Consumer medicine information

Dupixent

Dupilumab

BRAND INFORMATION

Brand name

Dupixent

Active ingredient

Dupilumab

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Dupixent.

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:

  1. 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.
  1. 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

S4

 

1 Name of Medicine

Dupilumab (rch).

2 Qualitative and Quantitative Composition

300 mg pre-filled syringe.

Each pre-filled syringe is designed to deliver 300 mg dupilumab in 2 mL (150 mg/mL) solution. It is supplied as a single-use pre-filled syringe with or without a needle shield.

200 mg pre-filled syringe.

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.
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

Atopic dermatitis.

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.

Asthma.

Dupixent is indicated as add on maintenance treatment in patients aged 12 years and older with moderate to severe asthma with type 2 inflammation (elevated eosinophils or elevated FeNO).
Dupixent is indicated as maintenance therapy for oral corticosteroid dependent asthma.

4.2 Dose and Method of Administration

Atopic dermatitis.

Dupixent treatment should be initiated and supervised by a dermatologist or immunologist.

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.

Adolescents.

The recommended dose of Dupixent for adolescent patients 12 to 17 years of age is specified in Table 1.
Dupixent can be used with or without topical therapy.

Asthma.

Dupixent treatment should be prescribed by a specialist experienced in the diagnosis and treatment of asthma.
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 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.

Missed dose.

If a 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.
Product is for single use in one patient only. Discard any residue.

Special populations.

Paediatric patients.

Atopic dermatitis.

Safety and efficacy in children below the age of 12 years with atopic dermatitis has not been established (see Section 5.2 Pharmacokinetic Properties).

Asthma.

Safety and efficacy in patients younger than 12 years with asthma have not been established (see Section 5.2 Pharmacokinetic Properties).

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.

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

Preparation and handling.

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

300 mg syringe.

Should be allowed to reach room temperature. Wait for 45 min without removing the needle cap.

200 mg syringe.

Wait for 30 min without removing the needle cap.
Inspect Dupixent visually for particulate matter and discoloration prior to administration. Dupixent is a clear to slightly opalescent, colorless to pale yellow solution. Do not use if the liquid contains visible particulate matter, is discolored or cloudy (other than clear to slightly opalescent, colorless 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 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 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.

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. 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.

If a systemic hypersensitivity reaction occurs, administration of Dupixent should be discontinued immediately and appropriate therapy initiated. Hypersensitivity reactions, including anaphylaxis, serum sickness or serum sickness-like reactions and angioedema, have been reported (see Section 4.8 Adverse Effects (Undesirable Effects)).

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.

Conjunctivitis and keratitis related events.

Conjunctivitis and keratitis related events 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)).
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 (see Section 4.8 Adverse Effects (Undesirable Effects)). Advise patients to report new onset or worsening eye symptoms to their healthcare provider.

Concomitant atopic conditions.

Patients with atopic dermatitis 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 and of vasculitis consistent with eosinophilic granulomatosis with polyangiitis have been reported with Dupixent in adult patients who participated in the asthma development program. A causal association between dupilumab and these conditions has not been established.

Acute asthma symptoms or deteriorating disease.

Dupixent should not be used to treat acute asthma symptoms or acute exacerbations. 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.

Use in the elderly.

Of the 1472 patients with atopic dermatitis exposed to Dupixent in a phase 2 dose-ranging study or phase 3 placebo-controlled studies, a total of 67 were 65 years or older. Although no differences in safety or efficacy were observed between older and younger adult atopic dermatitis patients, the number of patients aged 65 and over is not sufficient to determine whether they respond differently from younger patients.
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.

Paediatric use.

Atopic dermatitis.

Safety and efficacy in children below the age of 12 years with atopic dermatitis have not been established.

Asthma.

Safety and efficacy in children below the age of 12 years with asthma 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 breast-feeding or to discontinue Dupixent therapy taking into account the benefit of breast feeding 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.

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%).
The adverse reactions in Table 2 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 3 summarizes 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.

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.

Asthma.

A total of 2888 adult and adolescent patients with moderate-to-severe asthma were evaluated in 3 randomized, placebo-controlled, multicenter 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 4 summarizes 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 5.

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).

Conjuctivitis and keratitis related events.

Conjunctivitis was the most frequently reported eye disorder. Most subjects with conjunctivitis recovered or were recovering during the treatment period. Among asthma patients the frequency of conjunctivitis 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. Eosinophil counts declined to near baseline levels during study treatment.
The incidence of treatment-emergent eosinophilia (≥ 500 cells/microliter) was similar in Dupixent and placebo groups. Treatment-emergent eosinophilia (≥ 5,000 cells/microliter) was reported in < 2% of Dupixent-treated patients and < 0.5% in placebo-treated 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.

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.
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.

Immunogenicity.

As with all therapeutic proteins, there is a potential for immunogenicity with dupilumab.
Approximately 6% of patients with atopic dermatitis or asthma 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.
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 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.
ADA responses were not generally associated with impact on Dupixent exposure, safety, or efficacy. Less than 0.4% 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 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 Australian Poison Information Centre on 131126.

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), as well as fractional exhaled nitric oxide (FeNO), a marker of lung inflammation. Blocking the IL-4/IL-13 pathway with dupilumab in humanized 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 normalized 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 normalized 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.

Clinical trials.

Atopic dermatitis - adults.

The efficacy and safety of Dupixent as monotherapy and with concomitant topical corticosteroids (TCS) were evaluated in three pivotal randomized, 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:
1. an initial dose of 600 mg Dupixent (two 300 mg injections) on day 1, followed by 300 mg once every other week (Q2W);
2. an initial dose of 600 mg Dupixent on day 1, followed by 300 mg once weekly (QW); or
3. 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 standardized 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 (study 1334 and study 1416).

In Study 1334 and Study 1416, from baseline to week 16, a significantly greater proportion of patients randomized 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 6).
A significantly greater proportion of patients randomized 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 (study 1224).

In Study 1224, a significantly greater proportion of patients randomized 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 7).
A significantly greater proportion of patients randomized 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 29.9% of patients in the placebo group, 70.7% 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-randomized 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 summarized in Table 8.
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.

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 9.
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.

Asthma.

The asthma development program included three randomized, double-blind, placebo-controlled, parallel-group, multi-center 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/microliter 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/microliter (< 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 randomized 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 annualized 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/microliter and < 300 cells/microliter).
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, Standardized 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 randomized to receive either 200 mg (N=631) or 300 mg (N=633) Dupixent every other week (or matching placebo for either 200 mg [N = 317] or 300 mg [N = 321] every other week) following an initial dose of 400 mg, 600 mg or placebo respectively.
The primary endpoints were the annualized rate of severe exacerbation events during the 52-week placebo controlled period and change from baseline in pre-bronchodilator FEV1 at Week 12 in 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 annualized 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 10.

Exacerbations.

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 11).
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/microliter. In subjects with baseline blood eosinophil count < 150 cells/microliter, 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 12 and Figure 6.
The cumulative mean number of severe exacerbation events in DRI12544, Quest, and Venture studies (Overall Population and Baseline Eosinophils ≥ 300 cells/microliter) during the 24- or 52-week treatment period is shown in Figure 7.
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/microliter in DRI12544 and the overall population in the Quest trial). See Figure 8.
Subgroup analysis of DRI12544, Quest, and Venture studies demonstrated that patients with baseline blood eosinophil count of ≥ 150 and ≥ 300 cells/microliter showed greater improvement in FEV1 compared with the overall population (see Table 13).
Clinically meaningful improvements in FEV1 were observed in patients with baseline eosinophils < 300 cells/microliter, although less than in the population with baseline blood eosinophil count ≥ 300 cells/microliter. 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 14.
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) (Figure 9).

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 Standardized 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 15.

5.2 Pharmacokinetic Properties

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

Absorption.

After a single subcutaneous (SC) dose of 75-600 mg dupilumab, median times to maximum concentration in serum (tmax) were 3-7 days. The absolute bioavailability of dupilumab following a SC dose is similar between AD and asthma patients, ranging 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 70-74 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, the median time for dupilumab concentrations to decrease below the lower limit of detection, determined by population PK analysis, was 9 weeks for the 200 mg Q2W, 10-11 weeks for the 300 mg Q2W regimen and 13 weeks for the 300 mg QW regimen.

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.

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.

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.
The pharmacokinetics of dupilumab in paediatric patients below 12 years of age with atopic dermatitis have not been fully established.
A total of 107 adolescents (range: 30 kg to 122 kg) aged 12 to 17 years with moderate to severe asthma were enrolled in Quest study and received either 200 mg (N=21) or 300 mg (N=18) 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.
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.
For both the 200 mg and 300 mg every other week doses, significant improvements in FEV1 (LS mean change from baseline at Week 12) were observed (0.36 L and 0.27 L, respectively). For the 200 mg every other week dose, patients had a reduction in the rate of severe exacerbations that was consistent with adults.
Safety and efficacy in paediatric patients (< 12 years of age) with asthma have not been studied.
The adverse event profile in adolescents was generally similar to the adults (see Section 4.8 Adverse Effects (Undesirable Effects)).

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.

Arginine hydrochloride (25 mM), histidine (20 mM), polysorbate 80 (0.2% (w/v)), sodium acetate trihydrate (12.5 mM), sucrose (5% (w/v)), water for injections, and glacial acetic acid.

200 mg pre-filled syringe.

Arginine hydrochloride (50 mM), L-histidine (20 mM), polysorbate 80 (0.2% (w/v)), sodium acetate trihydrate (12.5 mM), sucrose (5% (w/v)) water for injections and glacial acetic acid.

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

300 mg pre-filled syringe.

Dupixent 300 mg is available in pack sizes of 1* or 2, 3* and 6* per carton in the following presentations.
Pre-filled Syringe;
Pre-Filled Syringe with needle shield - the pre-filled syringe has a needle shield to reduce the risk of accidental needle stick injuries.

200 mg pre-filled syringe.

Dupixent 200 mg is available in pack sizes of 1* or 2, 3* and 6* per carton.
Pre-Filled Syringe with needle shield - the pre-filled syringe has a needle shield to reduce the risk of accidental needle stick injuries.
* Presentations currently not marketed.

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 stabilize 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).

Summary Table of Changes