Adverse reactions : תופעות לוואי

6.            ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling: •   Hypersensitivity [see Warnings and Precautions (5.1)]
•   Conjunctivitis and Keratitis [see Warnings and Precautions (5.2)] •   Arthralgia [see Warnings and Precautions (5.7)]
•   Parasitic (Helminth) Infections [see Warnings and Precautions (5.8)] 
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.
Adults with Atopic Dermatitis
Three randomized, double-blind, placebo-controlled, multicenter trials (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 AD. 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 AD.
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 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.
Table 5 :            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         Placebo                      DUPIXENT         Placebo + 300 mg Q2Wc                                300 mg Q2Wc + TCS      TCS 
N=529                  N=517                   N=110                   N=315 n (%)                  n (%)                   n (%)                   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               10 (2)                  6 (1)                  1 (1)                  1 (<1) virus infectionf
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 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 AD (AD-1526). The safety profile of DUPIXENT in these subjects through Week 16 was similar to the safety profile seen in adults with AD.
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 AD (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 AD.
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 AD (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 AD.

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 AD (AD-1434). Among subjects who entered this study, 110 (30%) had moderate and 72 (20%) had severe AD 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 AD1652. 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 AD [see Use in Specific Populations (7.3)].

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 AD (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 AD.

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 AD (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 AD. 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 Specific Populations (7.3)].



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 Clinical Studies (12)]. 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 Dosage and Administration (3.3)]. 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 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 6 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 6:           Adverse Reactions Occurring in ≥1% of Adult and Pediatric Subjects 12 Years of Age and Older with Asthma in the DUPIXENT Groups in
DRI12544 and QUEST and Greater than Placebo (6 Month Safety Pool)
Adverse Reaction                                            DRI12544 and QUEST DUPIXENT                        DUPIXENT                 Placebo
200 mg Q2W                      300 mg Q2W

N=779                        N=788                     N=792 n (%)                       n (%)                     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 [see Warnings and Precautions (5.3)].


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 7 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 7:            Adverse Reactions Occurring in ≥1% of Adult Subjects with CRSwNP in 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                                         Placebo
300 mg Q2W

N=440                                        N=282 n (%)                                       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.

Eosinophilic Esophagitis

Adults and Pediatric Subjects 12 Years of Age and Older with EoE
A total of 239 adult and pediatric subjects 12 years of age and older, weighing at least 40 kg, with EoE were evaluated in a randomized, double-blind, parallel-group, multicenter, placebo- controlled trial, including two 24-week treatment periods (Parts A and B) and received either DUPIXENT 300 mg QW or placebo [see Clinical Studies (12.4)].
The proportion of subjects who discontinued treatment due to adverse events was 2% of the placebo group and 2% of the DUPIXENT 300 mg QW group.
Table 8 summarizes the adverse reactions that occurred at a rate of at least 2% in subjects treated with DUPIXENT and at a higher rate than in their respective comparator group in Parts A and B.

Table 8: Adverse Reactions Occurring in ≥2% of Adult and Pediatric Subjects 12 Years of Age and Olderwith EoE Treated with DUPIXENT in a Placebo Controlled Trial (Parts A and B; 24-Week Safety Pool)

Parts A and B
DUPIXENT 300 mg QW                                Placebo
Adverse Reaction                                        N=122                                       N=117 n (%)                                        n (%)

Injection site reactionsa                                  46 (38%)                                39 (33%) 
Upper respiratory tract infectionsb                        22 (18%)                                12 (10%) 
Arthralgia                                                  3 (2%)                                  1 (1%) 
Herpes viral infectionsc                                    3 (2%)                                  1 (1%) a
Injection site reactions are composed of several terms including, but not limited to, injection site swelling, pain, and bruising.
b
Upper respiratory tract infections are composed of several terms including, but not limited to, COVID-19, sinusitis, and upper respiratory tract infection.
c
Herpes viral infections are composed of oral herpes and herpes simplex.
The safety profile of DUPIXENT in 72 pediatric subjects 12 to 17 years of age, weighing at least 40 kg, and adults in Parts A and B was similar.
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.
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.
The safety population had a mean age of 49 years; 65% of subjects were female, 56% were White, 34% were Asian, and 6% were Black or African American. Subjects with co-morbid conditions included 43% of subjects with a history of atopy (defined as having a medical history of AD, allergic rhinitis/rhinoconjunctivitis, asthma, or food allergy), 8% of subjects with a history of hypothyroidism and 9% of subjects with a history of diabetes mellitus type 2.
Table 9 summarizes the adverse reactions that occurred at a rate of at least 2% in subjects treated with DUPIXENT and at a higher rate than in their respective comparator group in PRIME and PRIME2.
Table 9: Adverse Reactions Occurring in ≥2% of the DUPIXENT Group in PRIME and PRIME2 and Greater than Placebo
Adverse Reaction                                           PRIME and PRIME2 
DUPIXENT                          Placebo
300 mg Q2W

N=152                         N=157 n (%)                         n (%)
Nasopharyngitisa                                 8 (5%)                        3 (2%) 
Conjunctivitisb                                 6 (4%)                        2 (1%) 
Herpes Infectionc                                5 (3%)                          0% 
Dizzinessd                                    5 (3%)                        2 (1%) 
Myalgiae                                     5 (3%)                        2 (1%) 
Diarrhea                                     4 (3%)                        1 (1%) a
Nasopharyngitis includes pharyngitis b
Conjunctivitis includes conjunctivitis and allergic conjunctivitis.
c
Herpes infection includes oral herpes, genital herpes simplex, herpes zoster and ophthalmic herpes zoster d
Dizziness includes dizziness postural, vertigo and vertigo positional e
Myalgia includes musculoskeletal pain and musculoskeletal chest pain

Specific Adverse Reactions
Conjunctivitis and Keratitis
In adult subjects with AD, 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 AD 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 AD 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 DUPIXENT + topical corticosteroids (TCS) AD 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 AD 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 subjects with asthma, the frequency of conjunctivitis and keratitis was similar between DUPIXENT and placebo.
In adult 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 adult 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 Warnings and Precautions (5.2)].
Among subjects with EoE, there were no reportsof conjunctivitis and keratitis in the DUPIXENT group in placebo controlled trials [see Warnings and Precautions (5.2)].
Among subjects with PN, the frequency of conjunctivitis was 4% in the DUPIXENT group compared to 1% in the placebo group; all of these subjects recovered or were recovering during the treatment period. There were no cases of keratitis reported in the PN development program [see Warnings and Precautions (5.2)].
Eczema Herpeticum and Herpes Zoster
The rate of eczema herpeticum was similar in the placebo and DUPIXENT groups in the AD 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 AD monotherapy trials. In the 52-week DUPIXENT + TCS AD 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 subjects with CRSwNP or EOE there were no reported cases of herpes zoster or eczema herpeticum.



Among subjects with PN, herpes zoster and ophthalmic herpes zoster were each reported in <1% of the DUPIXENT group (1 per 100 subject-years) and 0% of the placebo group.
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 [see Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (10.4)].
Eosinophils
DUPIXENT-treated subjects with AD, asthma and CRSwNP had a greater initial increase from baseline in blood eosinophil count compared to subjects treated with placebo. In adult subjects with AD (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 AD, 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.

An increase from baseline in blood eosinophil count was not observed in adult and pediatric subjects 12 years of age and older with EoE treated with DUPIXENT as compared to placebo.
In subjects with PN (PRIME and PRIME2), the mean and median decrease in blood eosinophils from baseline to Week 4 were 9 and 10 cells/mcL, respectively.
Across the trials for AD, 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 PN 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). Blood eosinophil counts declined to near baseline levels or remained below baseline levels (PRIME and PRIME2) 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 Warnings and Precautions (5.3)].
Cardiovascular thromboembolic events
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 AD (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 adult 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 adult 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.
In the 24-week placebo-controlled trial in subjects with EoE (Parts A and B), there were no cases of cardiovascular thromboembolic events (cardiovascular deaths, non-fatal myocardial infarctions, and non-fatal strokes) reported in any treatment arm.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval 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 [see Warnings and Precautions (5.1)] 
Skin and subcutaneous tissue disorders: Facial skin reactions, including erythema, rash, scaling, edema, papules, pruritus, burning, and pain.

6.3 Additional adverse reactions in clinical trials

Viral infection, headache, back pain, urinary tract infection, rhinitis.
6.4 Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important.
It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form at https://sideeffects.health.gov.il/.




7.            USE IN SPECIFIC POPULATIONS
7.1           Pregnancy
Risk Summary
Available data from case reports and case series with DUPIXENT use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Human IgG antibodies are known to cross the placental barrier; therefore, DUPIXENT may be transmitted from the mother to the developing fetus. There are adverse effects on maternal and fetal outcomes associated with asthma in pregnancy (see Clinical Considerations). In an enhanced pre- and post-natal developmental study, no adverse developmental effects were observed in offspring born to pregnant monkeys after subcutaneous administration of a homologous antibody against interleukin-4-receptor alpha (IL-4Rα) during organogenesis through parturition at doses up to 10-times the maximum recommended human dose (MRHD) (see Data).
The background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes.
Clinical Considerations
Disease-Associated Maternal and/or Embryo-fetal Risk
In women with poorly or moderately controlled asthma, evidence demonstrates that there is an increased risk of preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. The level of asthma control should be closely monitored in pregnant women and treatment adjusted as necessary to maintain optimal control.
Data
Animal Data
In an enhanced pre- and post-natal development toxicity study, pregnant cynomolgus monkeys were administered weekly subcutaneous doses of homologous antibody against IL-4Rα up to 10 times the MRHD (on a mg/kg basis of 100 mg/kg/week) from the beginning of organogenesis to parturition. No treatment-related adverse effects on embryo-fetal toxicity or malformations, or on morphological, functional, or immunological development were observed in the infants from birth through 6 months of age.

7.2           Lactation
Risk Summary
There are no data on the presence of dupilumab in human milk, the effects on the breastfed infant, or the effects on milk production. Maternal IgG is known to be present in human milk.
The effects of local gastrointestinal exposure and limited systemic exposure to dupilumab on the breastfed infant are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for DUPIXENT and any potential adverse effects on the breastfed child from DUPIXENT or from the underlying maternal condition.


7.3           Pediatric Use
Atopic Dermatitis
The safety and effectiveness of DUPIXENT have been established in pediatric patients 6 months of age and older with moderate-to-severe AD, whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable [see Clinical studies 12.1].Use of DUPIXENT in this age group is supported by data from the following clinical trials:
• AD-1526 which included 251 pediatric subjects 12 to 17 years of age with moderate-to severe AD. Of the 251 subjects, 82 were treated with DUPIXENT 200 mg Q2W (<60 kg) or 300 mg Q2W (≥60 kg) and 85 were treated with matching placebo
• AD-1652 which included 367 pediatric subjects 6 to 11 years of age with severe AD. Of the 367 subjects, 120 were treated with DUPIXENT 300 mg Q4W + TCS (15 to <30 kg) or 200 mg Q2W + TCS (≥30 kg) and 123 were treated with matching placebo + TCS
• AD-1539 which included 162 pediatric subjects 6 months to 5 years of age with moderate-to- severe AD. Of the 162 subjects, 83 were treated with DUPIXENT 200 mg Q4W + TCS (5 to <15 kg) or 300 mg Q4W + TCS (15 to <30 kg) and 79 subjects were assigned to be treated with matching placebo + TCS
• AD-1434, an open-label extension study that enrolled 275 pediatric subjects 12 to 17 years of age treated with DUPIXENT ± TCS, 368 pediatric subjects 6 to 11 years of age treated with DUPIXENT ± TCS, and 180 pediatric subjects 6 months to 5 years of age treated with DUPIXENT ± TCS
• Liberty-AD-HAFT which included 27 pediatric subjects 12 to 17 years of age with atopic dermatitis with moderate-to-severe hand and/or foot involvement treated with DUPIXENT (N=14) or matching placebo (N=13)
The safety and efficacy were generally consistent between pediatric and adult patients [see Adverse Reactions (6.1) and Clinical Studies (12.1)]. In addition, hand-foot-and-mouth disease was reported in 9 (5%) pediatric subjects and skin papilloma was reported in 4 (2%) pediatric subjects 6 months to 5 years of age treated with DUPIXENT ± TCS in AD-1434. These cases did not lead to study drug discontinuation [see Adverse Reactions (6.1)].
Safety and effectiveness in pediatric patients younger than 6 months of age with AD have not been established.

Asthma

The safety and effectiveness of DUPIXENT for an add-on maintenance treatment in patients with moderate-to-severe asthma characterized by an eosinophilic phenotype or with oral corticosteroid dependent asthma have been established in pediatric patients 6 years of age and older. Use of DUPIXENT for this indication is supported by evidence from adequate and well controlled studies in adult and pediatric patients 6 years and older [see Clinical Studies (12.2)].



Pediatric Subjects 12 to 17 Years of Age:

A total of 107 pediatric subjects 12 to 17 years of age with moderate-to-severe asthma were enrolled in QUEST and received either 200 mg (N=21) or 300 mg (N=18) DUPIXENT (or matching placebo either 200 mg [N=34] or 300 mg [N=34]) Q2W. Asthma exacerbations and lung function were assessed in both pediatric subjects 12 to 17 years of age and adults. For both the 200 mg and 300 mg Q2W doses, improvements in FEV1 (LS mean change from baseline at Week 12) were observed (0.36 L and 0.27 L, respectively). For the 200 mg Q2W dose, subjects had a reduction in the rate of severe exacerbations that was consistent with adults.
Dupilumab exposure was higher in pediatric subjects 12 to 17 years of age than that in adults at the respective dose level which was mainly accounted for by difference in body weight [see Clinical Pharmacology (10.3)].
The adverse event profile in pediatric subjects 12 to 17 years of age was generally similar to the adults [see Adverse Reactions (6.1)].

Pediatric Subjects 6 to 11 Years of Age:

A total of 408 pediatric subjects 6 to 11 years of age with moderate-to-severe asthma were enrolled in VOYAGE, which evaluated doses of 100 mg Q2W or 200 mg Q2W. Improvement in asthma exacerbations and lung function were demonstrated [see Clinical Studies (12.2)]. The effectiveness of DUPIXENT 300 mg Q4W in subjects 6 to 11 years of age with body weight 15 to <30 kg was extrapolated from efficacy of 100 mg Q2W in VOYAGE with support from population pharmacokinetic analyses showing higher drug exposure levels with 300 mg Q4W [see Clinical Pharmacology (10.3)]. Subjects who completed the treatment period of the VOYAGE study could participate in the open-label extension study (LTS14424). Eighteen subjects (≥15 to <30 kg) out of 365 subjects were exposed to 300 mg Q4W in this study, and the safety profile in these eighteen subjects was consistent with that seen in VOYAGE. Additional safety for DUPIXENT 300 mg Q4W is based upon available safety information from the pediatric AD indication [see Adverse Reactions (6.1) and Clinical Pharmacology (10.3)].

Safety and effectiveness in pediatric patients younger than 6 years of age with asthma have not been established.

CRSwNP

Safety and effectiveness in pediatric patients younger than 18 years of age with CRSwNP have not been established.

EoE
The safety and effectiveness of DUPIXENT for the treatment of EoE have been established in pediatric patients 12 years of age and older, weighing at least 40 kg. Use of DUPIXENT in this population is supported by an adequate and well-controlled study in adults (Parts A and B) which included 72 pediatric patients 12 to 17 years of age, weighing at least 40 kg, and additional pharmacokinetic data. The safety and effectiveness in adults and pediatric patients were similar [see Adverse Reactions (6.1), Clinical Pharmacology (10.3) and Clinical Studies (12.4)].

DUPIXENT is not indicated for the treatment of EoE in pediatric patients less than 12 years of age and weighing less than 40 kg.

Prurigo Nodularis
Safety and effectiveness in pediatric patients younger than 18 years of age with PN have not been established.

7.4           Geriatric Use
Of the 1539subjects with AD exposed to DUPIXENT in a dose-ranging study and placebo- controlled trials, 70 subjects were 65 years or older. Clinical studies of DUPIXENT in AD did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects [see Clinical Pharmacology (10.3)].
Of the 1977 subjects with asthma exposed to DUPIXENT, a total of 240 subjects were 65 years or older. Efficacy and safety in this age group was similar to the overall study population.
Of the 440 subjects with CRSwNP exposed to DUPIXENT, a total of 79 subjects were 65 years or older. Efficacy and safety in this age group were similar to the overall study population.
Clinical studies of DUPIXENT in EoE did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger adult subjects.
Of the 152 subjects with PN exposed to DUPIXENT, a total of 37 were 65 years or older including 8 subjects 75 years or older. Clinical trials did not include a sufficient number of subjects 65 years of age and older to determine whether they respond differently from younger adult subjects.