Dupixent 300mg solution for injection in pre-filled syringe

Section 4.8

Tabulated list of adverse reactions

The safety of dupilumab was evaluated in four randomized, double-blind, placebo-controlled studies and one dose-ranging study in patients with moderate-to-severe atopic dermatitis. In these 5 trials, 1,689 subjects were treated with subcutaneous injections of dupilumab, with or without concomitant topical corticosteroids (TCS). A total of 305 patients were treated with dupilumab for at least 1 year.

Listed in Table 2 are adverse reactions observed in atopic dermatitis 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). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness

Table 2: List of adverse reactions in atopic dermatitis

* From postmarketing reporting

Listed in Table 3 are adverse reactions observed in asthma 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). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 3: List of adverse reactions in asthma

* From postmarketing reporting

Listed in Table 4 are adverse reactions observed in CRSwNP 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). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 4. List of adverse reactions in CRSwNP

* From postmarketing reporting

1.       NAME OF THE MEDICINAL PRODUCT

Dupixent 300 mg solution for injection in pre-filled syringe

Dupixent 300 mg solution for injection in pre-filled pen

2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

Dupilumab 300 mg solution for injection in pre-filled syringe

Each single-use pre-filled syringe contains 300 mg of dupilumab in 2 ml solution (150 mg/ml).

Dupilumab 300 mg solution for injection in pre-filled pen

Each single-use pre-filled pen syringe contains 300 mg of dupilumab in 2 ml solution (150 mg/ml).

Dupilumab is a fully human monoclonal antibody against interleukin (IL)-4 receptor alpha that inhibits IL-4/IL-13 signalling, produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology.

For the full list of excipients, see section 6.1.

3.       PHARMACEUTICAL FORM

Solution for injection (injection)

Clear to slightly opalescent, colourless to pale yellow sterile solution, which is free from visible particulates, with a pH of approximately 5.9.

6.       PHARMACEUTICAL PARTICULARS

6.1     List of excipients

arginine hydrochloride

histidine

polysorbate 80 (E433)

sodium acetate trihydrate

glacial acetic acid (E260)

sucrose

water for injections

6.2     Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3     Shelf life

30 months.

If necessary, pre-filled syringes or pre-filled pens may be kept at room temperature up to 25°C for a maximum of 14 days. Do not store above 25°C. If the carton needs to be removed permanently from refrigerator, the date of removal may be recorded on the outer carton. After removal from the refrigerator, Dupixent must be used within 14 days or discarded.

6.5     Nature and contents of container

2 ml solution in a siliconised type-1 clear glass pre-filled syringe with or without needle shield, with a fixed 27 gauge 12.7 mm (½ inch), thin wall stainless steel staked needle.

Dupixent 300 mg solution for injection in pre-filled syringe

2 ml solution in a siliconised type-1 clear glass pre-filled syringe with or without needle shield, with a fixed 27 gauge 12.7 mm (½ inch), thin wall stainless steel staked needle.

Pack size:

• 1 pre-filled syringe
• 2 pre-filled syringes
• Multipack containing 3 (3 packs of 1) pre-filled syringes
• Multipack containing 6 (3 packs of 2) pre-filled syringes

Dupixent 300 mg solution for injection in pre-filled pen

2 ml solution in a siliconised type-1 clear glass syringe in a pre-filled pen, with a fixed 27 gauge 12.7 mm (½ inch), thin wall stainless steel staked needle.

Pack size:

• 1 pre-filled pen
• 2 pre-filled pens
• 3 pre-filled pens
• 6 pre-filled pens

Not all pack sizes may be marketed.

6.6     Special precautions for disposal and other handling

The instructions for the preparation and administration of Dupixent in a pre-filled syringe or in a pre-filled pen are given in the package leaflet.

The solution should be clear to slightly opalescent, colourless to pale yellow. If the solution is cloudy, discoloured or contains visible particulate matter, the solution should not be used.

After removing the 300 mg pre-filled syringe or pre-filled pen from the refrigerator, it should be allowed to reach room temperature by waiting for 45 min before injecting Dupixent.

The pre-filled syringe or pre-filled pen should not be exposed to heat or direct sunlight and should not be shaken.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements. After use, place the pre-filled syringe or the pre-filled pen into a puncture-resistant container and discard as required by local regulations. Do not recycle the container. Keep the container out of sight and reach of children.

8.       MARKETING AUTHORISATION NUMBER(S)

EU/1/17/1229/001

EU/1/17/1229/002

EU/1/17/1229/003

EU/1/17/1229/004

EU/1/17/1229/005

EU/1/17/1229/006

EU/1/17/1229/007

EU/1/17/1229/008

EU/1/17/1229/017

EU/1/17/1229/018

EU/1/17/1229/019

EU/1/17/1229/020

4.1     Therapeutic indications

Atopic Dermatitis

Dupixent is indicated for the treatment of moderate-to-severe atopic dermatitis in adult adults and adolescents patientsaged12 years and older who are candidates for systemic therapy.

Asthma

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 FeNO (see section 5.1), who are inadequately controlled with high dose ICS plus another medicinal product for maintenance treatment.

4.2     Posology and method of administration

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

The recommended dose of dupilumabDupixent for adolescent patients 12 to 17 years of age is specified in Table 1.

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

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. In case treatment needs to be interrupted for some reasonIf dupilumab treatment interruption becomes necessary, patients can still be successfully re-treated.with dupilumab and expected to get substantial clinical benefit.

Asthma

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 (see section 5.2).

For patients 12 to 17 years of age with atopic dermatitis, the recommended every other week dose is 200 mg (< 60 kg) or 300 mg (≥ 60 kg).

Paediatric patients

The safety and efficacy of dupilumab in children with atopic dermatitis below the age of 18 12 years have not been established (see section 5.2). No data are available. No data are available.

The safety and efficacy of dupilumab in children with severe asthma below the age of 12 years have not been established (see section 5.2). No data are available.

4.8     Undesirable effects

Atopic dermatitis

Adults with atopic dermatitis

Summary of the safety profile

Adolescents with atopic dermatitis

The safety of dupilumabDupixent 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 dupilumabDupixent in these patients followed through wWeek 16 was similar to the safety profile from studies in adults with atopic dermatitis.

The long-term safety of dupilumabDupixent was assessed in an open-label extension study in patients 12 to 17 years of age with moderate-to-severe atopic dermatitis (AD-1434). The safety profile of dupilumabDupixent in patients followed through wWeek 52 was similar to the safety profile observed at wWeek 16 in AD-1526 study. The long-term safety profile of dupilumabDupixent observed in adolescents was consistent with that seen in adults with atopic dermatitis.

Paediatric population

The safety profile observed in adolescents paediatricaged 12 to 17 years populationin atopic dermatitis clinical trials was similar to that seen in adults.

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.

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.

Asthma

PaediatricAdolescents with atopic dermatitis

The efficacy and safety of dupilumabDupixent 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.

Patients received 1) an initial dose of 400 mg dupilumabDupixent (two 200 mg injections) on day 1, followed by 200 mg once every other week (Q2W) for patients with baseline weight of <60 kg or an initial dose of 600 mg dupilumabDupixent (two 300 mg injections) on day 1, followed by 300 mg Q2W for patients with baseline weight of ≥ 60 kg; 2) an initial dose of 600 mg dupilumabDupixent (two 300 mg injections) on day 1, followed by 300 mg every 4 weeks (Q4W) regardless of baseline body weight; or 3) matching placebo. DupilumabDupixent was administered by subcutaneous (SC) injection. If needed to control intolerable symptoms, patients were permitted to receive rescue treatment at the discretion of the investigator. Patients who received rescue treatment were considered non-responders.

​In this study, the mean age was 14.5 years, the median weight was 59.4 kg, 41.0 % were female, 62.5% were White, 15.1% were Asian, and 12.0% were Black. At baseline 46.2% of patients had a baseline IGA score of 3 (moderate AD), 53.8% of patients had a baseline IGA of 4 (severe AD), the mean BSA involvement was 56.5%, and 42.4 % of patients had received prior systemic immunosuppressants. Also at baseline the mean Eczema Area and Severity Index (EASI) score was 35.5, the baseline weekly averaged pruritus Numerical Rating Scale (NRS) was 7.6, the baseline mean SCORing Atopic Dermatitis (SCORAD) score was 70.3, the baseline mean Patient Oriented Eczema Measure (POEM) score was 21.0, and the baseline mean Children Dermatology Life Quality Index (CDLQI) was 13.6. Overall, 92.0% of patients had at least one co-morbid allergic condition; 65.6% had allergic rhinitis, 53.6% had asthma, and 60.8% had food allergies.

The co-primary endpoint was the proportion of patients with IGA 0 or 1 (“clear” or “almost clear”) least a 2-point improvement and the proportion of patients with EASI-75 (improvement of at least 75% in EASI), from baseline to week 16. Other evaluated outcomes included the proportion of subjects with EASI-50 or EASI-90 (improvement of at least 50% or 90% in EASI from baseline respectively), reduction in itch as measured by the peak pruritus NRS, and percent change in the SCORAD scale from baseline to week 16. Additional secondary endpoints included mean change from baseline to week 16 in the POEM and CDLQI scores.

Clinical Response

The efficacy results at wWeek 16 for adolescent atopic dermatitis study are presented in Table 10.

Table 10: Efficacy results of dupilumabDupixent in the adolescent atopic dermatitis study at Week 16 (FAS)

^a Full Analysis Set (FAS) includes all patients randomised.

^b Responder was defined as a subject with IGA 0 or 1 (“clear” or “almost clear”) with a reduction of ≥2 points on a 0-4 IGA scale.

^c Patients who received rescue treatment or with missing data were considered as non-responders (58.8% and 20.7% in the placebo and dupilumab arms, respectively).

All p–values <0.0001

A larger percentage of patients randomised to placebo needed rescue treatment (topical corticosteroids, systemic corticosteroids, or systemic non-steroidal immunosuppressants) as compared to the dupilumabDupixent group (58.8% and 20.7%, respectively).

A significantly greater proportion of patients randomised to dupilumabDupixent achieved a rapid improvement in the pruritus NRS compared to placebo (defined as >4-point improvement as early as week 4; nominal p<0.001) and the proportion of patients responding on the pruritus NRS continued to increase through the treatment period (see Figure 5). The improvement in pruritus NRS occurred in conjunction with the improvement of objective signs of atopic dermatitis.

Figure 5: Proportion of adolescent patients with ≥4-point improvement on the pruritus NRS in AD-1526 study^a (FAS)^b

^a In the primary analyses of the efficacy endpoints, subjects who received rescue treatment or with missing data were considered non‑responders.

^b Full Analysis Set (FAS) includes all subjects randomised.

The dupilumabDupixent group significantly improved patient-reported symptoms, the impact of AD on sleep and health-related quality of life as measured by POEM, SCORAD, and CDLQI scores at 16 weeks compared to placebo.

The long-term efficacy of dupilumabDupixent in adolescent patients with moderate-to-severe AD who had participated in previous clinical trials of dupilumabDupixent was assessed in open-label extension study (AD-1434). Efficacy data from this study suggests that clinical benefit provided at week 16 was sustained through week 52.

Paediatric population

The pharmacokinetics of dupilumab in paediatric patients (< 18 12 years of age) with atopic dermatitis has not been studied.

For adolescents 12 to 17 years of age with atopic dermatitis receiving every other week dosing (Q2W) with either 200 mg (<60 kg) or 300 mg (≥60 kg), the mean ±SD steady state trough concentration of dupilumab was 54.5±27.0 mcg/ml.

A total of 107 adolescents aged 12 to 17 years with asthma were enrolled in QUEST study. The mean ±SD steady-state trough concentrations of dupilumab were 107±51.6 mcg/mL and 46.7±26.9

8.       MARKETING AUTHORISATION NUMBER(S)

EU/1/17/1229/001

EU/1/17/1229/002

EU/1/17/1229/003

EU/1/17/1229/004

EU/1/17/1229/005

EU/1/17/1229/006

EU/1/17/1229/007

EU/1/17/1229/008

EU/1/17/1229/009

EU/1/17/1229/010

EU/1/17/1229/011

EU/1/17/1229/012

EU/1/17/1229/013

EU/1/17/1229/014

EU/1/17/1229/015

EU/1/17/1229/016

Updated in all sections to add information regarding the Asthma indication

6.3       Shelf life

18 months. 2 years.

•  18 months

•  18 months