Dupixent

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 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 pemphigoi…

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 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…

5 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 de…

4 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 )

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to DUPIXENT during 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. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. 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. Fetal/Neonatal Adverse Reactions Transport of endogenous IgG antibodies across the placenta increases as pregnancy progresses, and peaks during the third trimester. Therefore, DUPIXENT may be present in infants exposed in utero . The potential clinical impact of dupilumab exposure in infants exposed in utero should be considered. 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.

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 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 o…