT in 2677 subjects, including 2254 exposed for at least 52 weeks, 1192 exposed for at least 100 weeks, and 357 exposed for at least 148 weeks. In AD-1225, 99.7% of subjects were exposed to DUPIXENT 300 mg weekly dosing (QW).

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 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

Adverse Reaction	DUPIXENT Monotherapya		DUPIXENT + TCSb
	DUPIXENT 300 mg Q2Wc N=529 n (%)	Placebo N=517 n (%)	DUPIXENT 300 mg Q2Wc + TCS N=110 n (%)	Placebo + TCS N=315 n (%)
Injection site reaction	51 (10)	28 (5)	11 (10)	18 (6)
Conjunctivitisd	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)
Keratitise	1 (<1)	0	4 (4)	0
Eye pruritus	3 (1)	1 (<1)	2 (2)	2 (1)
Other herpes simplex virus infectionf	10 (2)	6 (1)	1 (1)	1 (<1)
Dry eye	1 (<1)	0	2 (2)	1 (<1)
a Pooled analysis of SOLO 1, SOLO 2, and AD-1021. b Analysis of CHRONOS where subjects were on background TCS therapy. c DUPIXENT 600 mg at Week 0, followed by 300 mg every two weeks. d Conjunctivitis cluster includes conjunctivitis, allergic conjunctivitis, bacterial conjunctivitis, viral conjunctivitis, giant papillary conjunctivitis, eye irritation, and eye inflammation. e Keratitis cluster includes keratitis, ulcerative keratitis, allergic keratitis, atopic keratoconjunctivitis, and ophthalmic herpes simplex. f Other herpes simplex virus infection cluster includes herpes simplex, genital herpes, herpes simplex otitis externa, and herpes virus infection, but excludes eczema herpeticum.

 

Safety 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 148 Weeks (AD-1225)

The long-term safety profile observed in this trial through 148 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 adult 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 adult and pediatric subjects 12 to 17 years of age with atopic dermatitis [see Use In Specific Populations].

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 moderate-to-severe 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 2 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.

Table 2: Adverse Reactions Occurring in ≥1% of the DUPIXENT Groups in DRI12544 and QUEST and Greater than Placebo (6 Month Safety Pool)

Adverse Reaction	DRI12544 and QUEST
	DUPIXENT 200 mg Q2W N=779 n (%)	DUPIXENT 300 mg Q2W N=788 n (%)	Placebo N=792 n (%)
Injection site reactionsa	111 (14%)	144 (18%)	50 (6%)
Oropharyngeal pain	13 (2%)	19 (2%)	7 (1%)
Eosinophiliab	17 (2%)	16 (2%)	2 (<1%)
a Injection site reactions cluster includes erythema, edema, pruritus, pain, and inflammation. b Eosinophilia = blood eosinophils ≥3,000 cells/mcL, or deemed by the investigator to be an adverse event. None met the criteria for serious eosinophilic conditions.

 

Injection 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 405 pediatric subjects 6 to 11 years of age with moderate-to-severe asthma (VOYAGE). The safety profile of DUPIXENT in these subjects through Week 52 was similar to the safety profile from studies in adult and pediatric subjects 12 years of age and older with moderate-to-severe asthma with the addition of helminth infections. Helminth infections were reported in 2.2% (6 subjects) in the DUPIXENT group and 0.7% (1 subject) in the placebo group. The majority of cases were enterobiasis, reported in 1.8% (5 subjects) in the DUPIXENT group and none in the placebo group. There was one case of ascariasis in the DUPIXENT group. All helminth infection cases were mild to moderate and subjects recovered with anti-helminth treatment without DUPIXENT treatment discontinuation.

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 3 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.

Table 3: Adverse Reactions Occurring in ≥1% of the DUPIXENT Group in SINUS-24 and SINUS-52 and Greater than Placebo (24-Week Safety Pool)

Adverse Reaction	SINUS-24 and SINUS-52
	DUPIXENT 300 mg Q2W N=440 n (%)	Placebo N=282 n (%)
Injection site reactionsa	28 (6%)	12 (4%)
Conjunctivitisb	7 (2%)	2 (1%)
Arthralgia	14 (3%)	5 (2%)
Gastritis	7 (2%)	2 (1%)
Insomnia	6 (1%)	0 (<1%)
Eosinophilia	5 (1%)	1 (<1%)
Toothache	5 (1%)	1 (<1%)
a Injection site reactions cluster includes injection site reaction, pain, bruising and swelling. b Conjunctivitis cluster includes conjunctivitis, allergic conjunctivitis, bacterial conjunctivitis, viral conjunctivitis, giant papillary conjunctivitis, eye irritation, and eye inflammation.

 

The safety profile of DUPIXENT through Week 52 was generally consistent with the safety profile observed at Week 24.

Specific Adverse Reactions

Conjunctivitis and Keratitis

In adult subjects with atopic dermatitis, conjunctivitis was reported in 10% (34 per 100 subjectyears) 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 148 weeks (AD-1225), conjunctivitis was reported in 20% 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 148 weeks (AD-1225), keratitis was reported in 3% of the DUPIXENT group (2 per 100 subject-years).

Most subjects with conjunctivitis or keratitis recovered or were recovering during the treatment period.

Among asthma subjects, the frequency of conjunctivitis and keratitis was 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.

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 148 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 148 weeks (AD-1225), 1.9% of DUPIXENT-treated subjects reported herpes zoster (0.99 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 reactions, generalized urticaria, rash, erythema nodosum, and erythema multiforme.

Eosinophils

DUPIXENT-treated subjects had a greater initial increase from baseline in blood eosinophil count compared to subjects treated with placebo. In 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 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 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.

Across all indications, 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 <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). Blood eosinophil counts declined to near baseline levels during study treatment.

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 below with the incidence of antibodies in other studies or to other products may be misleading.

Approximately 5% of subjects with atopic dermatitis, 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 pediatric subjects 6 to 11 years of age with atopic dermatitis who received DUPIXENT 200 mg Q2W or 300 mg Q4W for 16 weeks and pediatric subjects 6 to 11 years of age with asthma who received DUPIXENT 100 mg Q2W or 200 mg Q2W for 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.

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.

Regardless of age or population, approximately 2% 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.

Two adult subjects who experienced high titer antibody responses developed serum sickness or serum sickness-like reactions during DUPIXENT therapy.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of DUPIXENT. Because these 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.

Skin and subcutaneous tissue disorders: Facial skin reactions, including erythema, rash, scaling, edema, papules, pruritus, burning, and pain