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نشرة الممارس الصحي | نشرة معلومات المريض بالعربية | نشرة معلومات المريض بالانجليزية | صور الدواء | بيانات الدواء |
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What Dupixent is
Dupixent contains the active substance dupilumab.
Dupilumab is a monoclonal antibody (a type of specialised protein) that blocks the action of proteins called interleukins (IL)-4 and IL-13. Both play a major role in causing the signs and symptoms of atopic dermatitis, asthma, and chronic rhinosinusitis with nasal polyposis (CRSwNP).
What Dupixent is used for
Dupixent is used to treat adults and adolescents 12 years and older with moderate-to-severe atopic dermatitis, also known as atopic eczemaDupixent is also used to treat children 6 to 11 years old with moderate to severe atopic dermatitis. Dupixent may be used with eczema medicines that you apply to the skin or it may be used on its own.
Dupixent is also used with other asthma medicines for the maintenance treatment of severe asthma in adults, adolescents, and children aged 6 years and older whose asthma is not controlled with their current asthma medicines (e.g. corticosteroids).
Dupixent is also used with other medicines for the maintenance treatment of CRSwNP in adults whose disease is not controlled with their current CRSwNP medicines. Dupixent can also reduce the need for surgery and the need for systemic corticosteroid use.
Dupixent is also used for the treatment of adult and pediatric patients aged 12 years and older,
weighing at least 40 kg, with eosinophilic esophagitis (EoE), who are inadequately controlled by, are intolerant to, or who are not candidates for conventional medicinal therapy
Dupixent is also used to treat adults with prurigo nodularis (PN), who are candidate for systemic therapy
How Dupixent works
Using Dupixent for atopic dermatitis (atopic eczema) can improve the condition of your skin and reduce itching. Dupixent has also been shown to improve symptoms of pain, anxiety, and depression associated with atopic dermatitis. In addition, Dupixent helps improve your sleep disturbance and overall quality of life.
Dupixent helps prevent severe asthma attacks (exacerbations) and can improve your breathing. Dupixent may also help reduce the amount of another group of medicines you need to control your asthma, called oral corticosteroids, while preventing severe asthma attacks and improving your breathing.
DUPIXENT works by blocking two proteins that contribute to a type of inflammation that plays a major role in atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyposis, eosinophilic esophagitis, and prurigo nodularis
Contraindications:
Do not use Dupixent
· if you are allergic to dupilumab or any of the other ingredients of this medicine (listed in section 6).
· if you think you may be allergic, or you are not sure, ask your doctor, pharmacist or nurse for advice before using Dupixent.
Warnings and precautions
Talk to your doctor, pharmacist or nurse before using Dupixent:
Dupixent is not a rescue medicine and should not be used to treat a sudden asthma attack.
Allergic reactions
· Rarely, Dupixent can cause serious side effects, including allergic (hypersensitivity) reactions and anaphylactic reaction and angioedema. These reactions can occur from minutes until seven days after Dupixent administration. You must look out for signs of these conditions (i.e. breathing problems, swelling of the face, lips, mouth, throat or tongue, fainting, dizziness, feeling lightheaded (low blood pressure), fever, general ill feeling, swollen lymph nodes, hives, itching, joint pain, skin rash) while you are taking Dupixent. Such signs are listed under “Serious side effects” in section 4.
· Stop using Dupixent and tell your doctor or get medical help immediately if you notice any signs of an allergic reaction.
Eosinophilic conditions
· Rarely patients taking an asthma medicine may develop inflammation of blood vessels or lungs due to an increase of certain white blood cells (eosinophilia).
· 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 symptoms such as a flu-like illness, pins and needles or numbness of arms or legs, worsening of pulmonary symptoms, and/or rash.
Parasitic (intestinal parasites) infection
· Dupixent may weaken your resistance to infections caused by parasites. If you already have a parasitic infection it should be treated before you start treatment with Dupixent.
· Check with your doctor if you have diarrhoea, gas, upset stomach, greasy stools, and dehydration which could be a sign of a parasitic infection.
· If you live in a region where these infections are common or if you are travelling to such a region check with your doctor.
Asthma
If you have asthma and are taking asthma medicines, do not change or stop your asthma medicine without talking to your doctor. Talk to your doctor before you stop Dupixent or if your asthma remains uncontrolled or worsens during treatment with this medicine.
Eye problems
Talk to your doctor if you have any new or worsening eye problems, including eye pain or changes in vision.
Tell your doctor if you have atopic dermatitis, chronic rhinosinusitis with nasal polyposis, eosinophilic esophagitis, or prurigo nodularis and also have asthma
Children and adolescents
· The safety and benefits of Dupixent are not yet known in children with atopic dermatitis below the age of 6 .
· . The safety and benefits of Dupixent are not yet known in children with asthma below the age of 6
· CRSwNP does not normally occur in children. The safety and benefits of Dupixent are not yet known in children with CRSwNP below the age of 18 years.
· The safety and effectiveness of DUPIXENT for the treatment of EoE in pediatric patients less than 12 years of age and weighing less than 40 kg have not been established
It is not known if DUPIXENT is safe and effective in children with prurigo nodularis under 18 years of age.
Other medicines and Dupixent
Tell your doctor or pharmacist
· if you are using, have recently used or might use any other medicines.
· if you have recently had or are due to have a vaccination.
Other medicines for asthma
Do not stop or reduce your asthma medicines, unless instructed by your doctor.
· These medicines (especially ones called corticosteroids) must be stopped gradually.
· This must be done under the direct supervision of your doctor and dependent on your response to Dupixent.
Pregnancy and breast-feeding
· If you are pregnant, think you may be pregnant, or are planning to have a baby, ask your doctor for advice before using this medicine. The effects of this medicine in pregnant women are not known; therefore, it is preferable to avoid the use of Dupixent in pregnancy unless your doctor advises to use it.
· If you are breast-feeding or are planning to breast-feed, talk to your doctor before using this medicine. You and your doctor should decide if you will breast-feed or use Dupixent. You should not do both.
Driving and using machines
Dupixent is unlikely to influence your ability to drive and use machines.
Dupixent contains sodium
This medicine contains less than 1 mmol sodium (23 mg) per 300 mg dose, that is to say essentially “sodium-free”.
Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.
How Dupixent is given
Dupixent is given by injection under the skin (subcutaneous injection).
How much Dupixent you will receive
Your doctor will decide which dose of Dupixent is right for you.
Recommended dose in adults with atopic dermatitis
For patients with atopic dermatitis, the recommended dose of Dupixent is:
· An initial dose of 600 mg (two 300 mg injections)
· Followed by 300 mg given every other week by subcutaneous injection.
Recommended dose in adolescents with atopic dermatitis
The recommended dose of Dupixent for adolescents (12 to 17 years of age) with atopic dermatitis is based on body weight:
Body Weight of Patient | Initial Dose | Subsequent Doses (every other week) |
less than 60 kg | 400 mg (two 200 mg injections) | 200 mg |
60 kg or more | 600 mg (two 300 mg injections) | 300 mg |
Recommended dose in children with atopic dermatitis
The recommended dose of Dupixent for children (6 to 11 years of age) with atopic dermatitis is based on body weight:
Body Weight of Patient | Initial Dose | Subsequent Doses
|
15 to less than 30 kg | 600 mg (two 300 mg injections) | 300 mg Q4W |
30 to less than 60 kg | 400 mg (two 200 mg injections) | 200 mg Q2W |
60 kg or more | 600 mg (two 300 mg injections) | 300 mg every other week |
* The dose may be increased to 200 mg every other week based on the doctor’s opinion.
Recommended dose in adult and adolescent patients with asthma (12 years of age and older)
For patients with severe asthma and who are on oral corticosteroids or for patients with severe asthma and co-morbid moderate-to-severe atopic dermatitis or adults with co-morbid severe chronic rhinosinusitis with nasal polyposis, the recommended dose of Dupixent is:
· An initial dose of 600 mg (two 300 mg injections)
· Followed by 300 mg given every other week administered as subcutaneous injection.
For all other patients with severe asthma, the recommended dose of Dupixent is:
· An initial dose of 400 mg (two 200 mg injections)
· Followed by 200 mg given every other week administered as subcutaneous injection.
Recommended dose children with asthma
The recommended dose of Dupixent for children (6 to 11 years of age) with asthma is based on body weight:
Body Weight of Patient | Initial and Subsequent Doses |
15 to less than 30 kg | 100 mg every other week or 300 mg every 4 weeks |
30 kg to less than 60 kg
| 200 mg every other week or 300 mg every 4 weeks |
60 kg or more | 200 mg every other week |
For patients 6 to 11 years old with asthma and coexisting severe atopic dermatitis, your doctor will decide which dose of Dupixent is right for you.
Recommended dose in adults with chronic rhinosinusitis with nasal polyposis (CRSwNP)
In CRSwNP, the recommended first dose of Dupixent is 300 mg followed by 300 mg given every two weeks by subcutaneous injection.
Recommended dose in adults and pediatric patients (12 years of age and older) with eosinophilic esophagitis (EoE)
The dosage of Dupixent is 300mg given every week by subcutaneous injection ( for patents with body weight of 40 kg or more).
Recommended dose in adult patients with Prurigo Nodularis:
Recommended dosage for adult patients is an initial dose of 600 mg (two 300 mg injections), followed by 300 mg given every other week (Q2W).
Injecting Dupixent
Dupixent is given by injection under your skin (subcutaneous injection). You and your doctor or nurse should decide if you should inject Dupixent yourself.
Before injecting Dupixent yourself you must have been properly trained by your doctor or nurse. Your Dupixent injection may also be given by a caregiver after proper training by a doctor or nurse.
Each pre-filled syringe contains one dose of Dupixent (300 mg). Do not shake the pre-filled syringe.
Read carefully the “Instructions for Use” included at the end of the package leaflet before using Dupixent.
If you use more Dupixent than you should
If you use more Dupixent than you should or the dose has been given too early, talk to your doctor, pharmacist or nurse.
If you forget to use Dupixent
If you have forgotten to inject a dose of Dupixent, talk to your doctor, pharmacist or nurse.
If you stop using Dupixent
Do not stop using Dupixent without speaking to your doctor first.
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Dupixent can cause serious side effects, including rare allergic (hypersensitivity) reactions, including anaphylactic reaction; the signs of allergic reaction or anaphylactic reaction may include:
· breathing problems
· swelling of the face, lips, mouth, throat or tongue (angioedema)
· fainting, dizziness, feeling lightheaded (low blood pressure)
· fever
· general ill feeling
· swollen lymph nodes
· hives
· itching
· joint pain
· skin rash
If you develop an allergic reaction, stop using Dupixent and talk to your doctor right away.
Other side effects
Common (may affect up to 1 in 10 people):
· injection site reactions (i.e. redness, swelling, itching, pain)
· eye redness and itching
· eye infection
· cold sores (on lips and skin)
· joint pain (arthralgia)
· upper respiratory tract infections
· herpes viral infections
Uncommon (may affect up to 1 in 100 people):
· swelling of the face, lips, mouth, throat or tongue (angioedema)
· eyelid itching, redness and swelling
· inflammation of the eye surface, sometimes with blurred vision (keratitis)
· facial rash or redness
· eye dryness
Rare (may affect up to 1 in 1,000 people):
· ulcers on the outer clear layer of the eye, sometimes with blurred vision (ulcerative keratitis)
Additional side effects in children 6 to 11 years old with asthma
Common: pinworms (enterobiasis)
Reporting of side effects
To report any side effect(s):
· Saudi Arabia: |
- The National Pharmacovigilance and Drug Safety Centre (NPC) |
· SFDA call center : 19999 |
· E-mail: npc.drug@sfda.gov.sa |
· Website: https://ade.sfda.gov.sa/ |
• Sanofi- Pharmacovigilance: KSA_Pharmacovigilance@sanofi.com |
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the label and carton after EXP. The expiry date refers to the last day of that month.
Store in a refrigerator (2°C to 8°C). 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. If you need to permanently remove the carton from the refrigerator, write down the date of removal in the space provided on the outer carton, and use Dupixent within 14 days.
Store in the original carton to protect from light.
Do not use this medicine if you notice that the medicine is cloudy, discoloured, or has particles in it.
Do not throw away any medicines via wastewater or household waste. Ask your doctor, pharmacist or nurse how to throw away medicines you no longer use. These measures will help protect the environment.
What Dupixent 300 mg, solution for injection in pre-filled syringe contains
· The active substance is dupilumab.
· Each pre-filled syringe contains 300 mg of dupilumab in 2 mL solution for injection (injection).
· The other ingredients are arginine hydrochloride, histidine, polysorbate 80 (E433), sodium acetate, glacial acetic acid (E260), sucrose, water for injections.
Marketing Authorisation Holder
sanofi-aventis groupe
54, rue La Boétie
75008 Paris
France
Manufacturer
Sanofi Winthrop Industrie
1051 Boulevard Industriel
76580 LE TRAIT
FRANCE
Sanofi-Aventis Deutschland GmbH
Brüningstrasse 50
Industriepark Hoechst
65926 FRANKFURT AM MAIN
GERMANY
ما هو دوبيكسنت
يحتوي دوبيكسنت على المادة الفاعلة دوبيلوماب.
دوبيلوماب هو جسم مضاد أحاديّ المنشأ (نوع من البروتين المتخصص) يمنع عمل بروتينين يُسميّان إنترلوكينIL-4 وIL-13 ويلعبان دورًا رئيسيًا في التسبب بإشارات وأعراض التهاب الجلد التأتبي والربو والتهاب الجيوب المزمن مع داء السلائل الأنفي.
ما هي دواعي استعمال دوبيكسنت
يُستعمل دوبيكسنت لعلاج البالغين والمراهقين في عمر 12 سنة وما فوق المصابين بالتهاب الجلد التأتبي المعتدل إلى الحاد، المعروف أيضًا بالأكزيما التأتبيّة. يمكن استعمال دوبيكسنت كذلك لدى الأطفال الذين تتراوح أعمارهم بين 6 إلى 11 سنة لعلاج التهاب الجلد التأتبي المعتدل إلى الحاد. يمكن استعمال دوبيكسنت مع أدوية الأكزيما التي تضعها على الجلد أو يمكن استعماله بمفرده.
يُستعمل دوبيكسنت أيضًا مع أدوية ربو أخرى كعلاج مداومة للربو الحاد لدى البالغين والمراهقين والأطفال بعمر 6 سنوات وما فوق الذين لا يكون الربو لديهم متحكّمًا به بأدوية الربو الحاليّة التي يأخذونها (مثلًا الكورتيكوستيرويد).
يُستعمل دوبيكسنت أيضًا مع أدوية ربو أخرى كعلاج مداومة لالتهاب الجيوب المزمن مع داء السلائل الأنفي لدى البالغين الذين لا يكون مرضهم متحكّمًا به بأدوية التهاب الجيوب المزمن مع داء السلائل الأنفي الحاليّة التي يأخذونها. كما يمكن أن يقلل دوبيكسنت من الحاجة إلى الجراحة والحاجة إلى استعمال الكورتيكوستيرويد.
يُستعمل دوبيكسنت أيضًا لعلاج المرضى البالغين والأطفال في الثانية عشرة من العمر وما فوق، والذين لا يقل وزنهم عن 40 كلغ، المصابين بالتهاب المريء اليوزيني، الذين لا يكون مرضهم متحكّمًا به بشكل كاف بالعلاج الطبي التقليدي، أو لا يتحمّلون هذا العلاج، أو ليسوا مرشّحين لتلقّيه.
يُستعمل دوبيكسنت أيضًا لعلاج البالغين الذين يعانون من الحكّة العقديّة، والمرشّحين للعلاج الجهازي.
كيف يعمل دوبيكسنت
إنّ استعمال دوبيكسنت لالتهاب الجلد التأتبي (الأكزيما التأتبيّة) يمكن أن يحسّن حالة جلدك ويخفّف من الحكّة. وقد ثَبت أيضًا أنّ دوبيكسنت يحسّن أعراض الألم والقلق والاكتئاب المرتبطة بالتهاب الجلد التأتبي. بالإضافة إلى ذلك، يساعد دوبيكسنت على تحسين اضطرابات النوم والجودة الشاملة للحياة.
يساعد دوبيكسنت على منع نوبات الربو الحادة (تفاقم الربو) ويمكنه أن يحسّن التنفّس لديك. يمكن أن يساعد دوبيكسنت أيضًا على الحدّ من كميّة مجموعة أخرى من الأدوية تحتاج إليها للتحكّم بالربو الذي تعاني منه وتُسمّى كورتيكوستيرويد عن طريق الفم، مانعًا نوبات الربو الحاد ومحسّنًا التنفّس لديك.
يعمل دوبيكسنت عن طريق حصر نوعين من البروتينات يساهمان في نوع من الالتهاب يلعب دورًا رئيسيًا في التهاب الجلد التأتبي والربو والتهاب الجيوب الأنفيّة المزمن مع داء السلائل الأنفي والتهاب المريء اليوزيني والحكّة العقدية.
موانع الاستعمال:
لا تستعمل دوبيكسنت
· إذا كنت تعاني من حساسية ضدّ دوبيلوماب أو ضدّ أيّ من المركّبات الأخرى في هذا الدواء (المذكورة في القسم 6).
· إذا كنت تعتقد أنّك قد تكون تعاني من حساسيّة أو إذا لم تكن واثقًا، استشر الطبيب أو الصيدلي أو الممرّضة قبل استعمال دوبيكسنت.
تحذيرات واحتياطات
تحدّث إلى الطبيب أو الصيدلي أو الممرّضة قبل استعمال دوبيكسنت:
دوبيكسنت ليس دواء إنقاذ ولا ينبغي استعماله لعلاج نوبة ربو مفاجئة.
الارتكاسات التحسسيّة
· يمكن أن يسبّب دوبيكسنت بشكل نادر تأثيرات جانبيّة خطيرة تتضمّن ارتكاسات تحسسيّة (فرط حساسيّة) وردّ فعل تأقيًّا ووذمة وعائية. يُمكِن أن تحدث هذه التفاعلات خلال دقائق وحتى سبعة أيام بعد استعمال دوبيكسنت. يجب عليك أن تنتبه إلى إشارات هذه الحالات (أيّ مشاكل في التنفّس، تورّم الوجه أو الشفتيْن أو الفم أو الحلق أو اللسان، إغماء، دوار، الشعور بدوخة (انخفاض ضغط الدم)، حمى، شعور عام بالتوعّك، تورّم الغدد الليمفاويّة، قشعريرة، حكّة، ألم في المفاصل، طفح جلدي) وأنت تأخذ دوبيكسنت. هذه الإشارات مذكورة في فقرة "التأثيرات الجانبيّة الخطيرة" في القسم 4.
· توقّف عن استعمال دوبيكسنت وأعلم طبيبك أو اطلب مساعدة طبيّة طارئة إذا لاحظت أيّ إشارات ارتكاس تحسسيّ.
فرط الحمضات
· نادرًا ما يُصاب المرضى الذين يأخذون دواء للربو بالتهاب في الأوعية الدمويّة أو الرئتين بسبب ارتفاع عدد بعض كريات الدم البيضاء (فرط الحمضات).
· من غير المعروف ما إذا كان السبب يعود إلى دوبيكسنت. يحصل هذا عادة ولكن ليس دائمًا لدى الأشخاص الذين يأخذون دواء ستيرويديًا يتمّ إيقافه أو يتمّ تخفيض جرعته.
· أعلم طبيبك على الفور إذا أصبت بمجموعة من الأعراض مثل مرض يشبه الانفلوانزا أو شعور بالوخز أو الخدر في الذراعين أو الساقين أو تفاقم الأعراض الرئويّة و/أو الطفح.
العدوى الطفيليّة (الطفيليّات المعويّة)
· يمكن أن يُضعف دوبيكسنت مقاومتك تجاه حالات العدوى التي تسبّبها الطفيليّات. إذا كنت مصابًا بعدوى طفيليّة يجب أن تُعالج قبل أن تبدأ العلاج بدوبيكسنت.
· تحقق مع الطبيب إذا كنت مصابًا بإسهال وغازات واضطرابات في المعدة وبراز دهني وجفاف مما يمكن أن يكون إشارة على عدوى طفيليّة.
· إذا كنت تعيش في منطقة تكون فيها حالات العدوى هذه شائعة أو إذا كنت تسافر إلى منطقة كهذه، تحقق مع طبيبك.
الربو
إذا كنت مصابًا بالربو وكنت تأخذ أدوية ربو، لا تغيّر أو توقف دواء الربو الذي تأخذه بدون التحدّث إلى طبيبك. تحدّث إلى طبيبك قبل أن توقف دوبيكسنت أو إذا بقي الربو الذي تعاني منه غير متحكّم به أو إذا تفاقم في خلال العلاج بهذا الدواء.
مشاكل العينين
تحدّث إلى طبيبك إذا أصبت بمشاكل جديدة في العينين أو إذا تفاقمت مشاكلك في العينين، بما في ذلك ألم العين أو التغييرات في الرؤية.
أعلم طبيبك إذا كنت تعاني من التهاب الجلد التأتبي، أو التهاب الجيوب الأنفيّة المزمن مع داء السلائل الأنفي، أو التهاب المريء اليوزيني، أو الحكة العقيدية، وتعاني كذلك من الربو.
الأطفال والمراهقون
· إنّ سلامة دوبيكسنت ومنافعه غير معروفة بعد لدى الأطفال المصابين بالتهاب الجلد التأتبي ما دون الـ6 من العمر.
· إنّ سلامة دوبيكسنت ومنافعه غير معروفة بعد لدى الأطفال المصابين بالربو ما دون عمر الـ6.
· لا يُصاب الأطفال عادة بالتهاب الجيوب المزمن مع داء السلائل الأنفي. إنّ سلامة دوبيكسنت ومنافعه غير معروفة بعد لدى الأطفال المصابين بالتهاب الجيوب المزمن مع داء السلائل الأنفي ما دون الثامنة عشرة من العمر.
· لم يتم التأكّد من سلامة وفعالية دوبيكسنت لعلاج التهاب المريء اليوزيني لدى المرضى الأطفال الذين تقلّ أعمارهم عن 12 عامًا ويزنون أقل من 40 كلغ.
· من غير المعروف ما إذا كان دوبيكسنت آمنًا وفعّالاً لدى الأطفال المصابين بالحكّة العقيديّة ما دون عمر 18 عامًا.
أدوية أخرى ودوبيكسنت
أعلم الطبيب أو الصيدلي
· إذا كنت تستعمل أو استعملت مؤخّرًا أو قد تستعمل أيّ أدوية أخرى.
· إذا تلقّيت لقاحًا مؤخّرًا أو كنت ستتلقّى لقاحًا.
أدوية أخرى للربو
لا توقف أدوية الربو التي تأخذها أو تخفف جرعتها إلاّ إذا طلب الطبيب ذلك.
· يجب إيقاف هذه الأدوية (بخاصة الأدوية المسمّاة كورتيكوستيرويد) بشكل تدريجيّ.
· يجب أن يتمّ هذا تحت الرقابة المباشرة لطبيبك وحسب تجاوبك مع دوبيكسنت.
الحمل والإرضاع
· إذا كنت حاملاً أو تعتقدين نفسك حاملاً أو كنت تخططين للحمل، استشيري طبيبك قبل استعمال هذا الدواء. إنّ تأثيرات هذا الدواء لدى النساء الحوامل غير معروفة؛ لذلك يُفضّل تفادي استعمال دوبيكسنت في خلال فترة الحمل إلاّ إذا أوصى الطبيب باستعماله.
· إذا كنت تُرضعين أو كنتِ تخططين للرضاعة الطبيعيّة، تحدّثي إلى طبيبك قبل استعمال هذا الدواء. يجب أن تقررا أنت وطبيبك إذا كنت ستُرضعين أو ستستعملين دوبيكسنت. لا يجدر بك فعل الأمرين معًا.
قيادة السيّارات واستعمال الآلات
من غير المحتمل أن يؤثّر دوبيكسنت على قدرتك على القيادة وعلى استعمال الآلات.
يحتوي دوبيكسنت على الصوديوم
يحتوي هذا الدواء على أقلّ من 1 ملمول من الصوديوم (23 ملغ) في كلّ جرعة من 300 ملغ، أي أنّه "خالٍ من الصوديوم" بشكل أساسيّ.
استعمل هذا الدواء دائمًا حسب تعليمات الطبيب أو الصيدلي تمامًا. تحقق مع الطبيب أو الصيدلي إذا لم تكن واثقًا.
كيف يُعطى دوبيكسنت
يُعطى دوبيكسنت عن طريق الحقن تحت الجلد (حقن تحت الجلد).
كميّة دوبيكسنت التي ستتلقّاها
سيقرّر طبيبك جرعة دوبيكسنت المناسبة لك.
الجرعة الموصى بها لدى البالغين المصابين بالتهاب الجلد التأتبي
للمرضى المصابين بالتهاب الجلد التأتبي، تبلغ الجرعة الموصى بها من دوبيكسنت:
· جرعة أوّليّة من 600 ملغ (حقنتان من 300 ملغ)
· تتبعها جرعة 300 ملغ تُعطى مرّة كلّ أسبوعين عن طريق الحقن تحت الجلد.
الجرعة الموصى بها لدى المراهقين المصابين بالتهاب الجلد التأتبي
ترتكز الجرعة الموصى بها من دوبيكسنت للمراهقين (12 إلى 17 عامًا) المصابين بالتهاب الجلد التأتبي على وزن الجسم:
وزن جسم المريض | الجرعة الأوّليّة | الجرعات اللاحقة (مرّة كلّ أسبوعين) |
أقلّ من 60 كلغ | 400 ملغ (حقنتان من 200 ملغ) | 200 ملغ |
60 كلغ أو أكثر | 600 ملغ (حقنتان من 300 ملغ) | 300 ملغ |
الجرعة الموصى بها لدى الأطفال المصابين بالتهاب الجلد التأتبي
ترتكز الجرعة الموصى بها من دوبيكسنت للأطفال (6 إلى 11 عام) المصابين بالتهاب الجلد التأتبي على وزن الجسم:
وزن جسم المريض | الجرعة الأوّلية | الجرعات اللاحقة |
15 إلى أقلّ من 30 كلغ | 600 ملغ (حقنتان من 300 ملغ) | 300 ملغ كلّ أربعة أسابيع |
30 إلى أقلّ من 60 كلغ | 400 ملغ (حقنتان من 200 ملغ) | 200 ملغ كلّ أسبوعين |
60 كلغ أو أكثر | 600 ملغ (حقنتان من 300 ملغ) | 300 ملغ كلّ أسبوعين |
* يمكن زيادة الجرعة حتّى 200 ملغ كلّ أسبوعيْن بحسب رأي الطبيب.
الجرعة الموصى بها لدى المرضى البالغين والمراهقين المصابين بالربو (12 عامًا وما فوق)
للمرضى المصابين بالربو الحاد ويأخذون كورتيكوستيرويد عن طريق الفم أو للمرضى المصابين بربو حاد وبالتهاب الجلد التأتبي المصاحب المعتدل إلى الشديد أو للبالغين المصابين بالتهاب الأنف والجيوب المزمن الحاد مع داء السّلائل الأنفي المصاحب، تبلغ جرعة دوبيكسنت الموصى بها:
· جرعة أوّلية من 600 ملغ (على حقنتين من 300 ملغ)
· تليها جرعة من 300 ملغ مرّة كلّ أسبوعين عن طريق الحقن تحت الجلد.
لجميع المرضى الآخرين المصابين بالربو الحاد، تبلغ جرعة دوبيكسنت الموصى بها:
· جرعة أوّلية من 400 ملغ (على حقنتين من 200 ملغ)
· تليها جرعة من 200 ملغ مرّة كلّ أسبوعين عن طريق الحقن تحت الجلد.
الجرعة الموصى بها لدى الأطفال المصابين بالربو
ترتكز الجرعة الموصى بها من دوبيكسنت للأطفال (6 إلى 11 عام) المصابين بالربو على وزن الجسم:
وزن جسم المريض | الجرعات الأوّليّة واللاحقة |
15 إلى أقلّ من 30 كلغ | 100 ملغ مرّة كلّ أسبوعين أو 300 ملغ مرّة كلّ 4 أسابيع |
30 إلى أقلّ من 60 كلغ | 200 ملغ مرّة كلّ أسبوعين أو 300 ملغ مرّة كلّ 4 أسابيع |
60 كلغ أو أكثر | 200 ملغ مرّة كلّ أسبوعين |
للمرضى من 6 إلى 11 عامًا المصابين بربو متصاحب مع التهاب الجلد التأتبي، سوف يقرّر طبيبك الجرعة المناسبة لك.
الجرعة الموصى بها لدى المرضى البالغين المصابين بالتهاب الجيوب المزمن مع داء السلائل الأنفي
في التهاب الجيوب المزمن مع داء السلائل الأنفي، تبلغ الجرعة الأولى الموصى بها من دوبيكسنت 300 ملغ تليها جرعة 300 ملغ تُعطى كلّ أسبوعين عن طريق الحقن تحت الجلد.
الجرعة الموصى بها للمرضى البالغين والأطفال (12 سنة وما فوق) المصابين بالتهاب المريء اليوزيني
تبلغ الجرعة الموصى بها من دوبيكسنت 300 ملغ وتُعطى كل أسبوع عن طريق الحقن تحت الجلد (للمرضى الذين يبلغ وزنهم 40 كلغ أو أكثر).
الجرعة الموصى بها للمرضى البالغين المصابين بالحكة العقدية:
الجرعة الموصى بها للمرضى البالغين هي جرعة أولية 600 ملغ (على حقنتين من 300 ملغ)، تليها 300 ملغ مرّة كلّ أسبوعين.
حقن دوبيكسنت
يُعطى دوبيكسنت عن طريق الحقن تحت الجلد (حقن تحت الجلد). يجب أن تقررا أنت وطبيبك أو الممرضة إذا كان يجدر بك حقن دوبيكسنت بنفسك.
قبل حقن دوبيكنست بنفسك، يجب أن يكون قد درّبك طبيبك أو ممرّضتك كما يجب. يمكن أيضًا أن يعطيك مقدّم الرعاية الصحيّة الخاص بك الحقنة بعد تدريب مناسب من قبل طبيب أو ممرّضة.
تحتوي كلّ حقنة معبّأة مسبقًا على جرعة واحدة من دوبيكسنت (300 ملغ). لا ترجّ الحقنة المعبّأة مسبقًا.
إقرأ بدقّة "تعليمات الاستعمال" المذكورة في نهاية النشرة الدوائيّة قبل استعمال دوبيكسنت.
إذا استعملت كميّة من دوبيكسنت أكثر مما يجب
إذا استعملت كميّة دوبيكسنت أكثر مما يجب أو إذا تمّ إعطاؤك الجرعة في موعد مبكر جدًا، تحدّث إلى الطبيب أو الصيدليّ أو الممرّضة.
إذا نسيت استعمال دوبيكسنت
إذا نسيت حقن جرعة من دوبيكسنت، تحدّث إلى الطبيب أو الصيدلي أو الممرّضة.
إذا توقفت عن استعمال دوبيكسنت
لا تتوقف عن استعمال دوبيكسنت بدون التحدّث إلى طبيبك أوّلاً.
إذا كان لديك أيّ أسئلة إضافيّة حول استعمال هذا الدواء، اطرحها على الطبيب أو الصيدلي أو الممرضة.
مثل الأدوية كلّها، يمكن أن يسبّب هذا الدواء تأثيرات جانبيّة لا تصيب المرضى كلّهم.
يمكن أن يسبّب دوبيكسنت تأثيرات جانبيّة خطيرة تتضمّن ارتكاسات تحسسيّة نادرة (فرط حساسيّة)، تتضمّن ردّ فعل تأقيًّا؛ قد تشمل إشارات الارتكاس التحسسيّ أو رد الفعل التأقيّ ما يلي:
· مشاكل في التنفّس
· تورّم الوجه أو الشفتيْن أو الفم أو الحلق أو اللسان (وذمة وعائية)
· إغماء، دوار، الشعور بدوخة (انخفاض ضغط الدم)
· حمى
· شعور عام بالتوعّك
· تورّم الغدد الليمفاوية
· شرى
· حكّة
· ألم في المفاصل
· طفح جلدي
إذا أصبت بارتكاس تحسسيّ، توقّف عن استعمال دوبيكسنت وتحدّث إلى طبيبك عل الفور.
تأثيرات جانبيّة أخرى
تأثيرات جانبيّة شائعة (قد تصيب حتّى شخص من أصل 10 أشخاص):
· ارتكاسات في موقع الحقن (أيّ احمرار وتورّم وحكّة وألم)
· احمرار وحكّة في العينين
· عدوى في العين
· قروح باردة (على الشفتين والجلد)
· ألم المفاصل
· التهابات الجهاز التنفسّي العلوي
· التهابات الهربس الفيروسيّة
تأثيرات جانبيّة غير شائعة (قد تصيب حتّى شخص من أصل 100 أشخاص):
· تورّم الوجه أو الشفتيْن أو الفم أو الحلق أو اللسان (وذمة وعائية)
· حكّة واحمرار وتورّم في الجفن
· التهاب سطح العين مع رؤية ضبابيّة احيانًا (التهاب القرنيّة)
· طفح جلدي أو احمرار الجلد
· جفاف في العينين
تأثيرات جانبيّة نادرة (قد تصيب حتّى شخص من أصل 1000 أشخاص)
· تقرّحات على الطبقة الخارجية الصافية للعين مع رؤية ضبابيّة أحيانًا (التهاب القرنية التقرحي)
تأثيرات جانبيّة إضافيّة لدى الأطفال من 6 إلى 11 عامًا المصابين بالربو
تأثيرات جانبيّة شائعة: الدودة الدبوسية (داء السرميات)
الإبلاغ عن التأثرات الجانبيّة
للإبلاغ عن أي أعراض جانبية:
· المملكة العربية السعودية: - المركز الوطني للتيقظ والسلامة الدوائية · الرقم المُوحّد للهيئة العامّة للغذاء والدّواء: 19999 · البريد الالكتروني: npc.drug@sfda.gov.sa · الموقع الالكتروني: https://ade.sfda.gov.sa/ |
· سانوفي للتيقظ الدوائي: KSA_Pharmacovigilance@sanofi.com
احفظ هذا الدواء بعيدًا عن نظر الأطفال ومتناولهم.
لا تستعمل هذا الدواء بعد انقضاء تاريخ الصلاحيّة المذكور على الملصق وعلبة الكرتون بعد كلمة EXP. يشير تاريخ انقضاء الصلاحيّة إلى اليوم الأخير من الشهر المذكور.
احفظ الدواء في البرّاد (بين درجتين مئويّتين و8 درجات مئويّة). عند الضرورة، يمكن حفظ الحقن المعبّأة مسبقًا في حرارة الغرفة حتّى 25 درجة مئويّة لمدّة 14 يومًا كحد أقصى. لا تحفظه في درجة حرارة تتجاوز 25 درجة مئويّة. إذا كنت تحتاج إلى إخراج علبة الكرتون بشكل دائم من البرّاد، دوّن تاريخ الإخراج في المكان المخصص لذلك على علبة الكرتون الخارجيّة، واستعمل دوبيكسنت في غضون 14 يومًا.
إحفظ الدواء في علبة الكرتون الأصليّة لحمايته من النور.
لا تستعمل هذا الدواء إذا لاحظت أنّه عكر أو تغيّر لونه أو به جزيئات.
لا تقم برمي أيّ أدوية في مياه الصرف الصحي أو مع النفايات المنزليّة. اسأل الطبيب أو الصيدلي أو الممرضة عن كيفيّة التخلّص من الأدوية التي لم تعد تستعملها، فمن شأن هذه الإجراءات حماية البيئة.
ماذا يحتوي دوبيكسنت 300 ملغ، محلول للحقن في حقنة معبّأة مسبقًا
· المادة الفاعلة هي دوبيلوماب.
· تحتوي كلّ حقنة معبّأة مسبقًا على 300 ملغ من الدوبيلوماب في 2 مل من محلول الحقن.
· المكوّنات الأخرى هي هيدروكلورايد الأرجينين، هيستيدين، بوليسوربات 80 (E433)، أسيتات الصوديوم، حمض الخليك الجليدي (E260)، سكروز، ماء للحقن.
كيف هو شكل دوبيكسنت 300 ملغ، محلول للحقن في حقنة معبّأة مسبقًا ومحتويات العلبة
دوبيكسنت هو محلول صافٍ إلى غميم (غير شفاف) بعض الشيء، عديم اللون إلى أصفر باهت يأتي في حقنة زجاجية معبّأة مسبقًا مع أو بدون حجاب واقٍ للإبرة.
يأتي دوبيكسنت على شكل حقن معبّأة مسبقًا من 300 ملغ في عبوة تحتوي على حقنة معبّأة مسبقًا أو على حقنتيْن معبّأتيْن مسبقًا أو في عبوة تحتوي على 3 (3 عبوات من 1) أو 6 (3 عبوات من 2) حقن معبّأة مسبقًا.
قد لا تكون أحجام العبوات كلّها مسوّقة.
حامل رخصة التسويق
sanofi-aventis groupe
54, rue La Boétie
75008 Paris
France
المصنّع
Sanofi Winthrop Industrie
1051 Boulevard Industriel
76580 LE TRAIT
FRANCE
Sanofi-Aventis Deutschland GmbH
Brüningstrasse 50
Industriepark Hoechst
65926 FRANKFURT AM MAIN
GERMANY
Atopic dermatitis
Adults and adolescents
Dupixent is indicated for the treatment of moderate-to-severe atopic dermatitis in adults and adolescents 12 years and older who are candidates for systemic therapy.
Children 6 years to 11 years of age
Dupixent is indicated for the treatment of severe atopic dermatitis in children 6 years to 11 years old who are candidates for systemic therapy.
Asthma
Adults and adolescents
Dupixent is indicated in adults and adolescents 12 years and older as add-on maintenance treatment for severe asthma with type 2 inflammation characterised by raised blood eosinophils and/or raised fraction of exhaled nitric oxide (FeNO), see section 5.1, who are inadequately controlled with high dose inhaled corticosteroids (ICS) plus another medicinal product for maintenance treatment.
Children 6 to 11 years of age
Dupixent is indicated in children 6 to 11 years old as add-on maintenance treatment for severe asthma with type 2 inflammation characterised by raised blood eosinophils and/or raised fraction of exhaled nitric oxide (FeNO), see section 5.1, who are inadequately controlled with medium to high dose inhaled corticosteroids (ICS) plus another medicinal product for maintenance treatment.
Chronic rhinosinusitis with nasal polyposis (CRSwNP)
Dupixent is indicated as an add-on therapy with intranasal corticosteroids for the treatment of adults with severe CRSwNP for whom therapy with systemic corticosteroids and/or surgery do not provide adequate disease control.
Eosinophilic Esophagitis
Dupixent is indicated for the treatment of eosinophilic esophagitis in adults and adolescents 12 years and older, weighing at least 40 kg, who are inadequately controlled by, are intolerant to, or who are not candidates for conventional medicinal therapy“
Prurigo nodularis
Dupixent is indicated for the treatment of adult patients with prurigo nodularis (PN), who are candidate for systemic therapy
Treatment should be initiated by healthcare professionals experienced in the diagnosis and treatment of conditions for which dupilumab is indicated (see section 4.1).
Posology
Atopic dermatitis
Adults
The recommended dose of dupilumab for adult patients is an initial dose of 600 mg (two 300 mg injections), followed by 300 mg given every other week administered as subcutaneous injection.
Children and Adolescents (6 to 17 years of age)
The recommended dose of dupilumab for adolescent patients 6 to 17 years of age is specified in Table 1.
Table 1: Dose of dupilumab for subcutaneous administration in children and adolescent patients 6 to 17 years of age with atopic dermatitis
Body Weight | Initial Dose | Subsequent Doses |
15 to less than 30 kg | 600 mg (two 300 mg injections) | 300 mg every 4 weeks (Q4W) |
30 to less than 60 kg | 400 mg (two 200 mg injections) | 200 mg every other week (Q2W) |
60 kg or more | 600 mg (two 300 mg injections) | 300 mg every other week (Q2W) |
Dupilumab can be used with or without topical corticosteroids. Topical calcineurin inhibitors may be used, but should be reserved for problem areas only, such as the face, neck, intertriginous and genital areas.
Consideration should be given to discontinuing treatment in patients who have shown no response after 16 weeks of treatment for atopic dermatitis. Some patients with initial partial response may subsequently improve with continued treatment beyond 16 weeks. If dupilumab treatment interruption becomes necessary, patients can still be successfully re-treated.
Asthma
The recommended dose of dupilumab for adults and adolescents (12 years of age and older) is:
· For patients with severe asthma and who are on oral corticosteroids or for patients with severe asthma and co-morbid moderate-to-severe atopic dermatitis or adults with co-morbid severe chronic rhinosinusitis with nasal polyposis, an initial dose of 600 mg (two 300 mg injections), followed by 300 mg every other week administered as subcutaneous injection.
· For all other patients, an initial dose of 400 mg (two 200 mg injections), followed by 200 mg every other week administered as subcutaneous injection.
Children 6 to 11 years of age
The recommended dose of dupilumab for paediatric patients 6 to 11 years of age is specified in Table 3.
Table 3: Dose of dupilumab for subcutaneous administration in children 6 to 11 years of age with asthma
Body weight | Initial and subsequent doses |
15 to less than 30 kg | 100 mg every other week (Q2W) or 300 mg every four weeks (Q4W) |
30 kg to less than 60 kg | 200 mg every other week (Q2W) or 300 mg every four weeks (Q4W) |
60 kg or more | 200 mg every other week (Q2W) |
For paediatric patients (6 to 11 years old) with asthma and co-morbid severe atopic dermatitis, as per approved indication, the recommended dose should be followed in Table 2.
Patients receiving concomitant oral corticosteroids may reduce their steroid dose once clinical improvement with dupilumab has occurred (see section 5.1). Steroid reductions should be accomplished gradually (see section 4.4).
Dupilumab is intended for long-term treatment. The need for continued therapy should be considered at least on an annual basis as determined by physician assessment of the patient’s level of asthma control.
Chronic rhinosinusitis with nasal polyposis (CRSwNP)
The recommended dose of dupilumab for adult patients is an initial dose of 300 mg followed by 300 mg given every other week.
Dupilumab is intended for long-term treatment. Consideration should be given to discontinuing treatment in patients who have shown no response after 24 weeks of treatment for CRSwNP. Some patients with initial partial response may subsequently improve with continued treatment beyond 24 weeks.
Eosinophilic Esophagitis
Recommended dosage for adult and pediatric patients 12 years of age and older, weighing at least 40 kg, is 300 mg given every week (QW).
Prurigo nodularis
The recommended dosage of DUPIXENT for adult patients is an initial dose of 600 mg (two 300 mg injections) followed by 300 mg given every other week (Q2W).
Missed dose
If a dose is missed, the dose should be administered as soon as possible. Thereafter, dosing should resume at the regular scheduled time.
Special populations
Elderly (≥ 65 years)
No dose adjustment is recommended for elderly patients (see section 5.2).
Renal impairment
No dose adjustment is needed in patients with mild or moderate renal impairment. Very limited data are available in patients with severe renal impairment (see section 5.2).
Hepatic impairment
No data are available in patients with hepatic impairment (see section 5.2).
Body weight
No dose adjustment for body weight is recommended for patients with asthma 12 years of age and older or in adults with atopic dermatitis or CRSwNP (see section 5.2).
Paediatric patients
The safety and efficacy of dupilumab in children with atopic dermatitis below the age of 6 months have not been established. The safety and efficacy of dupilumab in children with a body weight < 5 kg have not been established (see section 5.2). No data are available.
The safety and efficacy of dupilumab in children with severe asthma below the age of 6 years have not been established (see section 5.2). No data are available.
CRSwNP does not normally occur in children. The safety and efficacy in children with CRSwNP below the age of 18 years have not been established (see section 5.2). No data are available.
The safety and effectiveness of DUPIXENT for the treatment of EoE in pediatric patients less than 12 years of age and weighing less than 40 kg have not been established
· It is not known if DUPIXENT is safe and effective in children with prurigo nodularis under 18 years of age.
Method of administration
Subcutaneous use
The dupilumab pre-filled pen is not intended for use in children below 12 years of age. For children 6 months to 11 years of age with atopic dermatitis and asthma, the dupilumab pre-filled syringe is the presentation appropriate for administration to this population.
Dupilumab is administered by subcutaneous injection into the thigh or abdomen, except for the 5 cm around the navel. If somebody else administers the injection, the upper arm can also be used.
For the initial 600 mg dose, two 300 mg injections should be administered consecutively in different injection sites.
It is recommended to rotate the injection site with each injection. Dupilumab should not be injected into skin that is tender, damaged or has bruises or scars.
A patient may self-inject dupilumab or the patient's caregiver may administer dupilumab if their healthcare professional determines that this is appropriate. Proper training should be provided to patients and/or caregivers on the preparation and administration of dupilumab prior to use according to the Instructions for Use (IFU) section at the end of the package lea
Traceability
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Acute asthma exacerbations
Dupilumab should not be used to treat acute asthma symptoms or acute exacerbations. Dupilumab should not be used to treat acute bronchospasm or status asthmaticus.
Corticosteroids
Systemic, topical, or inhaled corticosteroids should not be discontinued abruptly upon initiation of therapy with dupilumab. Reductions in corticosteroid dose, if appropriate, should be gradual and performed under the direct supervision of a physician. Reduction in corticosteroid dose may be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy.
Biomarkers of type 2 inflammation may be suppressed by systemic corticosteroid use. This should be taken into consideration to determine type 2 status in patients taking oral corticosteroids (see section 5.1).
Hypersensitivity
If a systemic hypersensitivity reaction (immediate or delayed) occurs, administration of dupilumab should be discontinued immediately and appropriate therapy initiated. Cases of anaphylactic reaction, angioedema, and serum sickness/serum sickness-like reaction have been reported. Anaphylactic reactions and angioedema have occurred from minutes to up to seven days after the dupilumab injection (see section 4.8).
Eosinophilic conditions
Cases of eosinophilic pneumonia and cases of vasculitis consistent with eosinophilic granulomatosis with polyangiitis (EGPA) have been reported with dupilumab in adult patients who participated in the asthma development program. Cases of vasculitis consistent with EGPA have been reported with dupilumab and placebo in adult patients with co-morbid asthma in the CRSwNP development program. Physicians should be alert to vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients with eosinophilia. Patients being treated for asthma may present with serious systemic eosinophilia sometimes presenting with clinical features of eosinophilic pneumonia or vasculitis consistent with eosinophilic granulomatosis with polyangiitis, conditions which are often treated with systemic corticosteroid therapy. These events usually, but not always, may be associated with the reduction of oral corticosteroid therapy.
Helminth infection
Patients with known helminth infections were excluded from participation in clinical studies. Dupilumab may influence the immune response against helminth infections by inhibiting IL-4/IL-13 signaling. Patients with pre-existing helminth infections should be treated before initiating dupilumab. If patients become infected while receiving treatment with dupilumab and do not respond to anti- helminth treatment, treatment with dupilumab should be discontinued until infection resolves. Cases of enterobiasis were reported in children 6 to 11 years old who participated in the paediatric asthma development program (see section 4.8).
Conjunctivitis and keratitis related events
Conjunctivitis and keratitis related events have been reported with dupilumab, predominantly in atopic dermatitis patients. Some patients reported visual disturbances (e.g. blurred vision) associated with conjunctivitis or keratitis (see section 4.8).
Patients should be advised to report new onset or worsening eye symptoms to their healthcare provider. Patients treated with dupilumab who develop conjunctivitis that does not resolve following standard treatment or signs and symptoms suggestive of keratitis should undergo ophthalmological examination, as appropriate (see section 4.8).
In subjects with PN, the frequency of conjunctivitis was 4% in the DUPIXENT group compared to 1% in the placebo group; these subjects recovered or were recovering during the treatment period. There were no cases of keratitis reported in the PN development program [see Adverse Reactions (6.1)].
Atopic dermatitis or CRSwNP patients with comorbid asthma
Patients on dupilumab for moderate-to-severe atopic dermatitis or severe CRSwNP who also have co- morbid asthma should not adjust or stop their asthma treatments without consultation with their physicians. Patients with comorbid asthma should be monitored carefully following discontinuation of dupilumab.
Vaccinations
Live and live attenuated vaccines should not be given concurrently with dupilumab as clinical safety and efficacy has not been established. Immune responses to TdaP vaccine and meningococcal polysaccharide vaccine were assessed (see section 4.5). It is recommended that patients should be brought up to date with live and live attenuated immunisations in agreement with current immunisation guidelines prior to treatment with dupilumab.
Sodium content
This medicinal product contains less than 1 mmol sodium (23 mg) per 300 mg dose, that is to say essentially “sodium-free”.
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 dupilumab may receive concurrent inactivated or non-live vaccinations. For information on live vaccines see section 4.4.
In a clinical study of atopic dermatitis patients, the effects of dupilumab on the pharmacokinetics (PK) of CYP substrates were evaluated. The data gathered from this study did not indicate clinically relevant effects of dupilumab on CYP1A2, CYP3A, CYP2C19, CYP2D6, or CYP2C9 activity.
An effect of dupilumab on the PK of co-administered medications is not expected. Based on the population analysis, commonly co-administered medications had no effect on dupilumab pharmacokinetics on patients with moderate to severe asthma
Pregnancy
There is a limited amount of data from the use of dupilumab in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). Dupilumab should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
Breast-feeding
It is unknown whether dupilumab is excreted in human milk or absorbed systemically after ingestion. A decision must be made whether to discontinue breast-feeding or to discontinue dupilumab therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.
Fertility
Animal studies showed no impairment of fertility (see section 5.3).
Dupilumab has no or negligible influence on the ability to drive or operate machinery.
Summary of the safety profile
The most common adverse reactions are injection site reactions (includes erythema, oedema, pruritus, pain, and swelling), conjunctivitis, conjunctivitis allergic, arthralgia, oral herpes, and eosinophilia.
Rare cases of serum sickness, serum sickness-like reaction, anaphylactic reaction, and ulcerative keratitis have been reported (see section 4.4).
Tabulated list of adverse reactions
Dupilumab was studied in 12 randomised, placebo-controlled trials, including atopic dermatitis, asthma, and CRSwNP patients. The pivotal controlled studies involved 4,206 patients receiving dupilumab and 2,326 patients receiving placebo during the controlled period.
Listed in Table 4 are adverse reactions observed in clinical trials and/or postmarketing setting presented by system organ class and frequency, using the following categories: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 4: List of adverse reactions
MedDRA System Organ Class | Frequency | Adverse Reaction |
Infections and infestations | Common | Conjunctivitis* Oral herpes* |
Blood and lymphatic system disorders | Common | Eosinophilia |
Immune system disorders | Uncommon Rare | Angioedema# Anaphylactic reaction Serum sickness reaction Serum sickness-like reaction |
Eye disorders | Common Uncommon
Rare | Conjunctivitis allergic* Keratitis*# Blepharitis*† Eye pruritus*† Dry eye*† Ulcerative keratitis*†# |
Skin and subcutaneous tissue disorders | Uncommon | Facial rash# |
Musculoskeletal and connective tissue disorders | Common | Arthralgia# |
General disorders and administration site conditions | Common | Injection site reactions (includes erythema, oedema, pruritus, pain, and swelling) |
*Eye disorders and oral herpes occurred predominately in atopic dermatitis studies.
†The frequencies for eye pruritus, blepharitis, and dry eye were common and ulcerative keratitis was uncommon in atopic dermatitis studies.
#From postmarketing reporting.
Description of selected adverse reactions
Hypersensitivity
Cases of anaphylactic reaction, angioedema, and serum sickness/serum sickness-like reaction have been reported following administration of dupilumab (see section 4.4).
Conjunctivitis and keratitis related events
Conjunctivitis and keratitis occurred more frequently in atopic dermatitis patients who received dupilumab compared to placebo in atopic dermatitis studies. Most patients with conjunctivitis or keratitis recovered or were recovering during the treatment period. In the long-term OLE atopic dermatitis study (AD-1225) at 3 years, the respective rates of conjunctivitis and keratitis remained similar to those in the dupilumab arm in the placebo controlled atopic dermatitis studies. Among asthma patients frequency of conjunctivitis and keratitis was low and similar between dupilumab and placebo. Among CRSwNP patients the frequency of conjunctivitis was higher in dupilumab than placebo, though lower than that observed in atopic dermatitis patients. There were no cases of keratitis reported in the CRSwNP development program (see section 4.4).
Eczema herpeticum
Eczema herpeticum was reported in < 1% of the dupilumab groups and in < 1 % of the placebo group in the 16-week atopic dermatitis monotherapy adult studies. In the 52-week atopic dermatitis dupilumab + TCS adult study, eczema herpeticum was reported in 0.2 % of the dupilumab + TCS group and 1.9 % of the placebo + TCS group. These rates remained stable at 3 years in the long-term OLE study (AD-1225).
Eosinophilia
Dupilumab-treated patients had a greater mean initial increase from baseline in eosinophil count compared to patients treated with placebo. Eosinophil counts declined to near baseline levels during study treatment and returned to baseline during the asthma open-label extension safety study (TRAVERSE). The mean blood eosinophil levels decreased to below baseline by week 20 and was maintained up to 3 years in the long-term OLE study (AD-1225).
Treatment-emergent eosinophilia (≥ 5,000 cells/mcL) was reported in < 2 % of dupilumab-treated patients and < 0.5 % in placebo-treated patients (SOLO1, SOLO2, AD-1021, DRI12544, QUEST, SINUS-24 and SINUS-52 studies) (see section 4.4).
Infections
In the 16-week atopic dermatitis monotherapy clinical adult studies, serious infections were reported in
1.0 % of patients treated with placebo and 0.5 % of patients treated with dupilumab. In the 52-week atopic dermatitis CHRONOS adult study, serious infections were reported in 0.6 % of patients treated with placebo and 0.2 % of patients treated with dupilumab. The rates of serious infections remained stable at 3 years in the long-term OLE study (AD-1225).
No increase was observed in the overall incidence of infections with dupilumab compared to placebo in the safety pool for asthma clinical studies. In the 24-week safety pool, serious infections were reported in 1.0% of patients treated with dupilumab and 1.1% of patients treated with placebo. In the 52-week QUEST study, serious infections were reported in 1.3% of patients treated with dupilumab and 1.4% of patients treated with placebo.
No increase was observed in the overall incidence of infections with dupilumab compared to placebo in the safety pool for CRSwNP clinical studies. In the 52-week SINUS-52 study, serious infections were reported in 1.3 % of patients treated with dupilumab and 1.3 % of patients treated with placebo.
Immunogenicity
As with all therapeutic proteins, there is a potential for immunogenicity with dupilumab.
Anti-Drug-Antibodies (ADA) responses were not generally associated with impact on dupilumab exposure, safety, or efficacy.
Approximately 5 % of patients with atopic dermatitis, asthma, or CRSwNP who received dupilumab 300 mg Q2W for 52 weeks developed ADA to dupilumab; approximately 2 % exhibited persistent ADA responses and approximately 2 % had neutralizing antibodies. Similar results were observed in paediatric patients (6 months to 11 years of age) with atopic dermatitis who received either dupilumab 200 mg Q2W, 200mg Q4W or 300 mg Q4W for 16 weeks and patients (6 months to 11 years of age) with asthma who received dupilumab 100 mg Q2W or 200 mg Q2W for 52 weeks. Similar ADA responses were observed in adult patients with atopic dermatitis treated with dupilumab for up to 3 years in the long-term OLE study (AD- 1225).
Approximately 16 % of adolescent patients with atopic dermatitis who received dupilumab 300 mg or 200 mg Q2W for 16 weeks developed antibodies to dupilumab; approximately 3 % exhibited persistent ADA responses, and approximately 5 % had neutralizing antibodies.
Approximately 9 % of patients with asthma who received dupilumab 200 mg Q2W for 52 weeks developed antibodies to dupilumab; approximately 4 % exhibited persistent ADA responses and approximately 4 % had neutralizing antibodies.
Approximately 1% of subjects with EoE who received DUPIXENT 300 mg QW for 24 weeks developed antibodies to dupilumab
Regardless of age or population, approximately 2 to 4 % of patients in the placebo groups were positive for antibodies to dupilumab; approximately 2 % exhibited persistent ADA response and approximately 1 % had neutralizing antibodies.
Less than 1 % of patients who received dupilumab at approved dosing regimens exhibited high titer ADA responses associated with reduced exposure and efficacy. In addition, there was one patient with serum sickness and one with serum sickness-like reaction (< 0.1 %) associated with high ADA titers (see section 4.4).
Paediatric population
Atopic dermatitis
The safety of dupilumab was assessed in a study of 250 patients 12 to 17 years of age with moderate-to-severe atopic dermatitis (AD-1526). The safety profile of dupilumab in these patients followed through week 16 was similar to the safety profile from studies in adults with atopic dermatitis.
Children 6 to 11 years of age
The safety of dupilumab was assessed in a study of 367 patients 6 to 11 years of age with severe atopic dermatitis (AD- 1652). The safety profile of dupilumab with concomitant TCS in these patients through week 16 was similar to the safety profile from studies in adults and adolescents with atopic dermatitis.
Asthma
A total of 107 adolescents aged 12 to 17 years with asthma were enrolled in the 52 week QUEST study. The safety profile observed was similar to that seen in adults.
The long-term safety of dupilumab was assessed in 89 adolescent patients who were enrolled in an open-label extension study in moderate-to-severe asthma (TRAVERSE). In this study, patients were followed for up to 96 weeks. The safety profile of dupilumab in TRAVERSE was consistent with the safety profile observed in pivotal asthma studies for up to 52 weeks of treatment.
In children 6 to 11 years of age with moderate-to-severe asthma (VOYAGE), the additional adverse reaction of enterobiasis was reported in 1.8 % (5 patients) in the dupilumab groups and none in the placebo group. All enterobiasis cases were mild to moderate and patients recovered with anti-helminth treatment without dupilumab treatment discontinuation.
In children 6 to 11 years of age with moderate-to-severe asthma, eosinophilia (blood eosinophils
≥ 3,000 cells/mcL or deemed by the investigator to be an adverse event) was reported in 6.6 % of the dupilumab groups and 0.7% in the placebo group. Most eosinophilia cases were mild to moderate and not associated with clinical symptoms. These cases were transient, decreased over time, and did not lead to dupilumab treatment discontinuation.
Prurigo Nodularis
Approximately 8% of subjects with PN who received DUPIXENT 300 mg Q2W for 24 weeks developed antibodies to DUPIXENT; approximately 1% exhibited persistent ADA responses, and approximately 3% had neutralizing antibodies
Long-term safety
Atopic dermatitis
The safety profile of dupilumab + TCS (CHRONOS) in adult atopic dermatitis patients) through week 52 was consistent with the safety profile observed at week 16. The long-term safety of dupilumab was assessed in an open-label extension study in patients 6 to 17 years of age with moderate-to-severe atopic dermatitis (AD-1434). The safety profile of dupilumab in patients followed through week 52 was similar to the safety profile observed at week 16 in the AD-1526 and AD-1652 studies. The long- term safety profile of dupilumab observed in children and adolescents was consistent with that seen in adults with atopic dermatitis.
In a phase 3, multicentre, open label extension (OLE) study (AD-1225), the long-term safety of repeat doses of dupilumab was assessed in 2,677 adults with moderate-to-severe AD exposed to 300 mg weekly dosing (99.7 %), including 347 who completed at least 148 weeks of the study. The long-term safety profile observed in this study up to 3 years was generally consistent with the safety profile of dupilumab observed in controlled studies.
Asthma
The safety profile of dupilumab in the 96 weeks long term safety study (TRAVERSE) was consistent with the safety profile observed in pivotal asthma studies for up to 52 weeks of treatment.
CRSwNP
The safety profile of dupilumab in adults with CRSwNP through week 52 was consistent with the safety profile observed at week 24.
Eosinophilic Esophagitis
A total of 239 adult and pediatric subjects 12 to 17 years of age, weighing at least 40 kg, with EoE were evaluated in a randomized, double-blind, parallel-group, multicenter, placebocontrolled trial, including two 24-week treatment periods (Parts A and B) and received either
DUPIXENT 300 mg QW or placebo
The proportion of subjects who discontinued treatment due to adverse events was 2% of the placebo group and 2% of the DUPIXENT 300 mg QW group
Table 7 summarizes the adverse reactions that occurred at a rate of at least 2% in subjects treated with DUPIXENT and at a higher rate than in their respective comparator group in Parts A and B. Table 7: Adverse Reactions Occurring in ≥2% of Patients with EoE Treated with DUPIXENT in a Placebo Controlled Trial (Parts A and B; 24-Week Safety
Pool)
a Injection site reactions are composed of several terms including, but not limited to, injection site swelling, pain, and bruising.
b Upper respiratory tract infections are composed of several terms including, but not limited to, COVID-19, sinusitis, and upper respiratory tract infection.
c Herpes viral infections are composed of oral herpes and herpes simplex.
The safety profile of DUPIXENT in 72 pediatric subjects 12 to 17 years of age, weighing at least 40 kg, and adults in Parts A and B was similar.
Reporting of suspected adverse reactions
To report any side effect(s):
· Saudi Arabia: |
- The National Pharmacovigilance and Drug Safety Centre (NPC) |
· SFDA call center : 19999 |
· E-mail: npc.drug@sfda.gov.sa |
· Website: https://ade.sfda.gov.sa/ |
• Sanofi- Pharmacovigilance: KSA_Pharmacovigilance@sanofi.com |
There is no specific treatment for dupilumab overdose. In the event of overdose, monitor the patient for any signs or symptoms of adverse reactions and institute appropriate symptomatic treatment immediately.
Pharmacotherapeutic group: Other dermatological preparations, agents for dermatitis, excluding corticosteroids, ATC code: D11AH05
Mechanism of action
Dupilumab is a recombinant human IgG4 monoclonal antibody that inhibits interleukin-4 and interleukin-13 signaling. Dupilumab inhibits IL-4 signaling via the Type I receptor (IL-4Rα/γc), and both IL-4 and IL-13 signaling through the Type II receptor (IL-4Rα/IL-13Rα). IL-4 and IL-13 are major drivers of human type 2 inflammatory disease, such as atopic dermatitis, asthma, and CRSwNP. Blocking the IL-4/IL-13 pathway with dupilumab in patients decreases many of the mediators of type 2 inflammation.
Pharmacodynamic effects
In atopic dermatitis clinical trials, treatment with dupilumab was associated with decreases from baseline in concentrations of type 2 immunity biomarkers, such as thymus and activation-regulated chemokine (TARC/CCL17), total serum IgE and allergen-specific IgE in serum. A reduction of lactate dehydrogenase (LDH), a biomarker associated with AD disease activity and severity, was observed with dupilumab treatment in adults and adolescents with atopic dermatitis.
In adult and adolescent patients with asthma, dupilumab treatment relative to placebo markedly decreased FeNO and circulating concentrations of eotaxin-3, total IgE, allergen specific IgE, TARC, and periostin, the type 2 biomarkers evaluated in clinical trials. These reductions in type 2 inflammatory biomarkers were comparable for the 200 mg Q2W and 300 mg Q2W regimens. In paediatric (6 to 11 years of age) patients with asthma, dupilumab treatment relative to placebo markedly decreased FeNO and circulating concentrations of total IgE, allergen specific IgE, and TARC, the type 2 biomarkers evaluated in clinical trials. These markers were near maximal suppression after 2 weeks of treatment, except for IgE which declined more slowly. These effects were sustained throughout treatment.
Clinical efficacy and safety in atopic dermatitis
Adults with atopic dermatitis
The efficacy and safety of dupilumab as monotherapy and with concomitant topical corticosteroids were evaluated in three pivotal randomised, double-blind, placebo-controlled studies (SOLO 1, SOLO 2, and CHRONOS) in 2,119 patients 18 years of age and older with moderate to severe atopic dermatitis (AD) defined by Investigator’s Global Assessment (IGA) score ≥ 3, an Eczema Area and Severity Index (EASI) score ≥ 16, and a minimum body surface area (BSA) involvement of ≥ 10 %.
Eligible patients enrolled into the three studies had previous inadequate response to topical medication.
In all three studies, patients received 1) an initial dose of 600 mg dupilumab (two 300 mg injections) on day 1, followed by 300 mg once every two weeks (Q2W); 2) an initial dose of 600 mg dupilumab on day 1, followed by 300 mg once weekly (QW); or 3) matching placebo. Dupilumab was administered by subcutaneous (SC) injection in all studies. If needed to control intolerable symptoms of atopic dermatitis, patients were permitted to receive rescue treatment (which included higher potency topical steroids or systemic immunosuppressants) at the discretion of the investigator. Patients who received rescue treatment were considered non-responders.
SOLO 1 enrolled 671 patients (224 to placebo, 224 to dupilumab 300 mg Q2W, and 223 to dupilumab 300 mg QW) and had a treatment period of 16 weeks.
SOLO 2 enrolled 708 patients (236 to placebo, 233 to dupilumab 300 mg Q2W, and 239 to dupilumab 300 mg QW) and had a treatment period of 16 weeks.
CHRONOS enrolled 740 patients (315 to placebo + topical corticosteroid (TCS), 106 to dupilumab 300 mg Q2W + TCS, and 319 to dupilumab 300 mg QW + TCS) and had a treatment period of
52 weeks. Patients received dupilumab 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 co-primary endpoints were the proportion of patients with IGA 0 or 1 (“clear” or “almost clear”) with 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 % and 90 % in EASI (EASI-50 and 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 CHRONOS, efficacy was also evaluated at week 52.
Baseline Characteristics
In the monotherapy studies (SOLO 1 and SOLO 2), across all treatment groups, the mean age was 38.3, the mean weight was 76.9 kg, 42.1 % were female, 68.1 % were white, 21.8 % were Asian, and
6.8 % were black. In these studies, 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, the baseline mean SCORAD score was 67.8, the baseline mean POEM score was 20.5, the baseline mean DLQI was 15.0, and the baseline mean HADS total score was 13.3.
In the concomitant TCS study (CHRONOS), across all treatment groups, the mean age was 37.1, the mean weight was 74.5 kg, 39.7 % were female, 66.2 % were white, 27.2 % were Asian, and 4.6 % were black. In this study, 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, the baseline mean SCORAD score was 66.4, the baseline mean POEM score was 20.1, the baseline mean DLQI was 14.5, and the baseline mean HADS total score was 12.7.
Clinical Response
16-week Monotherapy Studies (SOLO 1 and SOLO 2)
In SOLO 1 and SOLO 2, from baseline to week 16, a significantly greater proportion of patients randomised to dupilumab 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 5).
A significantly greater proportion of patients randomised to dupilumab achieved a rapid improvement
in the pruritus NRS compared to placebo (defined as ≥ 4-point improvement as early as week 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 mean percent change from baseline in EASI and the mean percent change from baseline in NRS, respectively up to week 16.
Table 5: Efficacy results of dupilumab monotherapy at week 16 (FAS)
| SOLO 1 (FAS)a | SOLO 2 (FAS)a | ||||
| Placebo | Dupilumab 300 mg Q2W | Dupilumab 300 mg QW | Placebo | Dupilumab 300 mg Q2W | Dupilumab 300 mg QW |
Patients randomised | 224 | 224 | 223 | 236 | 233 | 239 |
IGA 0 or 1b, % respondersc | 10.3 % | 37.9 %e | 37.2 %e | 8.5 % | 36.1 %e | 36.4 %e |
EASI-50, % respondersc | 24.6 % | 68.8 %e | 61.0 %e | 22.0 % | 65.2 %e | 61.1 %e |
EASI-75, % respondersc | 14.7 % | 51.3 %e | 52.5 %e | 11.9 % | 44.2 %e | 48.1 %e |
EASI-90, % respondersc | 7.6 % | 35.7 %e | 33.2 %e | 7.2 % | 30.0 %e | 30.5 %e |
EASI, LS mean % change from baseline (+/- SE) | -37.6 % (3.28) | -72.3 %e (2.63) | -72.0 %e (2.56) | -30.9 % (2.97) | -67.1 %e (2.52) | -69.1 %e (2.49) |
SCORAD, LS mean % change from baseline (+/- SE) | -29.0 % (3.21) | -57.7 %e (2.11) | -57.0 %e (2.11) | -19.7 % (2.52) | -51.1 %e (2.02) | -53.5 %e (2.03) |
Pruritus NRS, LS mean % change from baseline (+/- SE) | -26.1 % (3.02) | -51.0 %e (2.50) | -48.9 %e (2.60) | -15.4 % (2.98) | -44.3 %e (2.28) | -48.3 %e (2.35) |
Number of patients with baseline pruritus NRS score > 4 | 212 | 213 | 201 | 221 | 225 | 228 |
Pruritus NRS (> 4-point improvement), % respondersc, d | 12.3 % | 40.8 %e | 40.3 %e | 9.5% | 36.0 %e | 39.0 %e |
LS = least squares; SE= standard error
a Full analysis set (FAS) includes all patients randomised.
b Responder was defined as a patient with IGA 0 or 1 (“clear” or “almost clear”) with a reduction of > 2 points on a 0-4 IGA scale.
c Patients who received rescue treatment or with missing data were considered as non-responders.
d a significantly greater proportion of patients on dupilumab had improvement in pruritus NRS of ≥ 4 points compared to placebo at week 2 (p < 0.01).
e p-value < 0.0001
Figure 1: Mean percent change from baseline in EASI in SOLO 1a and SOLO 2a (FAS)b SOLO 1 SOLO 2
LS = least squares
a In the primary analyses of the efficacy endpoints, patients who received rescue treatment or with missing data were considered non-responders.
b Full analysis set (FAS) includes all patients randomised.
Figure 2: Mean percent change from baseline in NRS in SOLO 1a and SOLO 2a (FAS)b SOLO 1 SOLO 2
LS = least squares
a In the primary analyses of the efficacy endpoints, patients who received rescue treatment or with missing data were considered non-responders
b Full analysis set (FAS) includes all patients randomised.
Treatment effects in subgroups (weight, age, gender, race, and background treatment, including immunosuppressants) in SOLO 1 and SOLO 2 were consistent with the results in the overall study population.
52-week concomitant TCS study (CHRONOS)
In CHRONOS, a significantly greater proportion of patients randomised to dupilumab 300 mg Q2W + TCS achieved an IGA 0 or 1 response, EASI-75, and/or an improvement of > 4 points on the pruritis NRS from baseline to week 16 and week 52 compared to placebo + TCS (see Table 6).
A significantly greater proportion of patients randomised to dupilumab + 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. The improvement in pruritus NRS occurred in conjunction with the improvement of objective signs of atopic dermatitis.
Figure 3 and Figure 4 show the mean percent change from baseline in EASI and the mean percent change from baseline in NRS, respectively, up to week 52 in CHRONOS.
Table 6: Efficacy results of dupilumab with concomitant TCSa at week 16 and week 52 in CHRONOS
| week 16 (FAS)b | week 52 (FAS Week 52)b | ||||
| Placebo + TCS | Dupilumab 300 mg Q2W + TCS | Dupilumab 300 mg QW + TCS | Placebo + TCS | Dupilumab 300 mg Q2W + TCS | Dupilumab 300 mg QW + TCS |
Patients randomised | 315 | 106 | 319 | 264 | 89 | 270 |
IGA 0 or 1c, % respondersd | 12.4 % | 38.7 %f | 39.2 %f | 12.5 % | 36.0 %f | 40.0 %f |
EASI-50, % respondersd | 37.5 % | 80.2 %f | 78.1 %f | 29.9 % | 78.7 %f | 70.0 %f |
EASI-75, % respondersd | 23.2 % | 68.9 %f | 63.9 %f | 21.6 % | 65.2 %f | 64.1 %f |
EASI-90, % respondersd | 11.1 % | 39.6 %f | 43.3 %f | 15.5 % | 50.6 %f | 50.7 %f |
EASI, LS mean % change from baseline (+/- SE) | -48.4 % (3.82) | -80.5 %f (6.34) | -81.5 %f (5.78) | -60.9 % (4.29) | -84.9 %g (6.73) | -87.8 %h (6.19) |
SCORAD, LS mean % change from baseline (+/- SE) | -36.2 % (1.66) | -63.9 %f (2.52) | -65.9 %f (1.49) | -47.3 % (2.18) | -69.7 %f (3.06) | -70.4 %f (1.72) |
Pruritus NRS, LS mean % change from baseline (+/- SE) | -30.3 % (2.36) | -56.6 %f (3.95) | -57.1 %f (2.11) | -31.7 % (3.95) | -57.0 %i (6.17) | -56.5 %f (3.26) |
Number of patients with baseline pruritus NRS score ≥ 4 | 299 | 102 | 295 | 249 | 86 | 249 |
Pruritus NRS (≥ 4-point improvement), % respondersd, e | 19.7 % | 58.8 %f | 50.8 %f | 12.9 % | 51.2 %f | 39.0 %f |
LS = least squares; SE = standard error
a All patients were on background topical corticosteroids therapy and patients were permitted to use topical calcineurin inhibitors.
b Full analysis set (FAS) includes all patients randomised. FAS week 52 includes all patients randomised at least one year before the cutoff date of the primary analysis.
c Responder was defined as a patient with IGA 0 or 1 (“clear” or “almost clear”) with a reduction of
≥ 2 points on a 0-4 IGA scale.
d Patients who received rescue treatment or with missing data were considered as non-responders.
e a significantly greater proportion of patients on dupilumab had improvement in pruritus NRS of ≥ 4 points compared to placebo at week 2 (p < 0.05).
f p-value < 0.0001
g p-value = 0.0015
h p-value = 0.0003
i p-value = 0.0005
Figure 3: Mean percent change from baseline in EASI in CHRONOSa (FAS week 52)b
CHRONOS
LS = least squares
a In the primary analyses of the efficacy endpoints, patients who received rescue treatment or with missing data were considered non-responders.
b FAS week 52 includes all patients randomised at least one year before the cutoff date of the primary analysis.
Figure 4: Mean percent change from baseline in NRS in CHRONOSa (FAS week 52)b
CHRONOS
LS = least squares
aIn the primary analyses of the efficacy endpoints, patients who received rescue treatment or with missing data were considered non-responders.
bFAS week 52 includes all patients randomised at least one year before the cutoff date of the primary analysis.
Treatment effects in subgroups (weight, age, gender, race, and background treatment, including immunosuppressants) in CHRONOS were consistent with the results in the overall study population.
Clinical response in patients not adequately controlled with, intolerant to, or for whom ciclosporin treatment was inadvisable (CAFE study)
CAFE study evaluated the efficacy of dupilumab compared to placebo during a 16-week treatment period, administered with concomitant TCS, in adult patients with AD who are not adequately controlled with, or are intolerant to, oral ciclosporin, or when this treatment is currently contraindicated or not medically advisable.
A total of 325 patients were enrolled, with 210 patients who were previously exposed to ciclosporin and 115 patients who have never been exposed to ciclosporin because ciclosporin treatment was medically inadvisable. The mean age was 38.4 years, 38.8 % were female, the baseline mean EASI score was 33.1, the mean BSA was 55.7, the baseline weekly average pruritis NRS was 6.4, the baseline mean SCORAD score was 67.2, and the baseline mean DLQI was 13.8.
The primary endpoint was the proportion of patients with EASI-75 at week 16.
Primary and secondary endpoints for the 16 week CAFE study are summarized in table 7.
Table 7: Results of the primary and secondary endpoints in CAFE study
| Placebo + TCS | Dupilumab 300 mg Q2W + TCS | Dupilumab 300 mg QW+TCS |
Patients randomised | 108 | 107 | 110 |
EASI-75, % responders | 29.6 % | 62.6 % | 59.1 % |
EASI, LS mean % change from baseline (+/- SE) | -46.6 (2.76) | -79.8 (2.59) | -78.2 (2.55) |
Pruritus NRS, LS mean % change from baseline (+/- SE) | -25.4 % (3.39) | -53.9 % (3.14) | -51.7 % (3.09) |
SCORAD, LS mean % change from baseline (+/- SE) | -29.5 % (2.55) | -62.4 % (2.48) | -58.3 % (2.45) |
DLQI, LS mean change from baseline (SE) | -4.5 (0.49) | -9.5 (0.46) | -8.8 (0.45) |
(all p-values <0.0001)
In the subgroup of patients resembling the CAFE study population within the 52 week CHRONOS study, 69.6 % of dupilumab 300 mg Q2W-treated patients reached EASI-75 vs 18.0 % placebo-treated patients at week 16, and 52.4 % of dupilumab 300 mg Q2W-treated vs 18.6 % placebo-treated at week 52. In this subset, the percent change of pruritus NRS from baseline was -51.4 % vs -30.2 % at week 16 and -54.8 % vs -30.9 % at week 52, for the dupilumab 300 mg Q2W and placebo groups respectively.
Maintenance and durability of response (SOLO CONTINUE study)
To evaluate maintenance and durability of response, subjects treated with dupilumab for 16 weeks in SOLO 1 and SOLO 2 studies who achieved IGA 0 or 1 or EASI-75 were re-randomised in SOLO CONTINUE study to an additional 36-week treatment of dupilumab 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.
Table 8: Results of the primary and secondary endpoints in SOLO CONTINUE study
| Placebo | Dupilumab 300 mg | ||
|
N=83 | Q8W N=84 | Q4W N=86 | Q2W/QW N=169 |
Co-Primary Endpoints |
|
|
|
|
LS mean change (SE) between baseline | 21.7 | 6.8*** | 3.8*** | 0.1*** |
and week 36 in percent change in EASI | (3.13) | (2.43) | (2.28) | (1.74) |
Score from Parent Study baseline |
|
|
|
|
Percent of patients with EASI-75 at | 24/79 | 45/82* | 49/84** | 116/162*** |
week 36 for patients with EASI-75 at | (30.4 %) | (54.9 %) | (58.3 %) | (71.6 %) |
baseline, n (%) |
|
|
|
|
Key Secondary Endpoints |
|
|
|
|
Percent of patients whose IGA | 18/63 | 32/64† | 41/66** | 89/126*** |
response at week 36 was maintained | (28.6) | (50.0) | (62.1) | (70.6) |
within 1 point of baseline in the subset |
|
|
|
|
of patients with IGA (0,1) at baseline, n |
|
|
|
|
(%) |
|
|
|
|
Percent of patients with IGA (0,1) at | 9/63 | 21/64† | 29/66** | 68/126*** |
week 36 in the subset of patients with | (14.3) | (32.8) | (43.9) | (54.0) |
IGA (0,1) at baseline, n (%) |
|
|
|
|
Percent of patients whose peak pruritus | 56/80 | 45/81 | 41/83† | 57/168*** |
NRS increased by ≥ 3 points from | (70.0) | (55.6) | (49.4) | (33.9) |
baseline to week 35 in the subset of |
|
|
|
|
patients with peak pruritus NRS ≤ 7 at |
|
|
|
|
baseline, n (%) |
|
|
|
|
†P< 0.05, *P< 0.01, **P< 0.001, ***P≤ 0.0001
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 %.
Quality of life/patient-reported outcomes in atopic dermatitis
In both monotherapy studies (SOLO 1 and SOLO 2), both dupilumab 300 mg Q2W and 300 mg QW groups significantly improved patient-reported symptoms and the impact of AD on sleep and health- related quality of life as measured by POEM and DLQI total scores, respectively, at 16 weeks compared to placebo. A significantly larger proportion of patients administered dupilumab groups had clinically meaningful reductions in POEM and DLQI total score (each defined as ≥ 4 points improvement) from baseline to week 16 compared to placebo group. In addition, anxiety and depression symptoms as measured by the HADS total score were significantly reduced in the dupilumab groups compared to placebo at 16 weeks. In a subset of patients with HADS-anxiety or HADS-depression subscale scores ≥ 8 at baseline (the cut-off value for anxiety or depression), a larger proportion of patients in the dupilumab groups achieved HADS-anxiety and HADS-depression scores
< 8 at week 16 compared to placebo (See Table 9).
Table 9: Additional secondary endpoint results of dupilumab monotherapy at week 16
| Monotherapy | |||||
| SOLO 1 at week 16 | SOLO 2 at week 16 | ||||
| Placebo | Dupilumab 300 mg Q2W | Dupilumab 300 mg QW | Placebo | Dupilumab 300 mg Q2W | Dupilumab 300 mg QW |
Patients randomised | 224 | 224 | 223 | 236 | 233 | 239 |
DLQI, LS mean change from baseline (SE) | -5.3 (0.50) | -9.3a (0.40) | -9.0a (0.40) | -3.6 (0.50) | -9.3a (0.38) | -9.5a (0.39) |
POEM, LS mean change from baseline (SE) | -5.1 (0.67) | -11.6a (0.49) | -11.0a (0.50) | -3.3 (0.55) | -10.2a (0.49) | -11.3a (0.52) |
HADS, LS mean change from baseline (SE) | -3.0 (0.65) | -5.2b (0.54) | -5.2b (0.51) | -0.8 (0.44) | -5.1a (0.39) | -5.8a (0.38) |
| ||||||
Number of patients with DLQI ≥4 at baseline |
213 |
209 |
209 |
225 |
223 |
234 |
DLQI (≥ 4-point improvement), % responders |
30.5 % |
64.1 %a |
58.4 %a |
27.6 % |
73.1 %a |
62.0 %a |
| ||||||
Number of patients with POEM ≥4 at baseline |
223 |
222 |
222 |
234 |
233 |
239 |
POEM (≥ 4-point improvement), % responders |
26.9 % |
67.6 %a |
63.1 %a |
24.4 % |
71.7 %a |
64.0 %a |
|
| Monotherapy | |||||
| SOLO 1 at week 16 | SOLO 2 at week 16 | ||||
Number of patients with HADS-anxiety ≥ 8 or HADS- depression ≥ 8 at baseline |
97 |
100 |
102 |
115 |
129 |
136 |
Patients achieving HADS- anxiety and HADS- depression score < 8, % |
12.4 % |
41.0 %a |
36.3 %b |
6.1 % |
39.5 %a |
41.2 %a |
LS = least squares; SE = standard error
a p-value < 0.0001
b p-value < 0.001
In the concomitant TCS study (CHRONOS), dupilumab 300 mg Q2W + TCS and dupilumab 300 mg QW + TCS improved patient-reported symptoms and the impact of AD on sleep and health-related quality of life as measured by POEM and DLQI total scores, respectively, at 52 weeks compared to placebo + TCS. A larger proportion of patients administered dupilumab 300 mg Q2W + TCS and
300 mg QW + TCS had clinically meaningful reductions in POEM and DLQI total score (each defined as ≥ 4-point improvement) from baseline to week 52 compared to the placebo + TCS. In addition, dupilumab 300 mg Q2W + TCS and 300 mg QW + TCS reduced anxiety and depression as measured by the HADS total score at 52 weeks compared to placebo + TCS. In a post-hoc analysis in a subset of patients with HADS-anxiety or HADS-depression subscale scores ≥ 8 at baseline (the cut-off value for anxiety or depression), a larger proportion of patients in the dupilumab 300 mg Q2W + TCS and 300 mg QW + TCS groups achieved HADS-anxiety and HADS-depression scores < 8 at week 52 compared to placebo + TCS (See Table 10).
Table 10: Other secondary endpoint results of dupilumab with concomitant TCS at week 16 and week 52 in CHRONOS
| Concomitant Use of TCS | |||||
| CHRONOS at week 16 | CHRONOS at week 52 | ||||
| Placebo | Dupilumab 300 mg Q2W + TCS | Dupilumab 300 mg QW + TCS | Placebo +TCS | Dupilumab 300 mg Q2W + TCS | Dupilumab 300 mg QW + TCS |
Patients randomised | 315 | 106 | 319 | 264 | 89 | 270 |
DLQI, LS mean change from baseline (SE) | -5.8 (0.34) | -10.0a (0.50) | -10.7a (0.31) | -7.2 (0.40) | -11.4a (0.57) | -11.1a (0.36) |
POEM, LS mean change from baseline (SE) | -5.3 (0.41) | -12.7a (0.64) | -12.9a (0.37) | -7.0 (0.57) | -14.2a (0.78) | -13.2a (0.45) |
HADS, LS mean change from baseline (SE) | -4.0 (0.37) | -4.9 (0.58) | -5.4c (0.35) | -3.8 (0.47) | -5.5c (0.71) | -5.9b (0.42) |
|
|
|
|
|
|
|
Number of patients with DLQI ≥ 4 at baseline |
300 |
100 |
311 |
254 |
85 |
264 |
DLQI | 43.0 % | 81.0 %a | 74.3 %a | 30.3 % | 80.0 %a | 63.3 %a |
(≥ 4-point improvement), % responders |
|
|
|
|
|
|
|
|
|
|
|
|
|
Number of patients with POEM ≥4 at baseline |
312 |
106 |
318 |
261 |
89 |
269 |
POEM (≥ 4-point improvement), % responders |
36.9 % |
77.4 %a |
77.4 %a |
26.1 % |
76.4 %a |
64.7 %a |
|
|
|
|
|
|
|
Number of patients with HADS-anxiety ≥ 8 or HADS- depression ≥ 8 at baseline |
148 |
59 |
154 |
133 |
53 |
138 |
Patients achieving HADS- anxiety and HADS- depression < 8, % | 26.4 % | 47.5 %c | 47.4 %b | 18.0 % | 43.4 %b | 44.9 %a |
LS = least squares; SE = standard error
a p-value < 0.0001
b p-value < 0.001
c p-value < 0.05
Adolescents with atopic dermatitis (12 to 17 years of age)
The efficacy and safety of dupilumab monotherapy in adolescent patients was evaluated in a multicentre, randomised, double-blind, placebo-controlled study (AD-1526) in 251 adolescent patients 12 to 17 years of age with moderate-to-severe atopic dermatitis (AD) defined by Investigator’s Global Assessment (IGA) score ≥ 3 in the overall assessment of AD lesions on a severity scale of 0 to 4, an Eczema Area and Severity Index (EASI) score ≥ 16 on a scale of 0 to 72, and a minimum body surface area (BSA) involvement of ≥10 %. Eligible patients enrolled into this study had previous inadequate response to topical medication.
Patients received 1) an initial dose of 400 mg dupilumab (two 200 mg injections) on day 1, followed by 200 mg once every other week (Q2W) for patients with baseline weight of < 60 kg or an initial dose of 600 mg dupilumab (two 300 mg injections) on day 1, followed by 300 mg Q2W for patients with baseline weight of ≥ 60 kg; 2) an initial dose of 600 mg dupilumab (two 300 mg injections) on day 1, followed by 300 mg every 4 weeks (Q4W) regardless of baseline body weight; or 3) matching placebo. Dupilumab was administered by subcutaneous (SC) injection. If needed to control intolerable symptoms, patients were permitted to receive rescue treatment at the discretion of the investigator. Patients who received rescue treatment were considered non- responders.
In this study, the mean age was 14.5 years, the median weight was 59.4 kg, 41.0 % were female,
62.5 % were White, 15.1 % were Asian, and 12.0 % were Black. At baseline 46.2 % of patients had a baseline IGA score of 3 (moderate AD), 53.8 % of patients had a baseline IGA of 4 (severe AD), the mean BSA involvement was 56.5 %, and 42.4 % of patients had received prior systemic immunosuppressants. Also at baseline the mean Eczema Area and Severity Index (EASI) score was 35.5, the baseline weekly averaged pruritus Numerical Rating Scale (NRS) was 7.6, the baseline mean SCORing Atopic Dermatitis (SCORAD) score was 70.3, the baseline mean Patient Oriented Eczema Measure (POEM) score was 21.0, and the baseline mean Children Dermatology
Life Quality Index (CDLQI) was 13.6. Overall, 92.0 % of patients had at least one co-morbid allergic condition; 65.6 % had allergic rhinitis, 53.6 % had asthma, and 60.8 % had food allergies. The co-primary endpoint was the proportion of patients with IGA 0 or 1 (“clear” or “almost clear”) least a 2-point improvement and the proportion of patients with EASI-75 (improvement of at least 75 % in EASI), from baseline to week 16. Other evaluated outcomes included the proportion of subjects with EASI-50 or EASI-90 (improvement of at least 50 % or 90 % in EASI from baseline respectively), reduction in itch as measured by the peak pruritus NRS, and percent change in the SCORAD scale from baseline to week 16. Additional secondary endpoints included mean change from baseline to week 16 in the POEM and CDLQI scores.
Clinical Response
The efficacy results at week 16 for adolescent atopic dermatitis study are presented in Table 11.
Table 11: Efficacy results of dupilumab in the adolescent atopic dermatitis study at week 16 (FAS)
| AD-1526(FAS)a | |
| Placebo | Dupilumab 200 mg (<60 kg) and 300 mg (≥60 kg) Q2W |
Patients randomised | 85a | 82a |
IGA 0 or 1b, % respondersc | 2.4 % | 24.4 % |
EASI-50, % respondersc | 12.9 % | 61.0 % |
EASI-75, % respondersc | 8.2 % | 41.5 % |
EASI-90, % respondersc | 2.4 % | 23.2 % |
EASI, LS mean % change from baseline (+/-SE) | -23.6 % (5.49) | -65.9 % (3.99) |
SCORAD, LS mean % change from baseline (+/- SE) | -17.6 % (3.76) | -51.6 % (3.23) |
Pruritus NRS, LS mean % change from baseline (+/- SE) | -19.0 % (4.09) | -47.9 % (3.43) |
Pruritus NRS (> 4-point improvement), % respondersc | 4.8 % | 36.6 % |
BSA LS mean % change from baseline (+/- SE) | -11.7 % (2.72) | -30.1 % (2.34) |
CDLQI, LS mean change from baseline (+/-SE) | -5.1 (0.62) | -8.5 (0.50) |
CDLQI, (≥ 6-point improvement), % responders | 19.7 % | 60.6 % |
POEM, LS mean change from baseline (+/- SE) | -3.8 (0.96) | -10.1 (0.76) |
POEM, (≥ 6-point improvement), % responders | 9.5 % | 63.4 % |
a Full Analysis Set (FAS) includes all patients randomised.
b Responder was defined as a subject with IGA 0 or 1 (“clear” or “almost clear”) with a reduction of
≥ 2 points on a 0-4 IGA scale.
c Patients who received rescue treatment or with missing data were considered as non-responders (58.8 % and 20.7 % in the placebo and dupilumab arms, respectively).
All p–values < 0.0001
A larger percentage of patients randomised to placebo needed rescue treatment (topical corticosteroids, systemic corticosteroids, or systemic non-steroidal immunosuppressants) as compared to the dupilumab group (58.8 % and 20.7 %, respectively).
A significantly greater proportion of patients randomised to dupilumab achieved a rapid improvement in the pruritus NRS compared to placebo (defined as > 4-point improvement as early as week 4; nominal p< 0.001) and the proportion of patients responding on the pruritus NRS continued to increase
through the treatment period (see Figure 5). The improvement in pruritus NRS occurred in conjunction with the improvement of objective signs of atopic dermatitis.
Figure 5: Proportion of adolescent patients with ≥ 4-point improvement on the pruritus NRS in AD-1526 studya (FAS)b
a In the primary analyses of the efficacy endpoints, subjects who received rescue treatment or with missing data were considered non-responders.
b Full Analysis Set (FAS) includes all subjects randomised.
The dupilumab group significantly improved patient-reported symptoms, the impact of AD on sleep and health-related quality of life as measured by POEM, SCORAD, and CDLQI scores at 16 weeks compared to placebo.
The long-term efficacy of dupilumab in adolescent patients with moderate-to-severe AD who had participated in previous clinical trials of dupilumab was assessed in open-label extension study (AD- 1434). Efficacy data from this study suggests that clinical benefit provided at week 16 was sustained through week 52.
Paediatrics (6 to 11 years of age)
The efficacy and safety of dupilumab in paediatric patients concomitantly with TCS was evaluated in a multicentre, randomised, double-blind, placebo-controlled study (AD-1652) in 367 subjects 6 to 11 years of age, with AD defined by an IGA score of 4 (scale of 0 to 4), an EASI score ≥ 21 (scale of 0 to 72), and a minimum BSA involvement of ≥ 15 %. Eligible patients enrolled into this trial had previous inadequate response to topical medication. Enrollment was stratified by baseline weight (< 30 kg; ≥ 30 kg).
Patients in the dupilumab Q2W + TCS group with baseline weight of < 30 kg received an initial dose 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 dupilumab Q4W + TCS group received an initial dose of 600 mg on Day 1, followed by 300 mg Q4W from week 4 to week 12, regardless of weight. Patients were permitted to receive rescue treatment at the discretion of the investigator. Patients who received rescue treatment were considered 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 co-primary endpoint was the proportion of patients with IGA 0 or 1 (“clear” or “almost clear”) at least a 2-point improvement and the proportion of patients with EASI-75 (improvement of at least 75 % in EASI), from baseline to week 16. Other evaluated outcomes included the proportion of patients with EASI-50 and EASI-90 (improvement of at least 50 % and 90 % in EASI from baseline, respectively), percent change in EASI score from baseline to week 16, and reduction in itch as measured by the peak pruritus NRS (≥ 4-point improvement). Additional secondary endpoints included mean change from baseline to week 16 in the POEM and CDLQI scores.
Clinical Response
Table 12 presents the results by baseline weight strata for the approved dose regimens.
Table 12: Efficacy results of dupilumab with concomitant TCS in AD-1652 at week 16 (FAS)a
| Dupilumab 300 mg Q4Wd + TCS | Placebo +TCS | Dupilumab 200 mg Q2We + TCS | Placebo + TCS |
(N=122) | (N=123) | (N=59) | (N=62) | |
| ≥ 15 kg | ≥ 15 kg | ≥ 30 kg | ≥ 30 kg |
IGA 0 or 1b, % respondersc | 32.8 % | 11.4 % | 39.0 % | 9.7 % |
EASI-50, % respondersc | 91.0 % | 43.1 % | 86.4 % | 43.5 % |
EASI-75, % respondersc | 69.7 % | 26.8 % | 74.6 % | 25.8 % |
EASI-90, % respondersc | 41.8 % | 7.3 % | 35.6 % | 8.1 % |
EASI, LS mean % change from baseline (+/-SE) | -82.1 % (2.37) | -48.6 % (2.46) | -80.4 % (3.61) | -48.3 % (3.63) |
SCORAD, LS mean % change from baseline (+/- SE) | -62.4 % (2.13) | -29.8 % (2.26) | -62.7 % (3.14) | -30.7 % (3.28) |
Pruritus NRS, LS mean % change from baseline (+/- SE) | -54.6 % (2.89) | -25.9 % (2.90) | -58.2 % (4.01) | -25.0 % (3.95) |
Pruritus NRS (≥4-point improvement), % respondersc | 50.8 % | 12.3 % | 61.4 % | 12.9 % |
BSA LS mean change from baseline (+/- SE) | -40.5 (1.65) | -21.7 (1.72) | -38.4 (2.47) | -19.8 (2.50) |
CDLQI, LS mean change from baseline (+/-SE) | -10.6 (0.47) | -6.4 (0.51) | -9.8 (0.63) | -5.6 (0.66) |
CDLQI, (≥ 6-point improvement), % responders | 77.3 % | 38.8 % | 80.8 % | 35.8 % |
POEM, LS mean change from baseline (+/- SE) | -13.6 (0.65) | -5.3 (0.69) | -13.6 (0.90) | -4.7 (0.91) |
POEM, (≥ 6-point improvement), % responders | 81.7 % | 32.0 % | 79.3 % | 31.1 % |
Full Analysis Set (FAS) includes all patients randomised.
b Responder was defined as a patient with an IGA 0 or 1 (“clear” or “almost clear”).
c Patients who received rescue treatment or with missing data were considered as non-responders.
d At Day 1, patients received 600 mg of dupilumab (see section 5.2).
e At Day 1, patients received 400 mg (baseline weight ≥ 30 kg) of dupilumab.
A greater proportion of patients randomised to dupilumab + TCS achieved an improvement in the peak pruritus NRS compared to placebo + TCS (defined as ≥4-point improvement at week 4). See Figure 6.
Figure 6: Proportion of paediatric patients with ≥4-point improvement on the peak pruritus NRS in AD-1652a (FAS)b
a In the primary analyses of the efficacy endpoints, patients who received rescue treatment or with missing data were considered non-responders.
b Full Analysis Set (FAS) includes all patients randomised.
c At Day 1, patients received 600 mg of dupilumab (see section 5.2)
d At Day 1, patients received 400 mg (baseline weight ≥ 30 kg) of dupilumab
The dupilumab groups significantly improved patient-reported symptoms, the impact of AD on sleep and health-related quality of life as measured by POEM, SCORAD, and CDLQI scores at 16 weeks compared to placebo.
The long-term efficacy and safety of dupilumab + TCS in paediatric patients with moderate to severe atopic dermatitis who had participated in the previous clinical trials of dupilumab + TCS was assessed in an open-label extension study (AD-1434). Efficacy data from this trial suggests that clinical benefit provided at week 16 was sustained through week 52. Some patients receiving dupilumab 300 mg Q4W
+ TCS showed further clinical benefit when escalated to dupilumab 200 mg Q2W + TCS. The safety profile of dupilumab in patients followed through week 52 was similar to the safety profile observed at week 16 in the AD-1526 and AD-1652 studies.
Clinical efficacy and safety in asthma
The asthma development program included three randomised, double-blind, placebo-controlled, parallel-group, multi-centre studies (DRI12544, QUEST, and VENTURE) of 24 to 52 weeks in treatment duration which enrolled a total of 2,888 patients (12 years of age and older). Patients were enrolled without requiring a minimum baseline blood eosinophil or other type 2 inflammatory biomarkers (e.g. FeNO or IgE) level. Asthma treatment guidelines define type 2 inflammation as eosinophilia ≥ 150 cells/mcL and/or FeNO ≥ 20 ppb. In DRI12544 and QUEST, the pre-specified subgroup analyses included blood eosinophils ≥ 150 and ≥ 300 cells/mcL, FeNO ≥ 25 and ≥ 50 ppb.
DRI12544 was a 24-week dose-ranging study which included 776 patients (18 years of age and older). Dupilumab compared with placebo was evaluated in adult patients with moderate to severe asthma on a medium-to-high dose inhaled corticosteroid and a long acting beta agonist. The primary endpoint was change from baseline to week 12 in FEV1 (L). Annualised rate of severe asthma exacerbation events during the 24-week placebo controlled treatment period was also determined. Results were evaluated in the overall population (unrestricted by minimum baseline eosinophils or other type 2 inflammatory biomarkers) and subgroups based on baseline blood eosinophil count.
QUEST was a 52-week confirmatory study which included 1,902 patients (12 years of age and older). Dupilumab compared with placebo was evaluated in 107 adolescent and 1,795 adult patients with persistent asthma on a medium-to-high dose inhaled corticosteroid (ICS) and a second controller
medication. Patients requiring a third controller were allowed to participate in this trial. Patients were randomised to receive either 200 mg (N=631) or 300 mg (N=633) Dupixent every other week (or matching placebo for either 200 mg (N = 317) or 300 mg (N= 321) every other week) following an initial dose of 400 mg, 600 mg or placebo respectively. The primary endpoints were the 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 the overall population (unrestricted by minimum baseline eosinophils or other type 2 inflammatory biomarkers) and subgroups based on baseline blood eosinophil count and FeNO.
VENTURE was a 24-week oral corticosteroid-reduction study in 210 patients with asthma unrestricted by baseline type 2 biomarker levels who required daily oral corticosteroids in addition to regular use of high dose inhaled corticosteroids plus an additional controller. After optimizing the OCS dose during the screening period, patients received 300 mg dupilumab (n=103) or placebo (n=107) once every other week for 24 weeks following an initial dose of 600 mg or placebo. Patients continued to receive their existing asthma medicine during the study; however their OCS dose was reduced every 4 weeks during the OCS reduction phase (week 4-20), as long as asthma control was maintained. The primary endpoint was the percent reduction in oral corticosteroid dose assessed in the overall population, based on a comparison of the oral corticosteroid dose at weeks 20 to 24 that maintained asthma control with
the previously optimized (at baseline) oral corticosteroid dose.
The demographics and baseline characteristics of these 3 studies are provided in Table 13 below.
Table 13: Demographics and baseline characteristics of asthma trials
Parameter | DRI12544 (n = 776) | QUEST (n = 1902) | VENTURE (n=210) |
Mean age (years) (SD) | 48.6 (13.0) | 47.9 (15.3) | 51.3 (12.6) |
% Female | 63.1 | 62.9 | 60.5 |
% White | 78.2 | 82.9 | 93.8 |
Duration of Asthma (years), mean ± SD | 22.03 (15.42) | 20.94 (15.36) | 19.95 (13.90) |
Never smoked, (%) | 77.4 | 80.7 | 80.5 |
Mean exacerbations in previous year ± SD | 2.17 (2.14) | 2.09 (2.15) | 2.09 (2.16) |
High dose ICS use (%)a | 49.5 | 51.5 | 88.6 |
Pre-dose FEV1 (L) at baseline ± SD | 1.84 (0.54) | 1.78 (0.60) | 1.58 (0.57) |
Mean percent predicted FEV1 at baseline (%)(± SD) | 60.77 (10.72) | 58.43 (13.52) | 52.18 (15.18) |
% Reversibility (± SD) | 26.85 (15.43) | 26.29 (21.73) | 19.47 (23.25) |
Mean ACQ-5 score (± SD) | 2.74 (0.81) | 2.76 (0.77) | 2.50 (1.16) |
Mean AQLQ score (± SD) | 4.02 (1.09) | 4.29 (1.05) | 4.35 (1.17) |
Atopic Medical History % Overall (AD %, NP %, AR %) | 72.9 (8.0, 10.6, 61.7) | 77.7 (10.3, 12.7, 68.6) | 72.4 (7.6, 21.0, 55.7) |
Mean FeNO ppb (± SD) | 39.10 (35.09) | 34.97 (32.85) | 37.61 (31.38) |
% patients with FeNO ppb ≥ 25 ≥ 50 |
49.9 21.6 |
49.6 20.5 |
54.3 25.2 |
Mean total IgE IU/mL (± SD) | 435.05 (753.88) | 432.40 (746.66) | 430.58 (775.96) |
Parameter | DRI12544 (n = 776) | QUEST (n = 1902) | VENTURE (n=210) |
Mean baseline Eosinophil count (± SD) cells/mcL | 350 (430) | 360 (370) | 350 (310) |
% patients with EOS ≥ 150 cells/mcL ≥ 300 cells/mcL |
77.8 41.9 |
71.4 43.7 |
71.4 42.4 |
ICS = inhaled corticosteroid; FEV1 = Forced expiratory volume in 1 second; ACQ-5 = Asthma Control Questionnaire-5; AQLQ = Asthma Quality of Life Questionnaire; AD = atopic dermatitis; NP = nasal polyposis; AR = allergic rhinitis; FeNO = fraction of exhaled nitric oxide; EOS = blood eosinophil aThe population in dupilumab asthma trials included patients on medium and high dose ICS. The medium ICS dose was defined as equal to 500 mcg fluticasone or equivalent per day.
Exacerbations
In the overall population in DRI12544 and QUEST subjects receiving either dupilumab 200 mg or
300 mg every other week had significant reductions in the rate of severe asthma exacerbations compared to placebo. There were greater reductions in exacerbations in subjects with higher baseline levels of type 2 inflammatory biomarkers such as blood eosinophils or FeNO (Table 14 and Table 15).
Table 14: Rate of severe exacerbations in DRI12544 and QUEST (baseline blood eosinophil
levels ≥ 150 and ≥ 300 cells/mcL)
Treatment | Baseline blood EOS | |||||||
| ≥150 cells/mcL | ≥300 cells/mcL | ||||||
Exacerbations per Year | % reduction | Exacerbations per Year | % reduction | |||||
N | Rate (95% CI) | Rate ratio (95%CI) | N | Rate (95% CI) | Rate ratio (95%CI) | |||
All Severe Exacerbations | ||||||||
DRI12544 study | ||||||||
Dupilumab 200 mg Q2W | 120 | 0.29 (0.16, 0.53) | 0.28a (0.14, 0.55) | 72 % | 65 | 0.30 (0.13, 0.68) | 0.29c (0.11, 0.76) | 71 % |
Dupilumab 300 mg Q2W | 129 | 0.28 (0.16, 0.50) | 0.27b (0.14, 0.52) | 73 % | 64 | 0.20 (0.08, 0.52) | 0.19d (0.07, 0.56) | 81 % |
Placebo | 127 | 1.05 (0.69, 1.60) |
|
| 68 | 1.04 (0.57, 1.90) |
|
|
QUEST study | ||||||||
Dupilumab 200 mg Q2W | 437 | 0.45 (0.37, 0.54) | 0.44e (0.34,0.58) | 56 % | 264 | 0.37 (0.29, 0.48) | 0.34e (0.24,0.48) | 66 % |
Placebo | 232 | 1.01 (0.81, 1.25) |
|
| 148 | 1.08 (0.85, 1.38) |
|
|
Dupilumab 300 mg Q2W | 452 | 0.43 (0.36, 0.53) | 0.40 e (0.31,0.53) | 60 % | 277 | 0.40 (0.32, 0.51) | 0.33e (0.23,0.45) | 67 % |
Placebo | 237 | 1.08 (0.88, 1.33) |
|
| 142 | 1.24 (0.97, 1.57) |
|
|
ap-value = 0.0003, bp-value = 0.0001, cp-value = 0.0116, dp-value = 0.0024, ep-value < 0.0001
Table 15. Rate of severe exacerbations in QUEST defined by baseline FeNO subgroups
Treatment | Exacerbations per Year | % reduction | ||
| N | Rate (95% CI) | Rate ratio (95%CI) | |
FeNO ≥ 25 ppb | ||||
Dupilumab 200 mg Q2W | 299 | 0.35 (0.27, 0.45) | 0.35 (0.25, 0.50)a | 65 % |
Placebo | 162 | 1.00 (0.78, 1.30) |
|
|
Dupilumab 300 mg Q2W | 310 | 0.43 (0.35, 0.54) | 0.39 (0.28, 0.54) a | 61 % |
Placebo | 172 | 1.12 (0.88, 1.43) |
|
|
FeNO ≥ 50 ppb | ||||
Dupilumab 200 mg Q2W | 119 | 0.33 (0.22, 0.48) | 0.31 (0.18, 0.52) a | 69 % |
Placebo | 71 | 1.057 (0.72, 1.55) |
|
|
Dupilumab 300 mg Q2W | 124 | 0.39 (0.27, 0.558) | 0.31 (0.19, 0.49) a | 69 % |
Placebo | 75 | 1.27 (0.90, 1.80) |
|
|
ap-value < 0.0001
In the pooled analysis of DRI12544 and QUEST, hospitalisations and/or emergency room visits due to severe exacerbations were reduced by 25.5 % and 46.9 % with dupilumab 200 mg or 300 mg every other week, respectively.
Lung function
Clinically significant increases in pre-bronchodilator FEV1 were observed at week 12 for DRI12544 and QUEST. There were greater improvements in FEV1 in the subjects with higher baseline levels of type 2 inflammatory biomarkers such as blood eosinophils or FeNO (Table 16 and Table 17).
Significant improvements in FEV1 were observed as early as week 2 following the first dose of dupilumab for both the 200 mg and 300 mg dose strengths and were maintained through week 24 (DRI12544) and week 52 in QUEST (see Figure 7).
Figure 7: Mean change from baseline in pre-bronchodilator FEV1 (L) over time (baseline
eosinophils ≥ 150 and ≥ 300 cells/mcL and FeNO ≥ 25 ppb) in QUEST
QUEST: blood eosinophils ≥ 150 cells/mcL | QUEST: blood eosinophils ≥ 300 cells/mcL | QUEST: FeNO ≥ 25 ppb |
Table 16: Mean change from baseline in pre-bronchodilator FEV1 at week 12 in DRI12544 and
QUEST (baseline blood eosinophil Levels ≥ 150 and ≥ 300 cells/mcL)
Treatment | Baseline blood EOS | |||||
| ≥ 150 cells/mcL | ≥ 300 cells/mcL | ||||
N | LS mean Δ from baseline L (%) | LS mean difference vs. placebo (95% CI) | N | LS mean Δ from baseline L (%) | LS mean difference vs. placebo (95% CI) | |
DRI12544 study | ||||||
Dupilumab 200 mg Q2W | 120 | 0.32 (18.25) | 0.23a (0.13, 0.33) | 65 | 0.43 (25.9) | 0.26c (0.11, 0.40) |
Dupilumab 300 mg Q2W | 129 | 0.26 (17.1) | 0.18b (0.08, 0.27) | 64 | 0.39 (25.8) | 0.21d (0.06, 0.36) |
Placebo | 127 | 0.09 (4.36) |
| 68 | 0.18 (10.2) |
|
QUEST study | ||||||
Dupilumab 200 mg Q2W | 437 | 0.36 (23.6) | 0.17e (0.11, 0.23) | 264 | 0.43 (29.0) | 0.21e (0.13, 0.29) |
Placebo | 232 | 0.18 (12.4) |
| 148 | 0.21 (15.6) |
|
Dupilumab 300 mg Q2W | 452 | 0.37 (25.3) | 0.15e (0.09, 0.21) | 277 | 0.47 (32.5) | 0.24e (0.16, 0.32) |
Placebo | 237 | 0.22 (14.2) |
| 142 | 0.22 (14.4) |
|
ap-value < 0.0001, bp-value = 0.0004, cp-value = 0.0008, dp-value = 0.0063, ep-value < 0.0001
Table 17: Mean change from baseline in pre-bronchodilator FEV1 at week 12 and week 52 in QUEST by baseline FeNO subgroups
Treatment |
| At week 12 | At week 52 | ||
N | LS mean Δ from baseline L (%) | LS mean difference vs. placebo (95% CI) | LS mean Δ from baseline L (%) | LS mean difference vs. placebo (95% CI) | |
FeNO ≥ 25 ppb | |||||
Dupilumab 200 mg Q2W | 288 | 0.44 (29.0 %) | 0.23 (0.15, 0.31)a | 0.49 (31.6 %) | 0.30 (0.22, 0.39)a |
Placebo | 157 | 0.21 (14.1 %) |
| 0.18 (13.2 %) |
|
Dupilumab 300 mg Q2W | 295 | 0.45 (29.8 %) | 0.24 (0.16, 0.31)a | 0.45 (30.5 %) | 0.23 (0.15, 0.31)a |
Placebo | 167 | 0.21 (13.7 %) |
| 0.22 (13.6 %) |
|
FeNO ≥ 50 ppb | |||||
Dupilumab 200 mg Q2W | 114 | 0.53 (33.5 %) | 0.30 (0.17, 0.44)a | 0.59 (36.4 %) | 0.38 (0.24, 0.53)a |
Placebo | 69 | 0.23 (14.9 %) |
| 0.21 (14.6 %) |
|
Dupilumab 300 mg Q2W | 113 | 0.59 (37.6 %) | 0.39 (0.26, 0.52)a | 0.55 (35.8 %) | 0.30 (0.16, 0.44)a |
Placebo | 73 | 0.19 (13.0 %) |
| 0.25 (13.6 %) |
|
ap-value < 0.0001
Quality of life/patient-reported outcomes in asthma
Pre-specified secondary endpoint of ACQ-5 and AQLQ(S) responder rates were analysed at 24 weeks (DRI12544 and VENTURE) and at 52 weeks (QUEST). The responder rate was defined as an improvement in score of 0.5 or more (scale range 0-6 for ACQ-5 and 1-7 for AQLQ(S)).
Improvements in ACQ-5 and AQLQ(S) were observed as early as week 2 and maintained for 24 weeks in DRI12544 study and 52 weeks in QUEST study. Similar results were observed in VENTURE. The ACQ-5 and AQLQ(S) responder rate results in patients with elevated baseline biomarkers of type 2 inflammation in QUEST at week 52 are presented in Table 18.
Table 18: ACQ-5 and AQLQ(S) responder rates at week 52 in QUEST
PRO | Treatment | EOS ≥ 150 cells/mcL | EOS ≥ 300 cells/mcL | FeNO ≥ 25 ppb | |||
N | Responder rate % | N | Responder rate (%) | N | Responder rate (%) | ||
ACQ-5 | Dupilumab 200 mg Q2W | 395 | 72.9 | 239 | 74.5 | 262 | 74.4 |
| Placebo | 201 | 64.2 | 124 | 66.9 | 141 | 65.2 |
Dupilumab 300 mg Q2W | 408 | 70.1 | 248 | 71.0 | 277 | 75.8 | |
Placebo | 217 | 64.5 | 129 | 64.3 | 159 | 64.2 | |
AQLQ(S) | Dupilumab 200 mg Q2W | 395 | 66.6 | 239 | 71.1 | 262 | 67.6 |
Placebo | 201 | 53.2 | 124 | 54.8 | 141 | 54.6 | |
Dupilumab 300 mg Q2W | 408 | 62.0 | 248 | 64.5 | 277 | 65.3 | |
Placebo | 217 | 53.9 | 129 | 55.0 | 159 | 58.5 |
Oral corticosteroid reduction study (VENTURE)
VENTURE evaluated the effect of dupilumab on reducing the use of maintenance oral corticosteroids. Baseline characteristics are presented in Table 13. All patients were on oral corticosteroids for at least 6 months prior to the study initiation. The baseline mean oral corticosteroid use was 11.75 mg in the placebo group and 10.75 mg in the group receiving dupilumab.
In this 24-week trial, asthma exacerbations (defined as a temporary increase in oral corticosteroid dose for at least 3 days) were reduced by 59 % in subjects receiving dupilumab compared with those receiving placebo (annualised rate 0.65 and 1.60 for the dupilumab and placebo group, respectively; rate ratio 0.41 [95% CI 0.26, 0.63]) and improvement in pre-bronchodilator FEV1 from baseline to week 24 was greater in subjects receiving dupilumab compared with those receiving placebo (LS mean difference for dupilumab versus placebo of 0.22 L [95% CI: 0.09 to 0.34 L]). Effects on lung function, on oral steroid and exacerbation reduction were similar irrespective of baseline levels of type 2 inflammatory biomarkers (e.g. blood eosinophils, FeNO). The ACQ-5 and AQLQ(S) were also assessed in VENTURE and showed improvements similar to those in QUEST.
The results for VENTURE by baseline biomarkers are presented in the Table 19.
Table 19: Effect of dupilumab on OCS dose reduction, VENTURE (baseline blood eosinophil
levels ≥ 150 and ≥ 300 cells/mcL and FeNO ≥ 25 ppb)
| Baseline blood EOS ≥ 150 cells/mcL | Baseline blood EOS ≥ 300 cells/mcL | FeNO ≥ 25 ppb | |||
Dupilumab 300 mg Q2W N=81 | Placebo N=69 | Dupilumab 300 mg Q2W N=48 | Placebo N=41 | Dupilumab 300 mg Q2W N=57 | Placebo N=57 | |
Primary endpoint (week 24) | ||||||
Percent reduction in OCS from baseline | ||||||
Mean overall percent |
|
46.51 |
|
42.71 |
|
42.93 |
reduction from baseline | 75.91 | 79.54 | 77.46 | |||
(%) |
|
|
| |||
Difference (% [95% | 29.39b | 36.83b | 34.53b | |||
CI]) (Dupilumab vs. | (15.67, 43.12) | (18.94, 54.71) | (19.08, 49.97) | |||
placebo) |
|
|
| |||
Median % reduction in daily OCS dose from baseline | 100 | 50 | 100 | 50 | 100 | 50 |
Percent reduction from |
|
|
|
|
|
|
baseline |
|
|
|
|
|
|
100% % | 54.3 | 33.3 | 60.4 | 31.7 | 52.6 | 28.1 |
≥ 90 % | 58.0 | 34.8 | 66.7 | 34.1 | 54.4 | 29.8 |
≥ 75 % | 72.8 | 44.9 | 77.1 | 41.5 | 73.7 | 36.8 |
≥ 50 % | 82.7 | 55.1 | 85.4 | 53.7 | 86.0 | 50.9 |
> 0 % | 87.7 | 66.7 | 85.4 | 63.4 | 89.5 | 66.7 |
| 12.3 | 33.3 | 14.6 | 36.6 | 10.5 | 33.3 |
No reduction or any increase in OCS dose, or dropped out of study |
|
|
|
|
|
|
Secondary endpoint (week 24)a | ||||||
Proportion of patients achieving a reduction of OCS dose to < 5 mg/day | 77 | 44 | 84 | 40 | 79 | 34 |
Odds ratio (95% CI) | 4.29c (2.04, 9.04) |
| 8.04d (2.71, 23.82) |
| 7.21b (2.69, 19.28) |
|
aModel estimates by logistic regression
bp-value < 0.0001
cp-value = 0.0001
dp-value = 0.0002
Long-term extension study (TRAVERSE)
The long-term safety of dupilumab in 2,193 adults and 89 adolescents with moderate-to-severe asthma,
including 185 adults with oral corticosteroid-dependent asthma, who had participated in previous clinical trials of dupilumab (DRI12544, QUEST, and VENTURE), was assessed in the open-label extension study (TRAVERSE) (see section 4.8). Efficacy was measured as a secondary endpoint, was similar to results observed in the pivotal studies and was sustained up to 96 weeks. In the adults with oral-corticosteroid-dependent asthma, there was sustained reduction in exacerbations and improvement in lung function up to 96 weeks, despite decrease or discontinuation of oral corticosteroid dose.
Paediatric study (6 to 11 years of age; VOYAGE)
The efficacy and safety of dupilumab in paediatric patients was evaluated in a 52-week multicentre, randomised, 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 randomised to dupilumab (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 populations with type 2 inflammation defined as blood eosinophil levels of ≥ 150 cells/mcL or FeNO
≥ 20 ppb.
The primary endpoint was the annualised 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 20 below.
Table 20. Demographics and baseline characteristics for VOYAGE
Parameter | EOS ≥ 150 cells/mcL or FeNO ≥ 20 ppb (N = 350) | EOS ≥ 300 cells/mcL (N = 259) |
Mean age (years) (SD) | 8.9 (1.6) | 9.0 (1.6) |
% Female | 34.3 | 32.8 |
% White | 88.6 | 87.3 |
Mean body weight (kg) | 36.09 | 35.94 |
Mean exacerbations in previous year (± SD) | 2.47 (2.30) | 2.64 (2.58) |
ICS dose (%) Medium High |
55.7 43.4 |
54.4 44.4 |
Pre-dose FEV1 (L) at baseline (± SD) | 1.49 (0.41) | 1.47 (0.42) |
Mean percent predicted FEV1 (%) (±SD) | 77.89 (14.40) | 76.85 (14.78) |
Mean % Reversibility (± SD) | 27.79 (19.34) | 22.59 (20.78) |
Mean ACQ-7-IA score (± SD) | 2.14 (0.72) | 2.16 (0.75) |
Mean PAQLQ(S)-IA score (± SD) | 4.94 (1.10) | 4.93 (1.12) |
Atopic Medical History % Overall (AD %, AR %) | 94 (38.9, 82.6) | 96.5 (44.4, 85.7) |
Median total IgE IU/mL (± SD) | 905.52 (1140.41) | 1077.00 (1230.83) |
Mean FeNO ppb (± SD) | 30.71 (24.42) | 33.50 (25.11) |
% patients with FeNO ppb ≥ 20 | 58 | 64.1 |
Mean baseline Eosinophil count (± SD) cells/mcL | 570 (380) | 710 (360) |
% patients with EOS ≥ 150 cells/mcL ≥ 300 cells/mcL |
94.6 74 |
0 100 |
ICS = inhaled corticosteroid; FEV1 = Forced expiratory volume in 1 second; ACQ-7-IA = Asthma Control Questionnaire-7 Interviewer Administered; PAQLQ(S)-IA = Paediatric Asthma Quality of Life Questionnaire with Standardised Activities–Interviewer Administered; AD = atopic dermatitis; AR = allergic rhinitis; EOS = blood eosinophil; FeNO = fraction of exhaled nitric oxide
Exacerbations were defined as deterioration of asthma requiring the use of systemic corticosteroids for at least 3 days or hospitalisation or emergency room visit due to asthma that required systemic corticosteroids. Dupilumab significantly reduced the annualised rate of severe asthma exacerbation events during the 52-week treatment period compared to placebo in the population with the type 2 inflammation and in population defined by baseline blood eosinophils ≥ 300 cells/mcL 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 21.
In the population with the type 2 inflammation, 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: 0.04, 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/mcL, 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).
In both primary efficacy populations, there was a rapid improvement in FEF25-75% and FEV1/FVC (onset of a difference was observed as early as week 2) and sustained over the 52-week treatment period, see Table 21.
Table 21: Rate of severe exacerbations, mean change from baseline in FEV1, ACQ-7-IA and PAQLQ(S)-IA responder rates in VOYAGE
Treatment | EOS ≥ 150 cells/mcL or FeNO ≥ 20 ppb | EOS ≥ 300 cells/mcL | FeNO ≥20 ppb | ||||||
Annualised severe exacerbations rate over 52 weeks | |||||||||
| N | Rate (95% CI) | Rate ratio (95% CI) | N | Rate (95% CI) | Rate ratio (95% CI) | N | Rate (95% CI) | Rate ratio (95% CI) |
Dupilumab | 236 | 0.305 | 0.407 | 175 | 0.235 | 0.353 | 141 | 0.271 | 0.384 |
100 mg Q2W | (0.223, 0.416) | (0.274, 0.605) | (0.160, 0.345) | (0.222, 0.562) | (0.170, 0.432) | (0.227, 0.649) | |||
(<30 kg)/ 200 mg Q2W (≥30 kg) |
|
|
|
|
|
| |||
Placebo | 114 | 0.748 |
| 84 | 0.665 |
| 62 | 0.705 |
|
(0.542, 1.034) | (0.467, 0.949) | (0.421, 1.180) | |||||||
Mean change from baseline in percent predicted FEV1 at week 12 | |||||||||
| N | LS mean Δ from baseline | LS mean difference vs. placebo | N | LS mean Δ from baseline | LS mean difference vs. placebo | N | LS mean Δ from baseline i | LS mean difference vs. placebo |
(95% CI) | (95% CI) | (95% CI) | |||||||
Dupilumab 100 mg Q2W | 229 | 10.53 | 5.21 (2.14, 8.27) | 168 | 10.15 | 5.32 (1.76, 8.88) | 141 | 11.36 | 6.74 (2.54, 10.93) |
(<30 kg)/ | |||||||||
200 mg Q2W | |||||||||
(≥30 kg) | |||||||||
Placebo | 110 | 5.32 |
| 80 | 4.83 |
| 62 | 4.62 |
|
Mean change from baseline in percent predicted FEF 25-75% at week 12 | |||||||||
| N | LS mean Δ from baseline | LS mean difference vs. placebo (95% CI) | N | LS mean Δ from baseline | LS mean difference vs. placebo (95% CI) | N | LS mean Δ from baseline | LS mean difference vs. placebo (95% CI) |
Dupilumab 100 mg Q2W | 229 | 16.70 | 11.93 (7.44, 16.43) | 168 | 16.91 | 13.92 (8.89, 18.95) | 141 | 17.96 | 13.97 (8.30, 19.65) |
(<30 kg)/ | |||||||||
200 mg Q2W | |||||||||
(≥30 kg) | |||||||||
Placebo | 110 | 4.76 |
| 80 | 2.99 |
| 62 | 3.98 |
|
Mean change from baseline in FEV1/FVC % at week 12 | |||||||||
| N | LS mean Δ from baseline | LS mean difference vs. placebo (95% CI) | N | LS mean Δ from baseline | LS mean difference vs. placebo (95% CI) | N | LS mean Δ from baseline | LS mean difference vs. placebo (95% CI) |
Dupilumab 100 mg Q2W | 229 | 5.67 | 3.73 (2.25, 5.21) | 168 | 6.10 | 4.63 (2.97, 6.29) | 141 | 6.84 | 4.95 (3.08, 6.81) |
(<30 kg)/ | |||||||||
200 mg Q2W | |||||||||
(≥30 kg) | |||||||||
Placebo | 110 | 1.94 |
| 80 | 1.47 |
| 62 | 1.89 |
|
ACQ-7-IA at week 24a | |||||||||
| N | Responder rate % | OR vs. placebo (95% CI) | N | Responder rate % | OR vs. placebo (95% CI) | N | Responder rate % | OR vs. placebo (95% CI) |
Dupilumab 100 mg Q2W (<30 kg)/ 200 mg Q2W | 236 | 79.2 | 1.82 (1.02, 3.24) | 175 | 80.6 | 2.79 (1.43, 5.44) | 141 | 80.9 | 2.60 (1.21, 5.59) |
(≥30 kg) | |||||||||
Placebo | 114 | 69.3 |
| 84 | 64.3 |
| 62 | 66.1 |
|
PAQLQ(S)-IA at week 24a | |||||||||
| N | Responder rate % | OR vs. placebo (95% CI) | N | Responder rate % | OR vs. placebo (95% CI) | N | Responder rate % | OR vs. placebo (95% CI) |
Dupilumab 100 mg Q2W | 211 | 73.0 | 1.57 (0.87, 2.84) | 158 | 72.8 | 1.84 (0.92, 3.65) | 131 | 75.6 | 2.09 (0.95, |
(<30 kg)/ | 4.61) | ||||||||
200 mg Q2W |
| ||||||||
(≥30 kg) |
| ||||||||
Placebo | 107 | 65.4 |
| 81 | 63.0 |
| 61 | 67.2 |
|
aThe responder rate was defined as an improvement in score of 0.5 or more (scale range 0-6 for ACQ-7-IA and 1-7 for PAQLQ(S))
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 8.
Figure 8: Mean change from baseline in percent predicted pre-bronchodilator FEV1 (L) over time in VOYAGE (baseline blood eosinophils ≥ 150 cells/mcL or FeNO ≥ 20 ppb, baseline eosinophils ≥ 300 cells/mcL, and baseline FeNO ≥ 20 ppb)
Baseline blood eosinophils ≥ 150 cells/mcL or FeNO ≥ 20 ppb | Baseline blood eosinophils ≥ 300 cells/mcL | Baseline FeNO ≥ 20 ppb |
In VOYAGE, in the population with the type 2 inflammation, the mean annualised 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/mcL, the mean annualised 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]).
Dupilumab improved the overall health status as measured by the European Quality of Life 5- Dimension Youth Visual Analog Scale (EQ-VAS) in both the type 2 inflammation and the baseline blood eosinophil count of ≥ 300 cells/mcL populations 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.
Dupilumab reduced the impact of paediatric patient’s asthma on the caregiver quality of life as measured by the Paediatric Asthma Quality of Life Questionnaire (PACQLQ) in both the type 2 inflammation and the baseline blood eosinophil count of ≥ 300 cells/mcL 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.
Clinical efficacy in chronic rhinosinusitis with nasal polyposis (CRSwNP)
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 dupilumab (N=143) or placebo (N=133) every other week for 24 weeks. In SINUS-52, 448 patients were randomised to receive either 300 mg dupilumab (N=150) every other week for 52 weeks, 300 mg dupilumab (N=145) every other week until week 24 followed by 300 mg dupilumab 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).
The co-primary efficacy endpoints were change from baseline to week 24 in bilateral endoscopic nasal polyps score (NPS) as graded by central blinded readers, and change from baseline to week 24 in nasal congestion/obstruction score averaged over 28 days (NC), 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 end-points 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 Sino-Nasal Outcome Test (SNOT-22). 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 22 below.
Table 22: Demographics and baseline characteristics of CRSwNP studies
Parameter | SINUS-24 (N=276) | SINUS-52 (N=448) |
Mean age (years) (SD) | 50.49 (13.39) | 51.95 (12.45) |
% Male | 57.2 | 62.3 |
Mean CRSwNP duration (years)(SD) | 11.11 (9.16) | 10.94 (9.63) |
Patients with ≥ 1 prior surgery (%) | 71.7 | 58.3 |
Patients with systemic corticosteroid use in the previous 2 years (%) | 64.9 | 80.1 |
Mean Bilateral endoscopic NPSa (SD), range 0–8 | 5.75 (1.28) | 6.10 (1.21) |
Mean Nasal congestion (NC) scorea (SD) range 0–3 | 2.35 (0.57) | 2.43 (0.59) |
Mean LMK sinus CT total scorea(SD), range 0–24 | 19.03 (4.44) | 17.96 (3.76) |
Mean Smell test (UPSIT) scorea (SD), range 0–40 | 14.56 (8.48) | 13.61 (8.02) |
Mean loss of smell scorea (AM), (SD) range 0–3 | 2.71 (0.54) | 2.75 (0.52) |
Mean SNOT-22 total scorea (SD), range 0–110 | 49.40 (20.20) | 51.86 (20.90) |
Mean Rhinosinusitis severity scalea (VAS), (SD) 0–10 cm | 7.68 (2.05) | 8.00 (2.08) |
Mean blood eosinophils (cells/mcL)(SD) | 437 (333) | 431 (353) |
Mean total IgE IU/mL (SD) | 211.97 (275.73) | 239.84 (341.53) |
Atopic (type 2 inflammatory disease) Medical History % Overall |
75.4 % |
82.4 % |
Asthma (%) | 58.3 | 59.6 |
Mean FEV1 (L)(SD) | 2.69 (0.96) | 2.57 (0.83) |
Mean FEV1 percent predicted (%)(SD) | 85.30 (20.23) | 83.39 (17.72) |
Mean ACQ-6 scorea (SD) | 1.62 (1.14) | 1.58 (1.09) |
NSAID-ERD (%) | 30.4 | 26.8 |
aHigher scores indicate greater disease severity except UPSIT where higher scores indicate lower disease severity; SD=standard deviation; AM = morning; NPS = nasal polyps score; UPSIT = University of Pennsylvania smell identification test; SNOT-22 = 22-item Sino-Nasal Outcome Test; VAS = visual analogue scale; FEV1 = Forced expiratory volume in 1 second; ACQ-6 = Asthma Control Questionnaire-6; NSAID-ERD= aspirin/nonsteroidal anti-inflammatory drug exacerbated respiratory disease
Clinical Response (SINUS-24 and SINUS-52)
The results for primary and secondary endpoints in CRSwNP studies are presented in the Table 23.
Table 23: Results of the primary and secondary endpoints in CRSwNP trials
| SINUS -24 | SINUS -52 | ||||||||
| Placebo (n=133) | Dupilumab 300mg Q2W (n=143) | LS mean difference vs. placebo (95%CI) | Placebo (n=153) | Dupilumab 300mg Q2W (n=295) | LS mean difference vs. placebo (95%CI) | ||||
Primary endpoints at week 24 | ||||||||||
Scores | Baseline mean | LS mean change | Baseline mean | LS mean change |
| Baseline mean | LS mean change | Baseline mean | LS mean change |
|
NPS | 5.86 | 0.17 | 5.64 | -1.89 | -2.06 (-2.43, -1.69) | 5.96 | 0.10 | 6.18 | -1.71 | -1.80 (-2.10, -1.51) |
NC | 2.45 | -0.45 | 2.26 | -1.34 | -0.89 (-1.07, -0.71) | 2.38 | -0.38 | 2.46 | -1.25 | -0.87 (-1.03, -0.71) |
Key secondary endpoints at week 24 | ||||||||||
Scores | Baseline mean | LS mean change | Baseline mean | LS mean change |
| Baseline mean | LS mean change | Baseline mean | LS mean change |
|
LMK sinus CT scan score |
19.55 |
-0.74 |
18.55 |
-8.18 |
-7.44 (-8.35, -6.53) |
17.65 |
-0.09 |
18.12 |
-5.21 |
-5.13 (-5.80, -4.46) |
Total symptom score |
7.28 |
-1.17 |
6.82 |
-3.77 | -2.61 (-3.04, -2.17) |
7.08 |
-1.00 |
7.30 |
-3.45 | -2.44 (-2.87, -2.02) |
UPSIT | 14.44 | 0.70 | 14.68 | 11.26 | 10.56 (8.79, 12.34) | 13.78 | -0.81 | 13.53 | 9.71 | 10.52 (8.98, 12.07) |
Loss of smell | 2.73 | -0.29 | 2.70 | -1.41 | -1.12 (-1.31, -0.93) | 2.72 | -0.23 | 2.77 | -1.21 | -0.98 (-1.15, -0.81) |
SNOT- 22 | 50.87 | -9.31 | 48.0 | -30.43 | -21.12 (-25.17, -17.06) | 53.48 | -10.40 | 51.02 | -27.77 | -17.36 (-20.87, -13.85) |
VAS | 7.96 | -1.34 | 7.42 | -4.54 | -3.20 (-3.79, -2.60) | 7.98 | -1.39 | 8.01 | -4.32 | -2.93 (-3.45, -2.40) |
A reduction in score indicates improvement, except UPSIT where an increase indicates improvement. Total symptom score is a composite severity score consisting of the sum of daily symptoms of NC, loss of smell, and anterior/posterior rhinorrhoea.
NC = nasal congestion, NPS = nasal polyposis score; LMK = Lund-MacKay total CT score; UPSIT = University of Pennsylvania smell identification test; SNOT-22 = 22-item Sino-Nasal Outcome Test;
TSS = total symptom score; VAS = visual analogue scale for rhinosinusitis (all p-values < 0.0001, nominal for VAS)
The results of SINUS-52 study at week 52 are presented in Table 24.
Table 24: Results of the efficacy at week 52 in SINUS-52 study
| Placebo (n=153) | Dupilumab 300mg Q2W (n=150) | LS mean difference vs. placebo (95%CI) | Dupilumab 300mg Q2W-Q4W (n=145) | LS mean difference vs. placebo (95%CI) | |||
Baseline mean | LS mean change | Baseline mean | LS mean change | Baseline mean | LS mean change | |||
NPS | 5.96 | 0.15 | 6.07 | -2.24 | -2.40 (-2.77, -2.02) | 6.29 | -2.06 | -2.21 (-2.59, -1.83) |
NC | 2.38 | -0.37 | 2.48 | -1.35 | -0.98 (-1.17, -0.79) | 2.44 | -1.48 | -1.10 (-1.29, -0.91) |
LMK sinus CT scan score | 17.65 | 0.11 | 18.42 | -6.83 | -6.94 (-7.87, -6.01) | 17.81 | -5.60 | -5.71 (-6.64, -4.77) |
Total symptom score |
7.08 |
-0.94 |
7.31 |
-3.79 | -2.85 (-3.35, -2.35) | 7.28 | -4.16 | -3.22 (-3.73, -2.72) |
UPSIT | 13.78 | -0.77 | 13.46 | 9.53 | 10.30 (8.50, 12.10) | 13.60 | 9.99 | 10.76 (8.95, 12.57) |
Loss of Smell | 2.72 | -0.19 | 2.81 | -1.29 | -1.10 (-1.31, -0.89) | 2.73 | -1.49 | -1.30 (-1.51, -1.09) |
SNOT-22 |
53.48 |
-8.88 |
50.16 |
-29.84 | -20.96 (-25.03, -16.89) | 51.89 | -30.52 | -21.65 (-25.71, - 17.58) |
VAS | 7.98 | -0.93 | 8.24 | -4.74 | -3.81 (-4.46, -3.17) | 7.78 | -4.39 | -3.46 (-4.10, -2.81) |
A reduction in score indicates improvement, except UPSIT where an increase indicates improvement. Total symptom score is a composite severity score consisting of the sum of daily symptoms of NC, loss of smell, and anterior/posterior rhinorrhoea.
NC = nasal congestion, NPS = nasal polyposis score; LMK = Lund-MacKay total CT score; UPSIT = University of Pennsylvania smell identification test; SNOT-22 = 22-item Sino-Nasal Outcome Test;
TSS = total symptom score; VAS = visual analogue scale for rhinosinusitis (all p-values < 0.0001)
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 9a). Similar results were also seen in SINUS-52 at both week 24 and week 52 with a progressive improvement over time (see Figure 9b).
Figure 9. LS mean change from baseline in bilateral nasal polyps score (NPS) in SINUS-24 and SINUS-52 - ITT population.
Figure 9a. SINUS-24 | Figure 9b. SINUS-52 |
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 dupilumab 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 dupilumab 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.
A reduction in the proportion of patients with anosmia was observed in SINUS-24 and SINUS-52. At baseline, 74 % to 79 % of patients had anosmia, which was reduced to 24 % in SINUS-24 and 30 % in SINUS-52 at week 24, compared to no change in placebo. 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.
Among the patients with rhinosinusitis VAS score > 7 at baseline, a higher percentage of patients achieved VAS ≤ 7 in the dupilumab group compared with the placebo group (83.3 % versus 39.4 % in SINUS-24 and 75.0 % versus 39.3 % in SINUS-52) at week 24.
In the pre-specified multiplicity-adjusted pooled analysis of two studies, treatment with dupilumab 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 10). 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).
Figure 10. Kaplan Meier Curve for time to first systemic corticosteroid use and/or sino-nasal surgery during treatment period - ITT population [SINUS-24 and SINUS-52 pooled]
The effects of dupilumab on the primary endpoints of NPS and nasal congestion and the key secondary endpoint of LMK sinus CT scan score were consistent in patients with prior surgery and without prior surgery.
In patients with co-morbid asthma, significant improvements in FEV1 and ACQ-6 were observed at week 24 irrespective of baseline blood eosinophil levels. The pooled LS Mean change from baseline in FEV1 at week 24 for dupilumab 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. 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. The LS mean difference in the dupilumab group versus placebo at week 24 was
-0.76 (95% CI: -1.00 to -0.51) in SINUS-24 and -0.94 (95% CI: -1.19, -0.69) in SINUS-52.
The ACQ-6 responder rate for dupilumab 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 dupilumab 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 dupilumab 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.
Paediatric population
Atopic dermatitis
The safety and efficacy of dupilumab have been established in 12 to 17 years old with moderate-to- severe atopic dermatitis in study AD-1526 which included 251 adolescents. The safety and efficacy of dupilumab have been established in 6 to 11 years old with severe atopic dermatitis in study AD-1652 which included 367 paediatric patients. Use is supported by study AD-1434 which enrolled patients who had completed AD-1526 (136 moderate and 64 severe at the time of enrolment in study AD- 1434) and patients who had completed study AD-1652 (110 moderate and 72 severe at the time of enrolment in in study AD-1434). The safety and efficacy were generally consistent between children 6 to 11 years old, adolescent, and adult patients with atopic dermatitis (see section 4.8).
Asthma
A total of 107 adolescents aged 12 to 17 years with moderate to severe asthma were enrolled in QUEST study and received either 200 mg (N=21) or 300 mg (N=18) dupilumab (or matching placebo either 200 mg [N=34] or 300 mg [N=34]) every other week. Efficacy with respect to severe asthma exacerbations and lung function was observed in both adolescents and adults. For both the 200 mg and
300 mg every other week doses, significant improvements in FEV1 (LS mean change from baseline at eek 12) were observed (0.36 L and 0.27 L, respectively). For the 200 mg every other week dose, patients had a reduction in the rate of severe exacerbations that was consistent with adults.. The safety profile in adolescents was generally similar to the adults.
A total of 89 adolescents aged 12 to 17 years with moderate-to-severe asthma were enrolled in the open label long-term study (TRAVERSE). In this study, efficacy was measured as a secondary endpoint, was similar to results observed in the pivotal studies and was sustained up to 96 weeks.
A total of 408 children aged 6 to 11 years with moderate-to-severe asthma was enrolled in the VOYAGE study, which evaluated doses of 100 mg Q2W and 200 mg Q2W. The efficacy of dupilumab 300 mg Q4W in children aged 6 to 11 years is extrapolated from the efficacy of 100 mg and 200 mg Q2W in VOYAGE and 200 mg and 300 mg Q2W in adults and adolescents (QUEST). Patients who completed the treatment period of the VOYAGE study could participate in the open label extension study (EXCURSION). Eighteen patients (≥ 15 kg to < 30 kg) out of 365 patients were exposed to 300 mg Q4W in this study, and the safety profile was similar to that seen in VOYAGE. Safety and efficacy in paediatric patients < 6 years of age with asthma have not been established.
The European Medicines Agency has deferred the obligation to submit the results of studies with dupilumab in one or more subset of the paediatric population in atopic dermatitis and asthma (see section 4.2 for information on paediatric use). The European Medicines Agency has waived the obligation to submit the results of studies with dupilumab in all subsets of the paediatric population in the treatment of nasal polyposis (see section 4.2 for information on paediatric use).
clinical safety and efficacy in Eosinophilic Esophagitis
A single randomized, double-blind, parallel-group, multicenter, placebo-controlled trial, including two 24-week treatment periods (Parts A and B), was conducted in adult and pediatric subjects 12 to 17 years of age, weighing at least 40 kg, with EoE. In both parts,
subjects were randomized to receive 300 mg DUPIXENT every week or placebo. Eligible subjects had ≥15 intraepithelial eosinophils per high-power field (eos/hpf) following a treatment course of a proton pump inhibitor (PPI) either prior to or during the screening period and symptoms of dysphagia as measured by the Dysphagia Symptom Questionnaire (DSQ). At baseline, 43% of subjects in Part A and 37% of subjects in Part B had a history of prior esophageal dilations.
Demographics and baseline characteristics were similar in Parts A and B. A total of 81 subjects (61 adults and 20 pediatric subjects) were enrolled in Part A and 159 subjects (107 adults and 52 pediatric subjects) were enrolled in Part B. The mean age in years was 32 years (range 13 to 62 years) in Part A and 28 years (range 12 to 66 years) in Part B. The majority of subjects were male (60% in Part A and 68% in Part B) and White (96% in Part A and 90% in Part B).
The mean baseline DSQ score (SD) was 33.6 (12.4) in Part A and 37.2 (10.7) in Part B.
The coprimary efficacy endpoints in Parts A and B were the (1) proportion of subjects achieving histological remission defined as peak esophageal intraepithelial eosinophil count of ≤6 eos/hpf at Week 24; and (2) the absolute change in the subject-reported DSQ score from baseline to Week 24.
Efficacy results for Parts A and B are presented in Table 18
Table 18: Efficacy Results of DUPIXENT at Week 24 in Subjects 12 Years of Age and Older with EoE (Parts A and B)
a Total biweekly DSQ scores range from 0 to 84; higher scores indicate greater frequency and severity of dysphagia
b For histological remission, the difference in percentages is estimated using the Cochran Mantel Haenszel method, adjusting for randomization stratification factors. For absolute change in DSQ score, the LS mean changes, standard errors, and differences are estimated using an ANCOVA model with treatment group, randomization stratification factors, and baseline measurement as covariates.
In Parts A and B, a greater proportion of subjects randomized to DUPIXENT achieved histological remission (peak esophageal intraepithelial eosinophil count ≤6 eos/hpf) compared to placebo. Treatment with DUPIXENT also resulted in a significant improvement in LS mean change in DSQ score compared to placebo at Week 24. The results of the anchor-based analyses that incorporated the subjects’ perspectives indicated that the observed improvement in dysphagia from Parts A and B is representative of a clinically meaningful within-subject improvement.
Prurigo Nodularis
A total of 309 adult subjects with prurigo nodularis (PN) were evaluated in two 24-week randomized, double-blind, placebo-controlled, multicenter trials (PRIME and PRIME2). The safety pool included data from the 24-week treatment and 12-week follow-up periods from both trials.
The proportion of subjects who discontinued treatment due to adverse events was 3% of the placebo group and 0% of the DUPIXENT 300 mg Q2W group.
The safety population had a mean age of 49 years; 65% of subjects were female, 56% were White, 34% were Asian, and 6% were Black or African American. Subjects with co-morbid conditions included 43% of subjects with a history of atopy (defined as having a medical history of AD, allergic rhinitis/ rhinoconjunctivitis, asthma, or food allergy), 8% of subjects with a history of hypothyroidism and 9% of subjects with a history of diabetes mellitus type 2.
Table 9 summarizes the adverse reactions that occurred at a rate of at least 2% in subjects treated with DUPIXENT and at a higher rate than in their respective comparator group in PRIME and PRIME2.
Table 9: Adverse Reactions Occurring in ≥2% of the DUPIXENT Group in PRIME and PRIME2 and Greater than Placebo
Adverse Reaction | PRIME and PRIME2 | |
DUPIXENT 300 mg Q2W
N=152 n (%) | Placebo
N=157 n (%) | |
Nasopharyngitisa | 8 (5%) | 3 (2%) |
Conjunctivitisb | 6 (4%) | 2 (1%) |
Herpes Infectionc | 5 (3%) | 0% |
Dizzinessd | 5 (3%) | 2 (1%) |
Myalgiae | 5 (3%) | 2 (1%) |
Diarrhea | 4 (3%) | 1 (1%) |
a Nasopharyngitis includes pharyngitis b Conjunctivitis includes conjunctivitis and allergic conjunctivitis. c Herpes infection includes oral herpes, genital herpes simplex, herpes zoster and ophthalmic herpes zoster d Dizziness includes dizziness postural, vertigo and vertigo positional e Myalgia includes musculoskeletal pain and musculoskeletal chest pain |
Among subjects with PN, the frequency of conjunctivitis was 4% in the DUPIXENT group compared to 1% in the placebo group; all of these subjects recovered or were recovering during the treatment period. There were no cases of keratitis reported in the PN development program
Among subjects with PN, herpes zoster and ophthalmic herpes zoster were each reported in <1% of the DUPIXENT group (1 per 100 subject-years) and 0% of the placebo group
In subjects with PN (PRIME and PRIME2), the mean and median decrease in blood eosinophils from baseline to Week 4 were 9 and 10 cells/mcL, respectively.
In the trials for the PN indication, the incidence of treatment-emergent eosinophilia (≥500 cells/mcL) was lower in DUPIXENT than in the placebo group
The pharmacokinetics of dupilumab is similar in patients with atopic dermatitis, asthma,CRSwNP and PN
Absorption
After a single subcutaneous (SC) dose of 75-600 mg dupilumab to adults, median times to maximum concentration in serum (tmax) were 3-7 days. The absolute bioavailability of dupilumab following a SC dose is similar between AD, asthma, CRSwNP and PN patients, ranging between 61 % and 64 %, as determined by a population pharmacokinetics (PK) analysis.
Steady-state concentrations were achieved by week 16 following the administration of 600 mg starting dose and 300 mg dose every other week or 300 mg dose every other week without a loading dose.
Across clinical trials, the mean ±SD steady-state trough concentrations ranged from
69.2±36.9 mcg/mL to 80.2±35.3 mcg/mL for 300 mg dose and from 29.2±18.7 to 36.5±22.2 mcg/mL for 200 mg dose administered every other week to adults.
Distribution
A volume of distribution for dupilumab of approximately 4.6 L was estimated by population PK analysis, indicating that dupilumab is distributed primarily in the vascular system.
Biotransformation
Specific metabolism studies were not conducted because dupilumab is a protein. Dupilumab is expected to degrade to small peptides and individual amino acids.
Elimination
Dupilumab elimination is mediated by parallel linear and nonlinear pathways. At higher concentrations, dupilumab elimination is primarily through a non-saturable proteolytic pathway, while at lower concentrations, the non-linear saturable IL-4R α target-mediated elimination predominates. After the last steady state dose, the median time for dupilumab concentrations to decrease below the lower limit of detection, estimated by population PK analysis, was 6-7 weeks for the 300 mg Q4W regimen, 9 weeks for the 200 mg Q2W regimen, 10-11 weeks for the 300 mg Q2W regimen, and 13 weeks for the 300 mg QW regimen. Population pharmacokinetic analyses indicate the median times to non-detectable concentration are approximately 1.5 times (up to 19 weeks) and 2.5 times (up to 32 weeks) longer in pediatric subjects 6 to 11 years of age.
Linearity/non-linearity
Due to nonlinear clearance, dupilumab exposure, as measured by area under the concentration-time curve, increases with dose in a greater than proportional manner following single SC doses from 75- 600 mg.
Special populations
Gender
Gender was not found to be associated with any clinically meaningful impact on the systemic exposure of dupilumab determined by population PK analysis.
Elderly
Of the 1,472 patients with atopic dermatitis exposed to dupilumab in a phase 2 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.
Age
Based on population pharmacokinetic analysis, age did not affect dupilumab clearance in adults and in pediatric subjects 6 to 17 years of age.
Of the 1,977 patients with asthma exposed to dupilumab, a total of 240 patients were 65 years or older and 39 patients were 75 years or older. Efficacy and safety in this age group were similar to the overall study population.
There were only 79 patients older than 65 years with CRSwNP exposed to dupilumab among them 11 patients were 75 years and older.
Of the 152 subjects with PN exposed to DUPIXENT, a total of 37 were 65 years or older including 8 subjects 75 years or older. Clinical trials did not include a sufficient number of subjects 65 years of age and older to determine whether they respond differently from younger adult subjects
Race
Race was not found to be associated with any clinically meaningful impact on the systemic exposure of dupilumab by population PK analysis.
Hepatic impairment
Dupilumab, as a monoclonal antibody, is not expected to undergo significant hepatic elimination. No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of dupilumab.
Renal impairment
Dupilumab, as a monoclonal antibody, is not expected to undergo significant renal elimination. No clinical studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of dupilumab. Population PK analysis did not identify mild or moderate renal impairment as having a clinically meaningful influence on the systemic exposure of dupilumab. Very
limited data are available in patients with severe renal impairment.
Body weight
Dupilumab trough concentrations were lower in subjects with higher body weight with no meaningful impact on efficacy. There were only 6 patients exposed to dupilumab with body weight ≥130 kg in CRSwNP clinical studies.
Paediatric population Atopic dermatitis
The pharmacokinetics of dupilumab in paediatric patients (< 6 years of age) or body weight < 15 kg with atopic dermatitis has not been studied.
For adolescents 12 to 17 years of age with atopic dermatitis receiving every other week dosing (Q2W) with either 200 mg (< 60 kg) or 300 mg (≥ 60 kg), the mean ±SD steady state trough concentration of dupilumab was 54.5±27.0 mcg/mL.
For children 6 to 11 years of age with atopic dermatitis receiving every four week dosing (Q4W) with 300 mg (≥ 15 kg) in AD-1652, the mean ± SD steady-state trough concentration was 76.3±37.2 mcg/mL. At week 16 in AD-1434 in children 6 to 11 years of age who initiated every four week dosing (Q4W) with 300 mg (≥ 15 kg), and whose dose was increased to every other week dosing (Q2W) with 200 mg (≥ 15 to < 60 kg) or 300 mg (≥ 60 kg), the mean±SD steady-state trough concentration was 108±53.8 mcg/mL. For children 6 to 11 years of age receiving 300 mg Q4W, initial doses of 300 mg on Days 1 and 15 produce similar steady-state exposure as an initial dose of 600 mg on Day 1, based on PK simulations.
Asthma
The pharmacokinetics of dupilumab in paediatric patients (< 6 years of age) with asthma has not been studied.
A total of 107 adolescents aged 12 to 17 years with asthma were enrolled in QUEST study. The mean
±SD steady-state trough concentrations of dupilumab were 107±51.6 mcg/mL and 46.7±26.9 mcg/mL, respectively, for 300 mg or 200 mg administered every other week. No age-related pharmacokinetic difference was observed in adolescent patients after correction for body weight.
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 volume of distribution for dupilumab of approximately 3.7 L was estimated by population PK analysis. Steady-state concentrations were achieved by week 12. The mean ± SD steady-state trough concentration was
58.4±28.0 mcg/mL and 85.1±44.9 mcg/mL, respectively. Simulation of a 300 mg Q4W subcutaneous dose in children aged 6 to 11 years with body weight of ≥ 15 kg to < 30 kg and ≥ 30 kg 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 kg to < 60 kg resulted in predicted steady-state trough concentrations similar to those demonstrated to be efficacious in adults and adolescents. After the last steady state dose, the median time for dupilumab concentrations to decrease below the lower limit of detection, estimated by population PK analysis, was 14 to 18 weeks for 100 mg Q2W, 200 mg Q2W or 300 mg Q4W.
CRSwNP
CRSwNP does not normally occur in children. The pharmacokinetics of dupilumab in paediatric
patients (< 18 years of age) with CRSwNP has not been studied.
Eosinophilic Esophagitis
In a clinical study (Parts A and B), dupilumab pharmacokinetics were investigated in 35 pediatric subjects 12 to 17 years of age, weighing at least 40 kg, with EoE, receiving 300 mg QW. The mean ± SD steady-state trough concentration of dupilumab was 227 ± 95.3 mcg/mL.
Prurigo Nodularis
The prurigo nodularis (PN) development program included two 24-week randomized, double-blind, placebo-controlled, multicenter, parallel-group trials (PRIME (NCT04183335) and PRIME 2 (NCT04202679)) in 311 adult subjects 18 years of age and older with pruritus (WI-NRS ≥ 7 on a scale of 0 to 10) and greater than or equal to 20 nodular lesions. PRIME and PRIME 2 assessed the effect of DUPIXENT on pruritus improvement as well as its effect on PN lesions.
In these two trials, subjects received either subcutaneous DUPIXENT 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 trials, the mean age was 49.5 years, the median weight was 71 kg, 65% of subjects were female, 57% were White, 6% were Black, and 34% were Asian. At baseline, the mean Worst Itch-Numeric Rating Scale (WI-NRS) was 8.5, 66% had 20 to 100 nodules (moderate), and 34% had greater than 100 nodules (severe). Eleven percent (11%) of subjects were taking stable doses of antidepressants at baseline and were instructed to continue taking these medications during the trial. Forty-three percent (43%) 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”). Subjects were asked to rate the intensity of their worst pruritus (itch) over the past 24 hours using this scale. The Investigator’s Global Assessment for Prurigo Nodularis-Stage (IGA PN-S) is a scale that measures the approximate number of nodules using a 5-point scale from 0 (clear) to 4 (severe).
Efficacy was assessed with the proportion of subjects with improvement (reduction) in WI-NRS by ≥4 points, the proportion of subjects 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 23 and Figures 14, 15 and 16.
Table 23: Efficacy Results of DUPIXENT in PRIME and PRIME2
| PRIME | PRIME2 | ||||
| Placebo | DUPIXENT 300 mg Q2W | Difference (95% CI) for DUPIXENT vs. Placebo | Placebo | DUPIXENT 300 mg Q2W | Difference (95% CI) for DUPIXENT vs. Placebo |
|
|
|
|
|
|
|
Proportion of subjects with both an improvement (reduction) in WI-NRS by ≥4 points from baseline to Week 24 and an IGA PN-S 0 or 1 at Week 24 b |
9.2% |
38.7% |
29.6% (16.4, 42.8)
|
8.5% |
32.1% |
25.5% (13.1, 37.9) |
Proportion of subjects with improvement (reduction) in WI-NRS by ≥4 points from baseline at Week 24b |
18.4% |
60.0% | 42.7% (27.8, 57.7)
|
19.5% |
57.7% | 42.6% (29.1, 56.1)
|
Proportion of subjects with IGA PN-S 0 or 1 at Week 24 b |
18.4% |
48.0% | 28.3% (13.4, 43. 2)
|
15.9% |
44.9% | 30.8% (16. 4, 45.2) |
Proportion of subjects with improvement (reduction) in WI-NRS by ≥4 points from baseline at Week 12 b |
15.8%a |
44.0%a | 29.2% (14.5, 43.8)a |
22.0% |
37.2% | 16.8% (2.3, 31.2) |
a Not adjusted for multiplicity in PRIME. | ||||||
b Subjects who received rescue treatment earlier or had missing data were considered as non-responders. |
Figure 14: Proportion of Adult Subjects with PN with Both WI-NRS ≥4-point Improvement and IGA PN-S 0 or 1 Over Time in PRIME and PRIME 2
Figure 15: Proportion of Adult Subjects with PN with WI-NRS ≥4-point Improvement Over Time in PRIME and PRIME2
Figure 16: Proportion of Adult Subjects with IGA PN-S 0 or 1 Over Time in PRIME and PRIME 2
The efficacy data did not show differential treatment effect across demographic subgroups.
Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity (including safety pharmacology endpoints) and toxicity to reproduction and development.
The mutagenic potential of dupilumab has not been evaluated; however monoclonal antibodies are not expected to alter DNA or chromosomes.
Carcinogenicity studies have not been conducted with dupilumab. An evaluation of the available evidence related to IL-4Rα inhibition and animal toxicology data with surrogate antibodies does not suggest an increased carcinogenic potential for dupilumab.
During a reproductive toxicology study conducted in monkeys, using a surrogate antibody specific to the monkey IL-4Rα, no fetal abnormalities were observed at dosages that saturate the IL-4Rα.
An enhanced pre- and post-natal developmental study revealed no adverse effects in maternal animals or their offspring up to 6 months post-partum/post-birth.
Fertility studies conducted in male and female mice using a surrogate antibody against IL-4Ra showed no impairment of fertility (see section 4.6).
Prurigo Nodularis
Safety and effectiveness in pediatric patients younger than 18 years of age with PN have not been established
arginine hydrochloride
histidine
polysorbate 80 (E433)
sodium acetate trihydrate
glacial acetic acid (E260)
sucrose
water for injections
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Store in a refrigerator (2°C - 8°C). Do not freeze.
Store in the original carton in order to protect from light.
Dupixent 300 mg solution for injection in pre-filled syringe
2 mL solution in a siliconised type-1 clear glass pre-filled syringe with or without needle shield, with a fixed 27 gauge 12.7 mm (½ inch), thin wall stainless steel staked needle.
Pack size:
· 1 pre-filled syringe
· 2 pre-filled syringes
· Multipack containing 3 (3 packs of 1) pre-filled syringes
· Multipack containing 6 (3 packs of 2) pre-filled syringes
Dupixent 300 mg solution for injection in pre-filled pen
2 mL solution in a siliconised type-1 clear glass syringe in a pre-filled pen, with a fixed 27 gauge 12.7 mm (½ inch), thin wall stainless steel staked needle.
Pack size:
· 1 pre-filled pen
· 2 pre-filled pens
· 3 pre-filled pens
· 6 pre-filled pens
Not all pack sizes may be marketed.
After removing the 300 mg pre-filled syringe or pre-filled pen from the refrigerator, it should be allowed to reach room temperature up to 25°C by waiting for 45 min before injecting Dupixent.
The pre-filled syringe or the pre-filled pen should not be exposed to heat or direct sunlight and should not be shaken.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements. After use, place the pre-filled syringe or the pre-filled pen into a puncture-resistant container and discard as required by local regulations. Do not recycle the container.