Dupilumab

1 INDICATIONS AND USAGE DUPIXENT is an interleukin-4 receptor alpha antagonist indicated: Atopic Dermatitis for the treatment of adult and pediatric patients aged 6 months and older with moderate-to-severe AD whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. DUPIXENT can be used with or without topical corticosteroids. ( 1.1 ) Asthma as an add-on maintenance treatment of adult and pediatric patients aged 6 years and older with moderate-to-severe asthma characterized by an eosinophilic phenotype or with oral corticosteroid dependent asthma. ( 1.2 ) Limitations of Use: Not for the relief of acute bronchospasm or status asthmaticus. ( 1.2 ) Chronic Rhinosinusitis with Nasal Polyps as an add-on maintenance treatment in adult and pediatric patients aged 12 years and older with inadequately controlled chronic rhinosinusitis with nasal polyps (CRSwNP). ( 1.3 ) Eosinophilic Esophagitis for the treatment of adult and pediatric patients aged 1 year and older, weighing at least 15 kg, with eosinophilic esophagitis (EoE). ( 1.4 ) Prurigo Nodularis for the treatment of adult patients with prurigo nodularis (PN). ( 1.5 ) Chronic Obstructive Pulmonary Disease as an add-on maintenance treatment of adult patients with inadequately controlled chronic obstructive pulmonary disease (COPD) and an eosinophilic phenotype. ( 1.6 ) Limitations of Use: Not for the relief of acute bronchospasm. ( 1.6 ) Chronic Spontaneous Urticaria for the treatment of adult and pediatric patients aged 12 years and older with chronic spontaneous urticaria (CSU) who remain symptomatic despite H1 antihistamine treatment. ( 1.7 ) Limitations of Use: Not indicated for other forms of urticaria. ( 1.7 ) Bullous Pemphigoid for the treatment of adult patients with bullous pemphigoid (BP). ( 1.8 ) Allergic Fungal Rhinosinusitis for the treatment of adult and pediatric patients aged 6 years and older with allergic fungal rhinosinusitis (AFRS) who have a history of sino-nasal surgery. ( 1.9 ) 1.1 Atopic Dermatitis DUPIXENT is indicated for the treatment of adult and pediatric patients aged 6 months and older with moderate-to-severe atopic dermatitis (AD) whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. DUPIXENT can be used with or without topical corticosteroids. 1.2 Asthma DUPIXENT is indicated as an add-on maintenance treatment of adult and pediatric patients aged 6 years and older with moderate-to-severe asthma characterized by an eosinophilic phenotype or with oral corticosteroid dependent asthma. Limitations of Use DUPIXENT is not indicated for the relief of acute bronchospasm or status asthmaticus. 1.3 Chronic Rhinosinusitis with Nasal Polyps DUPIXENT is indicated as an add-on maintenance treatment in adult and pediatric patients aged 12 years and older with inadequately controlled chronic rhinosinusitis with nasal polyps (CRSwNP). 1.4 Eosinophilic Esophagitis DUPIXENT is indicated for the treatment of adult and pediatric patients aged 1 year and older, weighing at least 15 kg, with eosinophilic esophagitis (EoE). 1.5 Prurigo Nodularis DUPIXENT is indicated for the treatment of adult patients with prurigo nodularis (PN). 1.6 Chronic Obstructive Pulmonary Disease DUPIXENT is indicated as an add-on maintenance treatment of adult patients with inadequately controlled chronic obstructive pulmonary disease (COPD) and an eosinophilic phenotype. Limitations of Use DUPIXENT is not indicated for the relief of acute bronchospasm. 1.7 Chronic Spontaneous Urticaria DUPIXENT is indicated for the treatment of adult and pediatric patients aged 12 years and older with chronic spontaneous urticaria (CSU) who remain symptomatic despite H1 antihistamine treatment. Limitations of Use: DUPIXENT is not indicated for treatment of other forms of urticaria. 1.8 Bullous Pemphigoid DUPIXENT is indicated for the treatment of adult patients with bullous pemphigoid (BP). 1.9 Allergic Fungal Rhinosinusitis DUPIXENT is indicated for the treatment of adult and pediatric patients aged 6 years and older with allergic fungal rhinosinusitis (AFRS) who have a history of sino-nasal surgery.

2 DOSAGE AND ADMINISTRATION DUPIXENT is administered by subcutaneous injection. ( 2.1 ) Atopic Dermatitis Dosage in Adults ( 2.3 ): Recommended dosage is an initial dose of 600 mg (two 300 mg injections), followed by 300 mg given every 2 weeks (Q2W). Dosage in Pediatric Patients 6 Months to 5 Years of Age ( 2.3 ): Body Weight Initial and Subsequent Dosage 5 to less than 15 kg 200 mg (one 200 mg injection) every 4 weeks (Q4W) 15 to less than 30 kg 300 mg (one 300 mg injection) every 4 weeks (Q4W) Dosage in Pediatric Patients 6 Years of Age and Older ( 2.3 ): Body Weight Initial Loading Dose Subsequent Dosage Q2W – every 2 weeks; Q4W – every 4 weeks 15 to less than 30 kg 600 mg (two 300 mg injections) 300 mg Q4W 30 to less than 60 kg 400 mg (two 200 mg injections) 200 mg Q2W 60 kg or more 600 mg (two 300 mg injections) 300 mg Q2W Asthma Dosage in Adult and Pediatric Patients 12 Years and Older ( 2.4 ): Initial Loading Dose Subsequent Dosage 400 mg (two 200 mg injections) 200 mg every 2 weeks (Q2W) Or 600 mg (two 300 mg injections) 300 mg every 2 weeks (Q2W) Dosage for patients with oral corticosteroid-dependent asthma or with co-morbid moderate-to-severe AD, CRSwNP, or AFRS For pediatric patients 12 to 17 years of age (≥60 kg) and adults with AFRS 600 mg (two 300 mg injections) 300 mg every 2 weeks (Q2W) Dosage in Pediatric Patients 6 to 11 Years of Age ( 2.4 ): Body Weight Initial Dose and Subsequent Dosage 15 to less than 30 kg 300 mg every 4 weeks (Q4W) ≥30 kg 200 mg every 2 weeks (Q2W) For pediatric patients 6 to 11 years old with asthma and co-morbid moderate-to-severe atopic dermatitis, follow the recommended dosage as per Table 2 which includes an initial loading dose. ( 2.3 ) Chronic Rhinosinusitis with Nasal Polyps ( 2.5 ): Recommended dosage for adult and pediatric patients 12 years of age and older is 300 mg given every 2 weeks (Q2W). Eosinophilic Esophagitis ( 2.6 ): Body Weight Recommended Dosage in Adult and Pediatric Patients 1 Year and Older, Weighing At Least 15 kg 15 to less than 30 kg 200 mg every 2 weeks (Q2W) 30 to less than 40 kg 300 mg every 2 weeks (Q2W) 40 kg or more 300 mg every week (QW) Prurigo Nodularis ( 2.7 ): Recommended dosage for adult patients is an initial dose of 600 mg (two 300 mg injections), followed by 300 mg given every 2 weeks (Q2W). Chronic Obstructive Pulmonary Disease ( 2.8 ): Recommended dosage for adult patients is 300 mg given every 2 weeks (Q2W). Chronic Spontaneous Urticaria Dosage in Adults ( 2.9 ): Recommended dosage is an initial dose of 600 mg (two 300 mg injections), followed by 300 mg given every 2 weeks (Q2W). Dosage in Pediatric Patients 12 to 17 Years of Age ( 2.9 ): Body Weight Initial Loading Dose Subsequent Dosage 30 to less than 60 kg 400 mg (two 200 mg injections) 200 mg Q2W 60 kg or more 600 mg (two 300 mg injections) 300 mg Q2W Bullous Pemphigoid ( 2.10 ): Recommended dosage for adult patients is an initial dose of 600 mg (two 300 mg injections), followed by 300 mg given every other week (Q2W). Use DUPIXENT in combination with a tapering course of oral corticosteroids. Allergic Fungal Rhinosinusitis Dosage in Adults ( 2.11 ): Recommended dosage is 300 mg given every 2 weeks (Q2W). Dosage in Pediatric Patients 6 to 17 Years of Age ( 2.11 ) : Body Weight Recommended Dosage a Q2W – every 2 weeks; Q4W – every 4 weeks 15 to less than 30 kg 300 mg Q4W 30 to less than 60 kg 200 mg Q2W 60 kg or more 300 mg Q2W 2.1 Important Administration Instructions DUPIXENT is administered by subcutaneous injection. DUPIXENT is intended for use under the guidance of a healthcare provider. Provide proper training to patients and/or caregivers on the preparation and administration of DUPIXENT prior to use according to the "Instructions for Use". Use of Pre-filled Pen or Pre-filled Syringe The DUPIXENT pre-filled pen is for use in adult and pediatric patients aged 2 years and older. The DUPIXENT pre-filled syringe is for use in adult and pediatric patients aged 6 months and older. A caregiver or patient 12 years of age and older may inject DUPIXENT using the pre-filled syringe or pre-filled pen. In pediatric patients 12 years of age and older, administer DUPIXENT under the supervision of an adult. In pediatric patients 6 months to less than 12 years of age, administer DUPIXENT by a caregiver. Administration Instructions For patients with AD, asthma, PN, CSU, and BP taking an initial 600 mg dose, administer each of the two DUPIXENT 300 mg injections at different injection sites. For patients with AD, asthma, and CSU taking an initial 400 mg dose, administer each of the two DUPIXENT 200 mg injections at different injection sites. Administer subcutaneous injection into the thigh or abdomen, except for the 2 inches (5 cm) around the navel. The upper arm can also be used if a caregiver administers the injection. Rotate the injection site with each injection. DO NOT inject DUPIXENT into skin that is tender, damaged, bruised, or scarred. The DUPIXENT "Instructions for Use" contains more detailed instructions on the preparation and administration of DUPIXENT [see Instructions for Use] . 2.2 Vaccination Prior to Treatment Consider completing all age-appropriate vaccinations as recommended by current immunization guidelines prior to initiating treatment with DUPIXENT [see Warnings and Precautions (5.10) ] . 2.3 Recommended Dosage for Atopic Dermatitis Dosage in Adults The recommended dosage of DUPIXENT for adult patients is an initial dose of 600 mg (two 300 mg injections), followed by 300 mg given every 2 weeks (Q2W). Dosage in Pediatric Patients 6 Months to 5 Years of Age The recommended dosage of DUPIXENT for pediatric patients 6 months to 5 years of age is specified in Table 1. Table 1: Dosage of DUPIXENT in Pediatric Patients 6 Months to 5 Years of Age with Atopic Dermatitis Body Weight Initial For pediatric patients 6 months to 5 years of age with AD, no initial loading dose is recommended. and Subsequent Dosage 5 to less than 15 kg 200 mg (one 200 mg injection) every 4 weeks (Q4W) 15 to less than 30 kg 300 mg (one 300 mg injection) every 4 weeks (Q4W) Dosage in Pediatric Patients 6 Years of Age and Older The recommended dosage of DUPIXENT for pediatric patients 6 years of age and older is specified in Table 2. Table 2: Dosage of DUPIXENT in Pediatric Patients 6 Years of Age and Older with Atopic Dermatitis Body Weight Initial Loading Dose Subsequent Dosage 15 to less than 30 kg 600 mg (two 300 mg injections) 300 mg every 4 weeks (Q4W) 30 to less than 60 kg 400 mg (two 200 mg injections) 200 mg every 2 weeks (Q2W) 60 kg or more 600 mg (two 300 mg injections) 300 mg every 2 weeks (Q2W) Concomitant Topical Therapies DUPIXENT can be used with or without topical corticosteroids. Topical calcineurin inhibitors may be used, but should be reserved for problem areas only, such as the face, neck, intertriginous and genital areas. 2.4 Recommended Dosage for Asthma Dosage in Adult and Pediatric Patients 12 Years and Older The recommended dosage of DUPIXENT for adult and pediatric patients 12 years of age and older is specified in Table 3. Table 3: Dosage of DUPIXENT in Adult and Pediatric Patients 12 Years and Older with Asthma Initial Loading Dose Subsequent Dosage 400 mg (two 200 mg injections) 200 mg every 2 weeks (Q2W) Or 600 mg (two 300 mg injections) 300 mg every 2 weeks (Q2W) Dosage for patients with oral corticosteroid-dependent asthma or with co-morbid moderate-to-severe AD, CRSwNP, or AFRS For pediatric patients 12 to 17 years of age (≥60 kg) and adults with AFRS 600 mg (two 300 mg injections) 300 mg every 2 weeks (Q2W) Dosage in Pediatric Patients 6 to 11 Years of Age The recommended dosage of DUPIXENT for pediatric patients 6 to 11 years of age is specified in Table 4. Table 4: Dosage of DUPIXENT in Pediatric Patients 6 to 11 Years of Age with Asthma Body Weight Initial For pediatric patients 6 to 11 years of age with asthma, no initial loading dose is recommended. and Subsequent Dosage 15 to less than 30 kg 300 mg every 4 weeks (Q4W) ≥30 kg 200 mg every 2 weeks (Q2W) For pediatric patients 6 to 11 years of age with asthma and co-morbid moderate-to-severe AD, follow the recommended dosage as per Table 2 which includes an initial loading dose [see Dosage and Administration (2.3) ] . 2.5 Recommended Dosage for Chronic Rhinosinusitis with Nasal Polyps The recommended dosage of DUPIXENT for adult and pediatric patients 12 years of age and older is 300 mg given every 2 weeks (Q2W). 2.6 Recommended Dosage for Eosinophilic Esophagitis The recommended dosage of DUPIXENT for adult and pediatric patients 1 year of age and older, weighing at least 15 kg, is specified in Table 5. Table 5: Dosage of DUPIXENT in Adult and Pediatric Patients 1 Year of Age and Older with Eosinophilic Esophagitis Body Weight Recommended Dosage 15 to less than 30 kg 200 mg every 2 weeks (Q2W) 30 to less than 40 kg 300 mg every 2 weeks (Q2W) 40 kg or more 300 mg every week (QW) 2.7 Recommended Dosage for Prurigo Nodularis The recommended dosage of DUPIXENT for adult patients is an initial dose of 600 mg (two 300 mg injections) followed by 300 mg given every 2 weeks (Q2W). 2.8 Recommended Dosage for Chronic Obstructive Pulmonary Disease The recommended dosage of DUPIXENT for adult patients is 300 mg given every 2 weeks (Q2W). 2.9 Recommended Dosage for Chronic Spontaneous Urticaria Dosage in Adults The recommended dosage of DUPIXENT for adult patients is an initial dose of 600 mg (two 300 mg injections), followed by 300 mg given every 2 weeks (Q2W). Dosage in Pediatric Patients 12 to 17 Years of Age The recommended dosage of DUPIXENT for pediatric patients 12 to 17 years of age is specified in Table 6. Table 6: Dosage of DUPIXENT in Pediatric Patients 12 to 17 Years of Age with CSU Body Weight Initial Loading Dose Subsequent Dosage 30 to less than 60 kg 400 mg (two 200 mg injections) 200 mg every 2 weeks (Q2W) 60 kg or more 600 mg (two 300 mg injections) 300 mg every 2 weeks (Q2W) 2.10 Recommended Dosage for Bullous Pemphigoid The recommended dosage of DUPIXENT for adult patients is an initial dose of 600 mg (two 300 mg injections) followed by 300 mg given every other week (Q2W). Concomitant Oral Corticosteroids: Use DUPIXENT in combination with a tapering course of oral corticosteroids. Once disease control has occurred, gradually taper corticosteroids after which continue DUPIXENT as monotherapy. In case of relapse, corticosteroids may be added if medically advisable. 2.11 Recommended Dosage for Allergic Fungal Rhinosinusitis Dosage in Adults The recommended dosage of DUPIXENT for adult patients is 300 mg given every two weeks (Q2W). Dosage in Pediatric Patients 6 to 17 Years of Age The recommended dosage of DUPIXENT for pediatric patients 6 to 17 years of age is specified in Table 7. Table 7: Dosage of DUPIXENT in Pediatric Patients 6 to 17 Years of Age with AFRS Body Weight Recommended Dosage 15 to less than 30 kg 300 mg every 4 weeks (Q4W) 30 to less than 60 kg 200 mg every 2 weeks (Q2W) 60 kg or more 300 mg every 2 weeks (Q2W) 2.12 Missed Doses If a weekly dose is missed, administer the dose as soon as possible, and start a new weekly schedule from the date of the last administered dose. If an every 2 week dose is missed, administer the injection within 7 days from the missed dose and then resume the patient's original schedule. If the missed dose is not administered within 7 days, administer the dose, starting a new schedule based on this date. If an every 4 week dose is missed, administer the injection within 7 days from the missed dose and then resume the patient's original schedule. If the missed dose is not administered within 7 days, administer the dose, starting a new schedule based on this date. 2.13 Preparation for Use Before injection, remove DUPIXENT from the refrigerator and allow DUPIXENT to reach room temperature (45 minutes for the 300 mg/2 mL pre-filled syringe or pre-filled pen, and 30 minutes for the 200 mg/1.14 mL pre-filled syringe or pre-filled pen) without removing the needle cap. After removal from the refrigerator, DUPIXENT must be used within 14 days or discarded. Inspect DUPIXENT visually for particulate matter and discoloration prior to administration. DUPIXENT is a clear to slightly opalescent, colorless to pale yellow solution. Do not use if the liquid contains visible particulate matter, is discolored or cloudy (other than clear to slightly opalescent, colorless to pale yellow). DUPIXENT does not contain preservatives; therefore, discard any unused product remaining in the pre-filled syringe or pre-filled pen.

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) ] Psoriasis [see Warnings and Precautions (5.7) ] Arthralgia and Psoriatic Arthritis [see Warnings and Precautions (5.8) ] Parasitic (Helminth) Infections [see Warnings and Precautions (5.9) ] Most common adverse reactions are: Atopic Dermatitis (incidence ≥1%): injection site reactions, conjunctivitis, blepharitis, oral herpes, keratitis, eye pruritus, other herpes simplex virus infection, dry eye, and eosinophilia. ( 6.1 ) Asthma (incidence ≥1%): injection site reactions, oropharyngeal pain, and eosinophilia. ( 6.1 ) Chronic Rhinosinusitis with Nasal Polyps (incidence ≥1%): injection site reactions, eosinophilia, insomnia, toothache, gastritis, arthralgia, and conjunctivitis. ( 6.1 ) Eosinophilic Esophagitis (incidence ≥2%): injection site reactions, upper respiratory tract infections, arthralgia, and herpes viral infections. ( 6.1 ) Prurigo Nodularis (incidence ≥2%): nasopharyngitis, conjunctivitis, herpes infection, dizziness, myalgia, and diarrhea. ( 6.1 ) Chronic Obstructive Pulmonary Disease (incidence ≥2%): viral infection, headache, nasopharyngitis, back pain, diarrhea, arthralgia, urinary tract infection, local administration reactions, rhinitis, eosinophilia, toothache, and gastritis. ( 6.1 ) Chronic Spontaneous Urticaria (incidence ≥2%): injection site reactions. ( 6.1 ) Bullous Pemphigoid (incidence ≥2%): arthralgia, conjunctivitis, vision blurred, herpes viral infections, keratitis. ( 6.1 ) Allergic Fungal Rhinosinusitis: similar to adverse reactions for Chronic Rhinosinusitis with Nasal Polyps. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Regeneron at 1-844-387-4936 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. Atopic Dermatitis 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 AD [see Clinical Studies (14.1) ] . 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 8 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 8: 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 Monotherapy Pooled analysis of SOLO 1, SOLO 2, and AD-1021. DUPIXENT + TCS Analysis of CHRONOS where subjects were on background TCS therapy. DUPIXENT 300 mg Q2W DUPIXENT 600 mg at Week 0, followed by 300 mg every 2 weeks. Placebo DUPIXENT 300 mg Q2W + TCS Placebo + TCS N=529 n (%) N=517 n (%) N=110 n (%) N=315 n (%) Injection site reaction 51 (10) 28 (5) 11 (10) 18 (6) Conjunctivitis Conjunctivitis 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) Keratitis Keratitis 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 infection Other 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 (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 Years of Age and Older with Atopic Dermatitis The safety of DUPIXENT was assessed in a trial of 250 pediatric subjects 12 years of age and older 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 years of age and older 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 years of age and older 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 years of age and older 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 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 years of age and older with AD. 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 years of age and older 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 years of age and older 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. 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 (14) ] . 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 (2.3) ] . 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 9 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 9: 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 200 mg Q2W DUPIXENT 300 mg Q2W Placebo N=779 n (%) N=788 n (%) N=792 n (%) Injection site reactions Injection site reactions cluster includes erythema, edema, pruritus, pain, and inflammation. 111 (14%) 144 (18%) 50 (6%) Oropharyngeal pain 13 (2%) 19 (2%) 7 (1%) Eosinophilia 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) ] . 17 (2%) 16 (2%) 2 (<1%) 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 Polyps A total of 722 adult subjects with chronic rhinosinusitis with nasal polyps (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 adult subjects who discontinued treatment due to adverse events was 5% of the placebo group and 2% of the DUPIXENT 300 mg Q2W group. Table 10 summarizes the adverse reactions that occurred at a rate of at least 1% in adult subjects treated with DUPIXENT and at a higher rate than in their respective comparator group in SINUS-24 and SINUS-52. Table 10: 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 300 mg Q2W Placebo N=440 n (%) N=282 n (%) Injection site reactions Injection site reactions cluster includes injection site reaction, pain, bruising and swelling. 28 (6%) 12 (4%) Conjunctivitis Conjunctivitis cluster includes conjunctivitis, allergic conjunctivitis, bacterial conjunctivitis, viral conjunctivitis, giant papillary conjunctivitis, eye irritation, and eye inflammation. 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%) 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 (Study EoE-1 Parts A and B) and received either DUPIXENT 300 mg QW or placebo [see Clinical Studies (14.4) ] . 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 11 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 11: Adverse Reactions Occurring in ≥2% of Adult and Pediatric Subjects 12 Years of Age and Older with EoE Treated with DUPIXENT in a Placebo-Controlled Trial (Study EoE-1 Parts A and B; 24-Week Safety Pool) Study EoE-1 Parts A and B Adverse Reaction DUPIXENT 300 mg QW N=122 n (%) Placebo N=117 n (%) Injection site reactions Injection site reactions are composed of several terms including, but not limited to, injection site swelling, pain, and bruising. 46 (38%) 39 (33%) Upper respiratory tract infections Upper respiratory tract infections are composed of several terms including, but not limited to, COVID-19, sinusitis, and upper respiratory tract infection. 22 (18%) 12 (10%) Arthralgia 3 (2%) 1 (1%) Herpes viral infections Herpes viral infections are composed of oral herpes and herpes simplex. 3 (2%) 1 (1%) 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. Pediatric Subjects 1 to 11 Years of Age, Weighing at least 15 kg, with EoE A total of 61 pediatric subjects 1 to 11 years of age, weighing at least 15 kg, with EoE were evaluated in a randomized, blinded, parallel-group, multicenter trial, including an initial 16-week placebo-controlled treatment period (Study EoE-2 Part A) and a 36-week extended active treatment period (Study EoE-2 Part B). Subjects in Part A received a weight-based dosing regimen of DUPIXENT or placebo [see Clinical Studies (14.4) ] . All subjects in Part B completed Part A and received active treatment with weight-based dosing regimens of DUPIXENT in Part B (N=47). The safety profile of DUPIXENT through Week 16 of Study EoE-2 Part A was generally similar to the safety profile in adult and pediatric subjects 12 years of age and older with EoE. In Part B, a helminth infection was reported in one DUPIXENT-treated subject. 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) [see Clinical Studies (14.5) ] . 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. Subjects with co-morbid conditions included 43% of subjects with a history of atopy (defined as having a medical history of AD, allergic rhinitis/rhino conjunctivitis, 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 12 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 12: Adverse Reactions Occurring in ≥2% of Adult Subjects with PN in the DUPIXENT Group in PRIME and PRIME2 and Greater than Placebo Adverse Reaction PRIME and PRIME2 DUPIXENT 300 mg Q2W Placebo N=152 n (%) N=157 n (%) Nasopharyngitis Nasopharyngitis includes pharyngitis 8 (5%) 3 (2%) Conjunctivitis Conjunctivitis includes conjunctivitis and allergic conjunctivitis. 6 (4%) 2 (1%) Herpes Infection Herpes infection includes oral herpes, genital herpes simplex, herpes zoster and ophthalmic herpes zoster 5 (3%) 0% Dizziness Dizziness includes dizziness postural, vertigo and vertigo positional 5 (3%) 2 (1%) Myalgia Myalgia includes musculoskeletal pain and musculoskeletal chest pain 5 (3%) 2 (1%) Diarrhea 4 (3%) 1 (1%) Chronic 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 Clinical Studies (14.6) ] . 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 13 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. Table 13: Adverse Reactions That Occurred in ≥2% of Adult Subjects with COPD Treated with DUPIXENT in BOREAS and NOTUS Trials (Pooled Safety Population) and Greater than Placebo Adverse Reaction BOREAS and NOTUS DUPIXENT 300 mg Q2W Placebo N=938 n (%) N=934 n (%) Viral Infection Consists of multiple similar terms. 133 (14.2) 115 (12.3) Headache 73 (7.8) 62 (6.6) Nasopharyngitis 73 (7.8) 69 (7.4) Back Pain 42 (4.5) 29 (3.1) Diarrhea 35 (3.7) 30 (3.2) Arthralgia 29 (3.1) 25 (2.7) Urinary Tract Infection 28 (3.0) 18 (1.9) Local Administration Reaction 26 (2.8) 6 (0.6) Injection Site Reaction 11 (1.2) 2 (0.2) Rhinitis 24 (2.6) 17 (1.8) Eosinophilia Eosinophilia was defined as blood eosinophils ≥3,000 cells/mcL or deemed by the investigator to be an adverse event. None met the criteria for serious eosinophilic conditions. 22 (2.3) 7 (0.7) Toothache 20 (2.1) 11 (1.2) Gastritis 19 (2) 7 (0.7) Less 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. Chronic Spontaneous Urticaria The pooled safety data below reflects the safety of DUPIXENT in adult and pediatric subjects 12 years of age and older with chronic spontaneous urticaria (CSU) who remain symptomatic despite H1 antihistamine treatment. A total of 392 adult and pediatric subjects 12 years of age and older with CSU were evaluated for safety in three randomized, double-blind, parallel-group, multicenter, placebo-controlled, studies, Study A, B, and C, conducted under a master protocol (CUPID) for 36 weeks [see Clinical Studies (14.7) ] . The pooled safety population received an initial dose of DUPIXENT 600 mg or 400 mg, followed by DUPIXENT 300 mg or 200 mg, respectively, or matching placebo, administered subcutaneously every 2 weeks (Q2W) [see Dosage and Administration (2.9) ] . Table 14 summarizes the adverse reactions that occurred in at least 2% in subjects treated with DUPIXENT and at a higher rate than placebo in CUPID Study A, B and C (pooled safety population). Table 14: Adverse Reactions That Occurred in ≥2% of Adult and Pediatric Subjects 12 Years of Age and Older with CSU Treated with DUPIXENT in CUPID Study A, B, and C (Pooled Safety Population) and Greater than Placebo Adverse Reaction CUPID Study A, B, and C DUPIXENT 200 mg Q2W or 300 mg Q2W Placebo N=195 n (%) N=197 n (%) Injection site reactions Injection site reactions cluster includes injection site dermatitis, injection site erythema, injection site hematoma, injection site induration, injection site pain, injection site pruritus, injection site reaction, injection site swelling 20 (10.3) 16 (8.1) Bullous Pemphigoid The safety of DUPIXENT was evaluated in a 52-week, randomized, double-blind, parallel-group, multicenter, placebo-controlled trial (ADEPT) in a total of 106 adult subjects with moderate-to-severe bullous pemphigoid (BP) [see Clinical Studies (14.8) ] . Of the 106 randomized subjects, all received at least one dose of DUPIXENT or placebo with a course of oral corticosteroids (OCS) with a prespecified taper. At the time of analysis, 87 subjects had completed Week 36 and 65 subjects had completed Week 52. Table 15 summarizes the adverse reactions that occurred in at least 2% of subjects treated with DUPIXENT and at a higher rate than placebo in the ADEPT trial. Table 15: Adverse Reactions Occurring in ≥2% of Adult Subjects with BP Treated with DUPIXENT in ADEPT and Greater than Placebo In combination with a tapering course of oral corticosteroids Adverse Reaction ADEPT DUPIXENT 300 mg Q2W + OCS Placebo + OCS N=53 n (%) N=53 n (%) Arthralgia 5 (9%) 3 (6%) Conjunctivitis 4 (8%) 0% Vision blurred 4 (8%) 0% Herpes viral infections Herpes viral infections include herpes simplex and herpes zoster 3 (6%) 0% Keratitis 2 (4%) 0% A case of AGEP was reported in 1 subject with BP treated with DUPIXENT compared with 0 subjects in the placebo group. Allergic Fungal Rhinosinusitis (AFRS) Adults and Pediatric Subjects 6 Years of Age and Older with AFRS A total of 62 adult and pediatric subjects 6 years of age and older with allergic fungal rhinosinusitis (AFRS) were evaluated in a randomized, double-blind, parallel-group, placebo-controlled trial (AIMS) with a 52-week treatment period [see Clinical Studies (14.9) ] . The adult subjects (n=30) received DUPIXENT 300 mg every 2 weeks and pediatric subjects aged 6 to 17 years (n=3) received DUPIXENT based on body weight [see Dosage and Administration (2.11) ] . The safety profile of DUPIXENT in patients with AFRS was similar to the safety profile of DUPIXENT in patients with CRSwNP (see Chronic Rhinosinusitis with Nasal Polyps ). Specific Adverse Reactions for AD, Asthma, CRSwNP, EoE, PN, COPD, CSU, BP, and AFRS Conjunctivitis and Keratitis In adult subjects with AD, conjunctivitis was reported in 10% (34 per 100 patient-years) in the 300 mg Q2W dose group and in 2% of the placebo group (8 per 100 patient-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 patient-years) and in 9% of the placebo + TCS group (10 per 100 patient-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 patient-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 patient-years) and in 0% of the placebo group (0 per 100 patient-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 patient-years) and in 2% of the placebo + TCS group (2 per 100 patient-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 patient-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. Among subjects with EoE, there were no reports of conjunctivitis and keratitis in the DUPIXENT group in placebo-controlled trials. In the 36-week active treatment extension period of Study EoE-2 Part B, conjunctivitis was reported in 4% of DUPIXENT-treated pediatric subjects with EoE. 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. Among subjects with COPD, the frequency of conjunctivitis and keratitis was 1.4% and 0.1% in the DUPIXENT group and 1% and 0% in the placebo group, respectively. Among subjects with CSU in the pooled safety population, the frequency of conjunctivitis was similar between DUPIXENT and placebo. Among subjects with BP, the frequency of conjunctivitis and keratitis was 8% and 4% in the DUPIXENT group and 0% and 0% in the placebo group, respectively. 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 patient-years) and in <1% of the placebo group (1 per 100 patient-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 patient-years) and 2% of the placebo + TCS group (2 per 100 patient-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 patient-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 patient-years) and 0% of the placebo group. Among subjects with COPD, herpes zoster was reported in 0.9% of the DUPIXENT group and 0.2% of the placebo group. Ophthalmic herpes zoster was reported in 0.1% of the DUPIXENT group and 0.2% of the placebo group. Among subjects with CSU in the pooled safety population, herpes zoster was reported in <1% of the DUPIXENT and placebo groups (1 per 100 patient-years). Among subjects with BP, herpes zoster was reported in 4% of the DUPIXENT group and 0% of the placebo group. Hypersensitivity Reactions Hypersensitivity reactions were reported in <1% of DUPIXENT-treated subjects. These included anaphylaxis, AGEP, serum sickness or serum sickness-like reactions, generalized urticaria, rash, erythema nodosum, and erythema multiforme [see Contraindications (4) and Clinical Pharmacology (12.6) ] . Eosinophils DUPIXENT-treated subjects with AD, asthma, CRSwNP, and COPD had a greater initial increase from baseline in blood eosinophil count compared to subjects receiving 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 less than 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. In subjects with COPD (BOREAS and NOTUS), the mean and median increases in blood eosinophils from baseline to Week 8 were 60 and 0 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 (Study EoE-1). In pediatric subjects 1 to 11 years of age with EoE (Study EoE-2 Part A), blood eosinophil counts were generally consistent with those observed in Study EoE-1. In adult and pediatric subjects with CSU (CUPID Study A, Study B, and Study C) treated with DUPIXENT, an increase from baseline in blood eosinophil count was not observed compared to placebo at Week 12. 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. In DUPIXENT-treated subjects with BP in ADEPT, all of whom received background oral corticosteroid (OCS) treatment, the mean and median decrease in blood eosinophils from baseline to Week 4 were 1022 and 485 cells/mcL, respectively. In the trials for the COPD indication, treatment-emergent eosinophilia (≥500 cells/mcL) was higher in DUPIXENT (41.7%) than in the placebo group (39.4%); none of the cases were associated with clinical symptoms, and treatment-emergent eosinophilia (≥1000 cells/mcL) was higher in DUPIXENT (13.6%) than in the placebo group (8.1%). Across the trials for AD, asthma, CRSwNP, CSU, and AFRS 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. In the trial for the BP indication, the incidence of treatment-emergent eosinophilia (≥500 cells/mcL) was higher in DUPIXENT (21%) than in the placebo group (11%). In adult and pediatric subjects with AFRS (AIMS) treated with DUPIXENT, an increase from baseline in blood eosinophil count was not observed compared to placebo at Week 12. Treatment-emergent eosinophilia (≥5,000 cells/mcL) was observed in <3% of DUPIXENT-treated subjects and <0.5% in subjects receiving placebo (SOLO 1, SOLO 2, and AD-1021; DRI12544, QUEST, and VOYAGE; SINUS-24 and SINUS-52; PRIME and PRIME2; BOREAS and NOTUS; CUPID Study A, B, and C). Blood eosinophil counts declined to near baseline or remained below baseline levels (PRIME and PRIME2; BOREAS and NOTUS; ADEPT) during treatment. In trial AD-1539, treatment-emergent eosinophilia (≥5,000 cells/mcL) was reported in 8% of DUPIXENT-treated subjects and 0% in subjects receiving placebo [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 (Study EoE-1 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. In the 24-week placebo-controlled trial in subjects with CSU (CUPID Study A, B, and C), 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 52-week placebo-controlled trial in subjects with AFRS (AIMS), 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 Musculoskeletal system disorders: psoriatic arthritis Skin and subcutaneous tissue disorders: Facial skin reactions, including erythema, rash, scaling, edema, papules, pruritus, burning, and pain; new-onset psoriasis, vasculitis

12.3 Pharmacokinetics The pharmacokinetics of dupilumab is similar in subjects with AD, asthma, CRSwNP, EoE, PN, COPD, CSU, BP, and AFRS. Absorption Following an initial subcutaneous (SC) dose of 600 mg, 400 mg, or 300 mg, dupilumab reached peak mean ± SD concentrations (C max ) of 70.1±24.1 mcg/mL, 41.8±12.4 mcg/mL, or 30.5±9.39 mcg/mL, respectively, by approximately 1 week post dose. Steady-state concentrations were achieved by Week 16 following the administration of 600 mg starting dose and 300 mg dose either weekly or Q2W, or 400 mg starting dose and 200 mg dose Q2W, or 300 mg Q2W without a loading dose. Across clinical trials, the mean ± SD steady-state trough concentrations ranged from 55.3±34.3 mcg/mL to 80.2±35.3 mcg/mL for 300 mg administered Q2W, from 173±75.9 mcg/mL to 195±71.7 mcg/mL for 300 mg administered weekly, and from 29.2±18.7 to 36.5±22.2 mcg/mL for 200 mg administered Q2W. The bioavailability of dupilumab following a SC dose is similar between AD, asthma, CRSwNP, EoE, PN, COPD, CSU, BP, and AFRS subjects, ranging between 61% and 66%. Distribution The estimated total volume of distribution was approximately 4.8±1.3 L. Elimination The metabolic pathway of dupilumab has not been characterized. As a human monoclonal IgG4 antibody, dupilumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG. After the last steady-state dose of 300 mg QW, 300 mg Q2W, 200 mg Q2W, 300 mg Q4W, or 200 mg Q4W dupilumab, the median times to non-detectable concentration (<78 ng/mL) ranged from 9 to 13 weeks in adults and pediatric subjects 12 years of age and older. Population pharmacokinetic analyses indicate the median times to non-detectable concentration are approximately 1.5 times (up to 19 weeks) and 2.5 times (up to 32 weeks) longer in pediatric subjects 6 to 11 years of age and pediatric subjects 6 months to 5 years of age, respectively. Dose Linearity Dupilumab exhibited nonlinear target-mediated pharmacokinetics with exposures increasing in a greater than dose-proportional manner. The systemic exposure increased by 30-fold when the dose increased 8-fold following a single dose of dupilumab from 75 mg to 600 mg (i.e., 0.25-times to 2-times the recommended dose). Weight Dupilumab trough concentrations were lower in subjects with higher body weight. Immunogenicity Development of antibodies to dupilumab was associated with lower serum dupilumab concentrations. A few subjects who had high antibody titers also had no detectable serum dupilumab concentrations. Specific Populations Age Based on population pharmacokinetic analysis, age did not affect dupilumab clearance in adults and in pediatric subjects 6 to 17 years of age. In pediatric subjects 6 months to 5 years of age, clearance increased with age. Geriatric Patients No overall differences in the pharmacokinetics of dupilumab were observed between elderly and younger adult subjects. Pediatric Patients Atopic Dermatitis For pediatric subjects 12 years of age and older with AD receiving every 2 week dosing (Q2W) with either 200 mg (<60 kg) or 300 mg (≥60 kg), the mean ± SD steady-state trough concentration of dupilumab was 54.5±27.0 mcg/mL. For pediatric subjects 6 to 11 years of age with AD receiving every 2 week dosing (Q2W) with 200 mg (≥30 kg) or every 4 week dosing (Q4W) with 300 mg (<30 kg), mean ± SD steady-state trough concentration was 86.0±34.6 mcg/mL and 98.7±33.2 mcg/mL, respectively. For pediatric subjects 6 months to 5 years of age with AD receiving every 4 week dosing (Q4W) with 300 mg (≥15 to <30 kg) or 200 mg (≥5 to <15 kg), the mean ± SD steady-state trough concentration was 110±42.8 mcg/mL and 109±50.8 mcg/mL, respectively. Asthma A total of 107 pediatric subjects 12 to 17 years of age with asthma were enrolled in QUEST. The mean ± SD steady-state trough concentrations of dupilumab were 107±51.6 mcg/mL and 46.7±26.9 mcg/mL, respectively, for 300 mg or 200 mg administered Q2W. In VOYAGE, dupilumab pharmacokinetics was investigated in 270 subjects with moderate-to-severe asthma following subcutaneous administration of either 100 mg Q2W (for 91 pediatric subjects weighing <30 kg) or 200 mg Q2W (for 179 pediatric subjects weighing ≥30 kg). The mean ± SD steady-state trough concentration was 58.4±28.0 mcg/mL and 85.1±44.9 mcg/mL, respectively. Simulation of a 300 mg Q4W subcutaneous dose in pediatric subjects 6 to 11 years of age with body weight of ≥15 to <30 kg resulted in predicted steady-state trough concentrations (98.7±41.0 mcg/mL) and average concentrations higher than the observed trough concentrations and average concentrations of 100 mg Q2W (<30 kg). CRSwNP Clinical studies have not been conducted in pediatric patients aged 12 years and older with CRSwNP. Dupilumab exposures are expected to be comparable between adults and pediatric patients aged 12 years and older at the recommended dosage for CRSwNP (300 mg every 2 weeks). Eosinophilic Esophagitis In Study EoE-1, dupilumab pharmacokinetics were investigated in 35 pediatric subjects 12 to 17 years of age, weighing at least 40 kg, with EoE, receiving 300 mg QW. The mean ± SD steady-state trough concentration of dupilumab was 227±95.3 mcg/mL. In Study EoE-2 Part A, dupilumab pharmacokinetics were investigated in 20 pediatric subjects 1 to 11 years of age with EoE receiving the following weight-based dosing regimens: ≥15 to <30 kg (200 mg Q2W) and ≥30 to <40 kg (300 mg Q2W). At Week 16, the mean ± SD steady-state trough concentration of dupilumab was 174±66.2 mcg/mL. The systemic exposure in pediatric subjects 1 to 11 years of age with a body weight ≥40 kg receiving 300 mg QW is expected to be comparable to adult and pediatric subjects 12 years and older with a body weight ≥40 kg. The systemic exposure in pediatric subjects 12 to 17 years of age with a body weight <40 kg receiving 300 mg Q2W is expected to be comparable to pediatric subjects 6 to 11 years of age. Chronic Spontaneous Urticaria A total of 12 pediatric subjects 12 to 17 years of age with CSU were enrolled in CUPID (Study A, B, and C), including 6 subjects who received DUPIXENT 200 mg Q2W (≥30 to <60 kg) and 300 mg Q2W (≥60 kg). At week 24, the mean ± SD observed steady-state trough concentration was 53.6 ± 19.4 mcg/mL, which was within the range of steady-state trough concentrations in adult subjects with CSU who received DUPIXENT 300 mg Q2W. Allergic Fungal Rhinosinusitis A total of 6 pediatric subjects 6 to 17 years of age with AFRS were enrolled in AIMS, including 3 subjects who received DUPIXENT 200 mg Q2W (≥30 to <60 kg) and 300 mg Q2W (≥60 kg). At week 52, the mean ± SD observed steady-state trough concentration was 72.3 ± 28.8 mcg/mL, which was within the range of steady-state trough concentrations in adult subjects with AFRS who received DUPIXENT 300 mg Q2W. Drug Interaction Studies An effect of dupilumab on the PK of co-administered medications is not expected. Based on the population analysis, commonly co-administered medications had no effect on DUPIXENT pharmacokinetics in subjects with moderate-to-severe asthma. Cytochrome P450 Substrates The effects of dupilumab on the pharmacokinetics of midazolam (metabolized by CYP3A4), warfarin (metabolized by CYP2C9), omeprazole (metabolized by CYP2C19), metoprolol (metabolized by CYP2D6), and caffeine (metabolized by CYP1A2) were evaluated in a study with 12-13 evaluable subjects with AD (a SC loading dose of 600 mg followed by 300 mg SC weekly for six weeks). No clinically significant changes in AUC were observed. The largest effect was observed for metoprolol (CYP2D6) with an increase in AUC of 29%.