DUPIXENT 200 MG SOLUTION FOR INJECTION IN A PRE-FILLED PEN - summary of medicine characteristics

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

Dupixent 200 mg solution for injection in pre-filled pen

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each single-use pre-filled pen contains 200 mg of dupilumab in 1.14 ml solution (175 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.

4.1 Therapeutic indications

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 to 11 years of age

Dupixent is indicated for the treatment of severe atopic dermatitis in children 6 to 11 years old 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 fraction of exhaled nitric oxide (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

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 years to 17 years of age with atopic dermatitis

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

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.

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.

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

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.

Patients receiving concomitant oral corticosteroids may reduce their steroid dose once clinical improvement with dupilumab has occurred (see section 5.1). Steroid reductions should 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.

Missed dose

If a dose is missed, administer the dose as soon as possible. Thereafter, resume dosing at the regular scheduled time.

Special populations

Elderly (> 65 years)

No dose adjustment is recommended for elderly 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 (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).

For patients 6 to 11 years of age with atopic dermatitis, the recommended doses are 300 mg Q4W with the possibility to increase to 200 mg Q2W (15 kg to < 60 kg), and 300 mg Q2W (> 60 kg).

Paediatric patients

The safety and efficacy of dupilumab in children with atopic dermatitis below the age of 6 years have not been established. The safety and efficacy of dupilumab in children with a body weight < 15 kg have not been established (see section 5.2). 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.

Method of administration

Subcutaneous use

The dupilumab pre-filled pen is not intended for use in children below 12 years of age. For children 6 to 11 years of age with atopic dermatitis, the dupilumab pre-filled syringe is the presentation appropriate for administration to this population.

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.

For the initial 400 mg dose, two 200 mg injections should be administered consecutively in different injection sites.

It is recommended to rotate the injection site with each injection. Dupilumab should not be injected 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. Proper training should be provided to patients and/or caregivers on the preparation and administration of dupilumab prior to use according to the Instructions for Use (IFU) section in the package leaflet.

4.3 Contraindications

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

4.4 Special warnings and precautions for use

Dupilumab should not be used to treat acute asthma symptoms or acute exacerbations. Dupilumab should not be used to treat acute bronchospasm or status asthmaticus.

Systemic, topical, or inhaled corticosteroids should 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).

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.

Hypersensitivity

If a systemic hypersensitivity reaction (immediate or delayed) occurs, administration of dupilumab should be discontinued immediately and appropriate therapy initiated. 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 (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 signaling. 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.

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 (section 4.8).

Patients should be advised 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 (section 4.8).

Atopic dermatitis or CRSwNP patients with comorbid asthma

Patients on dupilumab for moderate-to-severe atopic dermatitis or severe CRSwNP who also have comorbid asthma should not adjust or stop their asthma treatments without consultation with their physicians. Patients with comorbid asthma should be monitored carefully following discontinuation of dupilumab.

Vaccinations

Live and live attenuated vaccines should not be given concurrently with dupilumab as clinical safety and efficacy has not been established. Immune responses to TdaP vaccine and meningococcal polysaccharide vaccine were assessed, see section 4.5. It is recommended that patients should be brought up to date with live and live attenuated immunisations in agreement with current immunisation guidelines prior to treatment with dupilumab.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per 200 mg dose, i.e. essentially “sodium-free”.

4.5 Interaction with other medicinal products and other forms of interaction

Immune responses to vaccination were assessed in a study in which patients with atopic dermatitis were treated once weekly for 16 weeks with 300 mg of dupilumab. After 12 weeks of dupilumab administration, patients were vaccinated with a Tdap vaccine (T cell-dependent), and a meningococcal polysaccharide vaccine (T cellindependent) and immune responses were assessed 4 weeks later. Antibody responses to both tetanus vaccine and meningococcal polysaccharide vaccine were similar in dupilumab-treated and placebo-treated patients. No adverse interactions between either of the non-live vaccines and dupilumab were noted in the study.

Therefore, patients receiving dupilumab may receive concurrent inactivated or nonlive vaccinations. For information on live vaccines see section 4.4.

In a clinical study of AD patients, the effects of dupilumab on the pharmacokinetics (PK) of CYP substrates were evaluated. The data gathered from this study did not indicate clinically relevant effects of dupilumab on CYP1A2, CYP3A, CYP2C19, CYP2D6, or CYP2C9 activity.

An effect of dupilumab on the PK of co-administered medications is not expected. Based on the population analysis, commonly co-administered medications had no effect on dupilumab pharmacokinetics on patients with moderate to severe asthma.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are 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).

4.7 Effects on ability to drive and use machines

Dupilumab has no or negligible influence on the ability to drive or operate machinery.

4.8 Undesirable effects

Summary of the safety , profile

The most common adverse reactions in controlled clinical studies of dupilumab in atopic dermatitis, asthma and CRSwNP were injection site reactions (includes erythema, oedema, pruritis, pain, and swelling), conjunctivitis, arthralgia, oral herpes, and eosinophilia. Rare cases of serum sickness, serum sickness-like reaction, anaphylactic reaction, and ulcerative keratitis have been reported (see section 4.4).

In the monotherapy atopic dermatitis adult studies, the proportion of patients who discontinued treatment due to adverse events was 1.9 % of the placebo group, 1.9 % of the dupilumab 300 mg Q2W group, 1.5 % of the dupilumab 300 mg QW group. In the concomitant TCS adult study, the proportion of patients who discontinued treatment due to adverse events was 7.6 % of the placebo + TCS group, 1.8 % of the dupilumab 300 mg Q2W + TCS group, and 2.9 % of the dupilumab 300 mg QW + TCS group.

In DRI12544 and QUEST asthma studies, the proportion of patients who discontinued treatment due to adverse events was 4.3 % of the placebo group, 3.2 % of the dupilumab 200 mg Q2W group, and 6.1 % of the dupilumab 300 mg Q2W group.

In SINUS-24 and SINUS-52 CRSwNP studies, the proportion of patients who discontinued treatment due to adverse events was 2.0 % of the dupilumab 300 mg Q2W group and 4.6 % of the placebo group.

Tabulated list of adverse reactions

Dupilumab was studied in 12 randomised, placebo-controlled trials, including atopic dermatitis, asthma, and CRSwNP patients. The pivotal controlled studies involved 4,206 patients receiving dupilumab and 2,326 patients receiving placebo during the controlled period.

Listed in Table 3 are adverse reactions observed in atopic dermatitis, asthma, and 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).

Table 3: List of adverse reactions

*Eye disorders and oral herpes occurred predominately in atopic dermatitis studies. 'The frequencies for eye pruritus and blepharitis were common and ulcerative keratitis was uncommon in atopic dermatitis studies.

Description of selected adverse reactions in atopic dermatitis, asthma, and CRSwNP indications

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 3 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 patients frequency of conjunctivitis and keratitis was low and similar between dupilumab and placebo. Among CRSwNP patients the frequency of conjunctivitis was higher in dupilumab than placebo, though lower than that observed in atopic dermatitis patients. There were no cases of keratitis reported in the CRSwNP 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. The rates remained stable at 3 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. 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 3 years in the long-term OLE study (AD-1225).

Treatment-emergent eosinophilia (> 5,000 cells/mcL) was reported in < 2 % of dupilumab-treated patients and < 0.5 % in placebo-treated patients (see section 4.4).

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 3 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.

Immunogenicity

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

Anti-Drug-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 paediatric patients (6 to 11 years of age) with atopic dermatitis who received dupilumab 200 mg Q2W or 300 mg Q4W for 16 weeks. Similar ADA responses were observed in adult patients with atopic dermatitis treated with dupilumab for up to 3 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.

Regardless of age or population, approximately 2 to 4 % of patients in the placebo groups were positive for antibodies to dupilumab; approximately 2 % exhibited persistent ADA response and approximately 1 % 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.

Asthma

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.

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 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 and AD-1652 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 347 who completed at least 148 weeks of the study. The long-term safety profile observed in this study up to 3 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.

CRSwNP

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

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

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

5.1 Pharmacodynamic 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 signaling. Dupilumab inhibits IL-4 signaling via the Type I receptor (IL-4Ra/Yc), and both IL-4 and IL-13 signaling through the Type II receptor (IL-4Ra/IL-13Ra). IL-4 and IL-13 are major drivers of human type 2 inflammatory disease, such as atopic dermatitis and asthma. 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 asthma clinical trials, dupilumab treatment markedly decreased FeNO and circulating concentrations of eotaxin-3, total IgE, allergen specific IgE, TARC, and periostin in asthma subjects relative to placebo. These reductions in type 2 inflammatory biomarkers were comparable for the 200 mg Q2W and 300 mg Q2W regimens. 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.

Patients received 1) an initial dose of 400 mg dupilumab (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 dupilumab (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 dupilumab (two 300 mg injections) on day 1, followed by 300 mg every 4 weeks (Q4W) regardless of baseline body weight; or 3) matching placebo. Dupilumab 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 week 16 for adolescent atopic dermatitis study are presented in Table 4.

Table 4: Efficacy results of dupilumab 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 dupilumab group (58.8 % and 20.7 %, respectively).

A significantly greater proportion of patients randomised to dupilumab 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 1). The improvement in pruritus NRS occurred in conjunction with the improvement of objective signs of atopic dermatitis.

Figure 1: Proportion of adolescent patients with > 4-point improvement on the pruritus NRS in AD-1526 studya (FAS)b

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

bFull Analysis Set (FAS) includes all subjects randomised.

The dupilumab 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 dupilumab in adolescent patients with moderate-to-severe AD who had participated in previous clinical trials of dupilumab 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.

Paediatrics (6 to 11 years of age)

The efficacy and safety of dupilumab in paediatric patients concomitantly with TCS was evaluated in a multicentre, randomised, double-blind, placebo-controlled study (AD-1652) in 367 subjects 6 to 11 years of age, with AD defined by an IGA score of 4 (scale of 0 to 4), an EASI score > 21 (scale of 0 to 72), and a minimum BSA involvement of > 15 %. Eligible patients enrolled into this trial had previous inadequate response to topical medication. Enrollment was stratified by baseline weight (< 30 kg; > 30 kg).

Patients in the dupilumab Q2W + TCS group with baseline weight of < 30 kg received an initial dose of200 mg on Day 1, followed by 100 mg Q2W from week2 to week 14, and patients with baseline weight of > 30 kg received an initial dose of 400 mg on Day 1, followed by200 mg Q2W from week2 to week 14. Patients in the dupilumab Q4W + TCS group received an initial dose of 600 mg on Day 1, followed by 300 mg Q4W from week 4 to week 12, regardless of weight. Patients were permitted to receive rescue treatment at the discretion of the investigator. Patients who received rescue treatment were considered nonresponders.

In this study, the mean age was 8.5 years, the median weight was29.8 kg, 50.1 % of patients were female, 69.2 % were White, 16.9 % were Black, and 7.6 % were Asian. At baseline, the mean BSA involvement was 57.6 %, and 16.9 % had received prior systemic non-steroidal immunosuppressants. Also, at baseline the mean EASI score was 37.9, and the weekly average of daily worst itch score was 7.8 on a scale of 0–10, the baseline mean SCORAD score was 73.6, the baseline POEM score was20.9, and the baseline mean CDLQI was 15.1.

Overall, 91.7 % of subjects had at least one co-morbid allergic condition; 64.4 % had food allergies, 62.7 % had other allergies, 60.2 % had allergic rhinitis, and 46.7 % had asthma.

The co-primary endpoint was the proportion of patients with IGA 0 or 1 (“clear” or “almost clear”) at 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 patients with EASI-50 and EASI-90 (improvement of at least 50 % and 90 % in EASI from baseline, respectively), percent change in EASI score from baseline to week 16, and reduction in itch as measured by the peak pruritus NRS (> 4-point improvement). Additional secondary endpoints included mean change from baseline to week 16 in the POEM and CDLQI scores.

Clinical Response

Table 5 presents the results by baseline weight strata for the approved dose regimens.

TABLE 5: Efficacy Results of Dupilumab with Concomitant TCS in AD-1652 at Week 16 (FAS)a

Full Analysis Set (FAS) includes all patients randomised.

b Responder was defined as a patient with an IGA 0 or 1 (“clear” or “almost clear”).

c Patients who received rescue treatment or with missing data were considered as non-responders. d At Day 1, patients received 600 mg of dupilumab (see section 5.2).

e At Day 1, patients received 400 mg (baseline weight > 30 kg) of dupilumab.

A greater proportion of patients randomised to dupilumab + TCS achieved an improvement in the peak pruritus NRS compared to placebo + TCS (defined as >4-point improvement at week

4). See Figure 2.

Figure 2: Proportion of Paediatric Subjects with > 4-point Improvement on the Peak Pruritus NRS in AD-1652a (FAS)b

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

b Full Analysis Set (FAS) includes all patients randomised.

c At Day 1, patients received 600 mg of dupilumab (see section 5.2)

At Day 1, patients received 400 mg (baseline weight > 30 kg) of dupilumab

The dupilumab groups 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 and safety of dupilumab + TCS in paediatric patients with moderate to severe atopic dermatitis who had participated in the previous clinical trials of dupilumab + TCS was assessed in an open-label extension study (AD-1434). Efficacy data from this trial suggests that clinical benefit provided at week 16 was sustained through week 52. Some patients receiving dupilumab 300 mg Q4W + TCS showed further clinical benefit when escalated to dupilumab 200 mg Q2W + TCS. 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 and AD-1652 studies.

Adults with atopic dermatitis

For clinical data in adults with atopic dermatitis please refer to the dupilumab 300 mg Summary of Product Characteristics.

Clinical efficacy and safety in asthma

The asthma development program included three randomised, double-blind, placebo-controlled, parallel-group, multi-centre studies (DRI12544, QUEST, and VENTURE) of 24 to 52 weeks in treatment duration which enrolled a total of 2,888 patients (12 years of age and older). Patients were enrolled without requiring a minimum baseline blood eosinophil or other type 2 inflammatory biomarkers (e.g. FeNO or IgE) level. Asthma treatment guidelines define type 2 inflammation as eosinophilia > 150 cells/mcL and/or FeNO > 20 ppb. In DRI12544 and QUEST, the pre-specified subgroup analyses included blood eosinophils > 150 and > 300 cells/mcL, FeNO > 25 and > 50 ppb.

DRI12544 was a 24-week dose-ranging study which included 776 patients (18 years of age and older). Dupilumab compared with placebo was evaluated in adult patients with moderate to severe asthma on a medium-to-high dose inhaled corticosteroid and a long acting beta agonist. The primary endpoint was change from baseline to week 12 in FEV1 (L). Annualized rate of severe asthma exacerbation events during the 24-week placebo controlled treatment period was also determined. Results were evaluated in the overall population (unrestricted by minimum baseline eosinophils or other type 2 inflammatory biomarkers) and subgroups based on baseline blood eosinophil count.

QUEST was a 52-week confirmatory study which included 1,902 patients (12 years of age and older). Dupilumab compared with placebo was evaluated in 107 adolescent and 1,795 adult patients with persistent asthma on a medium-to-high dose inhaled corticosteroid (ICS) and a second controller medication. Patients requiring a third controller were allowed to participate in this trial. Patients were randomised to receive either 200 mg (N=631) or 300 mg (N=633) Dupixent every other week (or matching placebo for either 200 mg (N = 317) or 300 mg (N= 321) every other week) following an initial dose of 400 mg, 600 mg or placebo respectively. The primary endpoints were the annualized rate of severe exacerbation events during the 52-week placebo controlled period and change from baseline in pre-bronchodilator FEV1 at week 12 in the overall population (unrestricted by minimum baseline eosinophils or other type 2 inflammatory biomarkers) and subgroups based on baseline blood eosinophils count and FeNO.

VENTURE was a 24-week oral corticosteroid-reduction study in 210 patients with asthma unrestricted by baseline type 2 biomarker levels who required daily oral corticosteroids in addition to regular use of high dose inhaled corticosteroids plus an additional controller. After optimizing the OCS dose during the screening period, patients received 300 mg dupilumab (n=103) or placebo (n=107) once every other week for 24 weeks following an initial dose of 600 mg or placebo. Patients continued to receive their existing asthma medicine during the study; however their OCS dose was reduced every 4 weeks during the OCS reduction phase (week 4–20), as long as asthma control was maintained. The primary endpoint was the percent reduction in oral corticosteroid dose assessed in the overall population, based on a comparison of the oral corticosteroid dose at weeks 20 to 24 that maintained asthma control with the previously optimized (at baseline) oral corticosteroid do­se.

The demographics and baseline characteristics of these 3 studies are provided in Table 6 below.

ICS = inhaled corticosteroid; FEV1 = Forced expiratory volume in 1 second; ACQ-5 = Asthma Control Questionnaire-5; AQLQ = Asthma Quality of Life Questionnaire; AD = atopic dermatitis; NP = nasal polyposis; AR = allergic rhinitis; FeNO = fraction of exhaled nitric oxide; EOS = blood eosinophil aThe population in dupilumab asthma trials included patients on medium and high dose ICS. The medium ICS dose was defined as equal to 500 mcg fluticasone or equivalent per day.

Exacerbations

In the overall population in DRI12544 and QUEST subjects receiving either dupilumab 200 mg or 300 mg every other week had significant reductions in the rate of severe asthma exacerbations compared to placebo. There were greater reductions in exacerbations in subjects with higher baseline levels of type 2 inflammatory biomarkers such as blood eosinophils or FeNO (Table 7 and Table 8).

Table 7: Rate of Severe Exacerbations in DRI12544 and QUEST (Baseline Blood

Eosinophil Levels > 150 and > 300 cells/mcL)

ap-value = 0.0003, bp-value = 0.0001, cp-value = 0.0116, dp-value = 0.0024, ep-value < 0.0001

Table 8: Rate of Severe Exacerbations in QUEST Defined by Baseline FeNO Subgroups

ap-value < 0.0001

In the pooled analysis of DRI12544 and QUEST, hospitalizations and/or emergency room visits due to severe exacerbations were reduced by 25.5 % and 46.9 % with dupilumab 200 mg or 300 mg every other week, respectively.

Lung Function

Clinically significant increases in pre-bronchodilator FEV1 were observed at week 12 for DRI12544 and QUEST. There were greater improvements in FEV1 in the subjects with higher baseline levels of type 2 inflammatory biomarkers such as blood eosinophils or FeNO (Table 9 and Table 10).

Significant improvements in FEV1 were observed as early as week 2 following the first dose of dupilumab for both the 200 mg and 300 mg dose strengths and were maintained through week 24 (DRI12544) and week 52 in QUEST (see Figure 3).

QUEST: FeNO > 25 ppb

QUEST: Blood Eosinophils

QUEST: Blood Eosinophils

> 150 cells/mcL

> 300 cells/mcL

DUPIXENT3a0mgQ2W(M=­452)

-O DUPIXENT 203 mg Q2W (N=437)

Placebo 3Ö0 mg Q2W (N-237) -O- Placebo 200 mg Q2W (N-232)

Figure 3: Mean Change from Baseline in Pre-Bronchodilator FEV1 (L) Over Time (Baseline Eosinophils > 150 and > 300 cells/mcL and FeNO >25 ppb) in QUEST

Week(s)

Table 9: Mean Change from Baseline in Pre-Bronchodilator FEV1 at Week 12 in DRI12544 and QUEST (Baseline Blood Eosinophil Levels > 150 and > 300 cells/mcL)

ap-value < 0.0001, bp-value = 0.0004, cp-value = 0.0008, dp-value = 0.0063, ep-value < 0.0001

Table 10: Mean Change from Baseline in Pre-Bronchodilator FEV1 at Week 12 and Week 52 in QUEST by Baseline FeNO Subgroups

ap-value < 0.0001

Quality of Life/Patient-Reported Outcomes in Asthma

Pre-specified secondary endpoint of ACQ-5 and AQLQ(S) responder rates were analysed at 24 weeks (DRI12544 and VENTURE) and at 52 weeks (QUEST). The responder rate was defined as an improvement in score of 0.5 or more (scale range 0–6 for ACQ-5 and 1–7 for AQLQ(S)). Improvements in ACQ-5 and AQLQ(S) were observed as early as week 2 and maintained for 24 weeks in DRI12544 study and 52 weeks in QUEST study. Similar results were observed in VENTURE. The ACQ-5 and AQLQ(S) responder rate results in patients with elevated baseline biomarkers of type 2 inflammation in QUEST at week 52 are presented in Table 11.

Table 11: ACQ-5 and AQLQ(S) Responder Rates at Week 52 in QUEST

Oral Corticosteroid Reduction Study (VENTURE)

VENTURE evaluated the effect of dupilumab on reducing the use of maintenance oral corticosteroids. Baseline characteristics are presented in Table 6. All patients were on oral corticosteroids for at least 6 months prior to the study initiation. The baseline mean oral corticosteroid use was 11.75 mg in the placebo group and 10.75 mg in the group receiving dupilumab.

In this 24-week trial, asthma exacerbations (defined as a temporary increase in oral corticosteroid dose for at least 3 days) were reduced by 59 % in subjects receiving dupilumab compared with those receiving placebo (annualized rate 0.65 and 1.60 for the dupilumab and placebo group, respectively; rate ratio 0.41 [95% CI 0.26, 0.63]) and improvement in pre-bronchodilator FEV1 from baseline to week 24 was greater in subjects receiving dupilumab compared with those receiving placebo (LS mean difference for dupilumab versus placebo of 0.22 L [95% CI: 0.09 to 0.34 L]). Effects on lung function, on oral steroid and exacerbation reduction were similar irrespective of baseline levels of type 2 inflammatory biomarkers (e.g. blood eosinophils, FeNO). The ACQ-5 and AQLQ(S) were also assessed in VENTURE and showed improvements similar to those in QUEST.

The results for VENTURE by baseline biomarkers are presented in the Table 12.

Table 12: Effect of dupilumab on OCS dose reduction, VENTURE (Baseline

aModel estimates by logistic regression bp-value < 0.0001

cp-value = 0.0001

dp-value = 0.0002

Long-term extension trial (TRAVERSE)

The long-term safety of dupilumab in 2,193 adults and 89 adolescents with moderate-to-severe asthma, including 185 adults with oral corticosteroid-dependent asthma, who had participated in previous clinical trials of dupilumab (DRI12544, QUEST, and VENTURE), was assessed in the open-label extension study (TRAVERSE) (see section 4.8). Efficacy was measured as a secondary endpoint, was similar to results observed in the pivotal studies and was sustained up to 96 weeks. In the adults with oral-corticosteroid-dependent asthma, there was sustained reduction in exacerbations and improvement in lung function up to 96 weeks, despite decrease or discontinuation of oral corticosteroid do­se.

Paediatric population

Atopic dermatitis

The safety and efficacy of dupilumab have been established in 12 to 17 years old with moderate-to-severe atopic dermatitis in study AD-1526 which included 251 adolescents. The safety and efficacy of dupilumab have been established in 6 to 11 years old with severe atopic dermatitis in study AD-1652 which included 367 paediatric patients. Use is supported by study AD-1434 which enrolled patients who had completed AD-1526 (136 moderate and 64 severe at the time of enrolment in study AD-1434) and patients who had completed study AD-1652 (110 moderate and 72 severe at the time of enrolment in in study AD-1434). The safety and efficacy were generally consistent between children 6 to 11 years old, adolescent, and adult patients with atopic dermatitis (see section 4.8). Safety and efficacy in paediatric patients < 6 years of age with atopic dermatitis have not been established.

Asthma

A total of 107 adolescents aged 12 to 17 years with moderate to severe asthma were enrolled in

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. Safety and efficacy in paediatric patients (< 12 years of age) with severe asthma have not been established. The adverse event 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.

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 atopic dermatitis and asthma (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

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

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 and asthma 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 60.3±35.1 mcg/ml to 79.9±41.4 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 a target-mediated elimination predominates.

After the last steady state dose, the median time for dupilumab concentrations to decrease below the lower limit of detection, estimated by population PK analysis, was 6–7 weeks for the 300 mg Q4W regimen, 9 weeks for the 200 mg Q2W regimen, 1011 weeks for the 300 mg Q2W regimen, and 13 weeks for the 300 mg QW regimen.

Linearity/non-linearity

Due to nonlinear clearance, dupilumab exposure, as measured by area under the concentration-time curve, increases with dose in a greater than proportional manner following single SC doses from 75–600 mg.

Special populations

Gender

Gender was not found to be associated with any clinically meaningful impact on the systemic exposure of dupilumab determined by population PK analysis.

Elderly

Of the 1,472 patients with atopic dermatitis exposed to dupilumab in a phase 2 doseranging study or phase 3 placebo-controlled studies, a total of 67 were 65 years or older. Although no differences in safety or efficacy were observed between older and younger adult atopic dermatitis patients, the number of patients aged 65 and over is not sufficient to determine whether they respond differently from younger patients.

Age was not found to be associated with any clinically meaningful impact on the systemic exposure of dupilumab determined by population PK analysis. However, there were only 61 patients over 65 years of age included in this analysis.

Of the 1,977 patients with asthma exposed to dupilumab, a total of 240 patients were 65 years or older and 39 patients were 75 years or older. Efficacy and safety in this age group were similar to the overall study population.

Race

Race was not found to be associated with any clinically meaningful impact on the systemic exposure of dupilumab by population PK analysis.

Hepatic impairment

Dupilumab, as a monoclonal antibody, is not expected to undergo significant hepatic elimination. No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of dupilumab.

Renal impairment

Dupilumab, as a monoclonal antibody, is not expected to undergo significant renal elimination. No clinical studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of dupilumab. Population PK analysis did not identify mild or moderate renal impairment as having a clinically meaningful influence on the systemic exposure of dupilumab. Very limited data are available in patients with severe renal impairment.

Body Weight

Dupilumab trough concentrations were lower in subjects with higher body weight with no meaningful impact on efficacy.

Paediatric population

Atopic dermatitis

The pharmacokinetics of dupilumab in paediatric patients (< 6 years of age) or body weight < 15 kg 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.

For children 6 to 11 years of age with atopic dermatitis receiving every four week dosing (Q4W) with 300 mg (> 15 kg) in AD-1652, the mean ± SD steady-state trough concentration was 76.3±37.2 mcg/ml. At week 16 in AD-1434 in children 6 to 11 years of age who initiated every four week dosing (Q4W) with 300 mg (> 15 kg), and whose dose was increased to every other week dosing (Q2W) with 200 mg (> 15 to < 60 kg) or 300 mg (> 60 kg), the mean±SD steady-state trough concentration was 108±53.8 mcg/ml. For children 6 to 11 years of age receiving 300 mg Q4W, initial doses of 300 mg on Days 1 and 15 produce similar steady-state exposure as an initial dose of 600 mg on Day 1, based on PK simulations.

Asthma

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 mcg/ml, respectively, for 300 mg or 200 mg administered every other week. No age-related pharmacokinetic difference was observed in adolescent patients after correction for body weight.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity (including safety pharmacology endpoints) and toxicity to reproduction and development.

The mutagenic potential of dupilumab has not been evaluated; however monoclonal antibodies are not expected to alter DNA or chromosomes.

Carcinogenicity studies have not been conducted with dupilumab. An evaluation of the available evidence related to IL-4Ra inhibition and animal toxicology data with surrogate antibodies does not suggest an increased carcinogenic potential for dupilumab.

During a reproductive toxicology study conducted in monkeys, using a surrogate antibody specific to the monkey IL-4Ra, no fetal abnormalities were observed at dosages that saturate the IL-4Ra.

An enhanced pre- and post-natal developmental study revealed no adverse effects in maternal animals or their offspring up to 6 months post-partum/post-birth.

Fertility studies conducted in male and female mice using a surrogate antibody against IL-4Ra showed no impairment of fertility (see section 4.6).

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

3 years.

If necessary, 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.

6.4 Special precautions for storage

Store in a refrigerator (2°C – 8°C).

Do not freeze.

Store in the original carton in order to protect from light.

6.5 Nature and contents of container

1.14 ml solution in a siliconised type-1 clear glass syringe in a pre-filled pen, with a fixed 27 gauge 12.7 mm (^ 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

The instructions for the preparation and administration of Dupixent 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 200 mg pre-filled pen from the refrigerator, it should be allowed to reach room temperature up to 25°C by waiting for 30 min before injecting Dupixent.

The 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 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.