Consumer medicine information

Dupixent

Dupilumab

BRAND INFORMATION

Brand name

Dupixent

Active ingredient

Dupilumab

Schedule

What is in this leaflet

This leaflet answers some common questions about Dupixent.

It does not contain all the available information. It does not take the place of talking to your Doctor or Pharmacist.

All medicines have risks and benefits. Your Doctor has weighed the risks of you using Dupixent against the benefits they expect it will have for you.

If you have any concerns about using this medicine, ask your Doctor or Pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What DUPIXENT is used for

Dupixent contains the active substance dupilumab.

Dupixent is used to treat the following conditions:

moderate to severe atopic dermatitis (also known as atopic eczema), in patients aged 12 years and older.

In atopic dermatitis, Dupixent may be used with or without prescribed atopic dermatitis medicines that you apply to the skin.

maintenance treatment of moderate-to-severe asthma in patients 12 year and older whose asthma is not controlled with their current asthma medicines.

In asthma, Dupixent should be used in addition to your existing asthma medicines. Dupixent may also help reduce the amount of oral corticosteroids you need while preventing severe asthma attacks and improving your breathing.

Your doctor will assess if Dupixent is appropriate for your condition.

How it works

Dupixent is an injectable medicine that inhibits IL-4 and IL-13 proteins by blocking a shared receptor. IL-4 and IL-13 play a major role in the symptoms of atopic dermatitis and asthma.

Dupixent belongs to a class of medicines called monoclonal antibodies. Monoclonal antibodies are proteins that specifically recognise and bind to other unique proteins in the body.

Ask your Doctor if you have any questions about why Dupixent has been prescribed for you.

Before you use DUPIXENT

When you must not use Dupixent

Do not use Dupixent if you have an allergy to:

any medicine containing dupilumab (the active ingredient) or any of the ingredients listed at the end of this leaflet

Some of the symptoms of an allergic reaction may include:

rash, itching or hives on the skin
shortness of breath
wheezing or difficulty breathing
swelling of the face, lips, tongue or other parts of the body

Tell your doctor if you are experiencing these symptoms

Dupixent should not be used after the expiry date (exp) printed on the pack. If you use this medicine after the expiry date has passed, it may not work as well, or have an unexpected effect.

Dupixent should not be used if the packaging is torn or shows signs of tampering.

Do not use Dupixent if the product appears cloudy, discoloured or contains particles, or if the syringe and/or needle cap appear damaged.

Atopic Dermatitis:

Do not use Dupixent in patients under 12 years old. The safety and benefits of Dupixent are not yet known in this patient group.

Asthma:

Do not use Dupixent in patients under 12 years old. The safety and benefits of Dupixent are not yet known in this patient group.

Dupixent is not a rescue medicine and should not be used to treat a sudden asthma attack.

If you are not sure whether you should start using this medicine, talk to your Doctor.

Before you start to use DUPIXENT

Tell your doctor or pharmacist if you have allergies to any other medicines, or substances such as foods, preservatives or dyes.

Tell your Doctor if you have any of the following, or if any of the following apply to you:

have a parasitic (helminth) infection
are pregnant or plan to become pregnant. It is not known if Dupixent will harm your unborn baby.
are breastfeeding or plan to breastfeed. It is not known whether Dupixent passes into breast milk.
have recently received or are scheduled to receive a vaccine
any new or worsening eye problems, including eye pain or changes in vision.
are taking oral, or using topical, or inhaled corticosteroid medicines
have any other medical conditions

If you have not told your Doctor about any of the above, tell them before you start using Dupixent.

Taking other medicines

Tell your Doctor or pharmacist if you are taking any other medicines, have recently taken, or might take any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Do not stop taking your corticosteroid medicines unless instructed by your doctor. This may cause other symptoms that were controlled by the corticosteroid medicine to come back.

You should not receive certain type of vaccines while taking Dupixent. Tell your Doctor if you have recently received a vaccine or planned to receive a vaccine.

How to use DUPIXENT

Dupixent comes as a single-dose (1 time use) pre-filled syringe with or without needle shield. Your healthcare provider will prescribe the type that is best for you. Follow all directions given to you by your doctor and pharmacist carefully.

Carefully read the "Dupixent Instructions for Use" provided in the carton. If you do not understand the instructions on the label or in this leaflet, ask your doctor or pharmacist for help.

How to use it

Always check the syringe label before each injection to make sure you are using the right medicine.

Dupixent is a clear and colourless to pale yellow solution that should not be shaken before use. Do not use Dupixent if it is not clear to pale yellow or if it contains particles.

To avoid discomfort, Dupixent should be removed from the refrigerator before your injection so that it reaches room temperature.

Remove Dupixent 300mg syringes from the refrigerator at least 45 minutes before injection.
Remove Dupixent 200mg syringes from the refrigerator at least 30 minutes before injection.

The syringe should not be exposed to heat or direct sunlight.

The injection can be self-administered or given by another person, after proper training in injection technique.

Dupixent syringes are pre-filled and ready to use. Once the contents have been injected, the syringe cannot be re-used.

Never use a syringe if it is damaged, or you are not sure that it is working properly. Use a new syringe.

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

Dupixent is intended for injection under the skin.

If you do not understand the instructions, ask your Doctor or Pharmacist.

How much to use

Use the dose that your doctor prescribes for you.

Dupixent is given as an injection under the skin (subcutaneously) once every two weeks.

Where to inject

Dupixent is injected under the skin (subcutaneous injection). You can inject into the thigh or abdomen, except for the 2 inches (5 cm) around the navel, using a single-dose pre-filled syringe. If somebody else administers the injection, the upper arm can also be used. Use a different injection site each injection so that the same site is not used.

Do not inject in an area where the skin that is tender, damaged, sunburnt or has bruises or scars.

Do not inject Dupixent with other injectable medicines, at the same injection site.

How long to use Dupixent

Continue using Dupixent for as long as your doctor recommends.

Make sure you keep enough Dupixent to last when you go on holidays.

If you forget to use it

If you miss a dose of DUPIXENT, give the injection within 7 days from the missed dose, then continue with the original schedule.

If the missed dose is not given within 7 days, wait until the next scheduled dose to give your DUPIXENT injection.

In case you are not sure when to inject Dupixent, call your doctor or pharmacist.

It is important to use Dupixent as prescribed by your doctor.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (13 11 26) or go to accident and emergency at your nearest hospital, if you think that you have taken too much Dupixent. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Always take the outer carton of the medicine with you.

While you are using DUPIXENT

If you experience any symptoms of an allergic reaction, stop using Dupixent and talk to your doctor immediately.

Things you must do

Always follow your doctor’s instructions carefully.

Keep Dupixent in a refrigerator (2°C - 8°C). Do not freeze. Do not expose to extreme heat.

Dupixent should be removed from the refrigerator before your injection to avoid discomfort.

Dupixent 300 mg syringes should be removed from the refrigerator at least 45 minutes before your injection.
Dupixent 200 mg syringes should be removed from the refrigerator at least 30 minutes before your injection.

Dupixent should not be exposed to heat or direct sunlight.

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

It is important to keep using Dupixent even if you feel well.

Continuous use of Dupixent helps to control your condition.

If you become pregnant while you are using Dupixent, tell your doctor.

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

If you have asthma and are taking asthma medicines, do not change or stop your asthma medicine without talking to your doctor.

If you are about to be started on any new medicine, tell your doctor and pharmacist that you are taking Dupixent.

Things you must not do

Do not use Dupixent if you think it has been frozen or exposed to excessive heat (temperatures above 25°C).

Do not give Dupixent to anyone else, even if they have the same condition as you.

Do not stop taking your corticosteroid medicines unless instructed by your doctor. This may cause other symptoms that were controlled by the corticosteroid medicine to come back

Do not stop taking your medicine without checking with your doctor.

Things to be aware of

Dupixent is unlikely to influence your ability to drive and use machines.

Side effects

Tell your Doctor as soon as possible if you do not feel well while you are using Dupixent.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your Doctor or Pharmacist to answer any questions you may have.

Tell your doctor if you notice any of them and they worry you or it does not go away:

Injection site reactions
headache
Eye dryness, eye infection, eye and eyelid inflammation (including redness/swelling/ itching) (if you also have atopic dermatitis)
eye pain
blurred vision
sensitivity to light
oral herpes (cold sores)
a specific form of allergic reaction resulting in inflammation of your blood vessels. Rarely, this can happen in people with asthma who receive Dupixent.

In rare cases, patients taking an asthma medicine may develop an inflammation of blood vessels or lungs. It is not known whether this is caused by Dupixent. This usually, but not always, happens in people who also take a steroid medicine which is being stopped or for which the dose is being lowered.

Tell your doctor immediately if you develop a combination of the following symptoms:

a flu-like illness
pins and needles or numbness of arms or legs
worsening of lung symptoms including breathing problems,
and/or rash.

Dupixent can cause serious side effects, including: generalized allergic (hypersensitivity) reactions including anaphylaxis can happen after you get your Dupixent injection.

If you have any signs of allergic (hypersensitivity) reaction stop using Dupixent, tell your Doctor immediately or go to Accident and Emergency at your nearest hospital.

Symptoms of allergic reactions include:

shortness of breath
persistent fever
chest pain
general ill feeling
swollen lymph nodes
swelling of the face, mouth, and tongue
hives
itching
fainting, dizziness, feeling lightheaded (low blood pressure)
joint pain
skin rash
a feeling of pins and needles or numbness of your arms or legs

These are not all of the possible side effects of Dupixent. Call your Doctor for medical advice about side effects.

Other side effects not listed above may also occur in some patients. Tell your doctor if you notice anything else that is making you feel unwell.

After using DUPIXENT

Storage

All medicines should be kept where children cannot reach them.

Before use, keep Dupixent syringes in a refrigerator where the temperature is between 2-8°C. If necessary, pre-filled syringes can be kept at room temperature up to 25°C for a maximum of 14 days.

Keep the syringes in the original carton to protect from light.

Do not allow it to freeze. Discard if frozen.

Do not expose to heat. Do not shake.

If you need to travel, make sure the medicine is kept at the right temperature. This is important whether travelling by car, bus, train, plane or any other form of transport.

Disposal

After injecting Dupixent, immediately throw away the used pre-filled syringe in a sharps container as instructed by your doctor or pharmacist.

If your Doctor tells you to stop using Dupixent or the expiry date has passed, ask your Pharmacist what to do with any medicine that is left over.

Product description

What it looks like

Dupixent is a clear and colourless to pale yellow, preservative-free liquid solution available in a pre-filled syringe with or without needle shield.

The needle shield reduces the risk of accidental needle stick injuries.

Dupixent is available in two different strengths:

300 mg in 2 mL solution
200 mg in 1.14 mL solution

Ingredients

Active Ingredient:

dupilumab

Inactive Ingredients:

acetic acid
arginine hydrochloride
histidine
polysorbate 80
sodium acetate
sucrose
water for injections

Supplier

Dupixent is supplied in Australia by:

sanofi-aventis australia pty ltd
12-24 Talavera Road
Macquarie Park NSW 2113
Freecall No: 1800 818 806

sanofi-aventis new zealand limited
Level 8, James and Wells Tower
56 Cawley Street, Ellerslie,
Auckland
New Zealand
Freecall No:0800 283 684

Dupixent 300 mg (150 mg/mL) pre-filled syringe with needle shield
AUST R 283127

Dupixent 300 mg (150mg/mL) pre-filled syringe
AUST R 282981

Dupixent 200 mg (175 mg/mL) pre-filled syringe with needle shield
AUST R 302463

This leaflet was prepared in October 2020

dupi-ccdsv13-cmiv8-06oct20

Published by MIMS November 2020

BRAND INFORMATION

Brand name

Dupixent

Active ingredient

Dupilumab

Schedule

1 Name of Medicine

Dupilumab (rch).

2 Qualitative and Quantitative Composition

300 mg pre-filled syringe with needle shield.

Each pre-filled syringe contains 300 mg dupilumab in 2 mL (150 mg/mL solution). It is supplied as a single-use pre-filled syringe with a needle shield.

300 mg pre-filled pen.

Each single-use pre-filled pen contains 300 mg dupilumab in 2 mL (150 mg/mL) solution. It is supplied as a single-use pre-filled pen with a needle cap.

200 mg pre-filled syringe with needle shield.

Each single-use pre-filled syringe contains 200 mg dupilumab in 1.14 mL (175 mg/mL) solution. It is supplied as a single-use pre-filled syringe with a needle shield.

200 mg pre-filled pen.

Each pre-filled pen is designed to deliver 200 mg of dupilumab in 1.14 mL (175 mg/mL) solution. It is supplied as a single-use pre-filled pen with a needle cap.
Dupilumab is a fully human monoclonal antibody produced by recombinant DNA technology in Chinese hamster ovary cell suspension culture.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for injection.
Dupixent is a sterile, preservative-free, clear to slightly opalescent, colourless to pale yellow solution for subcutaneous injection which is free from visible particulates, pH 5.9.

4 Clinical Particulars

4.1 Therapeutic Indications

Dupixent is indicated for the following type 2 inflammatory diseases:

Atopic dermatitis.

Adults and adolescents.

Dupixent is indicated for the treatment of moderate to severe atopic dermatitis in patients aged 12 years and older who are candidates for chronic systemic therapy. Dupixent is not intended for episodic use.

Children 6 months to 11 years of age.

Dupixent is indicated for the treatment of severe atopic dermatitis in patients aged 6 months to 11 years old who are candidates for chronic systemic therapy. Dupixent is not intended for episodic use.

Prurigo nodularis.

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

Asthma.

Dupixent is indicated as add on maintenance treatment in patients aged 6 years and older with moderate to severe asthma with type 2 inflammation (elevated eosinophils or elevated fractional exhaled nitric oxide [FeNO]) that is inadequately controlled despite therapy with other medicinal products for maintenance treatment (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Chronic rhinosinusitis with nasal polyposis (CRSwNP).

Dupixent is indicated as an add-on maintenance treatment in adult patients with inadequately controlled chronic rhinosinusitis with nasal polyposis (CRSwNP).

Chronic obstructive pulmonary disease.

Dupixent is indicated in adults as add-on maintenance treatment for uncontrolled chronic obstructive pulmonary disease (COPD) characterised by raised blood eosinophils on a stable 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 Pharmacodynamic Properties, Clinical trials).

4.2 Dose and Method of Administration

Atopic dermatitis.

Dupixent treatment should be initiated and supervised by a dermatologist or immunologist.
Dupixent can be used with or without topical therapy, including corticosteroids and/or calcineurin inhibitors as appropriate.
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.

Adults.

The recommended dose of Dupixent for adult patients is as follows:
Initial dose of 600 mg by subcutaneous injection (two 300 mg injections consecutively in different injection sites), followed by 300 mg given every other week.

Children and adolescents (6 to 17 years of age).

The recommended dose of Dupixent for children and adolescents 6 to 17 years of age is specified in Table 1.

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 2.

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

Treatment interruption.

If Dupixent treatment interruption becomes necessary, patients can still be successfully re-treated.

Prurigo nodularis.

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

Asthma.

Dupixent treatment should be prescribed by a specialist experienced in the diagnosis and treatment of asthma including paediatric specialists. Maintenance treatment should be optimised prior to commencement of and during therapy with Dupixent.

Adults and adolescents.

The recommended dose of Dupixent for adults and adolescents (12 years of age and older) is:
Initial dose of 400 mg by subcutaneous injection (two 200 mg injections consecutively in different injection sites) followed by 200 mg given every other week.
Patients with oral corticosteroids-dependent asthma or with co-morbid moderate-to-severe atopic dermatitis or adults with co-morbid severe chronic rhinosinusitis with nasal polyposis for which Dupixent is indicated:
Initial dose of 600 mg by subcutaneous injection (two 300 mg injections consecutively in different injection sites) followed by 300 mg given every other week.

Children (6-11 years of age).

The recommended dose of Dupixent for children 6 to 11 years of age is specified in Table 3.

For children (6-11 years old) with asthma and co-morbid severe atopic dermatitis, the recommended dose should be followed in Table 1.

Chronic rhinosinusitis with nasal polyposis.

The recommended dose of Dupixent for adult patients is an initial dose of 300 mg followed by 300 mg given every other week.
Dupixent 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.
If after 24 weeks of treatment a patient's disease is stable, Dupixent may be given at a dose of 300 mg every four weeks in patients with CRSwNP who do not have comorbid asthma.

Chronic obstructive pulmonary disease.

The recommended dose of Dupixent for adult patients is 300 mg given every other week.
Dupixent should be initiated and monitored by a specialist experienced in the diagnosis and treatment of COPD.
Dupixent 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.

Missed dose.

If an every other week dose is missed, instruct the patient to 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, instruct the patient to wait until the next dose on the original schedule.
If an every 4 week dose is missed, instruct the patient to 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, instruct the patient to administer the dose, starting a new schedule based on this date.
Product is for single use in one patient only. Discard any residue.

Special populations.

Elderly patients.

No dose adjustment is recommended for elderly patients (see Section 5.2 Pharmacokinetic Properties).

Hepatic impairment.

No data are available in patients with hepatic impairment (see Section 5.2 Pharmacokinetic Properties).

Renal impairment.

No dosage adjustment is needed in patients with mild or moderate renal impairment. No data are available in patients with severe renal impairment (see Section 5.2 Pharmacokinetic Properties).

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, CRSwNP, PN or COPD (see Section 5.2 Pharmacokinetic Properties).
See Table 1 and Table 2 for dose adjustments based on body weight for adolescents and children with atopic dermatitis, and Table 3 for dose adjustments based on body weight for children with asthma.

Preparation and handling.

Before injection, remove Dupixent pre-filled syringe/pre-filled pen from the refrigerator to allow to reach to room temperature.

300 mg syringe/pre-filled pen.

Wait for 45 min without removing the needle cap.

200 mg syringe/pre-filled pen.

Wait for 30 min without removing the needle cap.
Inspect Dupixent visually for particulate matter and discolouration prior to administration. Dupixent is a clear to slightly opalescent, colourless to pale yellow solution. Do not use if the liquid contains visible particulate matter, is discoloured or cloudy (other than clear to slightly opalescent, colourless to pale yellow).
Dupixent does not contain preservatives; therefore, discard any unused product remaining in the pre-filled syringe.
Comprehensive instructions for administration are given in the package leaflet.
If necessary, pre-filled syringes or pens may be kept at room temperature up to 25°C for a maximum of 14 days. Do not store above 25°C. After removal from the refrigerator, Dupixent must be used within 14 days or discarded.
The pre-filled syringe or pen should not be exposed to heat or direct sunlight.
Any unused medicinal product or waste material should be disposed. A puncture-resistant container for disposal of syringes should be used and should be kept out of the reach of children.

Administration.

The pre-filled pen is for use in adult and paediatric patients aged 2 years and older. The pre-filled syringe is for use in adult and paediatric patients aged 6 months and older. The pre-filled pen is not intended for use in children below 2 years of age.
Dupixent is intended for use under the guidance of a healthcare provider. The patient's caregiver may administer Dupixent or the patient may self-inject it after guidance has been provided by a healthcare professional on proper subcutaneous injection technique. In children 12 years of age and older, it is recommended that Dupixent be administered by or under supervision of an adult. In children 6 months to less than 12 years of age, Dupixent should be given by a caregiver.
Provide proper training to patients and/or caregivers on the preparation and administration of Dupixent prior to use according to the instruction leaflet inside the pack.
Administer subcutaneous injection into the thigh or abdomen, except for the 5 cm (2 inches) around the navel, using a single-dose pre-filled syringe. If somebody else administers the injection, the upper arm can also be used. Rotate the injection site with each injection.
Do not inject Dupixent into skin that is tender, damaged or has bruises or scars.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

4.3 Contraindications

Dupixent is contraindicated in patients who have known hypersensitivity to dupilumab or any of its excipients (see Section 4.4 Special Warnings and Precautions for Use).

4.4 Special Warnings and Precautions for Use

In order to improve the traceability of biological medicines, the trade name and the batch number of the administered product should be clearly recorded in the patient's medical record and/or dispensing record.

Hypersensitivity.

Hypersensitivity reactions, including anaphylaxis, serum sickness or serum sickness-like reactions and angioedema, have been reported. Anaphylactic reactions and angioedema have occurred from minutes to up to seven days after the dupilumab injection (see Section 4.8 Adverse Effects (Undesirable Effects)). If a systemic hypersensitivity reaction occurs, administration of Dupixent should be discontinued immediately and appropriate therapy initiated.

Helminth infection.

Patients with known helminth infections were excluded from participation in clinical studies. It is unknown if Dupixent will influence the immune response against helminth infections. Treat patients with pre-existing helminth infections before initiating Dupixent. If patients become infected while receiving treatment with Dupixent and do not respond to anti-helminth treatment, discontinue treatment with Dupixent 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 5.1 Pharmacodynamic Properties, Clinical trials.

Conjunctivitis and keratitis.

Conjunctivitis and keratitis have been reported with Dupixent, predominantly in atopic dermatitis patients. Some patients reported visual disturbances (e.g. blurred vision) associated with conjunctivitis or keratitis. Advise patients to report new onset or worsening eye symptoms to their healthcare provider. Patients treated with Dupixent 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 Adverse Effects (Undesirable Effects)).

Concomitant atopic conditions.

Patients with atopic dermatitis or CRSwNP and comorbid atopic conditions (such as asthma) should be advised not to adjust their treatment without consultation with their physicians. When discontinuing Dupixent consider the potential effects on other atopic conditions.

Eosinophilic conditions.

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. Physicians should be alert to vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients with eosinophilia. Cases of eosinophilic pneumonia were reported in adult patients who participated in the asthma development program, and cases of vasculitis consistent with eosinophilic granulomatosis with polyangiitis (EGPA) have been reported with Dupixent in adult patients who participated in the asthma development program, as well as in adult patients with co-morbid asthma in the CRSwNP development program. A causal association between dupilumab and these conditions has not been established.

Acute symptoms of asthma or chronic obstructive pulmonary disease or acute deteriorating disease.

Dupixent should not be used to treat acute symptoms or acute exacerbations of asthma or COPD. Do not use Dupixent to treat acute bronchospasm or status asthmaticus.

Reduction of corticosteroid dosage.

Do not discontinue systemic, topical, or inhaled corticosteroids abruptly upon initiation of therapy with Dupixent. Reductions in corticosteroid dose, if appropriate, should be gradual and performed under the direct supervision of a physician. Reduction in corticosteroid dose may be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy.

Arthralgia.

Arthralgia has been reported with the use of Dupixent with some patients reporting gait disturbances or decreased mobility associated with joint symptoms; some cases resulted in hospitalisation (see Section 4.8 Adverse Effects (Undesirable Effects)). In postmarketing reports, onset of arthralgia was variable, ranging from days to months after the first dose of Dupixent. Some patients' symptoms resolved while continuing treatment with Dupixent and other patients recovered or were recovering following discontinuation of Dupixent. Advise patients to report new onset or worsening joint symptoms to their healthcare provider. If symptoms persist or worsen, consider rheumatological evaluation and/or discontinuation of Dupixent.

Use in the elderly.

Of the 1539 patients with atopic dermatitis, including patients with atopic dermatitis of the hand and foot, exposed to Dupixent in a phase 2 dose-ranging study or phase 3 placebo-controlled studies, a total of 71 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.
Of the 1977 patients with asthma exposed to Dupixent, 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 was similar to the overall study population.
Of the 938 patients with COPD exposed to Dupixent, a total of 551 were 65 years of age and older including 116 patients 75 years of age and older. Efficacy and safety in this age group were similar to the overall study population.

Paediatric use.

Atopic dermatitis.

Safety and efficacy in children below the age of 6 months with atopic dermatitis have not been established.

Asthma.

Safety and efficacy in children below the age of 6 years with asthma have not been established (see Section 5.2 Pharmacokinetic Properties).

Prurigo nodularis.

The safety and efficacy of dupilumab in children with PN below the age of 18 years have not been established. No data are available (see Section 5.2 Pharmacokinetic Properties).

Chronic rhinosinusitis with nasal polyposis.

CRSwNP does not normally occur in children. Safety and efficacy in paediatric patients with CRSwNP younger than 18 years have not been established. (see Section 5.2 Pharmacokinetic Properties).

Chronic obstructive pulmonary disease.

COPD does not normally occur in children. Safety and efficacy in pediatric patients with COPD younger than 18 years have not been established (see Section 5.2 Pharmacokinetic Properties).

Effects on laboratory tests.

There is no known interference between Dupixent and routine laboratory tests.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Live vaccines.

The safety and efficacy of concurrent use of Dupixent with live vaccines has not been studied.

Non-live vaccines.

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 cell-independent) 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 Dupixent may receive concurrent inactivated or non-live vaccinations.

Interactions with CYP450 substrates.

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

Other.

There are no data on the safety of Dupixent when co-administered with other immunomodulators.

Use with other drugs for treatment of asthma.

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

Effects on fertility.

Fertility studies conducted in male and female mice using a surrogate antibody against IL-4Rα showed no impairment of fertility. The no-observed-effect-level (NOEL) was the maximum dose studied, 200 mg/kg/week administered subcutaneously which yielded a high multiple of the exposure (serum AUC) in patients at the recommended dose.
(Category B1)
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.
Dupixent should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus. Like other IgG antibodies, dupilumab is expected to cross the placental barrier.
In an enhanced pre- and postnatal development study, pregnant cynomolgus monkeys were administered a surrogate antibody against IL-4Rα by subcutaneous injection once weekly at doses up to 100 mg/kg/week, from the beginning of organogenesis to parturition. The surrogate antibody used displayed considerably lower affinity for monkey IL-4Rα compared to dupilumab for human IL-4Rα, but the doses used in the study were sufficient to saturate maternal IL-4Rα receptors throughout the treatment period. No treatment-related effects on embryofetal survival, malformations, or on growth, functional development or immunology were observed in the offspring, monitored from birth through to 6 months of age.
There are no specific data on the presence of dupilumab in human milk, but human IgG is known to be excreted in human milk. A decision must be made whether to discontinue breastfeeding or to discontinue Dupixent therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

4.7 Effects on Ability to Drive and Use Machines

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

4.8 Adverse Effects (Undesirable Effects)

Atopic dermatitis.

Adults.

In the overall exposure pool, a total of 2526 patients with atopic dermatitis were treated with Dupixent in controlled and uncontrolled clinical trials. 739 patients were exposed for at least 1 year. In controlled trials, 1564 patients received Dupixent alone (monotherapy) and 740 received Dupixent with concomitant topical corticosteroid therapy. The monotherapy study was of 16 weeks duration. The concomitant topical corticosteroid therapy study was of 52 weeks duration and, 739 patients were exposed for at least 1 year.
In the monotherapy study, the reported co-morbid atopic conditions were asthma (39.6%), allergic rhinitis (49%), food allergy (37%), and allergic conjunctivitis (23.1%). In the concomitant topical corticosteroid therapy study, the reported co-morbid atopic conditions were asthma (39.3%), allergic rhinitis (42.8%), food allergy (33.4%), and allergic conjunctivitis (23.2%).
In the analysis of a phase 3, multicentre, open label extension (OLE) study (AD-1225), the long-term safety of repeat doses of Dupixent was assessed in adults with moderate-to-severe AD who had previously participated in controlled studies of Dupixent or had been screened for a phase 3 study (SOLO 1 or SOLO 2). The safety data in AD-1225 reflect the exposure to Dupixent in 2677 adult atopic dermatitis patients, including 2254 exposed for at least 52 weeks, 1224 exposed for at least 100 weeks, 561 exposed for at least 148 weeks and 179 exposed for at least 260 weeks of the study. The majority of the patients in AD-1225 (99.7%) were exposed to Dupixent 300 mg weekly dosing (QW). The long-term safety profile observed in this analysis of up to 5 years was generally consistent with that observed in controlled studies.
The adverse reactions in Table 4 are listed by system organ class and frequency using the following convention: very common > 10%; common > 1 and < 10%; uncommon > 0.1 and < 1%; rare > 0.01 and < 0.1%; very rare < 0.01%; not known (cannot be estimated from available data).

Table 5 summarises the adverse reactions that occurred in ≥ 1% of patients treated with Dupixent during the first 16-weeks of treatment in placebo-controlled trials.

The safety profile of Dupixent + TCS through week 52 is consistent with the safety profile observed at week 16.

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

The safety of Dupixent 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 Dupixent in these patients followed through Week 16 was similar to the safety profile from studies in adults with atopic dermatitis.
The long-term safety of Dupixent was assessed in an open-label extension study in patients 12 to 17 years of age with moderate to severe atopic dermatitis (AD-1434). The safety profile of Dupixent in patients followed through Week 52 was similar to the safety profile observed at Week 16 in AD-1526 study. The long-term safety profile of Dupixent observed in adolescents was consistent with that seen in adults with atopic dermatitis. Use is supported by study AD-1924 which enrolled 27 adolescent patients aged 12 to 17 years of age with moderate-to-severe atopic dermatitis of the hand and foot.

Children (6 to 11 years of age) with atopic dermatitis.

The safety of Dupixent was assessed in a trial of 367 patients 6 to 11 years of age with severe atopic dermatitis (AD-1652). The safety profile of Dupixent + TCS in these patients through Week 16 was similar to the safety profile from studies in adults and adolescents with atopic dermatitis.
The long-term safety of Dupixent + TCS was assessed in an open-label extension study of 368 patients 6 to 11 years of age with atopic dermatitis (AD-1434). Among patients who entered this study, 110 (29.9%) had moderate and 72 (19.6%) had severe atopic dermatitis at the time of enrolment in study AD-1434. The safety profile of Dupixent + TCS in patients followed through Week 52 was similar to the safety profile observed at Week 16 in AD-1652. The long-term safety profile of Dupixent + TCS observed in paediatric patients was consistent with that seen in adults and adolescents with atopic dermatitis.

Atopic dermatitis of the hand and foot.

The safety of Dupixent was assessed in 133 adult and adolescent patients 12 to 17 years of age with moderate-to-severe atopic dermatitis of the hand and foot (R668-AD-1924). The safety profile of Dupixent in these patients through Week 16 was consistent with the safety profile from studies in adult and paediatric patients, 6 month of age and older, with moderate-to-severe AD.

Children (6 months to 5 years of age).

The safety of Dupixent with concomitant TCS was assessed in a study of 161 patients 6 months to 5 years of age with moderate-to-severe atopic dermatitis, including a subgroup of 124 patients with severe atopic dermatitis (AD-1539) of which 6 patients 6 months to < 2 years of age were exposed to dupilumab. The safety profile of Dupixent 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. The safety profile of Dupixent in patients 6 months to < 2 years of age was consistent with that of the overall population of patients aged ≥ 6 months to 5 years.
The long-term safety of Dupixent was assessed in an open-label extension study of 180 patients 6 months to 5 years of age with atopic dermatitis (AD-1434) of which 19 patients 6 months to < 2 years of age were exposed to dupilumab. The safety profile of Dupixent + TCS in subjects followed through Week 52 was similar to the safety profile observed through Week 16 in (AD-1539). The long-term safety profile of Dupixent + TCS observed in children 6 months to 5 years of age was consistent with that seen in adults and paediatric patients 6 to 17 years old with atopic dermatitis. The safety profile of Dupixent in patients 6 months to < 2 years of age was consistent with that of the overall population of patients aged ≥ 6 months to 5 years.

Prurigo nodularis.

A total of 309 adult patients with prurigo nodularis (PN) were evaluated in two 24-week randomized, double-blind, placebo-controlled, multicentre trials (PRIME and PRIME2). The safety pool included data from the 24 week treatment and 12 week follow-up periods from both studies.
In the safety pool, the proportion of patients who discontinued treatment due to adverse events was 3% of the placebo group and 0% of the Dupixent 300 mg Q2W group.
Table 6 summarises the adverse reactions that occurred at a rate of at least 2% in patients treated with Dupixent and at a higher rate than in their respective comparator group in PRIME and PRIME2.

In PRIME and PRIME2 PN studies, the proportion of patients who discontinued treatment due to adverse events was 0% of the dupilumab 300 mg Q2W group and 2.5% of the placebo group.

Asthma.

Adults and adolescent patients.

A total of 2888 adult and adolescent patients with moderate-to-severe asthma were evaluated in 3 randomised, placebo-controlled, multicentre trials of 24 to 52 weeks duration (DRI12544, QUEST, and VENTURE).
Of these, 2678 had a history of 1 or more severe exacerbations in the year prior to enrollment despite regular use of medium to high-dose inhaled corticosteroids plus an additional controller(s) (DRI12544 and QUEST).
A total of 210 patients with oral corticosteroid-dependent asthma receiving high-dose inhaled corticosteroids plus up to two additional controllers were enrolled (VENTURE).
Table 7 summarises the adverse reactions that occurred at a rate of at least 3% of patients treated with Dupixent and at higher rate than in their respective comparator groups in DRI12544 and QUEST studies.

See Table 8.

The long-term safety of Dupixent was assessed in an open-label extension study in 2282 patients 12 years and older with moderate-to-severe asthma (TRAVERSE). In this study, patients were followed for up to 96 weeks, resulting in 3169 patient-years cumulative exposure to Dupixent. The safety profile of Dupixent in TRAVERSE was consistent with the safety profile observed in pivotal asthma studies for up to 52 weeks of treatment. No additional adverse reactions were identified.
The safety profile of Dupixent 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.

Children (6 to 11 years of age).

The safety of Dupixent was assessed in 405 patients 6 to 11 years of age with moderate to severe asthma (VOYAGE). The safety profile of Dupixent in these patients through Week 52 was similar to the safety profile from studies in adults and adolescents with moderate to severe asthma, with the additional adverse reactions of enterobiasis and eosinophilia. Enterobiasis was reported in 1.8% (5 patients) in the Dupixent groups and none in the placebo group. All enterobiasis cases were mild to moderate and patients recovered with antihelminth treatment without Dupixent treatment discontinuation. Eosinophilia (blood eosinophils ≥ 3,000 cells/microL or deemed by the investigator to be an adverse event) was reported in 6.6% of the Dupixent groups and 0.7% in the placebo group.
The long-term safety of Dupixent 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 of weeks treatment and 228 patients completed a cumulative treatment duration of 104 weeks (VOYAGE and EXCURSION). The long-term safety profile of Dupixent in EXCURSION was consistent with the safety profile observed in the pivotal asthma study (VOYAGE) for 52 weeks of treatment.

Chronic rhinosinusitis with nasal polyposis.

A total of 722 adult patients with chronic rhinosinusitis with nasal polyposis (CRSwNP) were evaluated in 2 randomised, placebo-controlled, multicentre trials of 24 to 52 weeks duration (SINUS-24 and SINUS-52). The safety pool consisted of data from the first 24 weeks of treatment.
In the safety pool, the proportion of subjects who discontinued treatment due to adverse events was 2.0% of the Dupixent 300 mg Q2W group and 4.6% of the placebo group.
Table 9 summarises the adverse reactions that occurred at a rate of at least 1% in patients treated with Dupixent and at a higher rate than in their respective comparator group in SINUS-24 and SINUS-52.

See Table 10.

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

Chronic obstructive pulmonary disease.

A total of 1872 adult patients with chronic obstructive pulmonary disease (COPD) were evaluated in two randomised, double-blind, multicenter, parallel group, placebo-controlled trials with a 52-week treatment period (BOREAS and NOTUS). In both trials, patients were randomised to receive either Dupixent 300 mg Q2W or matching placebo.
The proportion of patients who discontinued treatment due to adverse events was 3% of the placebo group and 3% of Dupixent 300 mg Q2W group.
Table 11 summarises the adverse reactions that occurred at a rate of at least 2% in patients treated with Dupixent and at a higher rate than in their respective comparator group in BOREAS and NOTUS.

Description of selected adverse reactions.

Hypersensitivity.

Hypersensitivity reactions, including anaphylaxis and serum sickness or serum sickness-like reactions, have been reported (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

Conjunctivitis and keratitis related events.

Conjunctivitis was the most frequently reported eye disorder in atopic dermatitis patients who received Dupixent in the placebo controlled atopic dermatitis studies. Most subjects with conjunctivitis recovered or were recovering during the treatment period. The respective rates of conjunctivitis and keratitis remained similar at 3 years in long-term OLE study (AD-1225). Among asthma and COPD patients the frequency of conjunctivitis was low and similar between Dupixent and placebo. In patients with CRSwNP and PN, the frequency of conjunctivitis was low, although the frequency in the Dupixent group was higher than in the placebo group.
In the atopic dermatitis clinical program, keratitis was reported in < 1% of the Dupixent group (1 per 100 subject-years) and in 0% of the placebo group (0 per 100 subject-years) in the 16 week monotherapy trials. In the 52-week Dupixent + topical corticosteroids (TCS) trial in patients with atopic dermatitis, keratitis was reported in 4% of the Dupixent + TCS group (12 per 100 subject-years) and in 0% of the placebo + TCS group (0 per 100 subject-years). Most subjects with keratitis recovered or were recovering during the treatment period. Advise patients to report new onset or worsening eye symptoms to their healthcare provider. There were no cases of keratitis reported in the CRSwNP or PN development programs. Among COPD patients the frequency of keratitis was low and similar between Dupixent and placebo.

Eosinophils.

Dupixent-treated patients had a greater mean initial increase from baseline in eosinophil count compared to patients treated with placebo in the atopic dermatitis, asthma and CRSwNP and COPD indications. Eosinophil counts declined to near baseline levels during study treatment. Compared to placebo, no increase in mean blood eosinophil counts was observed in PN (PRIME and PRIME2).
In COPD, the incidence of treatment-emergent eosinophilia (≥ 500 cells/microL) was higher in the Dupixent group than in the placebo; none of the cases were associated with clinical symptoms. Across atopic dermatitis, asthma and CRSwNP indications, the incidence of treatment-emergent eosinophilia (≥ 500 cells/microL) was similar in Dupixent and placebo groups. In PN, the incidence of treatment-emergent eosinophilia (≥ 500 cells/microL) was lower in Dupixent than in the placebo group. Treatment-emergent eosinophilia (≥ 5,000 cells/microL) was reported in < 3% of Dupixent-treated patients and < 0.5% in placebo-treated patients (SOLO 1, SOLO 2, DRI12544, QUEST, SINUS-24, SINUS-52, PRIME and PRIME2, BOREAS and NOTUS studies).
Treatment-emergent eosinophilia (≥ 5,000 cells/microL) was reported 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.
Eosinophil counts continued to decline below baseline during the open-label extension study in asthma patients.

Cardiovascular.

In the 1-year placebo controlled trial in subjects with asthma (QUEST), cardiovascular thromboembolic events (cardiovascular deaths, non-fatal myocardial infarctions, and non-fatal strokes) were reported in 1 (0.2%) of the Dupixent 200 mg Q2W group, 4 (0.6%) of the Dupixent 300 mg Q2W group, and 2 (0.3%) of the placebo group.
In the 1-year placebo controlled trial in subjects with atopic dermatitis (CHRONOS), cardiovascular thromboembolic events (cardiovascular deaths, non-fatal myocardial infarctions, and non-fatal strokes) were reported in 1 (0.9%) of the Dupixent + TCS 300 mg Q2W group, 0 (0.0%) of the Dupixent + TCS 300 mg QW group, and 1 (0.3%) of the placebo + TCS group.

Overall infections.

In atopic dermatitis, asthma, CRSwNP, PN and COPD the rate of serious infections was similar between Dupixent and placebo-treated patients.
No increase was observed in the overall incidence of infections or serious infections with Dupixent compared to placebo in atopic dermatitis clinical studies. In the 16-week monotherapy clinical studies, serious infections were reported in 1.0% of patients treated with placebo and 0.5% of patients treated with Dupixent. In the 52-week CHRONOS study serious infections were reported in 0.6% of patients treated with placebo and 0.2% of patients treated with Dupixent. 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 Dupixent 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 Dupixent and 1.3% of patients treated with placebo.
No increase was observed in the overall incidence of infections with Dupixent 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 Dupixent 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 Dupixent and 1.4% of patients treated with placebo.
No increase was observed in the overall incidence of infections with Dupixent compared to placebo in the safety pool for CRSwNP clinical studies. In the 24-week safety pool, serious infections were reported in 0.7% of patients treated with Dupixent and 1.1% of patients treated with placebo. In the 52-week SINUS-52 study, serious infections were reported in 1.3% of patients treated with Dupixent and 1.3% of patients treated with placebo.
No increase was observed in the overall incidence of infections with Dupixent compared to placebo in the safety pool for COPD clinical studies. Serious infections were reported in 4.9% of patients treated with Dupixent and 4.8% of patients treated with placebo.

Immunogenicity.

As with all therapeutic proteins, there is a potential for immunogenicity with dupilumab.
Approximately 5% of patients with atopic dermatitis, asthma and CRSwNP who received Dupixent 300 mg Q2W for 52 weeks developed anti-drug antibodies (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 Dupixent 300 mg Q2W for 24 weeks, paediatric patients (6 months to 11 years of age) with atopic dermatitis who received Dupixent either 200 mg Q2W, 200 mg Q4W or 300 mg Q4W for 16 weeks and paediatric patients (6-11 years of age) with asthma who received either Dupixent 100 mg Q2W or 200 mg Q2W up to 52 weeks.
Approximately 16% of adolescent patients with atopic dermatitis who received Dupixent 300 mg or 200 mg Q2W for 16 weeks developed antibodies to dupilumab; approximately 3% exhibited persistent ADA responses, and approximately 5% had neutralising antibodies.
Approximately 9% of patients with asthma who received Dupixent 200 mg Q2W for 52 weeks developed antibodies to dupilumab; approximately 4% exhibited persistent ADA responses and approximately 4% had neutralizing antibodies.
Approximately 8% of patients with COPD who received Dupixent 300 mg Q2W for 52 weeks developed antibodies to dupilumab; approximately 3% exhibited persistent ADA responses and approximately 3% had neutralizing antibodies.
Approximately 5% of patients with atopic dermatitis or asthma in the placebo groups in the 52 week studies were positive for antibodies to Dupixent; approximately 2% exhibited persistent ADA responses and approximately 1% had neutralizing antibodies.
Regardless of age or population, up to 4% of patients in the placebo groups were positive for antibodies to Dupixent; up to 2% exhibited persistent ADA responses and approximately 1% had neutralising antibodies. ADA responses were not generally associated with impact on Dupixent exposure, safety, or efficacy. Less than 1% of patients who received Dupixent 300 mg Q2W and less than 1% of patients who received Dupixent 200 mg Q2W 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 Special Warnings and Precautions for Use).
The observed incidence of persistent ADA responses and neutralizing activity in the assay are highly dependent on the sensitivity and specificity of the assay used. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease status of the individual patient. For these reasons, comparison of the incidence of antibodies to Dupixent with the incidence of antibodies to other products may be misleading.

Post marketing experience.

The following additional adverse reactions have been reported during post-approval use of Dupixent. The adverse reactions are derived from spontaneous reports and therefore, the frequency is "not known" (cannot be estimated from the available data).

Eye disorders.

Keratitis, ulcerative keratitis.

Immune system disorders.

Angioedema.

Musculoskeletal and connective tissue disorders.

Arthralgia.

Skin and subcutaneous tissue disorders.

Facial rash.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

In clinical studies, no safety issues were identified with single intravenous doses up to 12 mg/kg.
In the event of overdosage, monitor the patient for any signs or symptoms of adverse reactions and institute appropriate symptomatic treatment immediately.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Dupixent is a recombinant human IgG4 monoclonal antibody that inhibits interleukin-4 and interleukin-13 signalling by specifically binding to the IL-4Rα subunit shared by the IL-4 and IL-13 receptor complexes. Dupixent 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 key type 2 (including Th2) cytokines involved in atopic disease.
Type 2 inflammation plays an important role in the pathogenesis of multiple atopic conditions including asthma, where it contributes to airflow limitation and increases risk of exacerbations. IL-4 and IL-13 act as major drivers of type 2 inflammation by activating multiple cell types (e.g. mast cells, lymphocytes, eosinophils, neutrophils, macrophages) and inducing multiple mediators (e.g. IgE, histamine, eicosanoids, leukotrienes, chemokines and cytokines, including eotaxin/CCL11, TARC/CCL17, and IL-5) involved in Type 2 inflammation. Blocking the IL-4/IL-13 pathway with dupilumab in patients decreases many of these markers of Type 2 inflammation, including IgE, periostin, and multiple proinflammatory cytokines and chemokines (e.g. eotaxin, TARC, PARC), as well as fractional exhaled nitric oxide (FeNO), a marker of lung inflammation. Blocking the IL-4/IL-13 pathway with dupilumab in humanised animal models has been shown to prevent the downstream actions of these cytokines and chemokines, including goblet cell hyperplasia, airway smooth muscle hyperreactivity, eosinophilic lung inflammation, as well as other lung inflammatory processes, while also preventing lung function impairment; the decrease in eosinophilic lung inflammation occurs despite the presence of normal or increased blood eosinophil levels.

Pharmacodynamic effects.

Atopic dermatitis.

In clinical trials involving patients with atopic dermatitis, treatment with Dupixent was associated with decreases from baseline in concentrations of type 2-associated 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 Dupixent treatment.
Dupixent suppressed TARC relative to placebo as early as week 2, with a trend of continued decline to a maximal and sustained suppression by Week 12. The majority of patients treated with Dupixent in CHRONOS (87.0% and 84.9% of patients in the Dupixent 300 mg every two week dosing (Q2W) and 300 mg weekly dosing (QW), respectively) achieved normalised TARC levels compared to 20.0% in the placebo group at week 52.
Total IgE was reduced -74.8% and -73.9% by Week 52 (median change from baseline) with Dupixent 300 mg Q2W and 300 mg QW, respectively compared to -0% in the placebo group. Similar trends were observed for allergen specific IgEs. After 52 weeks of treatment, total IgE was normalised in 11.7% and 15.9% of patients receiving Dupixent 300 mg Q2W and 300 mg QW, respectively, compared to 4.4% in receiving placebo. Similar trends were observed with antigen-specific IgEs such as those against S. aureus specific enterotoxin A, grass and tree allergens.

Asthma.

Consistent with inhibition of IL-4 and IL-13 signaling, 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 biomarkers of inflammation 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.

CRSwNP.

Among CRSwNP subjects, urinary LTE4 (leukotriene E4), a marker associated with mast cell, basophil, and eosinophil activation was also suppressed by dupilumab treatment.

COPD.

In COPD patients, Dupixent 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 Dupixent.

Clinical trials.

Atopic dermatitis - adults.

The efficacy and safety of Dupixent as monotherapy and with concomitant topical corticosteroids (TCS) were evaluated in three pivotal randomised, double-blind, placebo-controlled studies, Study 1334 (SOLO 1), Study 1416 (SOLO 2), and Study 1224 (CHRONOS) 2119 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.
In all three studies, patients received:
an initial dose of 600 mg Dupixent (two 300 mg injections) on day 1, followed by 300 mg once every other week (Q2W);
an initial dose of 600 mg Dupixent on day 1, followed by 300 mg once weekly (QW); or
matching placebo.
Dupixent was administered by subcutaneous (SC) injection in all studies. 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.
Study 1334 enrolled 671 patients (224 to placebo, 224 to Dupixent 300 mg Q2W, and 223 to Dupixent 300 mg QW) and had a treatment period of 16 weeks.
Study 1416 enrolled 708 patients (236 to placebo, 233 to Dupixent 300 mg Q2W, and 239 to Dupixent 300 mg QW) and had a treatment period of 16 weeks.
Study 1224 enrolled 740 patients (315 to placebo + TCS, 106 to Dupixent 300 mg Q2W + TCS, and 319 to Dupixent 300 mg QW +TCS) and had a treatment period of 52 weeks. Patients received Dupixent or placebo with concomitant use of TCS starting at baseline using a standardised regimen. Patients were also permitted to use topical calcineurin inhibitors (TCI).
Endpoints. In all three pivotal studies, the endpoints were the proportion of patients with IGA 0 or 1 ("clear" or "almost clear") and a reduction of ≥ 2 points on a 0-4 IGA scale and the proportion of patients with improvement of at least 75% in EASI (EASI-75) from baseline to Week 16. Other evaluated outcomes included the proportion of patients with improvement of at least 50% or 90% in EASI (EASI-50 or EASI-90, respectively), reduction in itch as measured by the peak pruritus Numerical Rating Scale (NRS) and percent change in the SCORing Atopic Dermatitis (SCORAD) scale from baseline to Week 16. Additional secondary endpoints included mean change from baseline to week 16 in the Patient Oriented Eczema Measure (POEM), Dermatology Life Quality Index (DLQI), and Hospital Anxiety and Depression Scale (HADS) scores. In Study 1224, efficacy was also evaluated at Week 52.
IGA reflects physician's overall assessment (whole body average) of AD skin lesions. EASI is a composite score (ranging from 0-72) based on the extent and severity of the AD lesions assessed systematically for erythema, induration/papulation/edema, excoriation, and lichenification for each anatomical region. The pruritus NRS is a patient-reported measure which assesses maximum itch intensity in the previous 24-hours using a 0-10-point scale (0 = no itch; 10 = worst itch imaginable). The SCORAD is used to assess extent and severity of AD signs and includes two visual analogue scales for symptoms (itch and sleep). The POEM evaluates frequency of AD symptoms (including itch) and the impact of AD on sleep (score ranging from 0-28). The DLQI evaluates the health-related quality of life in dermatological patients (score ranging from 0-30). The HADS measures anxiety and depression symptoms (total score ranging from 0-42).
Baseline characteristics. In the monotherapy studies (Study 1334 and Study 1416), across all treatment groups, 51.6% of patients had a baseline IGA score of 3 (moderate AD), 48.3% of patients had a baseline IGA of 4 (severe AD) and 32.4% of patients had received prior systemic immunosuppressants. The baseline mean EASI score was 33.0, the baseline weekly averaged pruritus NRS was 7.4.
In the concomitant TCS study (Study 1224), across all treatment groups, 53.1% of patients had a baseline IGA score of 3 and 46.9% of patients had a baseline IGA of 4 and 33.6% of patients received prior systemic immunosuppressants. The baseline mean EASI score was 32.5, the baseline weekly pruritus NRS was 7.3.
Clinical response.

16-Week monotherapy studies [SOLO 1 (study 1334) and SOLO 2 (study 1416)].

In SOLO 1 and SOLO 2, from baseline to week 16, a significantly greater proportion of patients randomised to Dupixent achieved an IGA 0 or 1 response, EASI-75, and/or an improvement of ≥ 4 points on the pruritus NRS compared to placebo (see Table 12).
A significantly greater proportion of patients randomised to Dupixent achieved a rapid improvement in the pruritus NRS compared to placebo (defined as ≥ 4-point improvement as early as week 2; p < 0.01) and the proportion of patients responding on the pruritus NRS continued to increase through the treatment period. The improvement in pruritus NRS occurred in conjunction with the improvement of objective signs of atopic dermatitis.
Figure 1 and Figure 2 show the proportion of patients who achieved an IGA 0 or 1 response and EASI-75, respectively, up to Week 16.
EASI-90 response at Week 16 was achieved in 7.6% of patients in the placebo group, 35.7% in the Dupixent 300 mg Q2W group, and 33.2% in the Dupixent 300 mg QW group, respectively in Study 1334 and 7.2%, 30%, and 30.5% of patients, respectively in Study 1416.
EASI-50 response at Week 16 was achieved 24.6% of patients in the placebo group, 68.8% in the Dupixent 300 mg Q2W group, and 61.0% in the Dupixent 300 mg QW group, respectively in Study 1334 and 22%, 65.2%, and 61.1% of patients, respectively in Study 1416.

Treatment effects in subgroups (weight, age, gender, race, and background treatment, including immunosuppressants) in Study 1334 and Study 1416 were in general consistent with the results in the overall study population.

52-Week concomitant TCS study - CHRONOS (study 1224).

In CHRONOS (Study 1224), a significantly greater proportion of patients randomised to Dupixent 300 mg Q2W + TCS achieved an IGA 0 or 1 response, EASI-75, and/or an improvement of ≥ 4 points on the pruritus NRS from baseline to week 16 and week 52 compared to placebo + TCS (see Table 13).
A significantly greater proportion of patients randomised to Dupixent + TCS achieved a rapid improvement in the pruritus NRS compared to placebo + TCS (defined as ≥ 4-point improvement as early as week 2; p < 0.05) and the proportion of patients responding on the pruritus NRS continued to increase through the treatment period (see Figure 3). The improvement in pruritus NRS occurred in conjunction with the improvement of objective signs of atopic dermatitis.
Figure 3 and Figure 4 show the proportion of patients who achieved an IGA 0 or 1 response and EASI 75, respectively, up to Week 52 in Study 1224.
EASI-90 response was achieved in 15.5% of patients in the placebo group, 50.6% in the Dupixent 300 mg Q2W group, and 50.7% in the Dupixent 300 mg QW group, respectively, in the Study 1224 study at Week 52.
EASI-50 response was achieved in 29.9% of patients in the placebo group, 78.7% in the Dupixent 300 mg Q2W group, and 70.0% in the Dupixent 300 mg QW group, respectively, in Study 1224 at Week 52.

Treatment effects in evaluable subgroups (weight, age, gender, race, and background treatment, including immunosuppressants) in Study 1224 were in general consistent with the results in the overall study population.

Clinical response in patients for whom cyclosporin treatment was inadvisable.

In the monotherapy studies, across both Dupixent treatment groups, patients for whom cyclosporin treatment was inadvisable (uncontrolled with or ineligible to receive cyclosporin) had generally more severe AD at baseline based on mean EASI (36.3 vs 31.4), IGA (3.6 vs 3.4), mean BSA involvement (58.9% vs 52.5%), peak pruritus NRS (7.5 vs 7.3) and DLQI (16.2 vs 14.5) scores relative to the remainder of patients in these studies. Similar findings were observed for patients for whom cyclosporin treatment was inadvisable in the concomitant TCS study.
In patients for whom cyclosporin treatment was inadvisable, treatment with Dupixent monotherapy, across both Dupixent treatment groups, resulted in significant improvements in signs and symptoms of AD, compared to placebo-treated patients. A greater percentage of Dupixent-treated patients than placebo-treated patients achieved IGA 0 or 1 and a reduction from baseline of ≥ 2 points at week 16 (29.5% vs 6.8%), EASI-75 at week 16 (38% vs 11.4%), and a ≥ 4 points reduction in pruritus NRS from baseline to week 16 (34.9% vs 8%) (p < 0.001 for all 3 endpoints).
Similar results were observed in patients who received Dupixent concomitantly with TCS. The efficacy of Dupixent + TCS was sustained at week 52. In the combination therapy of Dupixent + TCS the proportion of patients achieving EASI-75 at week 16 was significantly higher in the dupilumab 300 mg Q2W + TCS (62.6%) and dupilumab 300 mg QW + TCS (59.1%) groups than the placebo + TCS group (29.6%). Both comparisons were statistically significant (p < 0.0001 for each). The efficacy of Dupixent + TCS was sustained at week 52.

Maintenance and durability of response (SOLO CONTINUE study).

To evaluate maintenance and durability of response, subjects treated with Dupixent for 16 weeks in SOLO 1 and SOLO 2 studies who achieved IGA 0 or 1 or EASI-75 were re-randomised in the SOLO CONTINUE study to an additional 36-week treatment of Dupixent or placebo, for a cumulative 52-week study treatment. Endpoints were assessed at weeks 51 or 52.
The co-primary endpoints were the difference between baseline (week 0) and week 36 in percent change in EASI from SOLO 1 and SOLO 2 studies baseline and percentage of patients with EASI-75 at week 36 in patients with EASI-75 at baseline.
Patients who continued on the same dose regimen received in the SOLO 1 and SOLO 2 studies (300 mg Q2W or 300 mg QW) showed the optimal effect in maintaining clinical response while efficacy for other dose regimens diminished in a dose-dependent manner.
Primary and secondary endpoints for the 52 week SOLO CONTINUE study are summarised in Table 14.

In SOLO CONTINUE, a trend for increased treatment-emergent ADA positivity with increased dosing intervals was observed. Treatment-emergent ADA: QW: 1.2%; Q2W: 4.3%; Q4W: 6.0%; Q8W: 11.7%. ADA responses lasting more than 12 weeks: QW: 0.0%; Q2W: 1.4%; Q4W: 0.0%; Q8W: 2.6%.

Adolescent atopic dermatitis (12 to 17 years of age).

The efficacy and safety of Dupixent 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 one of the following regimens:
1. an initial dose of 400 mg Dupixent (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 Dupixent (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 Dupixent (two 300 mg injections) on day 1, followed by 300 mg every 4 weeks (Q4W) regardless of baseline body weight;
3. matching placebo.
Dupixent 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.
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. 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") and at least a 2-point improvement. The other co-primary endpoint was the proportion of patients with EASI-75 (improvement of at least 75% in EASI). Both co-primary endpoints were measured 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 15.

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

The long-term efficacy of Dupixent in adolescent patients with moderate-to-severe AD who had participated in previous clinical trials of Dupixent 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.

Children atopic dermatitis (6 to 11 years of age).

The efficacy and safety of Dupixent 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 Dupixent Q2W + TCS group with baseline weight of < 30 kg received an initial dose of 200 mg on Day 1, followed by 100 mg Q2W from Week 2 to Week 14, and patients with baseline weight of ≥ 30 kg received an initial dose of 400 mg on Day 1, followed by 200 mg Q2W from week 2 to week 14. Patients in the Dupixent 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 non-responders.
In this study, the mean age was 8.5 years, the median weight was 29.8 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 was 20.9, 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 primary endpoint was the proportion of patients with an IGA 0 (clear) or 1 (almost clear) at week 16. Other evaluated outcomes included the proportion of patients with EASI-75 or EASI-90 (improvement of at least 75% or 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 16 presents the results by baseline weight strata for the approved dose regimens.

A greater proportion of patients randomised to Dupixent + TCS achieved an improvement in the peak pruritus NRS compared to placebo + TCS (defined as ≥ 4-point improvement at week 4). See Figure 6.

The Dupixent 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 of Dupixent + TCS in paediatric patients with atopic dermatitis who had participated in the previous clinical trials of Dupixent + 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.

Atopic dermatitis of the hand and foot.

The efficacy and safety of Dupixent was evaluated in a 16-week multicentre, randomized, double-blind, parallel-group, placebo-controlled trial (R668-AD-1924) in 133 adult and pediatric patients 12 to 17 years of age with moderate-to-severe atopic dermatitis of the hand and foot, defined by an IGA (hand and foot) score ≥ 3 (scale of 0 to 4) and a hand and foot Peak Pruritus Numeric Rating Scale (NRS) score for maximum itch intensity ≥ 4 (scale of 0 to 10). Eligible patients had previous inadequate response or intolerance to treatment of atopic dermatitis of the hand and foot with topical AD medications.
At baseline, 38% of patients were male, 80% were White, 72% of patients had a baseline IGA (hand and foot) score of 3 (moderate atopic dermatitis of the hand and foot), and 28% of patients had a baseline IGA (hand and foot) score of 4 (severe atopic dermatitis of the hand and foot). The baseline weekly averaged hand and foot Peak Pruritus NRS score was 7.1.
The primary endpoint was the proportion of patients with an IGA hand and foot score of 0 (clear) or 1 (almost clear) at Week 16. The key secondary endpoint was reduction of itch as measured by the hand and foot Peak Pruritus NRS (≥ 4-point improvement). Other patient reported outcomes included assessment of hand and foot skin pain NRS (0-10), quality of sleep NRS (0-10), quality of life in Hand Eczema Questionnaire (0-117) (QoLHEQ) and work productivity and impairment (WPAI) (0-100%).
The proportion of patients with an IGA (hand and foot) 0 (clear) to 1 (almost clear) at Week 16 was 40.3% for Dupixent and 16.7% for placebo (treatment difference 23.6, 95% CI: 8.84, 38.42; p-value =0.0030). The proportion of patients with improvement (reduction) of weekly averaged hand and foot Peak Pruritus NRS ≥ 4 at Week 16 was 52.2% for Dupixent and 13.6% for placebo (treatment difference 38.6, 95% CI: 24.06, 53.15; p-value < 0.0001).
Greater improvements for hand and foot skin pain NRS, quality of sleep NRS, QoLHEQ score and WPAI overall work impairment from baseline to week 16 were seen in the dupilumab group as compared to the placebo group (LS mean change of dupilumab vs placebo: -4.66 vs -1.93 [p < 0.0001], 0.88 vs -0.00 [p < 0.05], -40.28 vs -16.18 [p < 0.0001], -38.57% vs - 22.83%).

Children atopic dermatitis (6 months to 5 years of age).

The efficacy and safety of dupilumab + TCS in paediatric patients was evaluated in a multicentre, randomised, double-blind, placebo-controlled study (AD-1539) in 162 patients 6 months to 5 years of age, with moderate-to-severe AD (ITT population) defined by an IGA score ≥ 3 (scale of 0 to 4), an EASI score ≥ 16 (scale of 0 to 72), and a minimum BSA involvement of ≥ 10%. Of the 162 patients, 125 patients had severe AD defined by an IGA score of 4. Eligible patients enrolled into this study had previous inadequate response to topical medication. Enrolment was stratified by baseline weight (≥ 5 to < 15 kg and ≥ 15 to < 30 kg).
Patients in the dupilumab Q4W + TCS group with baseline weight of ≥ 5 to < 15 kg received an initial dose of 200 mg on Day 1, followed by 200 mg Q4W from week 4 to week 12, and patients with baseline weight of ≥ 15 to < 30 kg received an initial dose of 300 mg on Day 1, followed by 300 mg Q4W from week 4 to week 12. Patients were permitted to receive rescue treatment at the discretion of the investigator. Patients who received rescue treatment were considered non-responders.
In AD-1539, the mean age was 3.8 years, the median weight was 16.5 kg, 38.9% of patients were female, 68.5% were White, 18.5% were Black, and 6.2% were Asian. At baseline, the mean BSA involvement was 58.4%, and 15.5% had received prior systemic non-steroidal immunosuppressants. Also, at baseline the mean EASI score was 34.1, and the weekly average of daily worst itch score was 7.6 on a scale of 0-10. Overall, 81.4% of patients had at least one co-morbid allergic condition; 68.3% had food allergies, 52.8% had other allergies, 44.1% had allergic rhinitis, and 25.5% had asthma. These baseline disease characteristics were comparable between moderate-to-severe and severe AD populations.
The primary endpoint was the proportion of patients with an IGA 0 (clear) or 1 (almost clear) at week 16. Other evaluated outcomes included the proportion of patients with EASI-75 or EASI-90 (improvement of at least 75% or 90% in EASI from baseline, respectively), and reduction in itch as measured by the Worst Scratch/Itch NRS (≥ 4-point improvement). Additional secondary endpoints included mean change from baseline to week 16 in the POEM, CDLQI, and Infants' Dermatology Quality of Life Index (IDQOL) scores, skin pain NRS and sleep quality NRS.
The efficacy results at Week 16 for AD-1539 are presented in Table 17.

A significantly greater proportion of patients randomised to dupilumab + TCS achieved a rapid improvement in the Worst Scratch/Itch NRS compared to placebo + TCS (defined as ≥ 4-point improvement as early as week 3, nominal p < 0.005) and the proportion of patients responding on the Worst Scratch/Itch NRS continued to increase through the treatment period (see Figure 7).

In this study, Dupixent significantly improved health-related quality of life as measured by the CDLQI (in 85 patients 4 to 5 years old) and IDQOL (in 77 patients 6 months to 3 years old). In the ITT population, greater LS mean changes in CDLQI and IDQOL scores from baseline to week 16 were observed in the dupilumab + TCS (-10.0 and -10.9) group compared to the placebo + TCS group (-2.5 and -2.0), respectively (p < 0.0001). Similar improvements in both CDLQI and IDQOL were observed in the severe AD population.
The long-term efficacy and safety of Dupixent + TCS in paediatric patients with moderate to severe atopic dermatitis who had participated in the previous clinical trials of Dupixent + TCS were assessed in an open-label extension study (AD-1434). Efficacy data from this trial suggest that clinical benefit provided at week 16 was sustained through week 52. The safety profile of Dupixent in patients followed through week 52 was similar to the safety profile observed at week 16 in the AD-1539 study.

Prurigo nodularis.

The prurigo nodularis (PN) development program included two 24-week randomised, double-blind, placebo-controlled, multicentre, parallel-group studies (PRIME and PRIME2) in 311 patients 18 years of age and older with severe pruritus (WI-NRS > 7 on a scale of 0 to 10) and greater than or equal to 20 nodular lesions whose disease was not adequately controlled with topical prescription therapies or when those therapies were not advisable. PRIME and PRIME2 assessed the effect of dupilumab on itch improvement as well as its effect on PN lesions, dermatology life quality index (DLQI), hospital anxiety and depression scale (HADS) and skin pain.
In these two studies, patients received either subcutaneous dupilumab 600 mg (two 300 mg injections) on day 1, followed by 300 mg once every other week (Q2W) for 24 weeks, or matching placebo.
In these studies, the mean age was 49.5 years, the median weight was 71.3 kg, 65.3% of patients were female, 56.6% were white, 6.1% were black and 34.1% were Asian. At baseline, the mean WI-NRS was 8.5, 66.3% had 20 to 100 nodules (moderate), 33.7% had greater than 100 nodules (severe), 99.7% received prior topical therapies, 17.4% received prior systemic corticosteroids, 20.6% received prior systemic non-steroidal immunosuppressants and 2.6% received prior gabapentinoids. Eleven percent of patients were taking stable doses of antidepressants at baseline and were instructed to continue taking these medications during the study. Forty-three percent had a history of atopy (defined as having a medical history of AD, allergic rhinitis/rhinoconjunctivitis, asthma or food allergy).
The WI-NRS is comprised of a single item, rated on a scale from 0 ('no itch') to 10 ('worst imaginable itch'). Participants were asked to rate the intensity of their worst pruritus (itch) over the past 24 hours using this scale. The IGA PN-S is a scale that measures the approximate number of nodules using a 5-point scale from 0 (clear) to 4 (severe).
The primary efficacy endpoint was the proportion of patients with improvement (reduction) in WI-NRS by > 4 points. Key secondary endpoints included the proportion of participants with IGA PN-S 0 or 1 (the equivalent of 0-5 nodules) and the proportion of subjects who achieved a response in both WI-NRS and IGA PN-S per the criteria described above.
The efficacy results for PRIME and PRIME2 are presented in Table 18, Figure 8, Figure 9, Figure 10 and Figure 11.

The onset of action in change from baseline in WI-NRS, defined as the first timepoint at which difference from placebo was and remained significant (nominal p < 0.05) in the weekly average of daily WI-NRS, was observed as early as Week 3 in PRIME (Figure 8) and Week 4 in PRIME 2 (Figure 9).

A greater proportion of patients experienced WI-NRS improvements of ≥ 4 points from baseline by Weeks 4 and 11 in the dupilumab group as compared to the placebo group in PRIME (Figure 10, nominal p < 0.007) and PRIME2 (Figure 11, nominal p < 0.013) respectively and this difference remained significant throughout the treatment period.

Treatment effects on both pruritus and lesions in subgroups (weight, age, gender, race, medical history of atopy, prior use of immunosuppressants and neuromodulators, and concomitant treatment with TCS) were consistent with the results at Week 24 in the overall study population.
Once treatment was discontinued after 24 weeks, there was an indication towards recurrence of signs and symptoms within the 12-week follow-up period.

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 2888 patients (12 years of age and older).
Patients enrolled in DRI12544 and QUEST studies were required to have a history of 1 or more asthma exacerbations that required treatment with systemic corticosteroids or emergency department visit or hospitalization for the treatment of asthma in the year prior to study entry. Patients enrolled in VENTURE study required dependence on daily oral corticosteroids in addition to regular use of high-dose inhaled corticosteroids plus an additional controller(s).
The effects of Dupixent treatment discontinuation on severe exacerbations and FEV₁ were assessed in the DRI12544 study during the 16-week follow-up period. Patients in both the overall and the baseline blood eosinophil count of ≥ 300 cells/microL populations experienced a gradual return to baseline asthma status, with no evidence of rebound effect.
In all 3 studies, patients were enrolled without requiring a minimum baseline blood eosinophil or other Type 2 biomarker (e.g. FeNO or IgE) level.
In the QUEST and VENTURE studies, patients with baseline blood eosinophil level of > 1500 cells/microL (< 1.3%) were excluded.
Dupixent was administered as add-on to background asthma treatment.
Patients continued background asthma therapy throughout the duration of the studies except in VENTURE study in which OCS dose was tapered as described below.

DRI12544 study.

DRI12544 was a 24-week dose-ranging study which included 776 patients (18 years of age and older). Dupixent compared with placebo was evaluated in adult patients with moderate to severe asthma on a medium- or high-dose inhaled corticosteroid and a long acting beta agonist.
Patients were randomised to receive either 200 mg (N = 150) or 300 mg (N = 157) Dupixent every other week or 200 mg (N = 154) or 300 mg (N = 157) Dupixent every 4 weeks following an initial dose of 400 mg, 600 mg or placebo (N = 158), respectively.
The primary endpoint was change from baseline to Week 12 in FEV₁ (L). Other endpoints included percent change from baseline in FEV₁ and annualised rate of severe asthma exacerbation events during the 24-week placebo controlled treatment period.
Results were evaluated in the overall population and subgroups based on baseline blood eosinophil count (≥ 300 cells/microL and < 300 cells/microL).
Additional secondary endpoints included mean change from baseline and responder rates in the patient reported Asthma Control Questionnaire (ACQ-5) and Asthma Quality of Life Questionnaire, Standardised Version (AQLQ(S)) scores.

EFC13579 (QUEST) study.

QUEST was a 52-week study which included 1902 patients (12 years of age and older). Dupixent compared with placebo was evaluated in 107 adolescent and 1795 adult patients with moderate-to-severe asthma on a medium- or high-dose inhaled corticosteroid (ICS) and a minimum of one and up to two controller medications.
Patients requiring a third controller were allowed to participate in this study. 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 annualised rate of severe exacerbation events during the 52-week placebo controlled period and change from baseline in pre-bronchodilator FEV₁ at Week 12 in overall population (unrestricted by minimum baseline eosinophils or other Type 2 biomarkers).
Additional secondary endpoints included exacerbation rates and FEV₁ in patients with different baseline levels of eosinophils as well as mean change from baseline and responder rates in the ACQ-5 and AQLQ(S) scores.

EFC13691 (VENTURE) study.

VENTURE was a 24-week oral corticosteroid-reduction study in 210 patients with asthma 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 Dupixent (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 which was reduced every 4 weeks during the OCS reduction phase (Week 4-20), as long as asthma control was maintained. The OCS reduction was performed according to algorithm specified in the protocol.
The primary endpoint was the percent reduction of oral corticosteroid dose at Week 24 compared with the baseline dose, while maintaining asthma control in the overall population (unrestricted by minimum baseline eosinophils or other Type 2 biomarkers). The key secondary endpoints were the proportion of patients achieving a reduction of 50% or greater in their OCS dose compared with baseline and proportion of patients achieving a reduction of OCS dose to < 5 mg/day at Week 24 while maintaining asthma control.
Additional secondary endpoints included the annualised rate of severe exacerbation events during treatment period and mean change from baseline and responder rate in the ACQ-5 and AQLQ(S) scores.
The demographics and baseline characteristics of these 3 studies are provided in Table 19.

Exacerbations.

The DRI12544, QUEST, and VENTURE studies evaluated the frequency of severe asthma exacerbations. Exacerbations were defined as deterioration of asthma requiring the use of systemic corticosteroids for at least 3 days or hospitalization or emergency room visit due to asthma that required systemic corticosteroids. For patients on maintenance corticosteroids, an asthma exacerbation was defined as a temporary increase in oral corticosteroid dose for at least 3 days.
In the overall population, patients receiving either Dupixent 200 mg or 300 mg every other week had significant reductions in the rate of severe asthma exacerbations compared to placebo (see Table 20).
In the pooled analysis of the DRI12544 and QUEST studies, the rate of severe exacerbations leading to hospitalizations and/or emergency room visits was reduced by 25.5% and 46.9% with Dupixent 200 mg or 300 mg every other week, respectively.

Prespecified subgroup analyses of DRI12544, QUEST, and VENTURE studies demonstrated that there were greater reductions in severe exacerbations in patients with higher baseline levels of markers for Type 2 inflammation such as eosinophil level and FeNO.
Prespecified subgroup analyses of AS Trials 1 and 2 demonstrated that there were greater reductions in severe exacerbations in subjects with higher baseline blood eosinophil levels. In AS Trial 2, reductions in exacerbations were significant in the subgroup of subjects with baseline blood eosinophils ≥ 150 cells/microL. In subjects with baseline blood eosinophil count < 150 cells/microL, similar severe exacerbation rates were observed between Dupixent and placebo.
In all studies, when compared to placebo greater reductions in severe exacerbations were also seen in patients with baseline FeNO ≥ 25 ppb.
In the QUEST study, patients receiving medium dose ICS showed a similar reduction in rate of severe asthma exacerbations compared to patients receiving high dose ICS. See Table 21 and Figure 12.

The cumulative mean number of severe exacerbation events in DRI12544, QUEST, and VENTURE studies (Overall Population and Baseline Eosinophils ≥ 300 cells/microL) during the 24- or 52-week treatment period is shown in Figure 13.

Over the course of the studies, patients in both Dupixent dose groups had lower cumulative number of events compared with patients in their respective placebo groups.

Lung function.

Significant increases in pre-bronchodilator FEV₁ were observed at week 12 for DRI12544 and QUEST trials in the primary analysis populations (subjects with baseline blood eosinophil count of ≥ 300 cells/microL in DRI12544 and the overall population in the QUEST trial). See Figure 14.
Subgroup analysis of DRI12544, QUEST, and VENTURE studies demonstrated that patients with baseline blood eosinophil count of ≥ 150 and ≥ 300 cells/microL showed greater improvement in FEV₁ compared with the overall population (see Table 22).
Clinically meaningful improvements in FEV₁ were observed in patients with baseline eosinophils < 300 cells/microL, although less than in the population with baseline blood eosinophil count ≥ 300 cells/microL. Magnitude of effect was directly correlated with baseline eosinophil counts at all baseline eosinophil levels studied.
In the QUEST study, compared to placebo, greater improvements in FEV₁ were also seen in patients with FeNO ≥ 25 and ≥ 50 ppb. See Table 22 and Table 23.
Improvement in FEV₁ was similar whether patients were receiving medium dose ICS, high dose ICS, or OCS.

Significant improvements in FEV₁ were observed as early as Week 2 (DRI12544, QUEST, and VENTURE) following the first dose of Dupixent for both the 200 mg and 300 mg dose strengths and were maintained through Week 24 (DRI12544 and VENTURE) and Week 52 (QUEST) (see Figure 15).

Additional secondary endpoints.

ACQ-5 and AQLQ(S) were analysed at both a cohort level (mean change from baseline) and an individual-level (responder analyses) at 24 weeks (DRI12544) 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 the VENTURE study. In asthma patients with comorbid upper airway disease Dupixent treatment also reduced upper airway symptoms.
Patients with asthma and comorbid chronic rhinosinusitis (CRS) with or without nasal polyposis, and/or comorbid allergic rhinitis (AR), reported their health-related quality of life on disease-specific questionnaires; the 22-Item Sino Nasal Outcome Test (SNOT-22) for CRS patients and Standardised Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ(S)+12) for AR patients. Mean change from baseline in total scores on SNOT-22 and RQLQ(S)+12 were pre-specified endpoints in these subpopulations. Improvements in SNOT-22 and RQLQ(S)+12 total score were observed with Dupixent compared to placebo as early as week 12 and sustained over 52 weeks.

Oral corticosteroid reduction (VENTURE).

The VENTURE study evaluated the effect of Dupixent on reducing the use of maintenance oral corticosteroids. The baseline mean oral corticosteroid use was 11.75 mg in the placebo group and 10.75 mg in the group receiving Dupixent.
Compared with placebo, patients receiving Dupixent achieved greater reductions in daily maintenance oral corticosteroid dose, while maintaining asthma control.
The results for primary and secondary endpoints of the VENTURE study are presented in Table 24.

Long-term extension trial (TRAVERSE).

The long-term efficacy of Dupixent in 2282 adults and adolescents with moderate-to-severe asthma, and adults with oral corticosteroid-dependent asthma, who had participated in previous clinical trials of Dupixent, was assessed in the open-label extension study (TRAVERSE). In this study, the clinical benefit of Dupixent, including reduction in exacerbations and improvement in lung function, was sustained up to 96 weeks in patients with moderate to severe asthma with type 2 inflammation (see Table 25 and Table 26). In the population with oral-corticosteroid-dependent asthma, there was sustained reduction in exacerbations and maintained improvement in lung function, despite continued decrease or discontinuation of oral corticosteroid dose up to 96 weeks (see Table 26). Similar maintenance of effect was also observed for ACQ-5 and AQLQ(S) at week 48 (see Table 25). Consistent results were also observed in the subgroup of patients on high dose ICS.

Children asthma (patients aged 6-11 years of age).

The efficacy and safety of Dupixent in paediatric patients was evaluated in a 52-week multicenter, randomized, double-blind, placebo-controlled study (VOYAGE) in 408 patients 6 to 11 years of age, with moderate-to-severe asthma on a medium- or high-dose ICS and one controller medication or high dose ICS alone. Patients were randomized to Dupixent (N = 273) or matching placebo (N = 135) every other week based on body weight ≤ 30 kg or > 30 kg, respectively. The efficacy was evaluated in the populations with type 2 inflammation defined as blood eosinophils levels of ≥ 150 cells/microL or FeNO ≥ 20 ppb.
The primary endpoint was the annualized rate of severe exacerbation events during the 52 week placebo-controlled period and the key secondary endpoint was the change from baseline in pre-bronchodilator FEV₁ percent predicted at Week 12. Additional secondary endpoints included mean change from baseline and responder rates in the ACQ-7-IA and PAQLQ(S)-IA scores.
The demographics and baseline characteristics for VOYAGE are provided in Table 27.

Exacerbations were defined as deterioration of asthma requiring the use of systemic corticosteroids for at least 3 days or hospitalization or emergency room visit due to asthma that required systemic corticosteroids. Dupixent significantly reduced the annualized rate of severe asthma exacerbation events during the 52-week treatment period compared to placebo in the population with type 2 inflammation and in population defined by baseline blood eosinophils ≥ 300 cells/microL or by baseline FeNO ≥ 20 ppb. Clinically significant improvements in percent predicted pre-bronchodilator FEV₁ were observed at Week 12. Improvements were also observed for ACQ-7-IA and PAQLQ(S)-IA at Week 24 and were sustained at Week 52. Greater responder rates were observed for ACQ-7-IA and PAQLQ(S)-IA compared to placebo at Week 24. The efficacy results for VOYAGE are presented in Table 28.
In the population with type 2 inflammation, the LS mean change from baseline in prebronchodilator FEV₁ at Week 12 was 0.22 L in the Dupixent group and 0.12 L in the placebo group, with an LS mean difference versus placebo of 0.10 L (95% CI: 0.04, 0.16). The treatment effect was sustained over the 52-week treatment period, with an LS mean difference versus placebo at Week 52 of 0.17 L (95% CI: 0.09, 0.24).
In the population defined by baseline blood eosinophils > 300 cells/microL, the LS mean change from baseline in pre-bronchodilator FEV₁ at Week 12 was 0.22 L in the dupilumab group and 0.12 L in the placebo group, with an LS mean difference versus placebo of 0.10 L (95% CI: 0.03, 0.17). The treatment effect was sustained over the 52-week treatment period, with an LS mean difference versus placebo at Week 52 of 0.17 L (95% CI: 0.09, 0.26).

Response rates by baseline blood eosinophils and FeNO for VOYAGE are shown in Figure 16.

Improvements in percent predicted FEV₁ by baseline blood eosinophils and FeNO for VOYAGE are shown in Figure 17.

Significant improvements in percent predicted FEV₁ were observed as early as Week 2 and were maintained through Week 52 in VOYAGE study.
Improvements in percent predicted FEV₁ over time in VOYAGE are shown in Figure 18.

In VOYAGE, in the population with type 2 inflammation, the mean annualized total number of systemic corticosteroid courses due to asthma was reduced by 59.3% versus placebo (0.350 [95% CI: 0.256, 0.477] versus 0.860 [95% CI: 0.616, 1.200]). In the population defined by baseline blood eosinophils > 300 cells/microL, the mean annualized total number of systemic corticosteroid courses due to asthma was reduced by 66.0% versus placebo (0.274 [95% CI: 0.188, 0.399] versus 0.806 [95% CI: 0.563, 1.154]).
Dupixent improved the overall health status as measured by the European Quality of Life 5 Dimension Youth Visual Analog Scale (EQ-VAS) in both type 2 inflammation and the baseline blood eosinophil count of > 300 cells/microL population at Week 52; the LS mean difference versus placebo was 4.73 (95% CI: 1.18, 8.28), and 3.38 (95% CI: -0.66, 7.43), respectively.
Dupixent reduced the impact of paediatric patient's asthma on the caregiver quality of life as measured by the Paediatric Asthma Caregiver Quality of Life Questionnaire (PACQLQ) in both type 2 inflammation and the baseline blood eosinophil count of > 300 cells/microL population at Week 52; the LS mean difference versus placebo was 0.47 (95% CI: 0.22, 0.72), and 0.50 (95% CI: 0.21, 0.79), respectively.
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 Dupixent 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). Fourteen patients (≥ 15 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, efficacy, and pharmacokinetics in paediatric patients (< 6 years of age) with asthma have not been studied.

Long-term safety extension study (EXCURSION).

The efficacy of Dupixent, measured as a secondary endpoint, was assessed in 365 pediatric asthma patients (6 to 11 years of age) in the long-term safety open label extension study (EXCURSION). Compared to the parent study results there were reductions in exacerbations requiring hospitalization and/or emergency room visits and a reduction in exposure to systemic oral corticosteroids. Sustained improvements in lung function were observed across multiple parameters including percent predicted FEV₁, percent predicted FVC, FEV₁/FVC ratio and percent predicted FEF 25-75%. Furthermore, 75% of patients achieved and/or maintained normal lung function with pre-bronchodilator percent predicted FEV₁ > 80% by the end of EXCURSION. Efficacy was sustained for a cumulative treatment duration of up to 104 weeks (VOYAGE and EXCURSION).

Chronic rhinosinusitis with nasal polyposis.

The chronic rhinosinusitis with nasal polyposis (CRSwNP) development program included two randomised, double-blind, parallel group, multicentre, placebo-controlled studies (SINUS-24 and SINUS-52) in 724 patients aged 18 years and older on background intranasal corticosteroids (INCS). These studies included patients with severe CRSwNP despite prior sino-nasal surgery or treatment with, or who were ineligible to receive, systemic corticosteroids in the past 2 years. Rescue with systemic corticosteroids or surgery was allowed during the studies at the investigator's discretion.
In SINUS-24, a total of 276 patients were randomised to receive either 300 mg Dupixent (N = 143) or placebo (N = 133) every other week for 24 weeks.
In SINUS-52, 448 patients were randomised to receive either 300 mg Dupixent (N = 150) every other week for 52 weeks, 300 mg Dupixent (N = 145) every other week until week 24 followed by 300 mg Dupixent every 4 weeks until week 52, or placebo (N = 153).
All patients had evidence of sinus opacification on the Lund MacKay (LMK) sinus CT scan and 73% to 90% of patients had opacification of all sinuses. Patients were stratified based on their histories of prior surgery and co-morbid asthma/nonsteroidal anti-inflammatory drug exacerbated respiratory disease (NSAID-ERD). A total of 63% of patients reported previous sinus surgery, with a mean number of 2.0 prior surgeries, 74% used systemic corticosteroids in the previous 2 years, with a mean number of 1.6 systemic corticosteroid courses in the previous 2 years, 59% had co-morbid asthma, and 28% had NSAID-ERD.
The co-primary efficacy endpoints were change from baseline to week 24 in bilateral endoscopic nasal polyps score (NPS; 0-8 scale) as graded by central blinded readers and change from baseline to week 24 in nasal congestion/obstruction score averaged over 28 days (NC; 0-3 scale), as determined by patients using a daily diary. For NPS, polyps on each side of the nose were graded on a categorical scale (0 = no polyps; 1 = small polyps in the middle meatus not reaching below the inferior border of the middle turbinate; 2 = polyps reaching below the lower border of the middle turbinate; 3 = large polyps reaching the lower border of the inferior turbinate or polyps medial to the middle turbinate; 4 = large polyps causing complete obstruction of the inferior nasal cavity). The total score was the sum of the right and left scores. Nasal congestion was rated daily by the subjects on a 0 to 3 categorical severity scale (0 = no symptoms; 1 = mild symptoms; 2 = moderate symptoms; 3 = severe symptoms).
In both studies, key secondary endpoints at week 24 included change from baseline in: LMK sinus CT scan score, total symptoms score (TSS), University of Pennsylvania smell identification test (UPSIT), daily loss of smell, and 22-item sinal-nasal outcome test (SNOT-22). The LMK sinus CT scan score evaluated the opacification of each sinus using a 0 to 2 scale (0 = normal; 1 = partial opacification; 2 = total opacification), deriving a maximum score of 12 per side and a total maximum score of 24 (higher scores indicate more opacification). Olfactory function was assessed by UPSIT which is a 40-odorant test (score range 0-40) used to distinguish patients (mild [score of 31 34], moderate [score of 26 30], severe microsmia [score of 19 25] or anosmia [score of 0 18]). In the pool of the two studies, the reduction in the proportion of patients rescued with systemic corticosteroid and/or sino-nasal surgery as well as the improvement in FEV₁ in the asthma subgroup were evaluated. Additional secondary endpoints included 6-item Asthma Control Questionnaire (ACQ-6) in the co-morbid asthma subgroup.
The demographics and baseline characteristics of these 2 studies are provided in Table 29:

Clinical response (SINUS-24 and SINUS-52).

The results for primary and secondary endpoints in CRSwNP studies are presented in Table 30.

The results of SINUS-52 study at week 52 are presented in Table 31.

Statistically significant and clinically meaningful efficacy was observed in SINUS-24 with regard to improvement in bilateral endoscopic NPS score at week 24. In the post-treatment period when patients were off dupilumab, the treatment effect diminished over time (see Figure 19).

Statistically significant and clinically meaningful results were also seen in SINUS-52 at both week 24 and week 52 with a progressive improvement over time (see Figure 20).

A significant decrease in LMK sinus CT scan score was also observed in SINUS-52 study at week 24 with further improvement at week 52 (see Figure 21). Similar results were seen in SINUS-24 study at week 24.

In both studies, significant improvements in NC and daily loss of smell severity were observed as early as the first assessment at Week 4. The LS mean difference for NC at Week 4 in the Dupixent group versus placebo was 0.41 (95% CI: 0.52, 0.30) in SINUS-24 and -0.37 (95% CI: -0.46, -0.27) in SINUS-52. The LS mean difference for loss of smell at Week 4 in the Dupixent group versus placebo was 0.34 (95% CI: -0.44, -0.25) in SINUS-24 and -0.31 (95% CI: -0.41, -0.22) in SINUS-52.
Improvement in nasal peak inspiratory flow (NPIF) was observed in SINUS-24 and SINUS-52 at week 24. The LS mean difference in the dupilumab group versus placebo was 40.4 L/min (95% CI: 30.4, 50.4) and 36.6 L/min (95% CI: 28.0, 45.3), respectively.
A reduction in the proportion of patients with anosmia from 74% at baseline to 24% at week 24 was observed in the Dupixent arm of SINUS-24 study compared to no change (78% at both time points) in the placebo arm. A reduction in the proportion of subjects with anosmia from 79% at baseline to 30% at week 24 was observed in the Dupixent arm of SINUS-52 compared to no change (77% at both time points) in the placebo arm.
In SINUS-24, among the patients with rhinosinusitis VAS score > 7 at baseline, a higher percentage of patients achieved VAS in a non-severe category (≤ 7) in the Dupixent group compared with the placebo group (83.3% versus 39.4%) at week 24. In SINUS-52, among the patients with rhinosinusitis VAS score > 7 at baseline, at week 24, a higher percentage of patients had a VAS in a non-severe category (≤ 7) in the Dupixent 300 mg Q2W group compared with the placebo group (75.0% versus 39.3%).
In the pre-specified multiplicity-adjusted pooled analysis of two studies, treatment with Dupixent resulted in significant reduction of systemic corticosteroid use and need for sino-nasal surgery versus placebo (HR of 0.24; 95% CI: 0.17, 0.35) (see Figure 22). The proportion of patients who required systemic corticosteroids was reduced by 74% (HR of 0.26; 95% CI: 0.18, 0.38). The total number of systemic corticosteroid courses per year was reduced by 75% (RR of 0.25; 95% CI: 0.17, 0.37). The mean individual annualised prescribed total dose of systemic corticosteroids (in mg) during the treatment period was 71% lower in the pooled dupilumab group compared with the pooled placebo group (60.5 [531.3] mg versus 209.5 [497.2] mg, respectively). The proportion of patients who required surgery was reduced by 83% (HR of 0.17; 95% CI: 0.07, 0.46).

In patients with co-morbid asthma, significant improvement in pre-bronchodilator FEV₁ were observed at Week 24 in the pre-specified multiplicity-adjusted pool of the two studies irrespective of baseline blood eosinophils levels. The LS Mean change from baseline in FEV₁ at Week 24 for Dupixent 300 mg Q2W was 0.14 vs -0.07 L for placebo, for a difference of 0.21 L (95% CI: 0.13, 0.29).
In addition, improvements in FEV₁ were noted from the first post baseline assessment, at Week 8 in SINUS-24 and Week 4 in SINUS-52 (see Figure 23).

Improvements in ACQ-6 in patients with co-morbid asthma were observed in both studies. A response was defined as an improvement in score of 0.5 or more. In SINUS-24, at Week 24, the LS mean difference in the Dupixent group versus placebo was 0.76 (95% CI: 1.00 to 0.51).432. In SINUS-52, at Week 52, the LS mean difference in the Dupixent group versus placebo was 0.94 (95% CI: 1.19, 0.69).
The ACQ-6 responder rate for Dupixent 300 mg Q2W for SINUS-24 at Week 24 was 56% versus 28% in placebo (odds ratio 3.17; 95% CI: 1.65, 6.09). The ACQ-6 responder rate for Dupixent 300 mg Q2W for SINUS-52 was 46% versus 14% placebo at Week 52 (odds ratio 7.02; 95% CI: 3.10, 15.90).
In patients with NSAID-ERD, the effects of Dupixent on the primary endpoints of NPS and NC and the key secondary endpoint of LMK sinus CT scan score were consistent with that observed in the overall CRSwNP population.

Chronic obstructive pulmonary disease.

The chronic obstructive pulmonary disease (COPD) program included two randomised, double-blind, multicentre, parallel-group, placebo-controlled trials (BOREAS and NOTUS) of 52 weeks in treatment duration which enrolled a total of 1874 adult patients with COPD to evaluate Dupixent as add-on maintenance therapy.
Both trials enrolled patients with a diagnosis of COPD with moderate to severe airflow limitation (post-bronchodilator FEV₁/FVC ratio < 0.7 and post-bronchodilator FEV₁ of 30% to 70% predicted), chronic productive cough for at least 3 months in the past year, and evidence of type 2 inflammation defined as a minimum blood eosinophil count of 300 cells/microL at screening. Patients were uncontrolled with a Medical Research Council (MRC) dyspnoea score ≥ 2 (range 0-4) and an exacerbation history of at least 2 moderate or 1 severe exacerbation in the previous year despite receiving maintenance triple therapy consisting of a long-acting muscarinic antagonist (LAMA), long-acting beta agonist (LABA), and inhaled corticosteroid (ICS). Patients were allowed to receive maintenance therapy consisting of a LAMA and LABA if an ICS was contraindicated. Exacerbations were defined as moderate severity if treatment with systemic corticosteroids and/or antibiotics was required or severe if they resulted in hospitalization or observation for over 24 hours in an emergency department or urgent care facility.
In both trials, patients were randomised to receive Dupixent 300 mg every two weeks (Q2W) or placebo in addition to their background maintenance therapy for 52 weeks.
In both trials, the primary endpoint was the annualised rate of moderate or severe COPD exacerbations during the 52-week treatment period. Secondary endpoints included change from baseline in pre-bronchodilator FEV₁ in the overall population and in the subgroup of patients with baseline FeNO ≥ 20 ppb at Weeks 12 and 52, change from baseline in St. George's Respiratory Questionnaire (SGRQ) total score at Week 52, the SGRQ responder rate (defined as the proportion of patients with SGRQ improvement from baseline of at least 4 points) at Week 52, and annualised rate of moderate or severe COPD exacerbations in the subgroup of patients with baseline FeNO ≥ 20 ppb during the 52-week treatment period. Other multiplicity-adjusted endpoints included the change from baseline in Evaluating Respiratory Symptoms in COPD (E-RS:COPD) total score at Week 52. The E-RS:COPD scale is used to measure severity of respiratory symptoms in COPD, with higher scores indicating greater severity (range 0-40).
The demographics and baseline characteristics of BOREAS and NOTUS are provided in Table 32.

Exacerbations.

In both trials, Dupixent demonstrated a statistically significant reduction in the annualised rate of moderate or severe COPD exacerbations compared to placebo when added to background maintenance therapy (see Table 33).

In both trials, the cumulative mean number of moderate or severe exacerbations observed over 52 weeks was lower in subjects receiving Dupixent compared to placebo (see Figure 24 and Figure 25).

The time to first moderate or severe COPD exacerbation was longer for patients receiving Dupixent compared to placebo in BOREAS (HR: 0.80; 95% CI: 0.66, 0.98) and NOTUS (HR: 0.71.; 95% CI: 0.57, 0.889).
In the subgroup analysis of patients with a higher baseline FeNO (≥ 20 ppb) in BOREAS (N=383), treatment with Dupixent statistically significantly reduced the annualised rate of moderate or severe COPD exacerbations compared to placebo (rate ratio: 0.625; 95% CI: 0.45, 0.869; p=0.005). In NOTUS, treatment with Dupixent showed a nominally significant reduction in the annualised rate of moderate or severe COPD exacerbations in the subgroup of patients with a higher baseline FeNO (≥ 20 ppb) (N=355) compared to placebo (rate ratio: 0.47; 95% CI: 0.33, 0.68).
Reductions in the annualised rate of moderate or severe exacerbations were observed across all predefined subgroups including age, gender, race, smoking status, blood eosinophil counts, number of exacerbations in previous year (≤ 2, 3, and ≥ 4), high-dose ICS at baseline, and baseline percent predicted post-bronchodilator FEV₁ (< 50%, ≥ 50%). In patients with emphysema, reduction in the annualised rate of moderate or severe exacerbations was consistent with the overall population.

Lung function.

In both trials, Dupixent demonstrated a statistically significant improvement in pre-bronchodilator FEV₁ at Weeks 12 and 52 compared to placebo when added to background maintenance therapy (see Table 34). Greater improvements in lung function (LS mean change from baseline in pre-bronchodilator FEV₁) were observed in patients treated with Dupixent compared to placebo as early as Week 2 (BOREAS) (first assessment) and Week 4 (NOTUS) and were sustained at Week 52 (see Figure 26 and Figure 27).
In BOREAS, rapid improvements in post-bronchodilator FEV₁, post-bronchodilator FEV₁/FVC ratio, and pre-bronchodilator FVC were observed with Dupixent treatment compared to placebo as early as Week 2 (first assessment) and were maintained through Week 52. In NOTUS, rapid improvements in post-bronchodilator FEV₁ and post-bronchodilator FEV₁/FVC ratio were observed with Dupixent treatment compared to placebo as early as week 8 and week 2, respectively, and were maintained through Week 52.

In the subgroup analysis of patients with higher baseline FeNO (≥ 20 ppb) in BOREAS (N=383), treatment with Dupixent statistically significantly improved pre-bronchodilator FEV₁ from baseline at Week 12 (LS mean change: 0.232 Dupixent vs 0.108 placebo; LS mean difference: 0.124 [95% CI: 0.045, 0.203]; p=0.002) and Week 52 (LS mean change: 0.247 Dupixent vs 0.120 placebo; LS mean difference: 0.127 [95% CI: 0.042, 0.212]; p=0.003) compared to placebo. In NOTUS, statistically significant improvement from baseline was observed in the subgroup of patients with a higher baseline FeNO (≥ 20 ppb) treated with Dupixent compared to placebo at Week 12 (N=355; LS mean change: 0.221 Dupixent vs 0.081 placebo; LS mean difference: 0.141 [95% CI: 0.058, 0.223]; p=0.001). Treatment with Dupixent improved pre-bronchodilator FEV₁ at Week 52 in the subgroup of patients with higher baseline FeNO (≥ 20 ppb) compared to placebo in NOTUS (N=264; LS mean change: 0.176 Dupixent vs 0.095 placebo; LS mean difference: 0.081[95% CI: -0.019, 0.181]) but did not meet statistical significance.
Improvements in lung function as measured by pre-bronchodilator FEV₁ were observed across all predefined subgroups including age, gender, race, smoking status, blood eosinophil counts, number of exacerbations in previous year (≤ 2, 3, and ≥ 4), high-dose ICS at baseline, and baseline predicted post-bronchodilator FEV₁ (< 50%, ≥ 50%). In patients with emphysema, improvement in lung function as measured by pre-bronchodilator FEV₁ was consistent with the overall population.

Patient reported outcomes.

In both trials, health-related quality of life was measured by LS mean change in St. George's Respiratory Questionnaire (SGRQ) total score at Week 52. In BOREAS, a statistically significant improvement in SGRQ total score was observed in patients treated with Dupixent compared to placebo (LS mean change: -9.73 Dupixent vs -6.37 placebo; LS mean difference: -3.36 [95% CI: -5.46, -1.27]; p=0.002). In NOTUS, Dupixent nominally improved SGRQ total score at Week 52 compared to placebo (LS mean change: -9.82 Dupixent vs -6.44 placebo; LS mean difference: -3.37 [95% CI: -5.81, -0.93]; p=0.007). Greater improvements in SGRQ total score in patients treated with Dupixent were observed as early as Week 4 in BOREAS (first assessment) and Week 12 in NOTUS and were maintained through Week 52 (see Figure 28 and Figure 29). The responder rate was significantly greater for patients treated with Dupixent (51%) compared to placebo (43%) in BOREAS (odds ratio: 1.44; 95% CI: 1.10, 1.89). In NOTUS, the responder rate was numerically greater for patients treated with Dupixent (51%) compared to placebo (47%) but did not meet statistical significance (odds ratio: 1.16; 95% CI: 0.86, 1.58). Improvements were observed in all individual domains of Symptoms, Activity and impacts in patients treated with Dupixent compared to placebo.

In BOREAS, Dupixent significantly improved overall respiratory symptoms compared to placebo as measured by LS mean change from baseline in the E-RS:COPD total score at Week 52 (LS mean change: -2.69 Dupixent vs -1.56 placebo; LS mean difference: -1.14 [95% CI: -1.82, -0.45]; p=0.001). Greater improvements in overall respiratory symptoms in patients treated with Dupixent compared to placebo as measured by average weekly change from baseline in the E-RS:COPD total score were observed as early as Week 1 and were maintained through Week 52 (see Figure 30). Consistent improvements were observed across all individual E-RS: COPD domains (cough and sputum, breathlessness, and chest-related symptoms).
In NOTUS, Dupixent improved overall respiratory symptoms compared to placebo as measured by LS mean change from baseline in the E-RS:COPD total score at Week 52 (LS mean change: -2.39 Dupixent vs -1.77 placebo; LS mean difference: -0.62 [95% CI: -1.43, 0.19]) which was not statistically significant (see Figure 31).

5.2 Pharmacokinetic Properties

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

Absorption.

After a single subcutaneous (SC) dose of 75-600 mg dupilumab, median times to maximum concentration in serum (t_max) were 3-7 days. The absolute bioavailability of dupilumab following a SC dose is similar between AD, asthma, CRSwNP, PN and COPD patients ranging from 61% to 64%, as determined by a population pharmacokinetics (PK) analysis.
Administration of a single loading dose of 600 mg on Day 1 leads to rapid attainment of clinically effective concentrations within 2 weeks.
For every other week dosing (Q2W) with either 200 mg or 300 mg, starting with a respective loading dose of 400 mg or 600 mg, population PK analysis determined steady state concentrations to be achieved by 16 weeks in a typical patient. Mean steady state trough concentration were 39 mg/L at 200 mg Q2W and 55-80 mg/L at 300 mg Q2W.
For weekly dosing (QW) with 300 mg, starting with a loading dose of 600 mg, population PK analysis determined steady state concentrations to be achieved after 13 weeks in a typical patient. Mean steady state trough concentration was 189 mg/L.

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.

Metabolism.

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

Excretion.

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-4Rα 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, determined 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 patients less than 6 years of age, respectively.

Dose 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. Age was not found to be associated with any clinically meaningful impact on the systemic exposure of Dupixent determined by population PK analysis.
Of the 152 patients with PN exposed to Dupixent, a total of 37 were 65 years of age or older. A total of 8 patients were 75 years of age or older. Efficacy and safety in this age group were similar to the overall study population.
Of the 938 patients with COPD exposed to Dupixent, a total of 551 were 65 years of age and older including 116 patients 75 years of age and 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.
Paediatric patients.

Atopic dermatitis.

Based on population pharmacokinetic analysis, age did not affect dupilumab clearance in adults and in paediatric patients 6 to 17 years of age. In paediatric patients from 6 months to 5 years of age, clearance increased with age but is accommodated in the recommended dose regimen. The pharmacokinetics of dupilumab in paediatric patients below 6 months of age with atopic dermatitis have not been fully established.
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), mean ± SD steady state trough concentration of dupilumab was 54.5 ± 27.0 microgram/mL.
For children 6 to 11 years of age with atopic dermatitis receiving every other week dosing (Q2W) with 200 mg (≥ 30 kg) or every four week dosing (Q4W) with 300 mg (< 30 kg), mean ± SD steady state trough concentration was 86.0 ± 34.6 microgram/mL and 98.7 ± 33.2 microgram/mL, respectively.
For children 6 months to 5 years of age with atopic dermatitis receiving every four week dosing (Q4W) with 300 mg (≥ 15 to < 30 kg) or 200 mg (≥ 5 to < 15 kg) mean ± SD steady-state trough concentration was 110 ± 42.8 microgram/mL and 109 ± 50.8 microgram/mL, respectively.

PN.

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

Asthma.

A total of 107 adolescents (range: 30 kg to 122 kg) aged 12 to 17 years with moderate to severe asthma were enrolled in the QUEST study and received either 200 mg (N = 21) or 300 mg (N = 18) Dupixent (or matching placebo either 200 mg [N = 34] or 300 mg [N = 34]) every other week. Efficacy with respect to 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 mean ± SD steady-state trough concentrations of dupilumab were 46.7 ± 26.9 microgram/mL and 107 ± 51.6 microgram/mL, respectively, for 200 mg or 300 mg administered every other week.
The long-term safety and efficacy of Dupixent 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, resulting in 99 patient-years cumulative exposure to Dupixent. The safety profile of Dupixent in TRAVERSE was consistent with the safety profile observed in asthma pivotal studies for up to 52 weeks of treatment. No additional adverse reactions were identified. In this study, the clinical benefit of Dupixent, including reduction in exacerbations and improvement in lung function observed in pivotal asthma studies, was sustained up to 96 weeks.
The adverse event profile in adolescents was generally similar to the adults (see Section 4.8 Adverse Effects (Undesirable Effects)).

Children 6 to 11 years of age.

In the VOYAGE study, dupilumab pharmacokinetics was investigated in 270 patients with moderate-to-severe asthma following subcutaneous administration of either 100 mg Q2W (for 91 children weighing < 30 kg) or 200 mg Q2W (for 179 children weighing > 30 kg). The mean ± SD steady-state trough concentration was 58.4 ± 28.0 microgram/mL and 85.1 ± 44.9 microgram/mL, respectively. Simulation of a 300 mg Q4W subcutaneous dose in children aged 6 to 11 years with body weight of ≥ 15 to < 30 kg and > 30 to < 60 kg resulted in predicted steady-state trough concentrations similar to the observed trough concentrations of 200 mg Q2W (≥ 30 kg) and 100 mg Q2W (< 30 kg), respectively. In addition, simulation of a 300 mg Q4W subcutaneous dose in children aged 6 to 11 years with body weight of > 15 to < 60 kg resulted in predicted steady-state trough concentrations similar to those demonstrated to be efficacious in adults and adolescents.

CRSwNP.

CRSwNP does not normally occur in children. The pharmacokinetics of dupilumab has not been studied in children (< 18 years of age) with CRSwNP.

COPD.

COPD does not normally occur in children. The pharmacokinetics of dupilumab have not been studied in children (< 18 years of age) with COPD.
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. No data are available in patients with severe renal impairment.

5.3 Preclinical Safety Data

Genotoxicity.

No genotoxicity studies were conducted. As a monoclonal antibody, dupilumab is not expected to interact with DNA or other chromosomal material.

Carcinogenicity.

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

6 Pharmaceutical Particulars

6.1 List of Excipients

300 mg pre-filled syringe/pre-filled pen.

Arginine hydrochloride (10.5 mg), histidine (5.4 mg), histidine hydrochloride monohydrate (1 mg), polysorbate 80 (4 mg), sodium acetate trihydrate (2.6 mg), sucrose (100 mg), glacial acetic acid (0.3 mg) and water for injections.

200 mg pre-filled syringe/pre-filled pen.

Arginine hydrochloride (12.01 mg), histidine (3.10 mg), histidine hydrochloride monohydrate (0.6 mg), polysorbate 80 (2.28 mg), sodium acetate trihydrate (1.5 mg), sucrose (57 mg), glacial acetic acid (0.19 mg) and water for injections.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store in the refrigerator at 2°C to 8°C in the original carton to protect from light. Do not freeze. Do not expose to heat. Do not shake.
If necessary, pre-filled syringes may be kept at room temperature up to 25°C for a maximum of 14 days. Do not store above 25°C. After removal from the refrigerator, Dupixent must be used within 14 days or discarded.
Do not use after the expiry date stamped on the carton and container label.

6.5 Nature and Contents of Container

200 mg and 300 mg pre-filled syringe.

Dupixent pre-filled syringes are available in pack sizes of 2 per carton in the following presentations.
Pre-Filled Syringe with needle shield - the pre-filled syringe has a needle shield to reduce the risk of accidental needle stick injuries. The needle cap is not made with natural rubber latex.

200 mg and 300 mg pre-filled pen.

Dupixent pre-filled pens are available in pack sizes of 2 per carton.

6.6 Special Precautions for Disposal

Any unused medicine should be disposed of by taking to your local pharmacy. The syringe and the needle cap should be disposed of in a sharps container.

6.7 Physicochemical Properties

Chemical structure.

Dupilumab is a covalent heterotetramer consisting of two disulfide-linked human heavy chains, each covalently linked through a disulfide bond to a human kappa light chain. There is a single N-linked glycosylation site in each heavy chain, located within the CH2 domain of the Fc constant region of the molecule. The dupilumab heavy chain has an immunoglobulin (Ig) G4P isotype constant region. IgG4P is an IgG4 constant region with a single amino acid substitution in the hinge region that recreates the IgG1 hinge sequence in order to stabilise IgG4 dimer formation. The variable domains of the heavy and light chains combine to form the IL-4Rα binding site within the antibody. Dupilumab has a molecular weight of approximately 147 kDa.

CAS number.

1190264-60-8.

7 Medicine Schedule (Poisons Standard)

Schedule 4 (Prescription Only Medicine).

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