Dupilumab

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 2 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 2 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.

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 Recommended Dosage For pediatric patients 6 months to 5 years of age, no initial loading dose is recommended 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 to 17 Years of Age ( 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 years 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 Years to 11 Years of Age ( 2.4 ): Body Weight Recommended Dosage For pediatric patients 6 years to 11 years of age, no initial loading dose is recommended 15 to less than 30 kg 300 mg every 4 weeks (Q4W) 30 kg or more 200 mg every 2 weeks (Q2W) For pediatric patients 6 years 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 2 Years to 5 Years of Age ( 2.9 ): Body Weight Recommended Dosage For pediatric patients 2 years to 5 years of age with CSU, no initial loading dose is recommended 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 to 17 Years of Age ( 2.9 ): 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 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 Years to 17 Years of Age ( 2.11 ) : Body Weight Recommended Dosage 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 Recommended Dosage For pediatric patients 6 months to 5 years of age with AD, no initial loading dose is recommended. 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 to 17 Years of Age The recommended dosage of DUPIXENT for pediatric patients 6 years to 17 years of age is specified in Table 2. Table 2: Dosage of DUPIXENT in Pediatric Patients 6 Years to 17 Years of Age 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

WARNINGS AND PRECAUTIONS Hypersensitivity: Hypersensitivity reactions including anaphylaxis, acute generalized exanthematous pustulosis (AGEP), serum sickness, angioedema, urticaria, rash, erythema nodosum, and erythema multiforme have occurred. Discontinue DUPIXENT in the event of a hypersensitivity reaction. ( 5.1 ) Conjunctivitis, Keratitis, and Blepharitis: Advise patients to promptly report new onset or worsening eye symptoms to their healthcare provider. If symptoms persist or worsen, consider discontinuation of DUPIXENT. Consider ophthalmological examination, as appropriate. ( 5.2 ) Eosinophilic Conditions: Be alert to vasculitic rash, worsening pulmonary symptoms, cardiac complications, kidney injury and/or neuropathy, especially upon reduction of oral corticosteroids. ( 5.3 ) Reduction of Corticosteroid Dosage: Do not discontinue systemic, topical, or inhaled corticosteroids abruptly upon initiation of DUPIXENT. Decrease steroids gradually, if appropriate. ( 5.5 ) Psoriasis: Advise patients to report new-onset psoriasis symptoms to their healthcare provider. If symptoms persist or worsen, consider dermatologic evaluation and/or discontinuation of DUPIXENT. ( 5.7 ) Arthralgia and Psoriatic Arthritis: Advise patients to report new onset joint symptoms to their healthcare provider. If symptoms persist or worsen, consider rheumatological evaluation and/or discontinuation of DUPIXENT. ( 5.8 ) Parasitic (Helminth) Infections: Treat pre-existing helminth infections before initiating DUPIXENT. If patients become infected while receiving DUPIXENT and do not respond to anti-helminth treatment, discontinue DUPIXENT until the infection resolves. ( 5.9) Vaccinations: Avoid use of live vaccines. ( 5.10 ) 5.1 Hypersensitivity Hypersensitivity reactions, including anaphylaxis, acute generalized exanthematous pustulosis (AGEP), serum sickness or serum sickness-like reactions, angioedema, generalized urticaria, rash, erythema nodosum and erythema multiforme have been reported. A case of AGEP was reported in an adult subject who participated in the bullous pemphigoid development program. If a clinically significant hypersensitivity reaction occurs, institute appropriate therapy and discontinue DUPIXENT [see Adverse Reactions (6.1 , 6.2) and Clinical Pharmacology (12.6) ] . 5.2 Conjunctivitis, Keratitis, and Blepharitis Conjunctivitis and keratitis adverse reactions have been reported in clinical trials [see Adverse Reactions (6.1) ] . Conjunctivitis and keratitis occurred more frequently in AD subjects who received DUPIXENT compared to those who received placebo. Conjunctivitis was the most frequently reported eye disorder. Most subjects with conjunctivitis or keratitis recovered or were recovering during the treatment period. Among subjects with asthma, the frequencies of conjunctivitis and keratitis were 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. Among subjects with EoE, there were no reports of conjunctivitis and keratitis in the DUPIXENT group in placebo-controlled trials. In subjects with PN, the frequency of conjunctivitis was 4% in the DUPIXENT group compared to 1% in the placebo group; 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. In subjects with CSU, the frequency of conjunctivitis was similar between DUPIXENT and placebo. Among subjects with BP, the frequency of conjunctivitis and keratitis was 7.5% and 3.8% in the DUPIXENT group and 0% and 0% in the placebo group, respectively. Conjunctivitis, keratitis, and blepharitis adverse reactions have also been reported with DUPIXENT in postmarketing settings, predominantly in AD patients. Some patients reported varying degrees of transient or ongoing visual impairment including blindness associated with conjunctivitis, keratitis, or blepharitis leading to discontinuation of DUPIXENT and/or surgical intervention. Advise patients or their caregivers to promptly report new onset or worsening eye symptoms to their healthcare provider. Consider discontinuation of DUPIXENT and prompt ophthalmological examination for patients who develop signs and symptoms suggestive of keratitis, or when conjunctivitis or blepharitis do not resolve following standard treatment, as appropriate. Use with caution in patients with significant dry eye disease, history of significant lid abnormalities/surgeries, or history of nasolacrimal surgery [see Adverse Reactions (6.1 , 6.2) ] . 5.3 Eosinophilic Conditions Patients being treated for asthma may present with clinical features of eosinophilic pneumonia or eosinophilic granulomatosis with polyangiitis (EGPA). These events may be associated with the reduction of oral corticosteroid therapy. Healthcare providers should be alert to vasculitic rash, worsening pulmonary symptoms, cardiac complications, kidney injury, and/or neuropathy presenting in their patients with eosinophilia. Cases of eosinophilic pneumonia were reported in adults who participated in the asthma development program. Cases of EGPA have been reported with DUPIXENT in adults who participated in the asthma development program as well as in adults with co-morbid asthma in the CRSwNP development program. Advise patients to report signs of eosinophilic pneumonia and EGPA to their healthcare provider. Consider withholding DUPIXENT if eosinophilic pneumonia or EGPA are suspected. 5.4 Acute Symptoms of Asthma or Chronic Obstructive Pulmonary Disease or Acute Deteriorating Disease DUPIXENT should not be used to treat acute symptoms or acute exacerbations of asthma or COPD. Do not use DUPIXENT to treat acute bronchospasm or status asthmaticus. Patients should seek medical advice if their asthma or COPD remains uncontrolled or worsens after initiation of treatment with DUPIXENT. 5.5 Risk Associated with Abrupt Reduction of Corticosteroid Dosage Do not discontinue systemic, topical, or inhaled corticosteroids abruptly upon initiation of therapy with DUPIXENT. Reductions in corticosteroid dose, if appropriate, should be gradual and performed under the direct supervision of a healthcare provider. Reduction in corticosteroid dose may be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy. 5.6 Patients with Co-morbid Asthma Advise patients with co-morbid asthma not to adjust or stop their asthma treatments without consultation with their physicians. 5.7 Psoriasis Cases of new-onset psoriasis have been reported with the use of DUPIXENT for the treatment of atopic dermatitis and asthma, including in patients without a family history of psoriasis. In postmarketing reports, onset of psoriasis varied from weeks to months after the first dose of DUPIXENT and resulted in partial or complete resolution of psoriasis with discontinuation of dupilumab, with or without use of supplemental treatment for psoriasis (topical or systemic). Those who continued on dupilumab received supplemental treatment for psoriasis to improve associated symptoms. Advise patients to report new-onset psoriasis symptoms to their healthcare provider. If symptoms persist or worsen, consider dermatologic evaluation and/or discontinuation of DUPIXENT. 5.8 Arthralgia and Psoriatic Arthritis Arthralgia has been reported with the use of DUPIXENT with some patients reporting gait disturbances or decreased mobility associated with joint symptoms; some cases resulted in hospitalization [see Adverse Reactions (6.1) ] . In postmarketing reports, onset of arthralgia was variable, ranging from days to months after the first dose of DUPIXENT. Cases of new-onset psoriatic arthritis requiring systemic treatment have been reported with the use of DUPI

CONTRAINDICATIONS DUPIXENT is contraindicated in patients who have known hypersensitivity to dupilumab or any excipients of DUPIXENT [see Warnings and Precautions (5.1) ] . Known hypersensitivity to dupilumab or any excipients in DUPIXENT. ( 4 )

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 atopic dermatitis (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 9 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 9: 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

Mechanism of Action Dupilumab is a human monoclonal IgG4 antibody that inhibits interleukin-4 (IL-4) and interleukin-13 (IL-13) signaling by specifically binding to the IL-4Rα subunit shared by the IL-4 and IL-13 receptor complexes. Dupilumab inhibits IL-4 signaling via the Type I receptor and both IL-4 and IL-13 signaling through the Type II receptor. Inflammation driven by IL-4 and IL-13 is an important component in the pathogenesis of asthma, AD, CRSwNP, EoE, PN, COPD, CSU, BP, and AFRS. Multiple cell types that express IL-4Rα (e.g., mast cells, basophils, eosinophils, macrophages, lymphocytes, epithelial cells, goblet cells) and inflammatory mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines, chemokines) are involved in inflammation. Blocking IL-4Rα with dupilumab inhibits IL-4 and IL-13 cytokine-induced inflammatory responses, including the release of proinflammatory cytokines, chemokines, nitric oxide, and IgE. The mechanism of dupilumab action has not been definitively established.