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Dupilumab is a fully human monoclonal antibody of the immunoglobulin G4 subclass that binds to the interleukin-4 (IL-4) receptor, inhibiting the receptor signaling pathways.

As an interleukin-4 receptor alpha antagonist, dupilumab inhibits the signaling of pro-inflammatory cytokines, called interleukins (IL), that induce inflammatory and immunological reactions in several atopic or allergic conditions, such as eczema, allergic reaction, and rhinosinusitis.

Dupilumab was generated by recombinant DNA technology in Chinese Hamster Ovary cell suspension culture.

Dupilumab is commonly marketed as

Dupixent, which is available as a formulation for subcutaneous injection.

It was first approved by the

FDA in 2017.

It is currently used to treat atopic dermatitis, asthma as an add-on maintenance treatment, chronic rhinosinusitis with nasal polyposis, and eosinophilic esophagitis.

It is used as monotherapy or in combination with other drugs, such as corticosteroids. 7, 8, 13 Dupilumab is currently under investigations for potential therapeutic use in diseases driven by allergic reactions or type 2 inflammation, such as pediatric atopic dermatitis, and chronic obstructive pulmonary disease.

It is also being studied in combination with another antibody that which targets IL-33.

Dupilumab is indicated for several conditions across different age groups and regions.

In the US, it is approved for patients aged six months and older with moderate-to-severe disease not adequately controlled with topical prescription therapies or when those therapies are not advisable.

In Europe and

Canada, the drug is similarly approved for patients six months and older, 8, 13 though in Europe, children aged six months to 11 years must have severe atopic dermatitis and be candidates for systemic therapy.

Dupilumab may be used with or without topical corticosteroids in this indication. 7, 13 Asthma and COPD: Dupilumab is indicated as an add-on maintenance treatment for patients aged six years and older with moderate-to-severe asthma characterized by an eosinophilic phenotype or with oral corticosteroid-dependent asthma, though it is not approved for the relief of acute bronchospasm or status asthmaticus. 7, 8, 13 It is also indicated as an add-on maintenance treatment in adults with inadequately controlled chronic obstructive pulmonary disease (COPD) and an eosinophilic phenotype, but again not for acute bronchospasm relief.

In adults with inadequately controlled CRSwNP, dupilumab is approved as an add-on maintenance treatment, 7 and in Canada and Europe, it is specifically used with intranasal corticosteroids. 8, 13 Eosinophilic Esophagitis: In both the US and Europe, it is indicated for the treatment of adults and children aged one year and older weighing at least 15 kg with eosinophilic esophagitis (EoE). 8, 14, 16 as well as for adults with prurigo nodularis. 8, 14, 16 Prurigo Nodularis: In both the US and Europe, dupilumab is indication for the treatment of adults with moderate-to-severe prurigo nodularis (PN) who are candidates for systemic therapy. 19, 8 Chronic Spontaneous Urticaria: In the US, dupilumab is indicated for adults and pediatric patients aged 12 years and older with CSU who remain symptomatic despite H1 antihistamine treatment, though it is not indicated for other forms of urticaria.

In the US, dupilumab is indicated for adult and pediatric patients aged 6 years and older with allergic fungal rhinosinusitis (AFRS) who have a history of sino-nasal surgery.

Dupilumab is an recombinant human

IgG4 antibody to the IL-4 receptor that works by inhibiting the activation of certain pro-inflammatory cytokines that are implicated in the pathophysiology of several allergic and atopic conditions, including asthma, chronic rhinosinusitis with nasal polyps, and food and environmental allergies.

In vivo, dupilumab was shown to reduce the levels of type 2 inflammatory biomarkers associated with atopic dermatitis, such as thymus and activation-regulated chemokine (TARC/CCL17), total serum IgE, allergen-specific IgE, and lactate dehydrogenase (LDH).

A decrease in the levels of biomarkers of asthma, such as FeNO, eotaxin-3, IgE, periostin, and eotaxin-3 (CCL26) was also observed. 8, 9 Since dupilumab works to suppress the immune response, it is proposed that it may influence the immune response against some infections, such as helminth infections, by inhibiting IL-4/IL-13 signaling.

It is advised that infections are appropriately treated until resolved before initiating dupilumab therapy.

While findings of some in vitro and in vivo studies suggest that some cytokine modulators may influence the expression and activity of specific cytochrome P450 (CYP450) enzymes, an open-label drug-drug interaction study demonstrated that dupilumab displays no significant effect on the activity of CYP450 enzymes studied (CYP3A, CYP2C19, CYP2C9, CYP1A2, and CYP2D6).

Interleukin-4 receptor subunit alpha Inhibitor Antibody Interleukin-13 Inhibitor Antibody Interleukin-4 Inhibitor Antibody.

Cmax following administration of a single subcutaneous dose of 600 mg or 400 mg of dupilumab were 70.1 ± 24.1 mcg/mL or 41.8 ± 12.4 mcg/mL, respectively.

Tmax ranged from 3-7 days following administration of a single subcutaneous dose ranging from 75-600 mg.

Following a subcutaneous dose, the absolute bioavailability of dupilumab ranged between 61% and 64% in patients with atopic dermatitis or asthma.

In clinical trials, the steady-state concentrations were reached by week 16 following the administration of 600 mg starting dose and 300 mg dose every other week.

At these concentrations, the mean trough concentrations ranged from 60.3 ± 35.1 mcg/mL to 79.9 ± 41.4 mcg/mL for 300 mg dose and from 29.2 ± 18.7-36.5 ± 22.2 mcg/mL for 200 mg dose administered every other week.

The estimated volume of distribution is 4.8 ± 1.3 L.

Being a monoclonal antibody, dupilumab is not expected to undergo significant hepatic metabolism.

While the metabolism of dupilumab has not been characterized, it is speculated that dupilumab undergoes nonspecific degradation into smaller peptides and amino acids, as often observed with endogenous IgG.

Being a monoclonal antibody, dupilumab is not expected to undergo significant renal elimination.

It is proposed that dupilumab is eliminated via parallel linear and nonlinear pathways.

At higher concentrations, dupilumab is primarily cleared through a non-saturable proteolytic pathway.

At lower concentrations, it undergoes a non-linear saturable IL-4R α target-mediated elimination.

There is limited human data on the half-life of dupilumab.

In single-dose pharmacokinetic studies, the mean half-life of dupilumab following intravenous or subcutaneous administration ranged from 4.8-7 days in rats and 11.7-20.5 days in cynomolgus monkeys. 11, 12 In these studies, the mean half-life was comparable was comparable following intravenous and subcutaneous administration.

There is limited data on the clearance of dupilumab.

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There is limited data on the overdose of dupilumab.

As there is no specific treatment for dupilumab, close monitoring of the patient with appropriate symptomatic treatment is advised in case of suspected overdosage.

is contraindicated in patients who have known hypersensitivity to dupilumab or any excipients of DUPIXENT.

Known hypersensitivity to dupilumab or any excipients in DUPIXENT.

is administered by subcutaneous injection.

Recommended dosage is an initial dose of 600 mg (two 300 mg injections), followed by 300 mg given every 2 weeks (Q2W).

Patients 6 Months to 5 Years of Age: Body Weight Recommended Dosage For pediatric patients 6 months to 5 years of age, no initial loading dose is recommended 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: Body Weight Initial Loading Dose Subsequent Dosage Q2W – every 2 weeks; Q4W – every 4 weeks to less than 30 kg 600 mg (two 300 mg injections) 300 mg Q4W 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: 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: Body Weight Recommended Dosage For pediatric patients 6 years to 11 years of age, no initial loading dose is recommended 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.

Recommended dosage for adult and pediatric patients 12 years of age and older is 300 mg given every 2 weeks (Q2W).

Body Weight Recommended Dosage in Adult and Pediatric Patients 1 Year and Older, Weighing At Least 15 kg 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: 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).

Recommended dosage for adult patients is 300 mg given every 2 weeks (Q2W).

Patients 2 Years to 5 Years of Age: Body Weight Recommended Dosage For pediatric patients 2 years to 5 years of age with CSU, no initial loading dose is recommended 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: Body Weight Initial Loading Dose Subsequent Dosage Q2W – every 2 weeks; Q4W – every 4 weeks to less than 30 kg 600 mg (two 300 mg injections) 300 mg Q4W 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: 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).

DUPIXENT in combination with a tapering course of oral corticosteroids.

Allergic Fungal Rhinosinusitis Dosage in Adults

Recommended dosage is 300 mg given every 2 weeks (Q2W).

Patients 6 Years to 17 Years of Age: Body Weight Recommended Dosage Q2W – every 2 weeks; Q4W – every 4 weeks to less than 30 kg 300 mg Q4W 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.

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.

DUPIXENT "Instructions for Use" contains more detailed instructions on the preparation and administration of DUPIXENT. 2.2 Vaccination Prior to Treatment Consider completing all age-appropriate vaccinations as recommended by current immunization guidelines prior to initiating treatment with DUPIXENT. 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).

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 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 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 The recommended dosage of DUPIXENT for pediatric patients 6 years to 11 years of age is specified in Table 4.

Table 4: Dosage of DUPIXENT in Pediatric Patients 6 Years to 11 Years of Age with Asthma Body Weight Recommended Dosage For pediatric patients 6 years to 11 years of age with asthma, 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 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. 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 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).

Patients 2 Years to 5 Years of Age The recommended dosage of DUPIXENT for pediatric patients 2 years to 5 years of age is specified in Table 6.

Table 6: Dosage of DUPIXENT in Pediatric Patients 2 Years to 5 Years of Age with Chronic Spontaneous Urticaria 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 The recommended dosage of DUPIXENT for pediatric patients 6 years to 17 years of age is specified in Table 7.

Table 7: Dosage of DUPIXENT in Pediatric Patients 6 Years to 17 Years of Age with Chronic Spontaneous Urticaria Body Weight Initial Loading Dose Subsequent Dosage 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) 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).

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).

Patients 6 Yea.

DUPIXENT (dupilumab) Injection is a clear to slightly opalescent, colorless to pale yellow solution, supplied in single-dose pre-filled syringes with needle shield or pre-filled pens.

The pre-filled syringe with needle shield is designed to deliver: 300 mg of DUPIXENT in 2 mL solution (NDC 0024-5914-00) 200 mg of DUPIXENT in 1.14 mL solution (NDC 0024-5918-00) The pre-filled pen is designed to deliver: 300 mg of DUPIXENT in 2 mL solution (NDC 0024-5915-00) 200 mg of DUPIXENT in 1.14 mL solution (NDC 0024-5919-00) DUPIXENT is available in cartons containing 2 pre-filled syringes with needle shield or 2 pre-filled pens.

Size 300 mg/2 mL (150 mg/mL) Pre-filled Syringe with Needle Shield 200 mg/1.14 mL (175 mg/mL) Pre-filled Syringe with Needle Shield Pack of 2 syringes NDC 0024-5914-01 NDC 0024-5918-01 Pack Size 300 mg/2 mL (150 mg/mL) Pre-filled Pen 200 mg/1.14 mL (175 mg/mL) Pre-filled Pen Pack of 2 pens NDC 0024-5915-02 NDC 0024-5919-02 Storage and Handling DUPIXENT is sterile and preservative-free.

Discard any unused portion.

Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.

If necessary, DUPIXENT may be kept at room temperature up to 25°C (77°F) for a maximum of 14 days.

Do not store above 25°C (77°F).

After removal from the refrigerator, DUPIXENT must be used within 14 days or discarded.

Do not expose

DUPIXENT to heat or direct sunlight.

Do NOT freeze.

Do NOT shake.

DUPIXENT is sterile and preservative-free.

Discard any unused portion.

Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.

If necessary, DUPIXENT may be kept at room temperature up to 25°C (77°F) for a maximum of 14 days.

Do not store above 25°C (77°F).

After removal from the refrigerator, DUPIXENT must be used within 14 days or discarded.

Do not expose

DUPIXENT to heat or direct sunlight.

Do NOT freeze.

Do NOT shake.

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.

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.

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) .

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.

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.

• 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.

Atopic Dermatitis The safety and effectiveness of DUPIXENT have been established in pediatric patients 6 months of age and older with moderate-to-severe AD, whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.

Use of

DUPIXENT in this is supported by data from the following clinical trials: AD-1526 which included 251 pediatric subjects 12 years of age and older with moderate-to-severe AD.

Of the 251 subjects, 82 were treated with DUPIXENT 200 mg Q2W (<60 kg) or 300 mg Q2W (≥60 kg) and were treated with matching placebo AD-1652 which included 367 pediatric subjects to 11 years of age with severe AD.

Of the 367 subjects, 120 were treated with DUPIXENT 300 mg Q4W + TCS (15 to <30 kg) or 200 mg Q2W + TCS (≥30 kg) and were treated with matching placebo + TCS AD-1539 which included 162 pediatric subjects 6 months to 5 years of age with moderate-to-severe AD.

Of the 162 subjects, 83 were treated with DUPIXENT 200 mg Q4W + TCS (5 to <15 kg) or 300 mg Q4W + TCS (15 to <30 kg) and 79 subjects were assigned to be treated with matching placebo + TCS AD-1434, an open-label extension study that enrolled 275 pediatric subjects 12 years of age and older treated with DUPIXENT ± TCS, 368 pediatric subjects to 11 years of age treated with DUPIXENT ± TCS, and 180 pediatric subjects 6 months to 5 years of age treated with DUPIXENT ± TCS Liberty-AD-HAFT which included 27 pediatric subjects 12 years of age and older with atopic dermatitis with moderate-to-severe hand and/or foot involvement treated with DUPIXENT (N=14) or matching placebo (N=13) The safety and effectiveness were generally consistent between pediatric and adult patients.

In addition, hand-foot-and-mouth disease was reported in 9 (5%) pediatric subjects and skin papilloma was reported in 4 (2%) pediatric subjects 6 months to 5 years of age treated with DUPIXENT ± TCS in AD-1434.

These cases did not lead to study drug discontinuation.

Safety and effectiveness of

DUPIXENT have not been established in pediatric patients younger than 6 months of age with AD.

Asthma The safety and effectiveness of

DUPIXENT for an add-on maintenance treatment in patients with moderate-to-severe asthma characterized by an eosinophilic phenotype or with oral corticosteroid dependent asthma have been established in pediatric patients 6 years of age and older.

DUPIXENT for this indication is supported by evidence from adequate and well-controlled studies in adult and pediatric patients 6 years and older.

Subjects to 17 Years of Age: A total of 107 pediatric subjects to 17 years of age with moderate-to-severe asthma were enrolled in QUEST and received either 200 mg (N=21) or 300 mg (N=18) DUPIXENT (or matching placebo either 200 mg [N=34] or 300 mg [N=34]) Q2W.

Asthma exacerbations and lung function were assessed in both pediatric subjects to 17 years of age and adults.

For both the 200 mg and 300 mg Q2W doses, improvements in FEV 1 (LS mean change from baseline at Week 12) were observed (0.36 L and 0.27 L, respectively).

For the 200 mg Q2W dose, subjects had a reduction in the rate of severe exacerbations that was consistent with adults.

Dupilumab exposure was higher in pediatric subjects to 17 years of age than that in adults at the respective dose level which was mainly accounted for by difference in body weight.

The adverse event profile in pediatric subjects to 17 years of age was generally similar to the adults.

Subjects to 11 Years of Age: A total of 408 pediatric subjects to 11 years of age with moderate-to-severe asthma were enrolled in VOYAGE, which evaluated doses of 100 mg Q2W or 200 mg Q2W.

Improvement in asthma exacerbations and lung function were demonstrated.

The effectiveness of

DUPIXENT 300 mg Q4W in subjects to 11 years of age with body weight to <30 kg was extrapolated from efficacy of 100 mg Q2W in VOYAGE with support from population pharmacokinetic analyses showing higher drug exposure levels with 300 mg Q4W.

Subjects who completed the treatment period of the VOYAGE study could participate in the open-label extension study (LTS14424).

Eighteen subjects (≥15 to <30 kg) out of 365 subjects were exposed to 300 mg Q4W in this study, and the safety profile in these eighteen subjects was consistent with that seen in VOYAGE.

Additional safety for

DUPIXENT 300 mg Q4W is based upon available safety information from the pediatric AD indication.

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

CRSwNP The safety and effectiveness of

DUPIXENT for add-on maintenance treatment in patients with inadequately controlled CRSwNP have been established in pediatric patients aged 12 years and older.

DUPIXENT for this indication is supported by evidence from adequate and well-controlled studies of DUPIXENT as add-on maintenance treatment in adults with inadequately controlled CRSwNP (SINUS-24 and SINUS-52) with the following additional data: Pharmacokinetic (PK) data from adult and pediatric patients aged 12 years and older with moderate-to-severe asthma and adult patients with inadequately controlled CRSwNP Safety data in pediatric patients aged 12 years and older with moderate-to-severe asthma Safety and effectiveness of DUPIXENT have not been established in pediatric patients younger than 12 years of age with CRSwNP.

EoE The safety and effectiveness of DUPIXENT for the treatment of EoE have been established in pediatric subjects 1 year of age and older, weighing at least 15 kg. Use of DUPIXENT in this population is supported by an adequate well-controlled study in adults and 72 pediatric subjects to 17 years of age (Study EoE-1), a clinical study in 61 pediatric subjects to 11 years of age (Study EoE-2), and pharmacokinetic data in adult and pediatric subjects to 17 years of age.

The safety of

DUPIXENT in pediatric subjects to 17 years of age was similar to adults.

DUPIXENT have not been established in pediatric patients younger than 1 year of age, or weighing less than 15 kg, with EoE.

Prurigo Nodularis Safety and effectiveness of

DUPIXENT have not been established in pediatric patients with PN.

Chronic Obstructive Pulmonary Disease The safety and effectiveness of DUPIXENT have not been established in pediatric patients with COPD.

COPD is largely a disease of adult patients.

Chronic Spontaneous Urticaria The safety and effectiveness of DUPIXENT for the treatment of CSU in patients who remain symptomatic despite H1 antihistamine treatment have been established in pediatric patients 2 years of age and older.

DUPIXENT in this indication is supported by evidence from two adequate and well-controlled studies in adults and pediatric patients aged 12 years and older with the following additional data: Pharmacokinetic (PK) data in 6 pediatric patients to 17 years of age, PK data in 18 pediatric patients to 11 years of age, and safety data in pediatric patients in other indications Safety and effectiveness of DUPIXENT have not been established in pediatric patients younger than 2 years of age, and/or weighing less than 5 kg, with CSU.

Bullous Pemphigoid The safety and effectiveness of DUPIXENT have not been established in pediatric patients with BP.

BP is largely a disease of adult patients.

Allergic Fungal Rhinosinusitis The safety and effectiveness of DUPIXENT for the treatment of AFRS in patients who have a history of sino-nasal surgery have been established in pediatric patients 6 years of age and older.

DUPIXENT in this indication is supported by evidence from an adequate and well-controlled study (AIMS) in adults and pediatric patients aged 12 years and older, with the following additional data: Pharmacokinetic (PK) data in 3 pediatric patients 12 years of age and older with AFRS PK and safety data in pediatric patients 6 years to 11 years of age in other indications.

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

Of the 1539 subjects with AD exposed to DUPIXENT in a dose-ranging study and placebo-controlled trials, 70 subjects were 65 years or older.

Clinical trials of DUPIXENT in

AD did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects.

Of the 1977 subjects with asthma exposed to DUPIXENT, a total of 240 subjects were 65 years or older.

Efficacy and safety in this were similar to the overall study population.

Of the 440 subjects with CRSwNP exposed to DUPIXENT, a total of 79 subjects were 65 years or older.

Clinical studies of DUPIXENT in

EoE did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger adult subjects.

Of the 152 subjects with PN exposed to DUPIXENT, a total of were 65 years or older including 8 subjects 75 years or older.

Clinical trials did not include a sufficient number of subjects 65 years of age and older to determine whether they respond differently from younger adult subjects.

Of the 1874 subjects with COPD randomized in clinical trials of DUPIXENT, a total of were 65 years or older, while 244 subjects were 75 years or older.

No overall differences in safety or effectiveness of DUPIXENT have been observed between subjects 65 years of age and older and younger adult subjects.

Of the 198 subjects with CSU exposed to DUPIXENT, a total of 30 subjects were 65 years or older, including 7 subjects 75 years or older.

Efficacy and safety in subjects 65 years or older were similar to the overall study population.

Of the 53 subjects with BP exposed to DUPIXENT, a total of were 65 years or older, including 22 subjects 75 years or older.

Ten percent of subjects aged 65 years and older treated with DUPIXENT had an adverse reaction of vision blurred compared to zero in younger adult subjects.

AFRS did not include sufficient numbers of subjects aged and over to determine whether they respond differently from younger subjects.