Drug Safety-related Labeling Changes (SrLC)

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DUPIXENT (BLA-761055)

(DUPILUMAB)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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04/12/2024 (SUPPL-59)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Conjunctivitis and Keratitis

Additions and/or revisions underlined:

Conjunctivitis and keratitis adverse reactions have been reported in clinical trials.

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 [see Adverse Reactions (6.1)].

Among subjects with asthma, the frequencies of conjunctivitis and keratitis were similar between DUPIXENT and placebo [see Adverse Reactions (6.1)].

In 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. There were no cases of keratitis reported in the CRSwNP development program [see Adverse Reactions (6.1)].

Among subjects with EoE, there were no reports of conjunctivitis and keratitis in the DUPIXENT group in placebo-controlled trials [see Adverse Reactions (6.1)].

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. There were no cases of keratitis reported in the PN development program [see Adverse Reactions (6.1)].

Conjunctivitis and keratitis adverse events have also been reported with DUPIXENT in postmarketing settings, predominantly in AD patients. Some patients reported visual disturbances (e.g., blurred vision) associated with conjunctivitis or keratitis.

Advise patients or their caregivers to report new onset or worsening eye symptoms to their healthcare provider. Consider ophthalmological examination for patients who develop conjunctivitis that does not resolve following standard treatment or signs and symptoms suggestive of keratitis, as appropriate [see Adverse Reactions (6.1)].

5.8 Parasitic (Helminth) Infections

Additions and/or revisions underlined:

Patients with known helminth infections were excluded from participation in clinical studies. It is unknown if DUPIXENT will influence the immune response against helminth infections.

Treat patients with pre-existing helminth infections before initiating therapy with DUPIXENT. If patients become infected while receiving treatment with DUPIXENT and do not respond to anti- helminth treatment, discontinue treatment with DUPIXENT until the infection resolves. Adverse reactions of helminth infections (5 cases of enterobiasis and 1 case of ascariasis) were reported in pediatric subjects 6 to 11 years old who participated in the pediatric asthma development program [see Adverse Reactions (6.1)].

6 Adverse Reactions

Addition of the following to the bulleted line listing:

• Parasitic (Helminth) Infections [see Warnings and Precautions (5.8)]

6.1 Clinical Trials Experience

Extensive changes; please refer to label for complete information

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

…

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 12 to 17 years of age (Study EoE-1), a clinical study in 61 pediatric subjects 1 to 11 years of age (Study EoE-2), and pharmacokinetic data in adult and pediatric subjects 1 to 17 years of age. The safety of DUPIXENT in pediatric subjects 1 to 17 years of age was similar to adults [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.4)].

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

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT INFORMATION

Additions and/or revisions underlined:

What is DUPIXENT?

DUPIXENT is a prescription medicine used:

…

o   to treat adults and children 1 year of age and older with eosinophilic esophagitis (EoE), who weigh at least 33 pounds (15 kg).

…

·     It is not known if DUPIXENT is safe and effective in children with eosinophilic esophagitis under 1 year of age, or who weigh less than 33 pounds (15 kg).

…

01/25/2024 (SUPPL-57)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Conjunctivitis and Keratitis

Additions and/or revisions underlined:

…

Advise patients or their caregivers to report new onset or worsening eye symptoms to their healthcare provider. Consider ophthalmological examination for patients who develop conjunctivitis that does not resolve following standard treatment or signs and symptoms suggestive of keratitis, as appropriate [see Adverse Reactions (6.1)].

6 Adverse Reactions

Additions and/or revisions underlined:

…

• Parasitic (Helminth) Infections [see Warnings and Precautions (5.8)]

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

Eosinophilic Esophagitis

Adults and Pediatric Subjects 12 Years of Age and Older with EoE

…

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.

…

Specific Adverse Reactions

Conjunctivitis and Keratitis

…

Among subjects with EoE, there were no reports of conjunctivitis and keratitis in the DUPIXENT group in placebo-controlled trials [see Warnings and Precautions (5.2)]. 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.

…

Eczema Herpeticum and Herpes Zoster

…

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 subjects with PN (PRIME and PRIME2), the mean and median decrease in blood eosinophils from baseline to Week 4 were 9 and 10 cells/mcL, respectively.

Across the trials for AD, asthma, and CRSwNP indications, the incidence of treatment-emergent

eosinophilia (greater than or equal to 500 cells/mcL) was similar in DUPIXENT and placebo groups. In the trials for the PN indication, the incidence of treatment-emergent eosinophilia (greater than or equal to 500 cells/mcL) was lower in DUPIXENT than in the placebo group.

…

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

…

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 and72 pediatric subjects 12 to 17 years of age (Study EoE-1), a clinical study in 61 pediatric subjects 1 to 11 years of age (Study EoE-2), and pharmacokinetic data in adult and pediatric subjects 1 to 17 years of age. The safety of DUPIXENT in pediatric subjects 1 to 17 years of age was similar to adults [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.4)].

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

…

01/12/2024 (SUPPL-55)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Newly added information:

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.

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

Atopic Dermatitis

The safety and effectiveness of DUPIXENT have been established in pediatric patients 6 months of age and older with moderate-to-severe AD, whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable [see Clinical Studies (14.1)].

Use of DUPIXENT in this age group is supported by data from the following clinical trials:

• AD-1526 which included 251 pediatric subjects 12 to 17 years of age with moderate-to- severe AD. Of the 251 subjects, 82 were treated with DUPIXENT 200 mg Q2W (<60 kg) or 300 mg Q2W (greater than or equal to 60 kg) and 85 were treated with matching placebo

• AD-1652 which included 367 pediatric subjects 6 to 11 years of age with severe AD. Of the 367 subjects, 120 were treated with DUPIXENT 300 mg Q4W + TCS (15 to <30 kg) or 200 mg Q2W + TCS (greater than or equal to 30 kg) and 123 were treated with matching placebo + TCS

• AD-1539 which included 162 pediatric subjects 6 months to 5 years of age with moderate-to-severe AD. Of the 162 subjects, 83 were treated with DUPIXENT 200 mg Q4W + TCS (5 to <15 kg) or 300 mg Q4W + TCS (15 to <30 kg) and 79 subjects were assigned to be treated with matching placebo + TCS

• AD-1434, an open-label extension study that enrolled 275 pediatric subjects 12 to 17 years of age treated with DUPIXENT ± TCS, 368 pediatric subjects 6 to 11 years of age treated with DUPIXENT ± TCS, and 180 pediatric subjects 6 months to 5 years of age treated with DUPIXENT ± TCS

• Liberty-AD-HAFT which included 27 pediatric subjects 12 to 17 years of age with atopic dermatitis with moderate-to-severe hand and/or foot involvement treated with DUPIXENT (N=14) or matching placebo (N=13)

…

8.5 Geriatric Use

Additions and/or revisions underlined:

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.

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT INFORMATION

Additions and/or revisions underlined:

How should I use DUPIXENT?

…

• If you inject too much DUPIXENT, call your healthcare provider or Poison Help line at 1-800-222-1222 or go to the nearest hospital emergency room right away.

…

The most common side effects of DUPIXENT include:

• dry eye

…

09/29/2023 (SUPPL-54)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.9 Vaccinations

Additions and/or revisions underlined:

Consider completing all age-appropriate vaccinations as recommended by current immunization guidelines prior to initiating treatment with DUPIXENT. Avoid use of live vaccines during treatment with DUPIXENT.

…

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

Adults with Atopic Dermatitis

…

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.

…

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.

…

Specific Adverse Reactions

Conjunctivitis and Keratitis

…

During the 52-week treatment period of concomitant therapy AD trial (CHRONOS), conjunctivitis was reported in 16% of the DUPIXENT 300 mg Q2W + TCS group (20 per 100 subject-years) and in 9% of the placebo + TCS group (10 per 100 subject-years). During the long-term OLE trial with data through 260 weeks (AD-1225), conjunctivitis was reported in 21% of the DUPIXENT group (12 per 100 subject-years).

In DUPIXENT AD monotherapy trials (SOLO 1, SOLO 2, and AD-1021) through Week 16, keratitis was reported in <1% of the DUPIXENT group (1 per 100 subject-years) and in 0% of the placebo group (0 per 100 subject-years). In the 52-week DUPIXENT + topical corticosteroids (TCS) AD trial (CHRONOS), keratitis was reported in 4% of the DUPIXENT + TCS group (4 per 100 subject-years) and in 2% of the placebo + TCS group (2 per 100 subject- years). Conjunctivitis and keratitis occurred more frequently in AD subjects who received DUPIXENT. Conjunctivitis was the most frequently reported eye disorder. During the long-term OLE trial with data through 260 weeks (AD-1225), keratitis was reported in 3% of the DUPIXENT group (1 per 100 subject-years). Most subjects with conjunctivitis or keratitis recovered or were recovering during the treatment period.

…

Eczema Herpeticum and Herpes Zoster

The rate of eczema herpeticum was similar in the placebo and DUPIXENT groups in the AD trials. The rates remained stable through 260 weeks in the long-term OLE trial (AD-1225).

Herpes zoster was reported in <1% of the DUPIXENT groups (1 per 100 subject-years) and in <1% of the placebo group (1 per 100 subject-years) in the 16-week AD monotherapy trials. In the 52-week DUPIXENT + TCS AD trial, herpes zoster was reported in 1% of the DUPIXENT + TCS group (1 per 100 subject-years) and 2% of the placebo + TCS group (2 per 100 subject- years). During the long-term OLE trial with data through 260 weeks (AD-1225), 2.0% of DUPIXENT-treated subjects reported herpes zoster (0.94 per 100 subject-years of follow up).

…

09/28/2022 (SUPPL-44)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Conjunctivitis and Keratitis

Additions and/or revisions underlined

…

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. There were no cases of keratitis reported in the PN development program [see Adverse Reactions (6.1)].

…

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined

…

Prurigo Nodularis

A total of 309 adult subjects with prurigo nodularis (PN) were evaluated in two 24-week randomized, double-blind, placebo-controlled, multicenter trials (PRIME and PRIME2). The safety pool included data from the 24-week treatment and 12-week follow-up periods from both trials.

The proportion of subjects who discontinued treatment due to adverse events was 3% of the placebo group and 0% of the DUPIXENT 300 mg Q2W group.

The safety population had a mean age of 49 years; 65% of subjects were female, 56% were White, 34% were Asian, and 6% were Black or African American. Subjects with co-morbid conditions included 43% of subjects with a history of atopy (defined as having a medical history of AD, allergic rhinitis/ rhinoconjunctivitis, asthma, or food allergy), 8% of subjects with a history of hypothyroidism and 9% of subjects with a history of diabetes mellitus type 2.

Table 9 summarizes the adverse reactions that occurred at a rate of at least 2% in subjects treated with DUPIXENT and at a higher rate than in their respective comparator group in PRIME and PRIME2.

Please refer to label to view Table 9.

…

Among subjects with PN, the frequency of conjunctivitis was 4% in the DUPIXENT group compared to 1% in the placebo group; all of these subjects recovered or were recovering during the treatment period. There were no cases of keratitis reported in the PN development program [see Warnings and Precautions (5.2)].

…

Among subjects with PN, herpes zoster and ophthalmic herpes zoster were each reported in <1% of the DUPIXENT group (1 per 100 subject-years) and 0% of the placebo group.

…

In subjects with PN (PRIME and PRIME2), the mean and median decrease in blood eosinophils from baseline to Week 4 were 9 and 10 cells/mcL, respectively.

Across the trials for AD, asthma, and CRSwNP indications, the incidence of treatment-emergent eosinophilia (greater than or equal to 500 cells/mcL) was similar in DUPIXENT and placebo groups. In the trials for the PN indication, the incidence of treatment-emergent eosinophilia (greater than or equal to 500 cells/mcL) was lower in DUPIXENT than in the placebo group.

Treatment-emergent eosinophilia (greater than or equal to 5,000 cells/mcL) was reported in <3% of DUPIXENT- treated subjects and <0.5% in placebo-treated subjects (SOLO 1, SOLO 2, and AD-1021; DRI12544, QUEST, and VOYAGE; SINUS-24 and SINUS-52; PRIME and PRIME2). Blood eosinophil counts declined to near baseline or remained below baseline levels (PRIME and PRIME2) during study treatment. In study AD-1539, treatment-emergent eosinophilia (greater than or equal to 5,000 cells/mcL) was reported in 8% of DUPIXENT-treated subjects and 0% in placebo- treated subjects [see Warnings and Precautions (5.3)].

…

6.2 Immunogenicity

Additions and/or revisions underlined

…

Atopic Dermatitis

Approximately 6% of subjects with AD who received DUPIXENT 300 mg Q2W for 52 weeks developed antibodies to DUPIXENT; approximately 2% exhibited persistent ADA responses, and approximately 1% had neutralizing antibodies. Similar results were observed in pediatric subjects 6 months to 11 years of age with AD who received either DUPIXENT 200 mg Q2W, 200 mg Q4W, or 300 mg Q4W.

…

Asthma

Approximately 5% of subjects with asthma who received DUPIXENT 300 mg Q2W for 52 weeks developed antibodies to DUPIXENT; approximately 2% exhibited persistent ADA responses, and approximately 2% had neutralizing antibodies. Similar results were observed in pediatric subjects 6 to 11 years of age with asthma who received either DUPIXENT 100 mg Q2W or 200 mg Q2W up to 52 weeks.

…

Chronic Rhinosinusitis with Nasal Polyposis

Approximately 5% of subjects with CRSwNP who received DUPIXENT 300 mg Q2W for 52 weeks developed antibodies to DUPIXENT; approximately 2% exhibited persistent ADA responses, and approximately 3% had neutralizing antibodies.

Eosinophilic Esophagitis

Approximately 1% of subjects with EoE who received DUPIXENT 300 mg QW for 24 weeks developed antibodies to DUPIXENT.

Prurigo Nodularis

Approximately 8% of subjects with PN who received DUPIXENT 300 mg Q2W for 24 weeks developed antibodies to DUPIXENT; approximately 1% exhibited persistent ADA responses, and approximately 3% had neutralizing antibodies.

The antibody titers detected in subjects who received DUPIXENT were mostly low. In subjects who received DUPIXENT, development of high titer antibodies to DUPIXENT was associated with lower serum dupilumab concentrations [see Clinical Pharmacology (12.3)]

.…

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined

…

Prurigo Nodularis

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

8.5 Geriatric Use

Additions and/or revisions underlined

…

Of the 152 subjects with PN exposed to DUPIXENT, a total of 37 were 65 years or older including 8 subjects 75 years or older. Clinical trials did not include a sufficient number of subjects 65 years of age and older to determine whether they respond differently from younger adult subjects.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT INFORMATION

Additions and/or revisions underlined

What is DUPIXENT?

DUPIXENT is a prescription medicine used:

…

• to treat adults with prurigo nodularis (PN).

• DUPIXENT works by blocking two proteins that contribute to a type of inflammation that plays a major role in atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyposis, eosinophilic esophagitis, and prurigo nodularis.

  …

  It is not known if DUPIXENT is safe and effective in children with prurigo nodularis under 18 years of age.

  …

  How should I use DUPIXENT?

  …

• If your healthcare provider decides that you or a caregiver can give the injections of DUPIXENT, you or your caregiver should receive training on the right way to prepare and inject DUPIXENT. Do not try to inject DUPIXENT until you have been shown the right way by your healthcare provider. In children 12 years of age and older, it is recommended that DUPIXENT be given by or under the supervision of an adult. In children younger than 12 years of age, DUPIXENT should be given by a caregiver.

  …

  The most common side effects of DUPIXENT include:

• muscle pain

• diarrhea

• herpes virus infections

• common cold symptoms (nasopharyngitis)  

• high count of a certain white blood cell (eosinophilia)

…

How should I store DUPIXENT?

• Store DUPIXENT in the refrigerator at 36ºF to 46ºF (2ºC to 8ºC).

• Store DUPIXENT in the original carton to protect from light.

• DUPIXENT can be stored at room temperature up to 77°F (25°C) up to 14 days. Throw away (dispose of) any DUPIXENT that has been left at room temperature for longer than 14 days.

• Do not heat or put DUPIXENT into direct sunlight.

• Do not freeze. Do not shake.

Keep DUPIXENT and all medicines out of the reach of children.

…

06/07/2022 (SUPPL-42)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

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 atopic dermatitis (AD-1539). The safety profile of DUPIXENT + TCS in these subjects through Week 16 was similar to the safety profile from trials in adults and pediatric subjects 6 to 17 years of age with atopic dermatitis.

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 atopic dermatitis (AD-1434). The majority of subjects were treated with DUPIXENT 300 mg every 4 weeks. The safety profile of DUPIXENT ± TCS in subjects followed through Week 52 was similar to the safety profile observed through Week 16 in AD-1539. The long-term safety profile of DUPIXENT ± TCS observed in pediatric subjects 6 months to 5 years of age was consistent with that seen in adults and pediatric subjects 6 to 17 years old with atopic dermatitis. In addition, hand-foot-and-mouth disease was reported in 9 (5%) pediatric subjects and skin papilloma was reported in 4 (2%) pediatric subjects treated with DUPIXENT ± TCS. These cases did not lead to study drug discontinuation [see Use in Specific Populations (8.4)].

…

Eosinophils

…

In adult subjects with atopic dermatitis (SOLO 1, SOLO 2, and AD-1021), the mean and median increases in blood eosinophils from baseline to Week 4 were 100 and 0 cells/mcL, respectively. In pediatric subjects <6 years old with atopic dermatitis, 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.

Across atopic dermatitis, asthma, and CRSwNP indications, the incidence of treatment-emergent eosinophilia (greater than or equal to 500 cells/mcL) was similar in DUPIXENT and placebo groups. Treatment- emergent eosinophilia (greater than or equal to 5,000 cells/mcL) was reported in <3% of DUPIXENT-treated subjects and <0.5% in placebo-treated subjects (SOLO 1, SOLO 2, and AD-1021; DRI12544, QUEST, and VOYAGE; SINUS-24 and SINUS-52). Blood eosinophil counts declined to near baseline levels during study treatment. In study AD-1539, treatment-emergent eosinophilia

(greater than or equal to 5,000 cells/mcL) was reported in 8% of DUPIXENT-treated subjects and 0% in placebo- treated subjects [see Warnings and Precautions (5.3)].

6.2 Immunogenicity

Additions and/or revisions underlined:

Approximately 5% of subjects with atopic dermatitis, asthma, or CRSwNP who received DUPIXENT 300 mg Q2W for 52 weeks developed antibodies to dupilumab; approximately 2% exhibited persistent ADA responses, and approximately 2% had neutralizing antibodies. Similar results were observed in pediatric subjects 6 months to 11 years of age with atopic dermatitis who received either DUPIXENT 200 mg Q2W, 200 mg Q4W, or 300 mg Q4W and pediatric subjects 6 to 11 years of age with asthma who received either DUPIXENT 100 mg Q2W or 200 mg Q2W up to 52 weeks.

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

Atopic Dermatitis

The safety and effectiveness of DUPIXENT have been established in pediatric patients 6 months of age and older with moderate-to-severe atopic dermatitis [see Clinical Studies (14.1)].

Use of DUPIXENT in this age group is supported by data from the following clinical trials:

• AD-1526 which included 251 pediatric subjects 12 to 17 years of age with moderate-to- severe atopic dermatitis treated with DUPIXENT

• AD-1652 which included 367 pediatric subjects 6 to 11 years of age with severe atopic dermatitis treated with DUPIXENT + TCS

• AD-1539 which included 161 pediatric subjects 6 months to 5 years of age with moderate-to-severe atopic dermatitis treated with DUPIXENT + TCS

• AD-1434, an open-label extension study that enrolled 275 pediatric subjects 12 to 17 years of age treated with DUPIXENT, 368 pediatric subjects 6 to 11 years of age treated with DUPIXENT+TCS, and 180 pediatric subjects 6 months to 5 years of age treated with DUPIXENT+TCS

The safety and effectiveness were generally consistent between pediatric and adult patients [see Adverse Reactions (6.1) and Clinical Studies (14.1)]. In addition, hand-foot-and-mouth disease was reported in 9 (5%) pediatric subjects and skin papilloma was reported in 4 (2%) pediatric subjects 6 months to 5 years of age treated with DUPIXENT + TCS in AD-1434. These cases did not lead to study drug discontinuation. [see Adverse Reactions (6.1)].

Safety and effectiveness in pediatric patients younger than 6 months of age with atopic dermatitis have not been established.

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT INFORMATION

What is DUPIXENT?

DUPIXENT is a prescription medicine used:

• to treat adults and children 6 months of age and older with moderate-to-severe atopic dermatitis (eczema) that is not well controlled with prescription therapies used on the skin (topical), or who cannot use topical therapies. DUPIXENT can be used with or without topical corticosteroids.

• with other asthma medicines for the maintenance treatment of moderate-to-severe asthma in adults and children 6 years of age and older whose asthma is not controlled with their current asthma medicines. DUPIXENT helps prevent severe asthma attacks (exacerbations) and can improve your breathing. DUPIXENT may also help reduce the amount of oral corticosteroids you need while preventing severe asthma attacks and improving your breathing.

 DUPIXENT is not used to treat sudden breathing problems.

• with other medicines for the maintenance treatment of chronic rhinosinusitis with nasal polyposis (CRSwNP) in adults whose disease is not controlled.

• to treat adults and children 12 years of age and older, who weigh at least 88 pounds (40 kg), with eosinophilic esophagitis (EoE).

- DUPIXENT works by blocking two proteins that contribute to a type of inflammation that plays a major role in atopic dermatitis, asthma, and chronic rhinosinusitis with nasal polyposis.

- It is not known if DUPIXENT is safe and effective in children with atopic dermatitis under 6 months of age.

- It is not known if DUPIXENT is safe and effective in children with asthma under 6 years of age.

- It is not known if DUPIXENT is safe and effective in children with chronic rhinosinusitis with nasal polyposis under 18 years of age.

It is not known if DUPIXENT is safe and effective in children with eosinophilic esophagitis under 12 years of age and who weigh at least 88 pounds (40 kg).

…

How should I use DUPIXENT?

…

• DUPIXENT comes as a single-dose pre-filled syringe with needle shield or as a pre-filled pen.

  • The DUPIXENT pre-filled pen is only for use in adults and children 12 years of age and older.

  • The DUPIXENT pre-filled syringe is for use in adults and children 6 months of age and older.

• DUPIXENT is given as an injection under the skin (subcutaneous injection).

…

05/20/2022 (SUPPL-40)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Conjunctivitis and Keratitis

Additions and/or revisions underlined:

…

Among subjects with EoE, the frequency of conjunctivitis and keratitis was 0% and 0% in the DUPIXENT group and 2% and 0% in the placebo group, respectively [see Adverse Reactions (6.1)].

…

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive changes; please refer to label

6.2 Immunogenicity

Additions and/or revisions underlined:

…

Approximately 1% of subjects with EoE who received DUPIXENT 300 mg QW for 24 weeks developed antibodies to dupilumab.
Regardless of age or population, up to 4% of subjects in placebo groups were positive for antibodies to DUPIXENT; approximately 2% exhibited persistent ADA responses, and approximately 1% had neutralizing antibodies.

…

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

…

EoE

The safety and effectiveness of DUPIXENT for the treatment of EoE have been established in pediatric patients 12 years of age and older, weighing at least 40 kg. Use of DUPIXENT in this population is supported by an adequate and well-controlled study in adults (Parts A and B) which included 72 pediatric patients 12 to 17 years of age, weighing at least 40 kg, and additional pharmacokinetic data. The safety and effectiveness in adults and pediatric patients were similar [see Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14.4)].

The safety and effectiveness of DUPIXENT for the treatment of EoE in pediatric patients less than 12 years of age and weighing less than 40 kg have not been established.

 

8.5 Geriatric Use

Additions and/or revisions underlined:

…

Clinical studies of DUPIXENT in EoE did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger adult subjects.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT INFORMATION

Additions and/or revisions underlined:

What is DUPIXENT?

DUPIXENT is a prescription medicine used:

…

• to treat adults and children 12 years of age and older, who weigh at least 88 pounds (40 kg), with eosinophilic esophagitis (EoE).

• DUPIXENT works by blocking two proteins that contribute to a type of inflammation that plays a major role in atopic dermatitis, asthma, and chronic rhinosinusitis with nasal polyposis.

• It is not known if DUPIXENT is safe and effective in children with atopic dermatitis or asthma under 6 years of age.

• It is not known if DUPIXENT is safe and effective in children with chronic rhinosinusitis with nasal polyposis under 18 years of age.

• It is not known if DUPIXENT is safe and effective in children with eosinophilic esophagitis under 12 years of age and who weigh at least 88 pounds (40 kg).

…

How should I use DUPIXENT?

…

• If your dose schedule is every week and you miss a dose of DUPIXENT: Give the DUPIXENT injection as soon as possible and start a new every week dose schedule  from the time you remember to take your DUPIXENT injection.

...

The most common side effects of DUPIXENT include:

• injection site reactions

• upper respiratory tract infections

• eye and eyelid inflammation, including redness, swelling, and itching, sometimes with blurred vision

• pain in the throat (oropharyngeal pain)

• cold sores in your mouth or on your lips

• high count of a certain white blood cell (eosinophilia)

• trouble sleeping (insomnia)

• toothache

• gastritis

• joint pain (arthralgia)

• parasitic (helminth) infections

…

12/22/2021 (SUPPL-21)

Approved Drug Label (PDF)

6 Adverse Reactions

6.3 Postmarketing Experience

Additions and/or revisions underlined:

The following adverse reactions have been identified during postapproval use of DUPIXENT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune system disorders: angioedema [see Warnings and Precautions (5.1)]

Skin and subcutaneous tissue disorders: Facial skin reactions, including erythema, rash, scaling, edema, papules, pruritus, burning, and pain

12/22/2021 (SUPPL-27)

Approved Drug Label (PDF)

6 Adverse Reactions

6.3 Postmarketing Experience

Additions and/or revisions underlined:

The following adverse reactions have been identified during postapproval use of DUPIXENT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune system disorders: angioedema [see Warnings and Precautions (5.1)]

Skin and subcutaneous tissue disorders: Facial skin reactions, including erythema, rash, scaling, edema, papules, pruritus, burning, and pain

12/22/2021 (SUPPL-33)

Approved Drug Label (PDF)

6 Adverse Reactions

6.3 Postmarketing Experience

Additions and/or revisions underlined:

The following adverse reactions have been identified during postapproval use of DUPIXENT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune system disorders: angioedema [see Warnings and Precautions (5.1)]

Skin and subcutaneous tissue disorders: Facial skin reactions, including erythema, rash, scaling, edema, papules, pruritus, burning, and pain

10/20/2021 (SUPPL-31)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Hypersensitivity

(Additions and/or revisions underlined)

Hypersensitivity reactions, including generalized urticaria, rash, erythema nodosum, erythema multiforme, and serum sickness or serum sickness-like reactions, were reported in less than 1% of subjects who received DUPIXENT in clinical trials.

5.5 Risk Associated with Abrupt Reduction of Corticosteroid Dosage

(Section title revised)

5.7 Parasitic (Helminth) Infections

(Additions and/or revisions underlined)

Patients with known helminth infections were excluded from participation in clinical studies. It is unknown if DUPIXENT will influence the immune response against helminth infections.

Treat patients with pre-existing helminth infections before initiating therapy with DUPIXENT. If patients become infected while receiving treatment with DUPIXENT and do not respond to anti- helminth treatment, discontinue treatment with DUPIXENT until the infection resolves. Adverse reactions of helminth infections (5 cases of enterobiasis and 1 case of ascariasis) were reported in pediatric patients 6 to 11 years old who participated in the pediatric asthma development program [see Adverse Reactions (6.1)].

6 Adverse Reactions

6.1 Clinical Trials Experience

(Newly added information)

Pediatric Subjects with Asthma (6 to 11 Years of Age)

The safety of DUPIXENT was assessed in 405 subjects 6 to 11 years of age with moderate-to- severe asthma (AS Trial 4). The safety profile of DUPIXENT in these subjects through Week 52 was similar to the safety profile from studies in adults and adolescents 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.

Hypersensitivity Reactions

(Additions and/or revisions underlined)

Hypersensitivity reactions were reported in <1% of DUPIXENT-treated subjects. These included serum sickness reaction, serum sickness-like reaction, generalized urticaria, rash, erythema nodosum, erythema multiforme, and anaphylaxis [see Contraindications (4), Warnings and Precautions (5.1), and Adverse Reactions (6.2)].

Eosinophils

DUPIXENT-treated subjects had a greater initial increase from baseline in blood eosinophil count compared to subjects treated with placebo. In subjects with atopic dermatitis (Trial 1, 2 and 4), the mean and median increases in blood eosinophils from baseline to Week 4 were 100 and 0 cells/mcL, respectively. In adult and adolescent subjects with asthma (AS Trial 1 and 2), 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 (AS Trial 4), the mean and median increases in blood eosinophils from baseline to Week 12 were 124 and 0 cells/mcL, respectively. In subjects with CRSwNP (CSNP Trial 1 and 2), the mean and median increases in blood eosinophils from baseline to Week 16 were 150 and 50 cells/mcL, respectively.

Across all indications, the incidence of treatment-emergent eosinophilia (?500 cells/mcL) was similar in DUPIXENT and placebo groups. Treatment-emergent eosinophilia (?5,000 cells/mcL) was reported in <3% of DUPIXENT-treated patients and <0.5% in placebo-treated patients (Trials 1, 2, and 4; AS Trial 1, 2, and 4; CSNP Trial 1 and 2). Blood eosinophil counts declined to near baseline levels during study treatment [see Warnings and Precautions (5.3)].

6.2 Immunogenicity

(Additions and/or revisions underlined)

Similar results were observed in pediatric subjects (6 to 11 years of age) with atopic dermatitis who received DUPIXENT 200 mg Q2W or 300 mg Q4W for 16 weeks and patients (6 to 11 years of age) with asthma who received DUPIXENT 100 mg Q2W or 200 mg Q2W for 52 weeks.

8 Use in Specific Populations

8.5 Pediatric Use

(Additions and/or revisions underlined)

The safety and effectiveness of DUPIXENT for an add-on maintenance treatment in patients with moderate-to-severe asthma characterized by an eosinophilic phenotype or with oral corticosteroid dependent asthma have been established in pediatric patients 6 years of age and older. Use of DUPIXENT for this indication is supported by evidence from adequate and well- controlled studies in adult and pediatric patients 6 years and older [see Clinical Studies (14.2)].

Adolescent patients aged 12 to 17 years:

A total of 107 adolescents aged 12 to 17 years with moderate-to-severe asthma were enrolled in AS Trial 2 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 adolescents and adults. For both the 200 mg and 300 mg Q2W doses, improvements in FEV1 (LS mean change from baseline at Week 12) were observed (0.36 L and 0.27 L, respectively). For the 200 mg Q2W dose, subjects had a reduction in the rate of severe exacerbations that was consistent with adults. Dupilumab exposure was higher in adolescent patients than that in adults at the respective dose level which was mainly accounted for by difference in body weight [see Clinical Pharmacology (12.3)]. The adverse event profile in adolescents was generally similar to the adults [see Adverse Reactions (6.1)].

Pediatric Patients aged 6 to 11 years:

A total of 408 pediatric patients aged 6 to 11 years with moderate-to-severe asthma were enrolled in AS Trial 4, which evaluated doses of 100 mg Q2W or 200 mg Q2W. Improvement in asthma exacerbations and lung function were demonstrated [see Clinical Studies (14.2)]. The effectiveness of DUPIXENT 300 mg Q4W in patients aged 6 to 11 years old with body weight 15 to <30 kg was extrapolated from efficacy of 100 mg Q2W in AS Trial 4 with support from population pharmacokinetic analyses showing higher drug exposure levels with 300 mg Q4W [see Clinical Pharmacology (12.3)]. Patients who completed the treatment period of the AS Trial 4 study could participate in the open-label extension study (AS Trial 5). Eighteen patients (?15 to <30 kg) out of 365 patients were exposed to 300 mg Q4W in this study, and the safety profile in these eighteen patients was consistent with that seen in AS Trial 4. Additional safety for DUPIXENT 300 mg Q4W is based upon available safety information from the pediatric atopic dermatitis indication [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)].

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

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Patient Counseling Information

(Newly added information)

Parasitic (Helminth) Infections

Advise patients to notify their healthcare provider if they present with clinical features consistent with helminthic infection [see Warnings and Precautions (5.7)].

Patient Information

(Newly added section)

10/01/2021 (SUPPL-35)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

… Trials 1, 2, and 4 compared the safety of DUPIXENT monotherapy to placebo through Week 16. Trial 3 compared the safety of DUPIXENT + TCS to placebo + TCS through Week 52.

Trial 9 is a multicenter, open-label extension (OLE) study which assessed the long-term safety of repeat doses of DUPIXENT (through 148 weeks of treatment) in adults with moderate-to-severe AD who had previously participated in controlled studies of DUPIXENT or had been screened for Trial 1 or Trial 2. The safety data in Trial 9 reflect exposure to DUPIXENT in 2677 subjects, including 2254 exposed for at least 52 weeks, 1192 exposed for at least 100 weeks and 357 exposed for at least 148 weeks. In Trial 9, 99.7% of subjects were exposed to DUPIXENT 300 mg weekly dosing (QW).

Newly added information:

Safety through 148 Weeks (Trial 9)

The long-term safety profile observed in this trial through 148 weeks was generally consistent with the safety profile of DUPIXENT observed in controlled studies.

Specific Adverse Reactions

Additions and/or revisions underlined:

Conjunctivitis and Keratitis

In adult subjects with atopic dermatitis, conjunctivitis was reported in 10% (34 per 100 subject- years) in the 300 mg Q2W dose group and in 2% of the placebo group (8 per 100 subject-years) during the 16-week treatment period of the monotherapy trials (Trials 1, 2, and 4). During the 52-week treatment period of concomitant therapy atopic dermatitis trial (Trial 3), conjunctivitis was reported in 16% of the DUPIXENT 300 mg Q2W + TCS group (20 per 100 subject-years) and in 9% of the placebo + TCS group (10 per 100 subject-years). During the long-term OLE trial with data through 148 weeks (Trial 9), conjunctivitis was reported in 20% of the DUPIXENT group (12 per 100 subject-years) … In the 52-week atopic dermatitis DUPIXENT + topical corticosteroids (TCS) atopic dermatitis trial (Trial 3), keratitis was reported in 4% of the DUPIXENT + TCS group (4 per 100 subject-years) and in 2% of the placebo + TCS group (2 per 100 subject-years). During the long-term OLE trial with data through 148 weeks (Trial 9), keratitis was reported in 3% of the DUPIXENT group (2 per 100 subject-years). Most subjects with conjunctivitis or keratitis recovered or were recovering during the treatment period.

Eczema Herpeticum and Herpes Zoster

The rate of eczema herpeticum was similar in the placebo and DUPIXENT groups in the atopic dermatitis trials. The rates remained stable through 148 weeks in the long-term OLE trial (Trial 9).

Herpes zoster was reported in <1% of the DUPIXENT groups (1 per 100 subject-years) and in

<1% of the placebo group (1 per 100 subject-years) in the 16-week atopic dermatitis monotherapy trials. In the 52-week DUPIXENT + TCS atopic dermatitis trial, herpes zoster was reported in 1% of the DUPIXENT + TCS group (1 per 100 subject-years) and 2% of the placebo

+ TCS group (2 per 100 subject-years). During the long-term OLE trial with data through 148 weeks (Trial 9), 1.9% of DUPIXENT-treated subjects reported herpes zoster (0.99 per 100 subject-years of follow up). Among asthma subjects the frequency of herpes zoster was similar between DUPIXENT and placebo. Among CRSwNP subjects there were no reported cases of herpes zoster or eczema herpeticum.

06/18/2020 (SUPPL-17)

Approved Drug Label (PDF)

8 Use in Specific Populations

Pregnancy

(Newly added information)

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to DUPIXENT during pregnancy.

Healthcare providers and patients may call 1-877-311-8972 or go to https://mothertobaby.org/ongoing-study/dupixent/ to enroll in or to obtain information about the registry.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Patient Counseling Information

(Newly added information)

Pregnancy Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to DUPIXENT during pregnancy. Encourage participation and advise patients about how they may enroll in the registry [see Use in Specific Populations (8.1)].

Patient Information

(Additions and/or revisions underlined)

Pregnancy Exposure Registry. There is a pregnancy exposure registry for women who take DUPIXENT during pregnancy.

The purpose of this registry is to collect information about the health of you and your baby. Your healthcare provider can enroll

you in this registry. You may also enroll yourself or get more information about the registry by calling 1-877-311-8972 or going

to https://mothertobaby.org/ongoing-study/dupixent/.

How should I use DUPIXENT?

• See the detailed “Instructions for Use” that comes with DUPIXENT for information on how to prepare and inject

DUPIXENT and how to properly store and throw away (dispose of) used DUPIXENT pre-filled syringes and pre-filled

pens.

• DUPIXENT comes as a single-dose pre-filled syringe with needle shield or as a pre-filled pen.

If your dose schedule is every other week and you miss a dose of DUPIXENT: Give the DUPIXENT injection within 7 days

from the missed dose, then continue with your original schedule. If the missed dose is not given within 7 days, wait until the

next scheduled dose to give your DUPIXENT injection.

• If your dose schedule is every 4 weeks and you miss a dose of DUPIXENT: Give the DUPIXENT injection within 7 days

from the missed dose, then continue with your original schedule. If the missed dose is not given within 7 days, start a new

every 4 week dose schedule from the time you remember to take your DUPIXENT injection.

05/26/2020 (SUPPL-20)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

Adolescents with Atopic Dermatitis (12 to 17 Years of Age)

The safety of DUPIXENT was assessed in a trial of 250 subjects 12 to 17 years of age with moderate-to-severe atopic dermatitis (Trial 6).

Newly added information:

Children with Atopic Dermatitis (6 to 11 Years of Age)

The safety of DUPIXENT with concomitant TCS was assessed in a trial of 367 subjects 6 to 11 years of age with severe atopic dermatitis (Trial 8). The safety profile of DUPIXENT + TCS in these subjects through Week 16 was similar to the safety profile from trials in adults and adolescents with atopic dermatitis.

The long-term safety of DUPIXENT + TCS was assessed in an open-label extension study of 368 subjects 6 to 11 years of age with atopic dermatitis (Trial 7). Among subjects who entered this study, 110 (30%) had moderate and 72 (20%) had severe atopic dermatitis at the time of enrollment in Trial 7. The safety profile of DUPIXENT + TCS in subjects followed through Week 52 was similar to the safety profile observed through Week 16 in Trial 8. The long-term safety profile of DUPIXENT + TCS observed in pediatric subjects was consistent with that seen in adults and adolescents with atopic dermatitis [see Pediatric Use (8.4)].

Following Table 4: Adverse Reactions Occurring in greater than or equal to 1% of the DUPIXENT Group in CRSwNP Trials 1 and 2 and Greater than Placebo (24 Week Safety Pool, additions and/or revisions underlined:

Specific Adverse Reactions

Conjunctivitis and Keratitis

During the 52-week treatment period of concomitant therapy atopic dermatitis trial (Trial 3), conjunctivitis was reported in 16% of the DUPIXENT 300 mg Q2W + TCS group (20 per 100 subject-years) and in 9% of the placebo + TCS group (10 per 100 subject-years). In DUPIXENT atopic dermatitis monotherapy trials (Trials 1, 2, and 4) through Week 16, keratitis was reported in <1% of the DUPIXENT group (1 per 100 subject-years) and in 0% of the placebo group (0 per 100 subject-years). In the 52-week atopic dermatitis DUPIXENT + topical corticosteroids (TCS) atopic dermatitis trial (Trial 3), keratitis was reported in 4% of the DUPIXENT + TCS group (12 per 100 subject-years) and in 0% of the placebo + TCS group (0 per 100 subject-years). Most subjects with conjunctivitis or keratitis recovered or were recovering during the treatment period.

6.2 Immunogenicity

Additions and/or revisions underlined:

Approximately 5% of subjects with atopic dermatitis, asthma, or CRSwNP who received DUPIXENT 300 mg Q2W for 52 weeks developed antibodies to dupilumab; approximately 2% exhibited persistent ADA responses, and approximately 2% had neutralizing antibodies. Similar results were observed in pediatric subjects (6 to 11 years of age) with atopic dermatitis who received DUPIXENT 200 mg Q2W or 300 mg Q4W for 16 weeks …

… Regardless of age or population, approximately 2 to 4% of subjects in placebo groups were positive for antibodies to DUPIXENT; approximately 2% exhibited persistent ADA responses, and approximately 1% had neutralizing antibodies …

… Two adult subjects who experienced high titer antibody responses developed serum sickness or serum sickness-like reactions during DUPIXENT therapy.

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

Atopic Dermatitis

The safety and efficacy of DUPIXENT have been established in pediatric patients 6 years of age and older with moderate-to-severe atopic dermatitis.

Use of DUPIXENT in this age group is supported by Trial 6 which included 251 adolescents ages 12 to 17 years old with moderate-to-severe atopic dermatitis and Trial 8 which included 367 children ages 6 to 11 years old with severe atopic dermatitis. The safety and efficacy were generally consistent between pediatric and adult patients [see Adverse Reactions (6.1) and Clinical Studies (14.1)].

Use is also supported by Trial 7, an open-label extension study that enrolled subjects who completed Trials 6 and 8. Trial 7 included 136 adolescents from Trial 6 and 110 children from Trial 8 with moderate atopic dermatitis at enrollment into the extension study. Trial 7 included 64 adolescents from Trial 6 and 72 children from Trial 8 with severe atopic dermatitis at enrollment. No new safety signals were identified in Trial 7[see Adverse Reactions (6.1)].

Safety and efficacy in pediatric patients <6 years of age with atopic dermatitis have not been established.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT INFORMATION

Additions and/or revisions underlined:

What is DUPIXENT?

DUPIXENT is a prescription medicine used:

• to treat people aged 6 years and older with moderate-to-severe atopic dermatitis (eczema) …

• It is not known if DUPIXENT is safe and effective in children with atopic dermatitis under 6 years of age.

• It is not known if DUPIXENT is safe and effective in children with asthma under 12 years of age.

06/26/2019 (SUPPL-14)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2Conjunctivitis and Keratitis

(additions underlined)

…

In 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. There were no cases of keratitis reported in the CRSwNP development program.

…

5.3 Eosinophilic Conditions

(additions underlined)

… Cases of eosinophilic pneumonia were reported in adult patients who participated in the asthma development program and cases of vasculitis consistent with eosinophilic granulomatosis with polyangiitis have been reported with DUPIXENT in adult patients who participated in the asthma development program as well as in adult patients with co-morbid asthma in the CRSwNP development program. A causal association between DUPIXENT and these conditions has not been established.

5.6 Patients with Co-morbid Asthma

(addition underlined)

Advise patients with atopic dermatitis or CRSwNP who have co-morbid asthma not to adjust or stop their asthma treatments without consultation with their physicians.

6 Adverse Reactions

6.1 Clinical Trials Experience

(additions underlined)

…

 

Chronic Rhinosinusitis with Nasal Polyposis

A total of 722 adult subjects with chronic rhinosinusitis with nasal polyposis (CRSwNP) were evaluated in 2 randomized, placebo-controlled, multicenter trials of 24 to 52 weeks duration (CSNP Trials 1 and 2). The safety pool consisted of data from the first 24 weeks of treatment from both studies.

In the safety pool, the proportion of subjects who discontinued treatment due to adverse events was 5% of the placebo group and 2% of the DUPIXENT 300 mg Q2W group.

Table 4 summarizes the adverse reactions that occurred at a rate of at least 1% in subjects treated with DUPIXENT and at a higher rate than in their respective comparator group in CSNP Trials 1 and 2.

(Please refer to label to view Table 4)

The safety profile of DUPIXENT through Week 52 was generally consistent with the safety profile observed at Week 24.

Specific Adverse Reactions

Conjunctivitis

… In the 52-week CRSwNP study (CSNP Trial 2), the frequency of conjunctivitis was 3% in the DUPIXENT subjects and 1% in the placebo subjects; all of these subjects recovered.

Eczema Herpeticum and Herpes Zoster

… Among CRSwNP subjects there were no reported cases of herpes zoster or eczema herpeticum.

 

…

Eosinophils

... In subjects with CRSwNP, the mean and median increases in blood eosinophils from baseline to Week 16 were 150 and 50 cells/mcL, respectively.

Across all indications, the incidence of treatment-emergent eosinophilia (?500 cells/mcL) was similar in DUPIXENT and placebo groups.

…

 

Cardiovascular

…

In the 24-week placebo controlled trial in subjects with CRSwNP (CSNP Trial 1), 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 subjects with CRSwNP (CSNP Trial 2), there were no cases of cardiovascular thromboembolic events (cardiovascular deaths, non-fatal myocardial infarctions, and non-fatal strokes) reported in any treatment arm.

8 Use in Specific Populations

8.4 Pediatric Use

(additions underlined)

…

CRSwNP

CRSwNP does not normally occur in children. Safety and efficacy in pediatric patients (<18 years of age) with CRSwNP have not been established.

8.5 Geriatric Use

(additions underlined)

…

Of the 440 subjects with CRSwNP exposed to DUPIXENT, a total of 79 subjects were 65 years or older. Efficacy and safety in this age group were similar to the overall study population.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT INFORMATION

(additions underlined)

…

The most common side effects of DUPIXENT include:

…

 

• high count of a certain white blood cell (eosinophilia)

• trouble sleeping (insomnia)

• toothache

• gastritis

• joint pain (arthralgia)

…

03/11/2019 (SUPPL-12)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

Adolescents with Atopic Dermatitis

The safety of DUPIXENT was assessed in a trial of 250 subjects 12 to 17 years of age with moderate-to-severe atopic dermatitis (Trial 6). The safety profile of DUPIXENT in these subjects through Week 16 was similar to the safety profile from studies in adults with atopic dermatitis.

The long-term safety of DUPIXENT was assessed in an open-label extension study in subjects 12 to 17 years of age with moderate-to-severe atopic dermatitis (Trial 7). The safety profile of DUPIXENT in subjects followed through Week 52 was similar to the safety profile observed at Week 16 in Trial 6. The long-term safety profile of DUPIXENT observed in adolescents was consistent with that seen in adults with atopic dermatitis.

6.2 Immunogenicity

(Additions and/or revisions are underlined)

Approximately 16% of adolescent subjects with atopic dermatitis who received DUPIXENT 300 mg or 200 mg Q2W for 16 weeks developed antibodies to dupilumab; approximately 3% exhibited persistent ADA responses, and approximately 5% had neutralizing antibodies.

Approximately 4% of adolescent subjects with atopic dermatitis in the placebo group were positive for antibodies to DUPIXENT; approximately 1% exhibited persistent ADA responses, and approximately 1% had neutralizing antibodies.

8 Use in Specific Populations

8.4 Pediatric Use

(Additions and/or revisions are underlined)

Atopic Dermatitis

The safety and efficacy of DUPIXENT have been established in pediatric patients 12 years of age and older with moderate-to-severe atopic dermatitis. A total of 251 adolescents ages 12 to 17 years old with moderate-to-severe atopic dermatitis were enrolled in Trial 6. The safety and efficacy were generally consistent between adolescents and adults. Safety and efficacy in pediatric patients (<12 years of age) with atopic dermatitis have not been established.

10/19/2018 (SUPPL-7)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Hypersensitivity

Additions and/or revisions are underlined)

Hypersensitivity reactions, including generalized urticaria, rash, erythema nodosum and serum sickness or serum sickness-like reactions, were reported in less than 1% of subjects who received DUPIXENT in clinical trials. Two subjects in the atopic dermatitis development program experienced serum sickness or serum sickness-like reactions that were associated with high titers of antibodies to dupilumab.  One subject in the asthma development program experienced anaphylaxis. If a clinically significant hypersensitivity reaction occurs, institute appropriate therapy and discontinue DUPIXENT.

5.2 Conjunctivitis and Keratitis

(Additions and/or revisions are underlined)

Conjunctivitis and keratitis occurred more frequently in atopic dermatitis subjects who received DUPIXENT. Conjunctivitis was the most frequently reported eye disorder. Most subjects with conjunctivitis recovered or were recovering during the treatment period. Among asthma subjects the frequency of conjunctivitis was similar between DUPIXENT and placebo.

Keratitis was reported in <1% of the DUPIXENT group (1 per 100 subject-years) and in 0% of the placebo group (0 per 100 subject-years) in the 16-week atopic dermatitis monotherapy trials. In the 52-week DUPIXENT + topical corticosteroids (TCS) atopic dermatitis trial, keratitis was reported in 4% of the DUPIXENT + TCS group (12 per 100 subject-years) and in 0% of the placebo + TCS group (0 per 100 subject-years). Most subjects with keratitis recovered or were recovering during the treatment period. Among asthma subjects the frequency of keratitis was similar between DUPIXENT and placebo.

5.3 Eosinophilic Conditions

(Newly Added Subsection)

Patients being treated for asthma may present with serious systemic eosinophilia sometimes presenting with clinical features of eosinophilic pneumonia or vasculitis consistent with eosinophilic granulomatosis with polyangiitis, conditions which are often treated with systemic corticosteroid therapy. These events may be associated with the reduction of oral corticosteroid therapy. Physicians should be alert to vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients with eosinophilia. Cases of eosinophilic pneumonia and cases of vasculitis consistent with eosinophilic granulomatosis with polyangiitis have been reported with DUPIXENT in adult patients who participated in the asthma development program. A causal association between DUPIXENT and these conditions has not been established.

5.4 Acute Asthma Symptoms or Deteriorating Disease

(Newly Added Subsection)

DUPIXENT should not be used to treat acute asthma symptoms or acute exacerbations. Do not use DUPIXENT to treat acute bronchospasm or status asthmaticus. Patients should seek medical advice if their asthma remains uncontrolled or worsens after initiation of treatment with DUPIXENT.

5.5 Reduction of Corticosteroid Dosage

(Newly Added Subsection)

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 physician. Reduction in corticosteroid dose may be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy.

5.6 Atopic Dermatitis Patients with Comorbid Asthma

(Additions and/or revisions are underlined)

Advise atopic dermatitis patients with comorbid asthma not to adjust or stop their asthma treatments without consultation with their physicians.

5.7 Parasitic (Helminth) Infections

(Additions and/or revisions are underlined)

Patients with known helminth infections were excluded from participation in clinical studies. It is unknown if DUPIXENT will influence the immune response against helminth infections.

Treat patients with pre-existing helminth infections before initiating therapy with DUPIXENT. If patients become infected while receiving treatment with DUPIXENT and do not respond to anti- helminth treatment, discontinue treatment with DUPIXENT until the infection resolves.

6 Adverse Reactions

6.1 Clinical Trials Experience

(Extensive changes; please refer to labeling)

6.2 Immunogenicity

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Approximately 76% of subjects with atopic dermatitis or asthma who received DUPIXENT 300 mg Q2W for 52 weeks developed antibodies to dupilumab. Of the; approximately 2% exhibited persistent ADA responses, and approximately 2% had neutralizing antibodies.

Approximately 9% of subjects with asthma who received DUPIXENT 200 mg Q2W for 52 weeks developed antibodies to dupilumab; approximately 4% exhibited persistent ADA responses, and approximately 4% had neutralizing antibodies.

Approximately 5% of subjects in the placebo groups in the 52-week studies were positive for antibodies to DUPIXENT; approximately 2% exhibited persistent ADA responses, and approximately 1% had neutralizing antibodies.

In subjects who received DUPIXENT, development of high titer antibodies to dupilumab was associated with lower serum dupilumab concentrations.

Two subjects who experienced high titer antibody responses developed serum sickness or serum sickness-like reactions during DUPIXENT therapy.

8 Use in Specific Populations

8.1 Pregnancy

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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…

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.

8.2 Lactation

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Risk Summary

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

8.4 Geriatric Use

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Of the 1977 subjects with asthma exposed to DUPIXENT, a total of 240 subjects were 65 years or older. Efficacy and safety in this age group was similar to the overall study population.

8.4 Pediatric Use

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Atopic Dermatitis

Safety and efficacy in pediatric patients (<18 years of age) with atopic dermatitis have not been established.

Asthma

A total of 107 adolescents aged 12 to 17 years with moderate to severe asthma were enrolled in AS Trial 2 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 adolescents and adults. For both the 200 mg and 300 mg Q2W doses, improvements in FEV1 (LS mean change from baseline at Week 12) were observed (0.36 L and 0.27 L, respectively). For the 200 mg Q2W dose, subjects had a reduction in the rate of severe exacerbations that was consistent with adults. Safety and efficacy in pediatric patients (<12 years of age) with asthma have not been established. Dupilumab exposure was higher in

adolescent patients than that in adults at the respective dose level which was mainly accounted for by difference in body weight.

The adverse event profile in adolescents was generally similar to the adults.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

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Eosinophilic Conditions

Advise patients to notify their healthcare provider if they present with clinical features of eosinophilic pneumonia or vasculitis consistent with eosinophilic granulomatosis with polyangiitis.

Not for Acute Asthma Symptoms or Deteriorating Disease

Inform patients that DUPIXENT does not treat acute asthma symptoms or acute exacerbations. Inform patients to seek medical advice if their asthma remains uncontrolled or worsens after initiation of treatment with DUPIXENT.

Reduction in Corticosteroid Dosage

Inform patients to not discontinue systemic or inhaled corticosteroids except under the direct supervision of a physician. Inform patients that reduction in corticosteroid dose may be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy.

Atopic Dermatitis Patients with Comorbid Asthma

Advise atopic dermatitis patients with comorbid asthma not to adjust or stop their asthma treatment without talking to their physicians.

Patient Information

(Newly added - Patient Information)