dupilumab: prescribing information – dosing, contraindications, interactions, side effects

Atopic dermatitis

Adults and adolescents
Dupixent is indicated for the treatment of moderate-to-severe atopic dermatitis in adults and adolescents 12 years and older who are candidates for systemic therapy.

Children 6 months to 11 years of age
Dupixent is indicated for the treatment of severe atopic dermatitis in children 6 months to 11 years old who are candidates for systemic therapy.

Asthma

Adults and adolescents
Dupixent is indicated in adults and adolescents 12 years and older as add-on maintenance treatment for severe asthma with type 2 inflammation characterised by raised blood eosinophils and/or raised fraction of exhaled nitric oxide (FeNO), see section 5.1, who are inadequately controlled with high dose inhaled corticosteroids (ICS) plus another medicinal product for maintenance treatment.

Children 6 to 11 years of age
Dupixent is indicated in children 6 to 11 years old as add-on maintenance treatment for severe asthma with type 2 inflammation characterised by raised blood eosinophils and/or raised fraction of exhaled nitric oxide (FeNO), see section 5.1, who are inadequately controlled with medium to high dose inhaled corticosteroids (ICS) plus another medicinal product for maintenance treatment.

Chronic rhinosinusitis with nasal polyposis (CRSwNP)

Dupixent is indicated as an add-on therapy with intranasal corticosteroids for the treatment of adults with severe CRSwNP for whom therapy with systemic corticosteroids and/or surgery do not provide adequate disease control.

Prurigo Nodularis (PN)

Dupixent is indicated for the treatment of adults with moderate-to-severe prurigo nodularis (PN) who are candidates for systemic therapy.

Eosinophilic esophagitis (EoE)

Dupixent is indicated for the treatment of eosinophilic esophagitis in adults, adolescents and children aged 1 year and older, weighing at least 15 kg, who are inadequately controlled by, are intolerant to, or who are not candidates for conventional medicinal therapy (see section 5.1).

Chronic obstructive pulmonary disease (COPD)

Dupixent is indicated in adults as add-on maintenance treatment for uncontrolled chronic obstructive pulmonary disease (COPD) characterised by raised blood eosinophils on a combination of an inhaled corticosteroid (ICS), a long-acting beta2-agonist (LABA), and a long-acting muscarinic antagonist (LAMA), or on a combination of a LABA and a LAMA if ICS is not appropriate (see Section 5.1).

Chronic Spontaneous Urticaria (CSU)

Dupixent is indicated for the treatment of moderate to severe chronic spontaneous urticaria in adults, adolescents, and children (2 years and above) with inadequate response to H1 antihistamines and who are naive to anti-IgE therapy for CSU.

Atopic dermatitis

Adults and adolescents
Dupixent is indicated for the treatment of moderate-to-severe atopic dermatitis in adults and adolescents 12 years and older who are candidates for systemic therapy.

Children 6 months to 11 years of age
Dupixent is indicated for the treatment of severe atopic dermatitis in children 6 months to 11 years old who are candidates for systemic therapy.

Asthma

Adults and adolescents
Dupixent is indicated in adults and adolescents 12 years and older as add-on maintenance treatment for severe asthma with type 2 inflammation characterised by raised blood eosinophils and/or raised fraction of exhaled nitric oxide (FeNO), see section 5.1, who are inadequately controlled with high dose inhaled corticosteroids (ICS) plus another medicinal product for maintenance treatment.

Children 6 to 11 years of age

Dupixent is indicated in children 6 to 11 years old as add-on maintenance treatment for severe asthma with type 2 inflammation characterised by raised blood eosinophils and/or raised fraction of exhaled nitric oxide (FeNO), see section 5.1, who are inadequately controlled with medium to high dose inhaled corticosteroids (ICS) plus another medicinal product for maintenance treatment.

Eosinophilic esophagitis (EoE)

Dupixent is indicated for the treatment of eosinophilic esophagitis in adults, adolescents and children aged 1 year and older, weighing at least 15 kg, who are inadequately controlled by, are intolerant to, or who are not candidates for conventional medicinal therapy (see section 5.1).Error! No document variable supplied.

Chronic Spontaneous Urticaria (CSU)

Dupixent is indicated for the treatment of moderate to severe chronic spontaneous urticaria in adults, adolescents, and children (2 years and above) with inadequate response to H1 antihistamines and who are naive to anti-IgE therapy for CSU.

Treatment should be initiated by healthcare professionals experienced in the diagnosis and treatment of conditions for which dupilumab is indicated (see section 4.1).

Posology

Atopic dermatitis

Adults
The recommended dose of dupilumab for adult patients is an initial dose of 600 mg (two 300 mg injections), followed by 300 mg given every other week administered as subcutaneous injection.

Adolescents (12 to 17 years of age)
The recommended dose of dupilumab for adolescent patients 12 to 17 years of age is specified in Table 1.

Table 1: Dose of dupilumab for subcutaneous administration in adolescent patients 12 to 17 years of age with atopic dermatitis

Body weight of patient
Initial dose
Subsequent doses
(every other week) less than 60 kg
400 mg (two 200 mg injections)
200 mg
60 kg or more
600 mg (two 300 mg injections)
300 mg

Children 6 to 11 years of age
The recommended dose of dupilumab for children 6 to 11 years of age is specified in Table 2.

Table 2: Dose of dupilumab for subcutaneous administration in children 6 to 11 years of age with atopic dermatitis Body weight of patient Initial dose Subsequent doses

15 kg to less than 60 kg
300 mg (one 300 mg injection) on Day 1, followed by 300 mg on Day 15
300 mg every 4 weeks (Q4W)*, starting 4 weeks after Day 15 dose
60 kg or more
600 mg (two 300 mg injections)
300 mg every other week (Q2W)
*the dose may be increased to 200 mg Q2W in patients with body weight of 15 kg to less than 60 kg based on physician’s assessment.
Children 6 months to 5 years of age
The recommended dose of dupilumab for children 6 months to 5 years of age is specified in Table 3.

Table 3: Dose of dupilumab for subcutaneous administration in children 6 months to 5 years of age with atopic dermatitis Body Weight of Patient Initial Dose Subsequent Doses 5 kg to less than 15 kg 200 mg (one 200 mg injection) 200 mg every 4 weeks (Q4W) 15 kg to less than 30 kg 300 mg (one 300 mg injection) 300 mg every 4 weeks (Q4W)

Dupilumab 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.

Consideration should be given to discontinuing treatment in patients who have shown no response after 16 weeks of treatment for atopic dermatitis. Some patients with initial partial response may subsequently improve with continued treatment beyond 16 weeks. If dupilumab treatment interruption becomes necessary, patients can still be successfully re-treated.

Asthma

Adults and adolescents
The recommended dose of dupilumab for adults and adolescents (12 years of age and older) is:
- For patients with severe asthma and who are on oral corticosteroids or for patients with severe asthma and co-morbid moderate-to-severe atopic dermatitis or adults with co-morbid severe chronic rhinosinusitis with nasal polyposis, an initial dose of 600 mg (two 300 mg injections), followed by 300 mg every other week administered as subcutaneous injection.
- For all other patients, an initial dose of 400 mg (two 200 mg injections), followed by 200 mg every other week administered as subcutaneous injection.

Children 6 to 11 years of age
The recommended dose of dupilumab for paediatric patients 6 to 11 years of age is specified in Table 4.

Table 4: Dose of dupilumab for subcutaneous administration in children 6 to 11 years of age with asthma

Body weight
Initial and subsequent doses
15 to less than 30 kg
300 mg every four weeks (Q4W)
30 kg to less than 60 kg

200 mg every other week (Q2W) or
300 mg every four weeks (Q4W)
60 kg or more
200 mg every other week (Q2W)

For paediatric patients (6 to 11 years old) with asthma and co-morbid severe atopic dermatitis, as per approved indication, the recommended dose is provided in Table 2.

Patients receiving concomitant oral corticosteroids may reduce their steroid dose once clinical improvement with dupilumab has occurred (see section 5.1). It is recommended that steroid reductions be accomplished gradually (see section 4.4).

Dupilumab is intended for long-term treatment. The need for continued therapy should be considered at least on an annual basis as determined by physician assessment of the patient’s level of asthma control.

Chronic rhinosinusitis with nasal polyposis (CRSwNP)

The recommended dose of dupilumab for adult patients is an initial dose of 300 mg followed by 300 mg given every other week.

Dupilumab is intended for long-term treatment. Consideration should be given to discontinuing treatment in patients who have shown no response after 24 weeks of treatment for CRSwNP. Some patients with initial partial response may subsequently improve with continued treatment beyond 24 weeks.

Prurigo Nodularis (PN)

The recommended dose of dupilumab for adult patients is an initial dose of 600 mg (two 300 mg injections), followed by 300 mg given every other week.
Dupilumab can be used with or without topical corticosteroids.

PN clinical trial data are available for patients treated up to 24 weeks. Consideration should be given to discontinuing treatment in patients who have shown no response after 24 weeks of treatment for PN.

Eosinophilic esophagitis (EoE)

The recommended dose of dupilumab for adults, adolescents and children 1 year of age and older, weighing at least 15 kg, is specified in Table 5.
Table 5: Dose of dupilumab for subcutaneous administration in adults, adolescents and children 1 year of age and older with EoE Body Weight Dose 15 to less than 30 kg 200 mg every other week (Q2W) 30 to less than 40 kg 300 mg every other week (Q2W) 40 kg or more 300 mg every week (QW)

Dupilumab is intended for long-term treatment.

Chronic obstructive pulmonary disease (COPD)

The recommended dose of dupilumab for adult patients is 300 mg given every other week.

Dupilumab is intended for long-term treatment. Dosing beyond 52 weeks has not been studied.
Consideration should be given to discontinuing treatment in patients who have shown no response after 52 weeks of treatment for COPD.

Chronic Spontaneous Urticaria (CSU)

Adults
The recommended dose of dupilumab for adult patients is an initial dose of 600 mg (two 300 mg injections), followed by 300 mg given every other week.

Children and Adolescents (6 to 17 years of age)
The recommended dose of dupilumab for children and adolescent patients 6 to 17 years of age is specified in Table 6.

Table 6: Dose of dupilumab for subcutaneous administration in children and adolescent patients 6 to 17 years of age with CSU* Body Weight Initial Dose Subsequent Doses 15 to less than 30 kg 300 mg (one 300 mg injection) on Day 1, followed by 300 mg on Day 15 300 mg every four weeks (Q4W), starting 4 weeks after Day 15 dose 30 to less than 60 kg 400 mg (two 200 mg injections) 200 mg every other week (Q2W) 60 kg or more 600 mg (two 300 mg injections) 300 mg every other week (Q2W) *For patients weighing 5 to less than 15 kg the recommended dose is 200 mg every 4 weeks (Q4W).
Children 2 to 5 years of age
The recommended dose of dupilumab for children 2 to 5 years of age is specified in Table 7.

Table 7: Dose of dupilumab for subcutaneous administration in children 2 to 5 years of age with CSU Body Weight Initial and subsequent doses 5 to less than 15 kg 200 mg every four weeks (Q4W) 15 to less than 30 kg 300 mg every four weeks (Q4W)

Dupilumab dosing beyond 24 weeks has not been studied in CSU. After 24 weeks, the need for continued therapy should be periodically assessed. Consideration should be given to discontinuing treatment in patients who have shown no response after 24 weeks of treatment for CSU.

Missed dose

If a weekly dose is missed, administer the dose as soon as possible, starting a new schedule based on this date.

If an every other week dose is missed, administer the injection within 7 days from the missed dose and then resume the patient's original schedule. If the missed dose is not administered within 7 days, wait until the next dose on the original schedule.

If an every 4 week dose is missed, administer the injection within 7 days from the missed dose and then resume the patient's original schedule. If the missed dose is not administered within 7 days, administer the dose, starting a new schedule based on this date.

Special populations

Elderly
No dose adjustment is recommended for elderly (≥ 65 years) patients (see section 5.2).

Renal impairment
No dose adjustment is needed in patients with mild or moderate renal impairment. Very limited data are available in patients with severe renal impairment (see section 5.2).

Hepatic impairment
No data are available in patients with hepatic impairment (see section 5.2).

Body weight
No dose adjustment for body weight is recommended for patients with asthma and EoE 12 years of age and older or in adults with atopic dermatitis, CRSwNP, PN, COPD, or CSU (see section 5.2).

Paediatric population
The safety and efficacy of dupilumab in children with atopic dermatitis below the age of 6 months have not been established. The safety and efficacy of dupilumab in children with a body weight < 5 kg have not been established. No data are available.

The safety and efficacy of dupilumab in children with severe asthma below the age of 6 years have not been established. No data are available.

The safety and efficacy in children with CRSwNP below the age of 18 years have not been established. No data are available.

The safety and efficacy of dupilumab in children with PN below the age of 18 years have not been established. No data are available.

The safety and efficacy of dupilumab in children with EoE below the age of 1 year, or with a body weight < 15 kg have not been established.

The safety and efficacy of dupilumab in children with COPD below the age of 18 years have not been established. No data are available.

The safety and efficacy of dupilumab in children with CSU below the age of 2 years have not been established.

Method of administration

Subcutaneous use

The dupilumab pre-filled pen is for use in adult and paediatric patients aged 2 years and older.
The dupilumab pre-filled syringe is for use in adult and paediatric patients aged 6 months and older. The dupilumab pre-filled pen is not intended for use in children below 2 years of age.

Dupilumab is administered by subcutaneous injection into the thigh or abdomen, except for the 5 cm around the navel. If somebody else administers the injection, the upper arm can also be used.

Each pre-filled syringe or pre-filled pen is for single use only.

For indications that require an initial dose of 600 mg (see Posology in section 4.2), administer two 300 mg injections consecutively in different injection sites.

It is recommended to rotate the injection site with each injection. Avoid injecting dupilumab into skin that is tender, damaged or has bruises or scars.

A patient may self-inject dupilumab or the patient's caregiver may administer dupilumab if their healthcare professional determines that this is appropriate. Provide proper training to patients and/or caregivers on the preparation and administration of dupilumab prior to use according to the Instructions for Use (IFU) section at the end of the package leaflet. In children 12 years of age and older, it is recommended that dupilumab is administered by or under supervision of an adult. In children 6 months to less than 12 years of age, it is recommended that dupilumab is administered by a caregiver.

Treatment should be initiated by healthcare professionals experienced in the diagnosis and treatment of conditions for which dupilumab is indicated (see section 4.1).

Posology

Atopic dermatitis

Adults
The recommended dose of dupilumab for adult patients is an initial dose of 600 mg (two 300 mg injections), followed by 300 mg given every other week administered as subcutaneous injection.

Adolescents (12 to 17 years of age)
The recommended dose of dupilumab for adolescent patients 12 to 17 years of age is specified in Table 1.

Table 1: Dose of dupilumab for subcutaneous administration in adolescent patients 12 to 17 years of age with atopic dermatitis Body weight of patient Initial dose Subsequent doses (every other week) less than 60 kg 400 mg (two 200 mg injections) 200 mg 60 kg or more 600 mg (two 300 mg injections) 300 mg

Children 6 to 11 years of age
The recommended dose of dupilumab for children 6 to 11 years of age is specified in Table 2.

Table 2: Dose of dupilumab for subcutaneous administration in children 6 to 11 years of age with atopic dermatitis Body weight of patient Initial dose Subsequent doses

15 kg to less than 60 kg
300 mg (one 300 mg injection) on Day 1, followed by 300 mg on Day 15
300 mg every 4 weeks (Q4W)*, starting 4 weeks after Day 15 dose
60 kg or more
600 mg (two 300 mg injections)
300 mg every other week (Q2W)

*the dose may be increased to 200 mg Q2W in patients with body weight of 15 kg to less than 60 kg based on physician’s assessment.

Children 6 months to 5 years of age
The recommended dose of dupilumab for children 6 months to 5 years of age is specified in Table 3.

Table 3: Dose of dupilumab for subcutaneous administration in children 6 months to 5 years of age with atopic dermatitis Body Weight of Patient Initial Dose Subsequent Doses 5 kg to less than 15 kg 200 mg (one 200 mg injection) 200 mg every 4 weeks (Q4W) 15 kg to less than 30 kg 300 mg (one 300 mg injection) 300 mg every 4 weeks (Q4W)

Dupilumab 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.

Consideration should be given to discontinuing treatment in patients who have shown no response after 16 weeks of treatment for atopic dermatitis. Some patients with initial partial response may subsequently improve with continued treatment beyond 16 weeks. If dupilumab treatment interruption becomes necessary, patients can still be successfully re-treated.

Asthma

Adults and adolescents
The recommended dose of dupilumab for adults and adolescents (12 years of age and older) is:
- An initial dose of 400 mg (two 200 mg injections), followed by 200 mg given every other week administered as subcutaneous injection.
- For patients with severe asthma and who are on oral corticosteroids or for patients with severe asthma and co-morbid moderate-to-severe atopic dermatitis or adults with co-morbid severe chronic rhinosinusitis with nasal polyposis, an initial dose of 600 mg (two 300 mg injections), followed by 300 mg every other week administered as subcutaneous injection.

Children 6 to 11 years of age
The recommended dose of dupilumab for paediatric patients 6 to 11 years of age is specified in Table 4.

Table 4: Dose of dupilumab for subcutaneous administration in children 6 to 11 years of age with asthma Body weight Initial and subsequent doses 15 to less than 30 kg 300 mg every four weeks (Q4W) 30 kg to less than 60 kg

200 mg every other week (Q2W) or
300 mg every four weeks (Q4W)
60 kg or more
200 mg every other week (Q2W)

For paediatric patients (6 to 11 years old) with asthma and co-morbid severe atopic dermatitis, as per approved indication, the recommended dose is provided in Table 2.

Patients receiving concomitant oral corticosteroids may reduce their steroid dose once clinical improvement with dupilumab has occurred (see section 5.1). It is recommended that steroid reductions be accomplished gradually (see section 4.4).

Dupilumab is intended for long-term treatment. The need for continued therapy should be considered at least on an annual basis as determined by physician assessment of the patient’s level of asthma control.

Eosinophilic esophagitis (EoE)

The recommended dose of dupilumab for adults, adolescents and children 1 year of age and older, weighing at least 15 kg, is specified in Table 5.
Table 5: Dose of dupilumab for subcutaneous administration in adults, adolescents and children 1 year of age and older with EoE Body Weight Dose 15 to less than 30 kg 200 mg every other week (Q2W) 30 to less than 40 kg 300 mg every other week (Q2W) 40 kg or more 300 mg every week (QW)

Dupilumab is intended for long-term treatment.

Chronic Spontaneous Urticaria (CSU)

Adults
The recommended dose of dupilumab for adult patients is an initial dose of 600 mg (two 300 mg injections), followed by 300 mg given every other week.

Children and Adolescents (6 to 17 years of age)
The recommended dose of dupilumab for children and adolescent patients 6 to 17 years of age is specified in Table 6.

Table 6: Dose of dupilumab for subcutaneous administration in children and adolescent patients 6 to 17 years of age with CSU* Body Weight Initial Dose Subsequent Doses 15 to less than 30 kg 300 mg (one 300 mg injection) on Day 1, followed by 300 mg on Day 15 300 mg every four weeks (Q4W), starting 4 weeks after Day 15 dose 30 to less than 60 kg 400 mg (two 200 mg injections) 200 mg every other week (Q2W) 60 kg or more 600 mg (two 300 mg injections) 300 mg every other week (Q2W) *For patients weighing 5 to less than 15 kg the recommended dose is 200 mg every 4 weeks (Q4W).

Children 2 to 5 years of age
The recommended dose of dupilumab for children 2 to 5 years of age is specified in Table 7.

Table 7: Dose of dupilumab for subcutaneous administration in children 2 to 5 years of age with CSU Body Weight Initial and subsequent doses 5 to less than 15 kg 200 mg every four weeks (Q4W) 15 to less than 30 kg 300 mg every four weeks (Q4W)

Dupilumab dosing beyond 24 weeks has not been studied in CSU. After 24 weeks, the need for continued therapy should be periodically assessed. Consideration should be given to discontinuing treatment in patients who have shown no response after 24 weeks of treatment for CSU.

Missed dose

If a weekly dose is missed, administer the dose as soon as possible, starting a new schedule based on this date.

If an every other week dose is missed, administer the injection within 7 days from the missed dose and then resume the patient's original schedule. If the missed dose is not administered within 7 days, wait until the next dose on the original schedule.

If an every 4 week dose is missed, administer the injection within 7 days from the missed dose and then resume the patient's original schedule. If the missed dose is not administered within 7 days, administer the dose, starting a new schedule based on this date.

Special populations

Elderly
No dose adjustment is recommended for elderly (≥ 65 years) patients (see section 5.2).

Renal impairment
No dose adjustment is needed in patients with mild or moderate renal impairment. Very limited data are available in patients with severe renal impairment (see section 5.2).

Hepatic impairment
No data are available in patients with hepatic impairment (see section 5.2).

Body weight
No dose adjustment for body weight is recommended for patients with asthma 12 years of age and older or in adults with atopic dermatitis or CSU (see section 5.2).

Paediatric population
The safety and efficacy of dupilumab in children with atopic dermatitis below the age of 6 months have not been established. The safety and efficacy of dupilumab in children with a body weight < 5 kg have not been established. No data are available.

The safety and efficacy of dupilumab in children with severe asthma below the age of 6 years have not been established. No data are available.

The safety and efficacy of dupilumab in children with EoE below the age of 1 year, or with a body weight < 15 kg have not been established.

The safety and efficacy of dupilumab in children with CSU below the age of 2 years have not been established.

Method of administration

Subcutaneous use

The dupilumab pre-filled pen is for use in adult and paediatric patients aged 2 years and older.
The dupilumab pre-filled syringe is for use in adult and paediatric patients aged 6 months and older. The dupilumab pre-filled pen is not intended for use in children below 2 years of age.

Dupilumab is administered by subcutaneous injection into the thigh or abdomen, except for the 5 cm around the navel. If somebody else administers the injection, the upper arm can also be used.

Each pre-filled syringe or pre-filled pen is for single use only.

For indications that require an initial dose of 400 mg (see Posology in section 4.2), administer two 200 mg injections consecutively in different injection sites.

It is recommended to rotate the injection site with each injection. Avoid injecting dupilumab into skin that is tender, damaged or has bruises or scars.

A patient may self-inject dupilumab or the patient's caregiver may administer dupilumab if their healthcare professional determines that this is appropriate. Provide proper training to patients and/or caregivers on the preparation and administration of dupilumab prior to use according to the Instructions for Use (IFU) section at the end of the package leaflet. In children 12 years of age and older, it is recommended that dupilumab is administered by or under supervision of an adult. In children 6 months to less than 12 years of age, it is recommended that dupilumab is administered by a caregiver.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Summary of the safety profile

The most common adverse reactions in atopic dermatitis, asthma, and CRSwNP are injection site reactions (includes erythema, oedema, pruritus, pain, and swelling), conjunctivitis, conjunctivitis allergic, arthralgia, oral herpes, and eosinophilia. An additional adverse reaction of injection site bruising or haematoma was reported in EoE,COPD and CSU. Additional adverse reactions of injection site induration and injection site dermatitis were reported in COPD and CSU. Additional adverse reactions of injection site rash were reported in COPD. Rare cases of serum sickness, serum sickness- like reaction, anaphylactic reaction, and ulcerative keratitis have been reported (see section 4.4).

Tabulated list of adverse reactions

The dupilumab safety data presented in Table 8 were predominantly derived from 12 randomised, placebo-controlled trials, including atopic dermatitis, asthma, and CRSwNP patients. These studies involved 4,206 patients receiving dupilumab and 2,326 patients receiving placebo during the controlled period are representative of the overall safety profile for dupilumab.

Listed in Table 8 are adverse reactions observed in clinical trials and/or postmarketing setting presented by system organ class and frequency, using the following categories: very common (≥ 1/10);
common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 8: List of adverse reactions
MedDRA System
Organ Class
Frequency
Adverse Reaction
Infections and infestations
Common
Conjunctivitis*
Oral herpes*
Blood and lymphatic system disorders
Common
Eosinophilia
Immune system disorders
Uncommon
Rare

Angioedema#
Anaphylactic reaction
Serum sickness reaction
Serum sickness-like reaction
Eye disorders
Common
Uncommon

Rare
Conjunctivitis allergic*
Keratitis*#
Blepharitis*†
Eye pruritus*†
Dry eye*†
Ulcerative keratitis*†#
Skin and subcutaneous tissue disorders
Uncommon
Facial rash#
Musculoskeletal and connective tissue disorders
Common
Arthralgia#
General disorders and administration site conditions
Common

Injection site reactions (includes erythema, oedema, pruritus, pain, swelling, and bruising)

*eye disorders and oral herpes occurred predominately in atopic dermatitis studies.
†the frequencies for eye pruritus, blepharitis, and dry eye were common and ulcerative keratitis was uncommon in atopic dermatitis studies.
#from postmarketing reporting.

Description of selected adverse reactions

Hypersensitivity
Cases of anaphylactic reaction, angioedema, and serum sickness/serum sickness-like reaction have been reported following administration of dupilumab (see section 4.4).

Conjunctivitis and keratitis related events
Conjunctivitis and keratitis occurred more frequently in atopic dermatitis patients who received dupilumab compared to placebo in atopic dermatitis studies. Most patients with conjunctivitis or keratitis recovered or were recovering during the treatment period. In the long-term OLE atopic dermatitis study (AD-1225) at 5 years, the respective rates of conjunctivitis and keratitis remained similar to those in the dupilumab arm in the placebo controlled atopic dermatitis studies. Among asthma and COPD patients, the frequency of conjunctivitis and keratitis was low and similar between dupilumab and placebo. Among CRSwNP and Prurigo Nodularis (PN) patients the frequency of conjunctivitis was higher in dupilumab than placebo, though lower than that observed in atopic dermatitis patients. Among patients with EoE and CSU, the frequency of conjunctivitis was low and similar between dupilumab and placebo groups. There were no cases of keratitis in the CRSwNP, PN, EoE, and CSU development program (see section 4.4).

Eczema herpeticum
Eczema herpeticum was reported in < 1% of the dupilumab groups and in < 1 % of the placebo group in the 16-week atopic dermatitis monotherapy adult studies. In the 52-week atopic dermatitis dupilumab + TCS adult study, eczema herpeticum was reported in 0.2 % of the dupilumab + TCS group and 1.9 % of the placebo + TCS group. These rates remained stable at 5 years in the long-term OLE study (AD-1225).

Eosinophilia
Dupilumab-treated patients had a greater mean initial increase from baseline in eosinophil count compared to patients treated with placebo in the atopic dermatitis, asthma, CRSwNP, COPD and CSU indications. Eosinophil counts declined to near baseline levels during study treatment and returned to baseline during the asthma open-label extension safety study (TRAVERSE). The mean blood eosinophil levels decreased to below baseline by week 20 and was maintained up to 5 years in the long-term OLE study (AD-1225). Compared to placebo, no increase in mean blood eosinophil counts was observed in PN (PRIME and PRIME2). Mean and median blood eosinophil counts declined to near baseline or remained below baseline levels in EoE and COPD (BOREAS and NOTUS) during study treatment.

Treatment-emergent eosinophilia (≥ 5,000 cells/mcL) was observed in < 3 % of dupilumab-treated patients and < 0.5 % in placebo-treated patients (SOLO1, SOLO2, AD-1021, DRI12544, QUEST, and VOYAGE; SINUS-24 and SINUS-52, PRIME, and PRIME2 studies; TREET Parts A and B;
BOREAS and NOTUS; CUPID Study A, B, and C.)

Treatment-emergent eosinophilia (≥5,000 cells/mcL) was observed in 8.4% of dupilumab-treated patients and 0% in placebo-treated patients in study AD-1539, with median eosinophil counts declining below baseline at end of treatment period.

Infections
In the 16-week atopic dermatitis monotherapy clinical adult studies, serious infections were reported in 1.0 % of patients treated with placebo and 0.5 % of patients treated with dupilumab. In the 52-week atopic dermatitis CHRONOS adult study, serious infections were reported in 0.6 % of patients treated with placebo and 0.2 % of patients treated with dupilumab. The rates of serious infections remained stable at 5 years in the long-term OLE study (AD-1225).

No increase was observed in the overall incidence of infections with dupilumab compared to placebo in the safety pool for asthma clinical studies. In the 24-week safety pool, serious infections were reported in 1.0% of patients treated with dupilumab and 1.1% of patients treated with placebo. In the 52-week QUEST study, serious infections were reported in 1.3% of patients treated with dupilumab and 1.4% of patients treated with placebo.

No increase was observed in the overall incidence of infections with dupilumab compared to placebo in the safety pool for CRSwNP clinical studies. In the 52-week SINUS-52 study, serious infections were reported in 1.3 % of patients treated with dupilumab and 1.3 % of patients treated with placebo.

No increase was observed in the overall incidence of infections with dupilumab compared to placebo in the safety pool for PN clinical studies. In the safety pool, serious infections were reported in 1.3% of patients treated with dupilumab and 1.3% of patients treated with placebo.

The overall incidence of infections was numerically higher with dupilumab (32.0%) compared to placebo (24.8%) in the 24-week safety pool for the EoE TREET (Parts A and B) studies. The overall incidence of infections was numerically higher in placebo (41.2%) compared to dupilumab (35.8%) in the EoE KIDS (Part A) study. In the 24-week safety pool for the EoE TREET (Parts A and B) studies, serious infections were reported in 0.5% of patients treated with dupilumab and 0% of patients treated with placebo. No serious infections were reported in EoE KIDS (Part A) study. Upper respiratory tract infections composed of several terms, including, but not limited to, COVID-19, sinusitis, and upper

respiratory tract infection was numerically higher with dupilumab (17.2%) compared to placebo (10.3%) in EoE TREET (Parts A and B), and with dupilumab (26.9%) compared to placebo (20.6%) in EoE KIDS (Part A) study.

No increase was observed in the overall incidence of infections with dupilumab compared to placebo in the safety pool for COPD clinical studies. Serious infections were reported in 4.9% of patients treated with dupilumab and 4.8% of patients treated with placebo.

In the safety pool for CUPID studies (A, B, and C) no increase was observed in the overall incidence of infections with dupilumab compared to placebo. In the safety pool, serious infections were observed in 0.5% of patients treated with dupilumab and 0.5% of patients treated with placebo. No serious infections were observed in children treated with dupilumab in the PKM16982 study.

Immunogenicity
As with all therapeutic proteins, there is a potential for immunogenicity with dupilumab.

Antidrug Antibodies (ADA) responses were not generally associated with impact on dupilumab exposure, safety, or efficacy.

Approximately 5 % of patients with atopic dermatitis, asthma, or CRSwNP who received dupilumab 300 mg Q2W for 52 weeks developed ADA to dupilumab; approximately 2 % exhibited persistent ADA responses and approximately 2 % had neutralizing antibodies. Similar results were observed in adult patients with PN who received dupilumab 300 mg Q2W for 24 weeks, paediatric patients (6 months to 11 years of age) with atopic dermatitis who received either dupilumab 200 mg Q2W, 200 mg Q4W, or 300 mg Q4W for 16 weeks and patients (6 to 11 years of age) with asthma who received dupilumab 100 mg Q2W or 200 mg Q2W for 52 weeks. Similar ADA responses were observed in adult patients with atopic dermatitis treated with dupilumab for up to 5 years in the long-term OLE study (AD-1225).

Approximately 16 % of adolescent patients with atopic dermatitis who received dupilumab 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 9 % of patients with asthma who received dupilumab 200 mg Q2W for 52 weeks developed antibodies to dupilumab; approximately 4 % exhibited persistent ADA responses and approximately 4 % had neutralizing antibodies.

Approximately 1% of patients 1 year of age and older with EoE who received dupilumab 300 mg QW (≥40 kg), 300 mg Q2W (≥30 to <60 kg), 200 mg Q2W (≥15 to <30 kg), or 100 mg Q2W (≥5 to <15 kg) for 52 weeks developed antibodies to dupilumab; the ADA responses were neither persistent nor neutralizing..

Approximately 8% of patients with COPD who received dupilumab 300 mg Q2W for 52 weeks developed antibodies to dupilumab; approximately 3% exhibited persistent ADA responses and approximately 3% had neutralizing antibodies.
Approximately 4.7% of adult patients with CSU who received dupilumab 300 mg Q2W and adolescent patients with CSU who received dupilumab 300 mg or 200 mg Q2W for 24 weeks developed antibodies to dupilumab; approximately 0.5% exhibited persistent ADA responses and approximately 1% had neutralizing antibodies. No paediatric patients 2 to 11 years of age with CSU who received dupilumab 200 mg Q4W, 300 mg Q4W, or 200 mg Q2W for 24 weeks developed a positive ADA response to dupilumab.

Regardless of age or population, up to 7 % of patients in the placebo groups were positive for antibodies to dupilumab; up to 3 % exhibited persistent ADA response and up to 2 % had neutralizing antibodies.

Less than 1 % of patients who received dupilumab at approved dosing regimens exhibited high titer ADA responses associated with reduced exposure and efficacy. In addition, there was one patient with serum sickness and one with serum sickness-like reaction (< 0.1 %) associated with high ADA titers (see section 4.4).

Paediatric population

Atopic dermatitis

Adolescents (12 to 17 years of age)
The safety of dupilumab was assessed in a study of 250 patients 12 to 17 years of age with moderate-to-severe atopic dermatitis (AD-1526). The safety profile of dupilumab in these patients followed through week 16 was similar to the safety profile from studies in adults with atopic dermatitis.

Children 6 to 11 years of age
The safety of dupilumab was assessed in a study of 367 patients 6 to 11 years of age with severe atopic dermatitis (AD-1652). The safety profile of dupilumab with concomitant TCS in these patients through week 16 was similar to the safety profile from studies in adults and adolescents with atopic dermatitis.

Children 6 months to 5 years of age
The safety of dupilumab with concomitant TCS was assessed in a study of 161 patients 6 months to 5 years of age with moderate-to-severe atopic dermatitis, which included a subgroup of 124 patients with severe atopic dermatitis (AD-1539). The safety profile of dupilumab with concomitant TCS in these patients through week 16 was similar to the safety profile from studies in adults and paediatric patients 6 to 17 years of age with atopic dermatitis.

Atopic Hand and Foot Dermatitis
The safety of dupilumab was assessed in 27 paediatric patients 12 to 17 years of age with moderate-to- severe atopic hand and foot dermatitis (AD-1924). The safety profile of dupilumab in these patients through Week 16 was consistent with the safety profile from studies in adult and paediatric patients 6 months of age and older with moderate-to-severe AD.

Asthma

Adolescents (12 to 17 years of age)
A total of 107 adolescents aged 12 to 17 years with asthma were enrolled in the 52 week QUEST study. The safety profile observed was similar to that seen in adults.

The long-term safety of dupilumab was assessed in 89 adolescent patients who were enrolled in an open-label extension study in moderate-to-severe asthma (TRAVERSE). In this study, patients were followed for up to 96 weeks. The safety profile of dupilumab in TRAVERSE was consistent with the safety profile observed in pivotal asthma studies for up to 52 weeks of treatment.

Children 6 to 11 years of age
In children 6 to 11 years of age with moderate-to-severe asthma (VOYAGE), the additional adverse reaction of enterobiasis was reported in 1.8 % (5 patients) in the dupilumab groups and none in the placebo group. All enterobiasis cases were mild to moderate and patients recovered with anti-helminth treatment without dupilumab treatment discontinuation.

In children 6 to 11 years of age with moderate-to-severe asthma, eosinophilia (blood eosinophils ≥ 3,000 cells/mcL or deemed by the investigator to be an adverse event) was reported in 6.6 % of the dupilumab groups and 0.7% in the placebo group. Most eosinophilia cases were mild to moderate and not associated with clinical symptoms. These cases were transient, decreased over time, and did not lead to dupilumab treatment discontinuation.

The long-term safety of dupilumab was assessed in an open-label extension study (EXCURSION) in children 6 to 11 years of age with moderate-to-severe asthma who previously participated in VOYAGE. Among 365 patients who entered EXCURSION, 350 completed 52 weeks of treatment and 228 patients completed a cumulative treatment duration of 104 weeks (VOYAGE and EXCURSION).
The long-term safety profile of dupilumab in EXCURSION was consistent with the safety profile observed in the pivotal asthma study (VOYAGE) for 52 weeks of treatment.

EoE

Adolescents (12 to 17 years of age)

A total of 99 adolescents aged 12 to 17 years with EoE were enrolled in the TREET (Parts A and B) studies. The safety profile observed was similar to that seen in adults.

Children 1 to 11 years of age
The safety of dupilumab was assessed in a trial of 101 children 1 to 11 years of age with EoE (EoE KIDS Part A). The safety profile of dupilumab in these patients through Week 16 was similar with the safety profile seen in adult and adolescent patients 12 to 17 years of age with EoE.
A total of 98 patients completing Part A were provided an option to enrol in a 36-week active treatment extension period (EoE-KIDS Part B). The safety profile of dupilumab through Week 52 was similar to the safety profile observed at Week 16.

Chronic Spontaneous Urticaria

Adolescents (12 to 17 years of age)

The safety of dupilumab was assessed in 12 adolescents aged 12 to 17 years with CSU enrolled in CUPID (Study A, B, and C). An adverse event was reported in one adolescent treated with dupilumab.

Children (2 to 11 years of age)

The safety of dupilumab was assessed in 18 children aged 2 to 11 years with CSU enrolled in PKM16982 and CUPID (Study A and C). These data were generally consistent with the safety profile observed in CSU patients treated with dupilumab.

Long-term safety

Atopic dermatitis
The safety profile of dupilumab + TCS (CHRONOS) in adult atopic dermatitis patients) through week 52 was consistent with the safety profile observed at week 16. The long-term safety of dupilumab was assessed in an open-label extension study in patients 6 months to 17 years of age with moderate-to- severe atopic dermatitis (AD-1434). The safety profile of dupilumab in patients followed through week 52 was similar to the safety profile observed at week 16 in the AD-1526, AD-1652, and AD- 1539 studies. The long-term safety profile of dupilumab observed in children and adolescents was consistent with that seen in adults with atopic dermatitis.

In a phase 3, multicentre, open label extension (OLE) study (AD-1225), the long-term safety of repeat doses of dupilumab was assessed in 2,677 adults with moderate-to-severe AD exposed to 300 mg weekly dosing (99.7 %), including 179 who completed at least 260 weeks of the study. The long-term safety profile observed in this study up to 5 years was generally consistent with the safety profile of dupilumab observed in controlled studies.

Asthma
The safety profile of dupilumab in the 96 weeks long term safety study (TRAVERSE) was consistent with the safety profile observed in pivotal asthma studies for up to 52 weeks of treatment.

The safety profile of dupilumab in children with asthma 6 to 11 years of age who participated in the 52 weeks long-term safety study (EXCURSION) was consistent with the safety profile observed in the pivotal asthma study (VOYAGE) for 52 weeks of treatment.

CRSwNP
The safety profile of dupilumab in adults with CRSwNP through week 52 was consistent with the safety profile observed at week 24.

Eosinophilic esophagitis

The safety profile of dupilumab through week 52 in adult and adolescent patients 12 years of age and older (TREET Part C) and in children 1 to 11 years of age (EoE KIDS Part B) was generally consistent with the safety profile observed at week 24 in TREET Parts A and B and at Week 16 in EoE KIDS Part A.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Summary of the safety profile

The most common adverse reactions in atopic dermatitis, asthma, and CRSwNP are injection site reactions (includes erythema, oedema, pruritus, pain and swelling), conjunctivitis, conjunctivitis allergic, arthralgia, oral herpes, and eosinophilia. An additional adverse reaction of injection site bruising or haematoma was reported in EoE, COPD and CSU. Additional adverse reactions of injection site induration and injection site dermatitis were reported in COPD and CSU. Additional adverse reactions of injection site rash were reported in COPD.Rare cases of serum sickness, serum sickness-like reaction, anaphylactic reaction, and ulcerative keratitis have been reported (see section 4.4).

Tabulated list of adverse reactions

The dupilumab safety data presented in Table 8 were predominantly derived from 12 randomised, placebo-controlled trials, including atopic dermatitis, asthma, and CRSwNP patients. These studies involved 4,206 patients receiving dupilumab and 2,326 patients receiving placebo during the controlled period are representative of the overall safety profile for dupilumab.

Listed in Table 8 are adverse reactions observed in clinical trials and/or postmarketing setting presented by system organ class and frequency, using the following categories: very common (≥ 1/10);
common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very

rare (< 1/10 000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 8: List of adverse reactions
MedDRA System
Organ Class
Frequency
Adverse Reaction
Infections and infestations
Common
Conjunctivitis*
Oral herpes*
Blood and lymphatic system disorders
Common
Eosinophilia
Immune system disorders
Uncommon
Rare

Angioedema#
Anaphylactic reaction
Serum sickness reaction
Serum sickness-like reaction
Eye disorders
Common
Uncommon

Rare
Conjunctivitis allergic*
Keratitis*#
Blepharitis*†
Eye pruritus*†
Dry eye*†
Ulcerative keratitis*†#
Skin and subcutaneous tissue disorders
Uncommon
Facial rash#
Musculoskeletal and connective tissue disorders
Common
Arthralgia#
General disorders and administration site conditions
Common

Injection site reactions (includes erythema, oedema, pruritus, pain, swelling, and bruising)

*eye disorders and oral herpes occurred predominately in atopic dermatitis studies.
†the frequencies for eye pruritus, blepharitis, and dry eye were common and ulcerative keratitis was uncommon in atopic dermatitis studies.
#from postmarketing reporting.

Description of selected adverse reactions

Hypersensitivity
Cases of anaphylactic reaction, angioedema, and serum sickness/serum sickness-like reaction have been reported following administration of dupilumab (see section 4.4).

Conjunctivitis and keratitis related events
Conjunctivitis and keratitis occurred more frequently in atopic dermatitis patients who received dupilumab compared to placebo in atopic dermatitis studies. Most patients with conjunctivitis or keratitis recovered or were recovering during the treatment period. In the long-term OLE atopic dermatitis study (AD-1225) at 5 years, the respective rates of conjunctivitis and keratitis remained similar to those in the dupilumab arm in the placebo controlled atopic dermatitis studies. Among asthma and COPD patients, the frequency of conjunctivitis and keratitis was low and similar between dupilumab and placebo. Among CRSwNP and Prurigo Nodularis (PN) patients the frequency of conjunctivitis was higher in dupilumab than placebo, though lower than that observed in atopic dermatitis patients. Among patients with EoE and CSU, the frequency of conjunctivitis was low and similar between dupilumab and placebo groups. There were no cases of keratitis in the CRSwNP, PN, EoE, and CSU development program (see section 4.4).

Eczema herpeticum
Eczema herpeticum was reported in < 1 % of the dupilumab groups and in < 1 % of the placebo group in the 16-week atopic dermatitis monotherapy adult studies. In the 52-week atopic dermatitis dupilumab + TCS adult study, eczema herpeticum was reported in 0.2 % of the dupilumab + TCS

group and 1.9 % of the placebo + TCS group. These rates remained stable at 5 years in the long-term OLE study (AD-1225).

Eosinophilia
Dupilumab-treated patients had a greater mean initial increase from baseline in eosinophil count compared to patients treated with placebo in the atopic dermatitis, asthma, CRSwNP, COPD, and CSU indications. Eosinophil counts declined to near baseline levels during study treatment and returned to baseline during the asthma open-label extension safety study (TRAVERSE). The mean blood eosinophil levels decreased to below baseline by week 20 and was maintained up to 5 years in the long-term OLE study (AD-1225). Compared to placebo, no increase in mean blood eosinophil counts was observed in PN (PRIME and PRIME2). Mean and median blood eosinophil counts declined to near baseline or remained below baseline levels in EoE and COPD (BOREAS and NOTUS) during study treatment.

Treatment-emergent eosinophilia (≥ 5,000 cells/mcL) was observed in < 3 % of dupilumab-treated patients and < 0.5 % in placebo-treated patients (SOLO1, SOLO2, AD-1021, DRI12544, QUEST, and VOYAGE; SINUS-24 and SINUS-52; PRIME and PRIME2 studies; TREET Parts A and B; BOREAS and NOTUS; CUPID Study A, B, and C).

Treatment-emergent eosinophilia (≥5,000 cells/mcL) was observed in 8.4% of dupilumab-treated patients and 0% in placebo-treated patients in study AD-1539, with median eosinophil counts declining below baseline at end of treatment period.

Infections
In the 16-week atopic dermatitis monotherapy clinical adult studies, serious infections were reported in 1.0 % of patients treated with placebo and 0.5 % of patients treated with dupilumab. In the 52-week atopic dermatitis CHRONOS adult study, serious infections were reported in 0.6 % of patients treated with placebo and 0.2 % of patients treated with dupilumab. The rates of serious infections remained stable at 5 years in the long-term OLE study (AD-1225).

No increase was observed in the overall incidence of infections with dupilumab compared to placebo in the safety pool for asthma clinical studies. In the 24-week safety pool, serious infections were reported in 1.0% of patients treated with dupilumab and 1.1% of patients treated with placebo. In the 52-week QUEST study, serious infections were reported in 1.3% of patients treated with dupilumab and 1.4% of patients treated with placebo.

No increase was observed in the overall incidence of infections with dupilumab compared to placebo in the safety pool for CRSwNP clinical studies. In the 52-week SINUS-52 study, serious infections were reported in 1.3% of patients treated with dupilumab and 1.3 % of patients treated with placebo.
No increase was observed in the overall incidence of infections with dupilumab compared to placebo in the safety pool for PN clinical studies. In the safety pool, serious infections were reported in 1.3% of patients treated with dupilumab and 1.3% of patients treated with placebo.

The overall incidence of infections was numerically higher with dupilumab (32.0%) compared to placebo (24.8%) in the 24-week safety pool for the EoE TREET (Parts A and B) studies. The overall incidence of infections was numerically higher in placebo (41.2%) compared to dupilumab (35.8%) in the EoE KIDS (Part A) study. In the 24-week safety pool for the EoE TREET (Parts A and B) studies serious infections were reported in 0.5% of patients treated with dupilumab and 0% of patients treated with placebo. No serious infections were reported in EoE KIDS (Part A) study. Upper respiratory tract infections composed of several terms, including, but not limited to, COVID-19, sinusitis, and upper respiratory tract infection was numerically higher with dupilumab (17.2%) compared to placebo (10.3%) in EoE TREET (Parts A and B), and with dupilumab (26.9%) compared to placebo (20.6%) in EoE KIDS (Part A) study.

No increase was observed in the overall incidence of infections with dupilumab compared to placebo in the safety pool for COPD clinical studies. Serious infections were reported in 4.9% of patients treated with dupilumab and 4.8% of patients treated with placebo.

In the safety pool for CUPID studies (A, B, and C) no increase was observed in the overall incidence of infections with dupilumab compared to placebo. In the safety pool, serious infections were observed in 0.5% of patients treated with dupilumab and 0.5% of patients treated with placebo. No serious infections were observed in children treated with dupilumab in the PKM16982 study.

Immunogenicity
As with all therapeutic proteins, there is a potential for immunogenicity with dupilumab.

Antidrug Antibodies (ADA) responses were not generally associated with impact on dupilumab exposure, safety, or efficacy.

Approximately 5 % of patients with atopic dermatitis, asthma, or CRSwNP who received dupilumab 300 mg Q2W for 52 weeks developed ADA to dupilumab; approximately 2 % exhibited persistent ADA responses and approximately 2 % had neutralizing antibodies. Similar results were observed in adult patients with PN who received dupilumab 300 mg Q2W for 24 weeks, paediatric patients (6 months to 11 years of age) with atopic dermatitis who received either dupilumab 200 mg Q2W, 200 mg Q4W or 300 mg Q4W for 16 weeks and patients (6 to 11 years of age) with asthma who received dupilumab 100 mg Q2W or 200 mg Q2W for 52 weeks. Similar ADA responses were observed in adult patients with atopic dermatitis treated with dupilumab for up to 5 years in the long-term OLE study (AD-1225).

Approximately 16 % of adolescent patients with atopic dermatitis who received dupilumab 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 9 % of patients with asthma who received dupilumab 200 mg Q2W for 52 weeks developed antibodies to dupilumab; approximately 4 % exhibited persistent ADA responses and approximately 4 % had neutralizing antibodies.

Approximately 1% of patients 1 year of age and older with EoE who received dupilumab 300 mg QW (≥40 kg), 300 mg Q2W (≥30 to <60 kg), 200 mg Q2W (≥15 to <30 kg), or 100 mg Q2W (≥5 to <15 kg) for 52 weeks developed antibodies to dupilumab; the ADA responses were neither persistent nor neutralizing.

Approximately 8% of patients with COPD who received dupilumab 300 mg Q2W for 52 weeks developed antibodies to dupilumab; approximately 3% exhibited persistent ADA responses and approximately 3% had neutralizing antibodies.

Approximately 4.7% of adult patients with CSU who received dupilumab 300 mg Q2W and adolescent patients with CSU who received dupilumab 300 mg or 200 mg Q2W for 24 weeks developed antibodies to dupilumab; approximately 0.5% exhibited persistent ADA responses and approximately 1% had neutralizing antibodies. No paediatric patients 2 to 11 years of age with CSU who received dupilumab 200 mg Q4W, 300 mg Q4W, or 200 mg Q2W for 24 weeks developed a positive ADA response to dupilumab.

Regardless of age or population, up to 7 % of patients in the placebo groups were positive for antibodies to dupilumab; up to 3 % exhibited persistent ADA response and up to 2 % had neutralizing antibodies.

Less than 1 % of patients who received dupilumab at approved dosing regimens exhibited high titer ADA responses associated with reduced exposure and efficacy. In addition, there was one patient with serum sickness and one with serum sickness-like reaction (< 0.1 %) associated with high ADA titers (see section 4.4).

Paediatric population

Atopic dermatitis

Adolescents (12 t o17 years of age)
The safety of dupilumab was assessed in a study of 250 patients 12 to 17 years of age with moderate-to-severe atopic dermatitis (AD-1526). The safety profile of dupilumab in these patients followed through week 16 was similar to the safety profile from studies in adults with atopic dermatitis.

Children 6 to 11 years of age
The safety of dupilumab was assessed in a study of 367 patients 6 to 11 years of age with severe atopic dermatitis (AD-1652). The safety profile of dupilumab with concomitant TCS in these patients through week 16 was similar to the safety profile from studies in adults and adolescents with atopic dermatitis.

Children 6 months to 5 years of age
The safety of dupilumab with concomitant TCS was assessed in a study of 161 patients 6 months to 5 years of age with moderate-to-severe atopic dermatitis, which included a subgroup of 124 patients with severe atopic dermatitis (AD-1539). The safety profile of dupilumab with concomitant TCS in these patients, through week 16 was similar to the safety profile from studies in adults and paediatric patients 6 to 17 years of age with atopic dermatitis.

Atopic Hand and Foot Dermatitis
The safety of dupilumab was assessed in 27 paediatric patients 12 to 17 years of age with moderate-to- severe atopic hand and foot dermatitis (AD-1924). The safety profile of dupilumab in these patients through Week 16 was consistent with the safety profile from studies in adult and paediatric patients 6 months of age and older with moderate-to-severe AD.

Asthma

Adolescents (12 t o17 years of age)
A total of 107 adolescents aged 12 to 17 years with asthma were enrolled in the 52 week QUEST study. The safety profile observed was similar to that seen in adults.

The long-term safety of dupilumab was assessed in 89 adolescent patients who were enrolled in an open-label extension study in moderate-to-severe asthma (TRAVERSE). In this study, patients were followed for up to 96 weeks. The safety profile of dupilumab in TRAVERSE was consistent with the safety profile observed in pivotal asthma studies for up to 52 weeks of treatment.

Children 6 to 11 years of age
In children 6 to 11 years of age with moderate-to-severe asthma (VOYAGE), the additional adverse reaction of enterobiasis was reported in 1.8 % (5 patients) in the dupilumab groups and none in the placebo group. All enterobiasis cases were mild to moderate and patients recovered with anti-helminth treatment without dupilumab treatment discontinuation.

In children 6 to 11 years of age with moderate-to-severe asthma, eosinophilia (blood eosinophils ≥ 3,000 cells/mcL or deemed by the investigator to be an adverse event) was reported in 6.6 % of the dupilumab groups and 0.7% in the placebo group. Most eosinophilia cases were mild to moderate and not associated with clinical symptoms. These cases were transient, decreased over time, and did not lead to dupilumab treatment discontinuation.

The long-term safety of dupilumab was assessed in an open-label extension study (EXCURSION) in children 6 to 11 years of age with moderate-to-severe asthma who previously participated in VOYAGE. Among 365 patients who entered EXCURSION, 350 completed 52 weeks of treatment and 228 patients completed a cumulative treatment duration of 104 weeks (VOYAGE and EXCURSION).

The long-term safety profile of dupilumab in EXCURSION was consistent with the safety profile observed in the pivotal asthma study (VOYAGE) for 52 weeks of treatment.

EoE

Adolescents (12 to 17 years of age)

A total of 99 adolescents aged 12 to 17 years with EoE were enrolled in the TREET (Parts A and B) studies. The safety profile observed was similar to that seen in adults.

Children 1 to 11 years of age
The safety of dupilumab was assessed in a trial of 101 children 1 to 11 years of age with EoE (EoE KIDS Part A). The safety profile of dupilumab in these patients through Week 16 was similar with the safety profile seen in adult and adolescent patients 12 to 17 years of age with EoE.
A total of 98 patients completing Part A were provided an option to enrol in a 36-week active treatment extension period (EoE-KIDS Part B). The safety profile of dupilumab through Week 52 was similar to the safety profile observed at Week 16.

Chronic Spontaneous Urticaria

Adolescents (12 to 17 years of age)

The safety of dupilumab was assessed in 12 adolescents aged 12 to 17 years with CSU enrolled in CUPID (Study A, B, and C). An adverse event was reported in one adolescent treated with dupilumab.

Children (2 to 11 years of age)

The safety of dupilumab was assessed in 18 children aged 2 to 11 years with CSU enrolled in PKM16982 and CUPID (Study A and C). These data were generally consistent with the safety profile observed in CSU patients treated with dupilumab.

Long-term safety

Atopic dermatitis
The safety profile of dupilumab + TCS (CHRONOS) in adult atopic dermatitis patients) through week 52 was consistent with the safety profile observed at week 16. The long-term safety of dupilumab was assessed in an open-label extension study in patients 6 months to 17 years of age with moderate-to- severe atopic dermatitis (AD-1434). The safety profile of dupilumab in patients followed through week 52 was similar to the safety profile observed at week 16 in the AD-1526, AD-1652, and AD- 1539 studies. The long-term safety profile of dupilumab observed in children and adolescents was consistent with that seen in adults with atopic dermatitis.

In a phase 3, multicentre, open label extension (OLE) study (AD-1225), the long-term safety of repeat doses of dupilumab was assessed in 2,677 adults with moderate-to-severe AD exposed to 300 mg weekly dosing (99.7 %), including 179 who completed at least 260 weeks of the study. The long-term safety profile observed in this study up to 5 years was generally consistent with the safety profile of dupilumab observed in controlled studies.

Asthma

The safety profile of dupilumab in the 96 weeks long term safety study (TRAVERSE) was consistent with the safety profile observed in pivotal asthma studies for up to 52 weeks of treatment.

The safety profile of dupilumab in children with asthma 6 to 11 years of age who participated in the 52 weeks long-term safety study (EXCURSION) was consistent with the safety profile observed in the pivotal asthma study (VOYAGE) for 52 weeks of treatment.

CRSwNP
The safety profile of dupilumab in adults with CRSwNP through week 52 was consistent with the safety profile observed at week 24.

Eosinophilic esophagitis

The safety profile of dupilumab through week 52 in adult and adolescent patients 12 years of age and older (TREET Part C) and in children 1 to 11 years of age (EoE KIDS Part B) was generally consistent with the safety profile observed at week 24 in TREET Parts A and B and at Week 16 in EoE KIDS Part A.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Acute exacerbations of Asthma or COPD

Dupilumab must not be used to treat acute symptoms or acute exacerbations of asthma or COPD.
Dupilumab must not be used to treat acute bronchospasm or status asthmaticus.

Corticosteroids

It is recommended that systemic, topical, or inhaled corticosteroids not be discontinued abruptly upon initiation of therapy with dupilumab. 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.

Biomarkers of type 2 inflammation may be suppressed by systemic corticosteroid use. This should be taken into consideration to determine type 2 status in patients taking oral corticosteroids (see section 5.1).

Hypersensitivity

If a systemic hypersensitivity reaction (immediate or delayed) occurs, discontinue administration of dupilumab immediately and initiate appropriate therapy. Cases of anaphylactic reaction, angioedema, and serum sickness/serum sickness-like reaction have been reported. Anaphylactic reactions and angioedema have occurred from minutes to up to seven days after the dupilumab injection (see section 4.8).

Eosinophilic conditions

Cases of eosinophilic pneumonia and cases of vasculitis consistent with eosinophilic granulomatosis with polyangiitis (EGPA) have been reported with dupilumab in adult patients who participated in the asthma development program. Cases of vasculitis consistent with EGPA have been reported with dupilumab and placebo in adult patients with co-morbid asthma in the CRSwNP development program. Physicians should be alert to vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients with eosinophilia. 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 usually, but not always, may be associated with the reduction of oral corticosteroid therapy.

Helminth infection

Patients with known helminth infections were excluded from participation in clinical studies.
Dupilumab may influence the immune response against helminth infections by inhibiting IL-4/IL-13 signalling. Patients with pre-existing helminth infections should be treated before initiating dupilumab.
If patients become infected while receiving treatment with dupilumab and do not respond to anti- helminth treatment, treatment with dupilumab should be discontinued until infection resolves. Cases of enterobiasis were reported in children 6 to 11 years old who participated in the paediatric asthma development program (see section 4.8).

Conjunctivitis and keratitis related events

Conjunctivitis and keratitis related events have been reported with dupilumab, predominantly in atopic dermatitis patients. Some patients reported visual disturbances (e.g. blurred vision) associated with conjunctivitis or keratitis (see section 4.8).

Advise patients to report new onset or worsening eye symptoms to their healthcare provider. Patients treated with dupilumab who develop conjunctivitis that does not resolve following standard treatment or signs and symptoms suggestive of keratitis should undergo ophthalmological examination, as appropriate (see section 4.8).

Patients with comorbid asthma

Advise patients on dupilumab who also have co-morbid asthma to not adjust or stop their asthma treatments without consultation with their physicians. Monitor patients with comorbid asthma carefully following discontinuation of dupilumab.

Vaccinations

Concurrent use of live and live attenuated vaccines with dupilumab should be avoided as clinical safety and efficacy have not been established. It is recommended that patients are brought up to date with live and live attenuated immunisations in agreement with current immunisation guidelines prior to treatment with dupilumab. Clinical data are not available to support more specific guidance for live or live attenuated vaccines administration in patients treated with dupilumab. Immune responses to TdaP vaccine and meningococcal polysaccharide vaccine were assessed (see section 4.5).

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per 300 mg dose, that is to say essentially ‘sodium-free’.

Polysorbate 80 (E433)

This medicine contains 4 mg of polysorbate 80 in each 300 mg dose (2mL). Polysorbates may cause allergic reactions.

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Acute exacerbations of Asthma or COPD

Dupilumab must not be used to treat acute symptoms or acute exacerbations of asthma or COPD.
Dupilumab must not be used to treat acute bronchospasm or status asthmaticus.

Corticosteroids

It is recommended that systemic, topical, or inhaled corticosteroids not be discontinued abruptly upon initiation of therapy with dupilumab. 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.

Biomarkers of type 2 inflammation may be suppressed by systemic corticosteroid use. This should be taken into consideration to determine type 2 status in patients taking oral corticosteroids (see section 5.1).

Hypersensitivity

If a systemic hypersensitivity reaction (immediate or delayed) occurs, discontinue administration of dupilumab immediately and initiate appropriate therapy. Cases of anaphylactic reaction, angioedema, and serum sickness/serum sickness-like reaction have been reported. Anaphylactic reactions and angioedema have occurred from minutes to up to seven days after the dupilumab injection (see section 4.8).

Eosinophilic conditions

Cases of eosinophilic pneumonia and cases of vasculitis consistent with eosinophilic granulomatosis with polyangiitis (EGPA) have been reported with dupilumab in adult patients who participated in the asthma development program. Cases of vasculitis consistent with EGPA have been reported with dupilumab and placebo in adult patients with co-morbid asthma in the CRSwNP development program. Physicians should be alert to vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients with eosinophilia. 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 usually, but not always, may be associated with the reduction of oral corticosteroid therapy.

Helminth infection

Patients with known helminth infections were excluded from participation in clinical studies.
Dupilumab may influence the immune response against helminth infections by inhibiting IL-4/IL-13 signalling. Patients with pre-existing helminth infections should be treated before initiating dupilumab.
If patients become infected while receiving treatment with dupilumab and do not respond to anti- helminth treatment, treatment with dupilumab should be discontinued until infection resolves. Cases of enterobiasis were reported in children 6 to 11 years old who participated in the paediatric asthma development program (see section 4.8).

Conjunctivitis and keratitis related events

Conjunctivitis and keratitis related events have been reported with dupilumab, predominantly in atopic dermatitis patients. Some patients reported visual disturbances (e.g. blurred vision) associated with conjunctivitis or keratitis (see section 4.8).

Advise patients to report new onset or worsening eye symptoms to their healthcare provider. Patients treated with dupilumab who develop conjunctivitis that does not resolve following standard treatment or signs and symptoms suggestive of keratitis should undergo ophthalmological examination, as appropriate (see section 4.8).

Patients with comorbid asthma

Advise patients on dupilumab who also have comorbid asthma to not adjust or stop their asthma treatments without consultation with their physicians. Monitor patients with comorbid asthma carefully following discontinuation of dupilumab.

Vaccinations

Concurrent use of live and live attenuated vaccines with dupilumab should be avoided as clinical safety and efficacy have not been established. It is recommended that patients are brought up to date with live and live attenuated immunisations in agreement with current immunisation guidelines prior to treatment with dupilumab. Clinical data are not available to support more specific guidance for live or live attenuated vaccines administration in patients treated with dupilumab. Immune responses to TdaP vaccine and meningococcal polysaccharide vaccine were assessed (see section 4.5).

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per 200 mg dose, that is to say essentially ‘sodium-free’.

Polysorbate 80 (E433)

This medicine contains 2.28 mg of polysorbate 80 in each 200 mg dose (1.14 mL). Polysorbates may cause allergic reactions.

Baseline Total IgE (IU/mL,) median
101.0
107.3
103.0

The results for primary and secondary endpoints in CUPID Study A and Study C are presented in the Table 36.
Table 36: Results of the Primary and Secondary Endpoints in CUPID Study A and Study C

CUPID STUDY A
CUPID Study C

Dupilumab
(N=70)
Placebo
(N=68)
Difference
(95% CI) for
Dupilumab vs. Placebob
Dupilumab
(N=74)
Placebo
(N=77)
Difference
(95% CI) for
Dupilumab vs.
Placebob
Primary Endpoint
Change from baseline in
UAS7 at Week 24a
-20.53 (1.76) -12.00 (1.81) -8.53 (-13.16, -
3.90)
-15.86
(2.66)
-11.21
(2.65)
-4.65
(-8.65, -0.65)
Secondary Endpoints
Change from baseline in
ISS7 at Week 24a
-10.24 (0.91) -6.01 (0.94)
-4.23 (-6.63, -
1.84)
-8.64
(1.41)
-6.10
(1.40)
-2.54
(-4.65, -0.43)
Change from baseline in
HSS7 at Week 24a
-10.28 (0.91) -5.90 (0.93)
-4.38 (-6.78, -
1.98)
-7.27
(1.32)
-5.11
(1.31)
-2.17
(-4.15, -0.19)

Dupilumab
(N=70)
Placebo
(N=68)
Odds Ratio
(95% CI) for
Dupilumab vs. Placebob
Dupilumab
(N=74)
Placebo
(N=77)
Odds Ratio
(95% CI) for
Dupilumab vs.
Placebob
Proportion of patients with UAS7 ≤6 at Week
24a
32 (45.7)
16 (23.5)
2.848 (1.301,
6.234)
(40.5)
(23.4)
3.137
(1.371, 7.176)
Proportion of patients with UAS7 = 0 at Week
24a
22 (31.4)
9 (13.2)
2.908 (1.173,
7.209)
(29.7)
(18.2)
2.677
(1.127, 6.359) a Values presented are LS mean change from baseline (SE) for continuous variables and number and percent of responders for binary variables.
b Difference is LS mean difference for continuous variables and odds ratio for binary variables.

Dupilumab treatment led to an improvement over time in UAS7 through the 24-week treatment period (Figure 14).
Figure 13: LS mean change from baseline in UAS7 up to Week 24 in CUPID Study A and Study C ITT population Fig 13a. Study A Fig 13b. Study C

Similar improvement in HSS7 and ISS7 was observed over 24 weeks.
Paediatric population

Atopic dermatitis
The safety and efficacy of dupilumab have been established in paediatric patients 6 months of age and older with atopic dermatitis. Use of dupilumab in this age group is supported by study AD-1526 which included 251 adolescents aged 12 to 17 years old with moderate-to-severe atopic dermatitis, in study AD-1652 which included 367 paediatric patients aged 6 to 11 years old with severe atopic dermatitis, and study AD-1539 which included 162 children ages 6 months to 5 years old with moderate-to-severe atopic dermatitis (125 of whom had severe atopic dermatitis). Long term use is supported by study AD-1434 which enrolled 823 paediatric patients aged 6 months to 17 years of age, this included 275 adolescents, 368 children 6 to 11 years of age, and 180 children 6 months to 5 years of age. The safety and efficacy were generally consistent between children 6 months to 5 years old, 6 to 11 years old, adolescent (12 to 17 years old), and adult patients with atopic dermatitis (see section 4.8). Safety and efficacy in paediatric patients < 6 months 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 QUEST study and received either 200 mg (N=21) or 300 mg (N=18) dupilumab (or matching placebo either 200 mg [N=34] or 300 mg [N=34]) every other week. Efficacy with respect to severe asthma exacerbations and lung function was observed in both adolescents and adults. For both the 200 mg and 300 mg every other week doses, significant 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 every other week dose, patients had a reduction in the rate of severe exacerbations that was consistent with adults. The safety profile in adolescents was generally similar to the adults.

A total of 89 adolescents aged 12 to 17 years with moderate-to-severe asthma were enrolled in the open label long-term study (TRAVERSE). In this study, efficacy was measured as a secondary endpoint, was similar to results observed in the pivotal studies and was sustained up to 96 weeks.

A total of 408 children aged 6 to 11 years with moderate-to-severe asthma was enrolled in the VOYAGE study, which evaluated doses of 100 mg Q2W and 200 mg Q2W. The efficacy of dupilumab 300 mg Q4W in children aged 6 to 11 years is extrapolated from the efficacy of 100 mg and 200 mg Q2W in VOYAGE and 200 mg and 300 mg Q2W in adults and adolescents (QUEST).
Patients who completed the treatment period of the VOYAGE study could participate in the open label extension study (EXCURSION). Eighteen patients (≥ 15 kg to < 30 kg) out of 365 patients were exposed to 300 mg Q4W in this study, and the safety profile was similar to that seen in VOYAGE.
Safety and efficacy in paediatric patients < 6 years of age with asthma have not been established.

Eosinophilic Esophagitis
The safety and efficacy of dupilumab for the treatment of EoE have been established in paediatric patients 1 to 17 years of age. Use of dupilumab in this population is supported by adequate and well- controlled studies and additional pharmacokinetic data. A total of 72 paediatric patients 12 to 17 years of age received dupilumab 300 mg QW or placebo for 24 weeks (TREET Parts A and B). Of these, there were 37 dupilumab treated patients in Parts A and B; 34 continued treatment with 300 mg QW for an additional 28 weeks (TREET Part C). A total of 71 paediatric patients 1 to 11 years of age

received dupilumab 100 mg Q2W, 200 mg Q2W, 300 mg Q2W, or placebo for 16 weeks (EoE KIDS Part A). Of these, there were 37 dupilumab treated patients in Part A all of whom continued treatment with these dupilumab regimens for an additional 36 weeks (EoE KIDS Part B). The use of dupilumab 300 mg QW in patients 1 to 11 years of age with EoE with a body weight ≥ 40 kg is also supported by a population pharmacokinetic analysis [see section 5.1]. The safety and efficacy of dupilumab in adults and paediatric patients were similar [see section 4.8 and section 5.1].

Chronic Spontaneous Urticaria

The safety and efficacy of dupilumab for the treatment of CSU have been established in paediatric patients 2 to 17 years of age.
The safety and efficacy in paediatric patients < 2 years of age with CSU have not been established [see section 4.2].

A total of 12 adolescents aged 12 to 17 years with CSU were enrolled in CUPID Study A, B, and C and received dupilumab 200 mg Q2W (30 kg to <60 kg), 300 mg Q2W (≥60 kg) or placebo. The effectiveness of dupilumab for the treatment of CSU in adolescents is based on extrapolation of efficacy in adults with this condition. The recommended dosage in adolescents is based on body weight.

A total of 20 paediatric patients aged 2 to 11 years with CSU enrolled in CUPID Studies (A and C) and PKM16982. 18 children received dupilumab [200 mg Q4W (5 kg to <15 kg), 300 mg Q4W (15 kg to <30 kg), or 200 mg Q2W (30 kg to <60kg)] and 2 received placebo. The effectiveness of dupilumab for the treatment of CSU in paediatric patients 2 to 11 years is based on extrapolation of efficacy in adults with this condition. The recommended dosage in paediatric patients is based on body weight.
The efficacy of dupilumab for the treatment of CSU in children 2 to 11 years is further supported by Study PKM16982 which enrolled 15 patients, who received 200 mg Q4W (N=1), 300 mg Q4W (N=6), or 200 mg Q2W (N=8).

The European Medicines Agency has deferred the obligation to submit the results of studies with dupilumab in one or more subset of the paediatric population in asthma (see section 4.2 for information on paediatric use). The European Medicines Agency has waived the obligation to submit the results of studies with dupilumab in all subsets of the paediatric population in the treatment of nasal polyposis, prurigo nodularis, chronic obstructive pulmonary disease, and bullous pemphigoid (see section 4.2 for information on paediatric use).

Baseline Total IgE (IU/mL,) median
101.0
107.3
103.0

The results for primary and secondary endpoints in CUPID Study A and Study C are presented in the Table 23.

Table 23: Results of the Primary and Secondary Endpoints in CUPID Study A and Study C

CUPID STUDY A
CUPID Study C

Dupilumab
(N=70)
Placebo
(N=68)
Difference
(95% CI) for
Dupilumab vs. Placebob
Dupilumab
(N=74)
Placebo
(N=77)
Difference
(95% CI) for
Dupilumab vs.
Placebob
Primary Endpoint
Change from baseline in
UAS7 at Week 24a
-20.53 (1.76) -12.00 (1.81) -8.53 (-13.16, -
3.90)
-15.86
(2.66)
-11.21
(2.65)
-4.65
(-8.65, -0.65)
Secondary Endpoints
Change from baseline in
ISS7 at Week 24a
-10.24 (0.91) -6.01 (0.94)
-4.23 (-6.63, -
1.84)
-8.64
(1.41)
-6.10
(1.40)
-2.54
(-4.65, -0.43)
Change from baseline in
HSS7 at Week 24a
-10.28 (0.91) -5.90 (0.93)
-4.38 (-6.78, -
1.98)
-7.27
(1.32)
-5.11
(1.31)
-2.17
(-4.15, -0.19)

Dupilumab
(N=70)
Placebo
(N=68)
Odds Ratio
(95% CI) for
Dupilumab vs. Placebob
Dupilumab
(N=74)
Placebo
(N=77)
Odds Ratio
(95% CI) for
Dupilumab vs.
Placebob
Proportion of patients with UAS7 ≤6 at Week
24a
32 (45.7)
16 (23.5)
2.848 (1.301,
6.234)
(40.5)
(23.4)
3.137
(1.371, 7.176)
Proportion of patients with UAS7 = 0 at Week
24a
22 (31.4)
9 (13.2)
2.908 (1.173,
7.209)
(29.7)
(18.2)
2.677
(1.127, 6.359) a Values presented are LS mean change from baseline (SE) for continuous variables and number and percent of responders for binary variables.
b Difference is LS mean difference for continuous variables and odds ratio for binary variables.

Dupilumab treatment led to an improvement over time in UAS7 through the 24-week treatment period (Figure 3).
Figure 3: LS mean change from baseline in UAS7 up to Week 24 in CUPID Study A and Study C ITT population Fig 13a. Study A Fig 13b. Study C

Similar improvement in HSS7 and ISS7 was observed over 24 weeks.
Paediatric population

Atopic dermatitis
The safety and efficacy of dupilumab have been established in paediatric patients 6 months of age and older with atopic dermatitis. Use of dupilumab in this age group is supported by study AD-1526 which included 251 adolescents aged 12 to 17 years old with moderate-to-severe atopic dermatitis, in study

AD-1652 which included 367 paediatric patients aged 6 to 11 years old with severe atopic dermatitis, and study AD-1539 which included 162 children ages 6 months to 5 years old with moderate-to-severe atopic dermatitis (125 of whom had severe atopic dermatitis). Long term use is supported by study AD-1434 which enrolled 823 paediatric patients aged 6 months to 17 years of age; this included 275 adolescents, 368 children 6 to 11 years of age, and 180 children 6 months to 5 years of age. The safety and efficacy were generally consistent between children 6 months to 5 years old, 6 to 11 years old, adolescent (12 to 17 years old), and adult patients with atopic dermatitis (see section 4.8). Safety and efficacy in paediatric patients < 6 months 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 QUEST study and received either 200 mg (N=21) or 300 mg (N=18) dupilumab (or matching placebo either 200 mg [N=34] or 300 mg [N=34]) every other week. Efficacy with respect to severe asthma exacerbations and lung function was observed in both adolescents and adults. For both the 200 mg and 300 mg every other week doses, significant 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 every other week dose, patients had a reduction in the rate of severe exacerbations that was consistent with adults. The safety profile in adolescents was generally similar to the adults.

A total of 89 adolescents aged 12 to 17 years with moderate-to-severe asthma were enrolled in the open label long-term study (TRAVERSE). In this study, efficacy was measured as a secondary endpoint, was similar to results observed in the pivotal studies and was sustained up to 96 weeks.

A total of 408 children aged 6 to 11 years with moderate-to-severe asthma was enrolled in the VOYAGE study, which evaluated doses of 100 mg Q2W and 200 mg Q2W. The efficacy of dupilumab 300 mg Q4W in children aged 6 to 11 years is extrapolated from the efficacy of 100 mg and 200 mg Q2W in VOYAGE and 200 mg and 300 mg Q2W in adults and adolescents (QUEST).
Patients who completed the treatment period of the VOYAGE study could participate in the open label extension study (EXCURSION). Eighteen patients (≥ 15 kg to < 30 kg) out of 365 patients were exposed to 300 mg Q4W in this study, and the safety profile was similar to that seen in VOYAGE.
Safety and efficacy in paediatric patients < 6 years of age with asthma have not been established.

Eosinophilic Esophagitis
The safety and efficacy of dupilumab for the treatment of EoE have been established in paediatric patients 1 to 17 years of age. Use of dupilumab in this population is supported by adequate and well- controlled studies and additional pharmacokinetic data. A total of 72 paediatric patients 12 to 17 years of age received dupilumab 300 mg QW or placebo for 24 weeks (TREET Parts A and B). Of these, there were 37 dupilumab treated patients in Parts A and B; 34 continued treatment with 300 mg QW for an additional 28 weeks (TREET Part C). A total of 71 paediatric patients 1 to 11 years of age received dupilumab 100 mg Q2W, 200 mg Q2W, 300 mg Q2W, or placebo for 16 weeks (EoE KIDS Part A). Of these, there were 37 dupilumab treated patients in Part A all of whom continued treatment with these dupilumab regimens for an additional 36 weeks (EoE KIDS Part B). The use of dupilumab 300 mg QW in patients 1 to 11 years of age with EoE with a body weight 40 ≥ kg is also supported by a population pharmacokinetic analysis [see section 5.1]. The safety and efficacy of dupilumab in adults and paediatric patients were similar [see section 4.8 and section 5.1].

Chronic Spontaneous Urticaria

The safety and efficacy of dupilumab for the treatment of CSU have been established in paediatric patients 2 to 17 years of age.

The safety and efficacy in paediatric patients < 2 years of age with CSU have not been established [see section 4.2].

A total of 12 adolescents aged 12 to 17 years with CSU were enrolled in CUPID Study A, B, and C and received dupilumab 200 mg Q2W (30 kg to <60 kg), 300 mg Q2W (≥60 kg) or placebo. The effectiveness of dupilumab for the treatment of CSU in adolescents is based on extrapolation of

efficacy in adults with this condition. The recommended dosage in adolescents is based on body weight.

A total of 20 paediatric patients aged 2 to 11 years with CSU enrolled in CUPID Studies (A and C) and PKM16982. 18 children received dupilumab [200 mg Q4W (5 kg to <15 kg), 300 mg Q4W (15 kg to <30 kg), or 200 mg Q2W (30 kg to <60kg)] and 2 received placebo. The effectiveness of dupilumab for the treatment of CSU in paediatric patients 2 to 11 years is based on extrapolation of efficacy in adults with this condition. The recommended dosage in paediatric patients based on body weight.

The efficacy of dupilumab for the treatment of CSU in children 2 to 11 years is further supported by Study PKM16982 which enrolled 15 patients, who received 200 mg Q4W (N=1) , 300 mg Q4W (N=6), or 200 mg Q2W (N=8).

The European Medicines Agency has deferred the obligation to submit the results of studies with dupilumab in one or more subset of the paediatric population in asthma (see section 4.2 for information on paediatric use). The European Medicines Agency has waived the obligation to submit the results of studies with dupilumab in all subsets of the paediatric population in the treatment of nasal polyposis, prurigo nodularis, chronic obstructive pulmonary disease, and bullous pemphigoid (see section 4.2 for information on paediatric use).

Pregnancy

There is a limited amount of data from the use of dupilumab in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).
Dupilumab should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Breast-feeding

It is unknown whether dupilumab is excreted in human milk or absorbed systemically after ingestion.
A decision must be made whether to discontinue breast-feeding or to discontinue dupilumab therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

Animal studies showed no impairment of fertility (see section 5.3).

Dupilumab has no or negligible influence on the ability to drive and use machines.

There is no specific treatment for dupilumab overdose. In the event of overdose, monitor the patient for any signs or symptoms of adverse reactions and institute appropriate symptomatic treatment immediately.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Other dermatological preparations, agents for dermatitis, excluding corticosteroids, ATC code: D11AH05

Mechanism of action

Dupilumab is a recombinant human IgG4 monoclonal antibody that inhibits interleukin-4 and interleukin-13 signalling. Dupilumab inhibits IL-4 signaling via the Type I receptor (IL-4Rα/γc), and both IL-4 and IL-13 signaling through the Type II receptor (IL-4Rα/IL-13Rα). IL-4 and IL-13 are major drivers of human type 2 inflammatory disease, such as atopic dermatitis, asthma, CRSwNP, PN, EoE, COPD, and CSU. Blocking the IL-4/IL-13 pathway with dupilumab in patients decreases many of the mediators of type 2 inflammation.

Pharmacodynamic effects

In atopic dermatitis clinical trials, treatment with dupilumab was associated with decreases from baseline in concentrations of type 2 immunity biomarkers, such as thymus and activation-regulated chemokine (TARC/CCL17), total serum IgE and allergen-specific IgE in serum. A reduction of lactate dehydrogenase (LDH), a biomarker associated with AD disease activity and severity, was observed with dupilumab treatment in adults and adolescents with atopic dermatitis.

In adult and adolescent patients with asthma, dupilumab treatment relative to placebo markedly decreased FeNO and circulating concentrations of eotaxin-3, total IgE, allergen specific IgE, TARC, and periostin, the type 2 biomarkers evaluated in clinical trials. These reductions in type 2 inflammatory biomarkers were comparable for the 200 mg Q2W and 300 mg Q2W regimens. In paediatric (6 to 11 years of age) patients with asthma, dupilumab treatment relative to placebo markedly decreased FeNO and circulating concentrations of total IgE, allergen specific IgE, and TARC, the type 2 biomarkers evaluated in clinical trials. These markers were near maximal suppression after 2 weeks of treatment, except for IgE which declined more slowly. These effects were sustained throughout treatment.

In COPD patients, dupilumab treatment decreased type 2 biomarkers including FeNO and total IgE compared to placebo. Decreases in FeNO were observed by Week 4. These effects on type 2 biomarkers were sustained throughout treatment with dupilumab.

Clinical efficacy and safety in atopic dermatitis

Adults with atopic dermatitis

The efficacy and safety of dupilumab as monotherapy and with concomitant topical corticosteroids were evaluated in three pivotal randomised, double-blind, placebo-controlled studies (SOLO 1, SOLO 2, and CHRONOS) in 2,119 patients 18 years of age and older with moderate to severe atopic dermatitis (AD) defined by Investigator’s Global Assessment (IGA) score ≥ 3, an Eczema Area and Severity Index (EASI) score ≥ 16, and a minimum body surface area (BSA) involvement of ≥ 10 %.
Eligible patients enrolled into the three studies had previous inadequate response to topical medication.

Pharmacotherapeutic group: Other dermatological preparations, agents for dermatitis, excluding corticosteroids, ATC code: D11AH05

Mechanism of action

Dupilumab is a recombinant human IgG4 monoclonal antibody that inhibits interleukin-4 and interleukin-13 signalling. Dupilumab inhibits IL-4 signalling via the Type I receptor (IL-4Rα/γc), and both IL-4 and IL-13 signalling through the Type II receptor (IL-4Rα/IL-13Rα). IL-4 and IL-13 are major drivers of human type 2 inflammatory disease, such as atopic dermatitis, asthma, EoE, and CSU.
Blocking the IL-4/IL-13 pathway with dupilumab in patients decreases many of the mediators of type 2 inflammation.

Pharmacodynamic effects

In atopic dermatitis clinical trials, treatment with dupilumab was associated with decreases from baseline in concentrations of type 2 immunity biomarkers, such as thymus and activation-regulated chemokine (TARC/CCL17), total serum IgE and allergen-specific IgE in serum. A reduction of lactate dehydrogenase (LDH), a biomarker associated with AD disease activity and severity, was observed with dupilumab treatment in adults and adolescents with atopic dermatitis.

In adult and adolescent patients with asthma, dupilumab treatment relative to placebo markedly decreased FeNO and circulating concentrations of eotaxin-3, total IgE, allergen specific IgE, TARC, and periostin, the type 2 biomarkers evaluated in clinical trials. These reductions in type 2 inflammatory biomarkers were comparable for the 200 mg Q2W and 300 mg Q2W regimens. In paediatric (6 to 11 years of age) patients with asthma, dupilumab treatment relative to placebo markedly decreased FeNO and circulating concentrations of total IgE, allergen specific IgE, and TARC, the type 2 biomarkers evaluated in clinical trials. These markers were near maximal suppression after 2 weeks of treatment, except for IgE which declined more slowly. These effects were sustained throughout treatment.

Clinical efficacy and safety in atopic dermatitis

Adolescents with atopic dermatitis (12 to 17 years of age)

The efficacy and safety of dupilumab monotherapy in adolescent patients was evaluated in a multicentre, randomised, double-blind, placebo-controlled study (AD-1526) in 251 adolescent patients 12 to 17 years of age with moderate-to-severe atopic dermatitis (AD) defined by Investigator’s Global Assessment (IGA) score ≥3 in the overall assessment of AD lesions on a severity scale of 0 to 4, an Eczema Area and Severity Index (EASI) score ≥ 16 on a scale of 0 to 72, and a minimum body surface area (BSA) involvement of ≥10 %. Eligible patients enrolled into this study had previous inadequate response to topical medication.

The pharmacokinetics of dupilumab is similar in patients with atopic dermatitis, asthma, CRSwNP, PN EoE, COPD, and CSU.

Absorption

After a single subcutaneous (SC) dose of 75-600 mg dupilumab to adults, median times to maximum concentration in serum (tmax) were 3-7 days. The absolute bioavailability of dupilumab following a SC dose is similar between AD, asthma, CRSwNP, EoE, COPD, and CSU patients, ranging between 61 % and 64 %, as determined by a population pharmacokinetics (PK) analysis.

Steady-state concentrations were achieved by week 16 following the administration of 600 mg starting dose and 300 mg dose every other week or 300 mg dose every other week without a loading dose.
Across clinical trials, the mean ±SD steady-state trough concentrations ranged from 55.3±34.3 mcg/mL to 81.5±43.9 mcg/mL for 300 mg administered Q2W, from 172±76.6 mcg/ml to 195±71.7 mcg/ml for 300 mg administered weekly, and from 29.2±18.7 to 36.5±22.2 mcg/mL for 200 mg administered Q2W.

Distribution

A volume of distribution for dupilumab of approximately 4.6 L was estimated by population PK analysis, indicating that dupilumab is distributed primarily in the vascular system.

Biotransformation

Specific metabolism studies were not conducted because dupilumab is a protein. Dupilumab is expected to degrade to small peptides and individual amino acids.

Elimination

Dupilumab elimination is mediated by parallel linear and nonlinear pathways. At higher concentrations, dupilumab elimination is primarily through a non-saturable proteolytic pathway, while at lower concentrations, the non-linear saturable IL-4R α target-mediated elimination predominates.

The pharmacokinetics of dupilumab is similar in patients with atopic dermatitis, asthma, EoE, and CSU.

Absorption

After a single subcutaneous (SC) dose of 75-600 mg dupilumab to adults, median times to maximum concentration in serum (tmax) were 3-7 days. The absolute bioavailability of dupilumab following a SC dose is similar between AD, asthma, and CSU patients, ranging between 61 % and 64 %, as determined by a population pharmacokinetics (PK) analysis.

Steady-state concentrations were achieved by week 16 following the administration of 600 mg starting dose and 300 mg dose every other week. Across clinical trials, the mean ±SD steady-state trough concentrations ranged from 69.2±36.9 mcg/mL to 80.2±35.3 mcg/mL for 300 mg dose and from 29.2±18.7 to 36.5±22.2 mcg/mL for 200 mg dose administered every other week to adults.

Distribution

A volume of distribution for dupilumab of approximately 4.6 L was estimated by population PK analysis, indicating that dupilumab is distributed primarily in the vascular system.

Biotransformation

Specific metabolism studies were not conducted because dupilumab is a protein. Dupilumab is expected to degrade to small peptides and individual amino acids.

Elimination

Dupilumab elimination is mediated by parallel linear and nonlinear pathways. At higher concentrations, dupilumab elimination is primarily through a non-saturable proteolytic pathway, while at lower concentrations, the non-linear saturable IL-4R α target-mediated elimination predominates.
After the last steady state dose of 300 mg QW, 300 mg Q2W, 200 mg Q2W, 300 mg Q4W, or 200 mg Q4W dupilumab, the median times to decrease below the lower limit of detection, estimated by population PK analysis, ranged from 9-13 weeks in adults and adolescents and are approximately 1.5

times and 2.5 times longer in paediatric patients 6 to 11 years of age and paediatric subjects less than 6 years of age, respectively.

Linearity/non-linearity