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نشرة الممارس الصحي نشرة معلومات المريض بالعربية نشرة معلومات المريض بالانجليزية صور الدواء بيانات الدواء
  SFDA PIL (Patient Information Leaflet (PIL) are under review by Saudi Food and Drug Authority)

What Apriva is

Apriva contains the active substance ‘apremilast’. This belongs to a group of medicines called phosphodiesterase 4 inhibitors, which help to reduce inflammation.  

 

What Apriva is used for

Apriva is used to treat adults with the following conditions:

 

·  Psoriatic arthritis

- if you cannot use another type of medicine called ‘Disease-Modifying Antirheumatic Drugs’ (DMARDs) or when you have tried one of these medicines and it did not work.  

· Moderate to severe plaque psoriasis

- if you cannot use one of the following treatments or when you have tried one of these treatments and it did not work:

-  Phototherapy - a treatment where certain areas of skin are exposed to ultraviolet light  

-  Systemic therapy - a treatment that affects the entire body rather than just one local area, such as ‘ciclosporin’ or ‘methotrexate’.

 

What psoriatic arthritis is

Psoriatic arthritis is an inflammatory disease of the joints, usually accompanied by psoriasis, an inflammatory disease of the skin.

 

What plaque psoriasis is

Psoriasis is an inflammatory disease of the skin, which can cause red, scaly, thick, itchy, painful patches on your skin and can also affect your scalp and nails.

 

How Apriva works

Psoriatic arthritis and psoriasis are usually lifelong conditions and there is currently no cure. Apriva works by reducing the activity of an enzyme in the body called ‘phosphodiesterase 4’, which is involved in the process 2 of inflammation. By reducing the activity of this enzyme, Apriva can help to control the inflammation associated with psoriatic arthritis and psoriasis, and thereby reduce the signs and symptoms of these conditions.  

In psoriatic arthritis, treatment with Apriva results in an improvement in swollen and painful joints, and can improve your general physical function.

In psoriasis, treatment with Apriva results in a reduction in psoriatic skin plaques and other signs and symptoms of the disease.

Apremilast has also been shown to improve the quality of life in patients with psoriasis or psoriatic arthritis. This means that the impact of your condition on daily activities, relationships and other factors should be less than it was before.


Do not take Apriva

· If you are allergic to apremilast or any of the other ingredients of this medicine (listed in section 6).

· If you are pregnant or think you may be pregnant.

 

Warnings and precautions

Talk to your doctor or pharmacist before taking Apriva.

Symptoms you should be aware of:

If your doctor considers you to be underweight, and you observe an unintentional loss of body weight while being treated with Apriva, you should talk to your doctor.

If you have severe kidney problems then the recommended dose of Apriva is 30 mg once a day (morning dose). Your doctor will talk to you about how to increase your dose when you first start taking Apriva.

Before starting treatment with Apriva, inform your doctor if you are suffering from symptoms of worsening depression with suicidal thinking or behaviour especially if you take any additional medicines since some of those could increase the probability of these side effects. You or your caregiver should also immediately inform your doctor of any changes in behaviour or mood and of any suicidal thoughts you may have. You may also experience sleeplessness, or depressive mood.

If you experience severe diarrhoea, nausea, or vomiting, you should talk to your doctor.

 

Children and adolescents

Apremilast has not been studied in children and adolescents, therefore it is not recommended for use in children and adolescents aged 17 years and under.

 

Other medicines and Apriva

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This includes medicines obtained without a prescription and herbal medicines. This is because Apriva can affect the way some other medicines work. Also some other medicines can affect the way Apriva works.

In particular, tell your doctor or pharmacist before taking Apriva if you are taking any of the following medicines:

· Rifampicin - an antibiotic used for tuberculosis

· Phenytoin, phenobarbital and carbamazepine - medicines used in the treatment of seizures or epilepsy

· St John’s Wort - a herbal medicine for mild anxiety and depression.  

 

Pregnancy and breast-feeding

There is little information about the effects of apremilast in pregnancy. You should not become pregnant while taking this medicine and should use an effective method of contraception during treatment with Apriva. It is not known if this medicine passes into human milk. You should not use Apriva while breast-feeding.

Tell your doctor if you think you may be pregnant or are planning to have a baby, or if you are breast-feeding or intend to breast-feed.

 

Driving and using machines

Apriva has no effect on the ability to drive and use machines.

 

Apriva contains lactose monohydrate

Apriva contains lactose (a type of sugar). If you have been told by your doctor that you cannot tolerate or digest some sugars, talk to your doctor before taking this medicine.


Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.

How much to take

• When you first start taking Apriva, you will receive a ‘starter pack’ which contains all the doses as listed in the table below.

• The ‘starter pack’ is clearly labelled to make sure you take the correct tablet at the correct time.

• Your treatment will start at a lower dose and will gradually be increased over the first 6 days of treatment.

• The ‘starter pack’ will also contain enough tablets for another 8 days at the recommended dose (Days 7 to 14).

• The recommended dose of Apriva is 30 mg twice a day after the titration phase is complete - one 30 mg dose in the morning and one 30 mg dose in the evening, approximately 12 hours apart, with or without food.

• This is a total daily dose of 60 mg. By the end of Day 6 you will have reached this recommended dose.

Once the recommended dose has been reached, you will only get the 30 mg tablet strength in your prescribed packs. You will only ever need to go through this stage of gradually increasing your dose once even if you re-start treatment.

 

Day

Morning Dose

Evening Dose

Total Daily Dose

Day 1

10 mg (Red)

Do not take a dose

10 mg

Day 2

10 mg (Red)

10 mg (Red)

20 mg

Day 3

10 mg (Red)

20 mg (White)

30 mg

Day 4

20 mg (White)

20 mg (White)

40 mg

Day 5

20 mg (White)

30 mg (Pink)

50 mg

Day 6 onwards

30 mg (Pink)

30 mg (Pink)

60 mg

People with kidney problems

If you have severe kidney problems, then the recommended dose of Apriva is 30 mg once a day (morning dose). Your doctor will talk to you about how to increase your dose when you first start taking Apriva.

 

How and when to take Apriva

• Swallow the tablets whole, preferably with water.

• You can take the tablets either with or without food.

• Take Apriva at about the same time each day, one tablet in the morning and one tablet in the evening.

• If your condition has not improved after six months of treatment, you should talk to your doctor.

 

If you take more Apriva than you should

If you take more Apriva than you should, talk to a doctor or go to a hospital straight away. Take the medicine pack and this leaflet with you. 

 

If you forget to take Apriva

• If you miss a dose of Apriva, take it as soon as you remember. If it is close to the time for your next dose, just skip the missed dose. Take the next dose at your regular time.

• Do not take a double dose to make up for a forgotten dose.

 

If you stop taking Apriva

• You should continue taking Apriva until your doctor tells you to stop.

• Do not stop taking Apriva without talking to your doctor first.

If you have any further questions on the use of this medicine, ask your doctor, or pharmacist.

 


Like all medicines, this medicine can cause side effects, although not everybody gets them.

Some side effects could be serious. Uncommon instances of suicidal thinking and behaviour (including suicide) were reported. Please notify your doctor immediately of any feelings of depression, suicidal thoughts or suicidal behaviour you may have. You may also experience sleeplessness (common), or depressive mood (common).

Very common side effects (may affect more than 1 in 10 people)

•    Diarrhoea

•    Nausea

 

Common side effects (may affect up to 1 in 10 people)

• Cough

• Back pain

• Vomiting

• Feeling tired

• Stomach pain

• Loss of appetite

• Frequent bowel movements

• Difficulty sleeping (insomnia)

•  Indigestion or heartburn

• Headaches, migraines or tension headaches

• Upper respiratory tract infections such as cold, runny nose, sinus infection

• Inflammation and swelling of the tubes in your lungs (bronchitis)

• Common cold (nasopharyngitis)

• Depression

 

Uncommon side effects (may affect up to 1 in 100 people)

• Rash

• Hives (urticaria)

• Weight loss

• Allergic reaction

• Bleeding in the bowel or in the stomach

• Suicidal ideation or behavior

 

Not known side effects (frequency cannot be estimated from the available data):

• Severe allergic reaction (may include swelling of the face, lips, mouth, tongue, or throat that may lead to difficulty breathing or swallowing) 

If you are 65 years of age or older, you might have higher risk of complications of severe diarrhea, nausea and vomiting.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.


Keep this medicine out of the sight and reach of children.

Do not store above 30°C.  

Store in the original package.

Do not use this medicine after the expiry date which is stated on the package after “EXP”. The expiry date refers to the last day of that month.

Do not use this medicine if you notice any visible signs of deterioration.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.


The active substance is apremilast. Each film-coated tablet of Apriva 10 mg, 20 mg or 30 mg Film-coated Tablets contains 10 mg, 20 mg or 30 mg apremilast; respectively.

The other ingredients are microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, Opadry II 85F250081 Red (in 10 mg tablets only), Opadry II 85F28751 White (in 20 mg tablets only) and Opadry II 85F240174 Pink (in 30 mg tablets only).


Apriva 10 mg Film-coated Tablets are red elliptical shaped film-coated tablet embossed with “A” on one side and “10” on the other side in ALU/PVC/ACLAR packs. Apriva 20 mg Film-coated Tablets are white elliptical shaped film-coated tablet embossed with “A” on one side and “20” on the other side in ALU/PVC/ACLAR packs. Apriva 30 mg Film-coated Tablets are Pink oval shaped film-coated tablet embossed with “A” on one side and “30” on the other side in ALU/PVC/ACLAR packs. Pack sizes: • Starter pack: 28 film-coated tablets: 4 (10 mg) film-coated tablets, 4 (20 mg) film-coated tablets and 20 (30 mg) film-coated tablets. • Standard pack: 60 (30 mg) film-coated tablets.

Jazeera Pharmaceutical Industries
Al-Kharj Road
P.O. BOX 106229
Riyadh 11666, Saudi Arabia
Tel: + (966-11) 8107023, + (966-11) 2142472
Fax: + (966-11) 2078170
e-mail: jpimedical@hikma.com

Manufacturer

Jazeera Pharmaceutical Industries
Al-Kharj Road
P.O. BOX 106229
Riyadh 11666, Saudi Arabia
Tel: + (966-11) 8107023, + (966-11) 2142472
Fax: + (966-11) 2078170
e-mail: jpimedical@hikma.com


This leaflet was last revised in 12/2019; version number SA1.0.
  نشرة الدواء تحت مراجعة الهيئة العامة للغذاء والدواء (اقرأ هذه النشرة بعناية قبل البدء في استخدام هذا المنتج لأنه يحتوي على معلومات مهمة لك)

ما هو أبريڤا

يحتوي أبريڤا على المادة الفعّالة "أبريميلاست". ينتمي هذا الدواء لمجموعة من الأدوية تسمى مثبطات فسفودايستراز 4 التي تساعد على تخفيف الالتهاب.

 

ما هي دواعي استخدام أبريڤا

يستخدم أبريڤا لعلاج البالغين الذين يعانون من الحالات المرضية التالية:

·  التهاب المفاصل الصدفي

- إذا لم يكن بإمكانك استخدام نوع آخر من الأدوية التي تسمى "الأدوية المضادة للروماتيزم المعدّلة لسير المرض" أو عند تجربة أحد هذه الأدوية دون أن يكون لها تأثير. 

· الصدفية اللويحية المتوسطة إلى الشديدة

- إذا لم يكن بإمكانك استخدام أي من العلاجات التالية أو عند تجربة أحد هذه العلاجات دون أن يكون لها تأثير:

- العلاج بالضوء، وهو علاج يتم فيه تعريض مناطق معينة من الجلد لضوء الأشعة فوق البنفسجية. 

- العلاج الشامل، وهو علاج يؤثر على الجسم بالكامل وليس على منطقة موضعية واحدة فحسب مثل: "سيكلوسبورين" أو "ميثوتركسيت".

 

ما هو التهاب المفاصل الصدفي

التهاب المفاصل الصدفي هو مرض التهابي يصيب المفاصل، مصحوب عادة بمرض الصدفية، وهو مرض التهابي يصيب الجلد.

 

ما هي الصدفية اللويحية

الصدفية هي مرض التهابي يصيب الجلد، ويمكن أن يسبب بقعاً حمراء، وتشبه القشور، وسميكة، وتسبب الحكة، ومؤلمة على الجلد، ويمكن أيضاً أن تؤثر على فروة الرأس والأظافر.

 

    طريقة عمل أبريڤا

يكون التهاب المفاصل الصدفي والصدفية عادةً حالتين مرضيتين تستمران طوال العمر ولا يوجد لهما علاج حالياً. يؤدي أبريڤا مفعوله من خلال تقليل نشاط إنزيم في الجسم يسمى "فسفودايستراز 4" والذي يشترك في العملية رقم 2 من الالتهاب. يمكن لأبريڤا المساعدة على السيطرة على الالتهاب المرتبط بالتهاب المفاصل الصدفي والصدفية ومن ثم تقليل علامات هذه الحالات المرضية وأعراضها، وذلك من خلال تقليل نشاط هذا الإنزيم. 

يؤدي العلاج بأبريڤا في حالة التهاب المفاصل الصدفي إلى تحسن حالة المفاصل المتورمة والمؤلمة ويمكنه تحسين وظيفة الجسم العامة.

يؤدي العلاج بأبريڤا في حالة الصدفية إلى تقليل اللويحات على البشرة المصابة بالصدفية، وعلامات المرض وأعراضه الأخرى.

أظهر أبريميلاست كذلك تحسينه لنوعية حياة المرضى المصابين بالصدفية أو التهاب المفاصل الصدفي. يعني ذلك أن تأثير حالتك المرضية على الأنشطة اليومية والعلاقات والعوامل الأخرى يجب أن يكون أقل من ذي قبل.

لا تتناول أبريڤا

· إذا كنت تعاني من حساسية لأبريميلاست أو لأي من المواد الأخرى المستخدمة في تركيبة هذا الدواء (المذكورة في القسم 6).

· إذا كنتِ حاملاً أو تعتقدين بأنك حاملاً.

 

الاحتياطات والتحذيرات

تحدث مع طبيبك أو الصيدلي قبل تناول أبريڤا.

أعراض يجب أن تكون على دراية بها:

إذا كان طبيبك يرى أن وزنك أقل من المعدل الطبيعي، ولاحظت فقداناً غير متعمد في وزن الجسم أثناء علاجك بأبريڤا، فعليك التحدث إلى طبيبك.

إذا كنت تعاني من مشاكل شديدة في الكلى، فحينها تكون الجرعة الموصى بها من أبريڤا هي 30 ملغم مرة واحدة يومياً (جرعة صباحية). سيتحدث إليك طبيبك بشأن كيفية زيادة جرعتك عند بدء تناول أبريڤا للمرة الأولى.

قبل بدء العلاج بأبريڤا، أخبر طبيبك إذا كنت تعاني من أعراض اكتئاب متفاقم مع تفكير أو سلوك انتحاري، خاصة إذا كنت تأخذ أي أدوية إضافية، حيث يمكن لبعض هذه الأدوية زيادة احتمالية هذه الآثار الجانبية. يجب أيضاً أن تخبر طبيبك أو يخبره مقدم الرعاية الصحية لك على الفور بأي تغييرات تطرأ على السلوك أو الحالة المزاجية وكذلك أي أفكار انتحارية قد تراودك. قد تعاني أيضاً من الأرق أو من حالة مزاجية اكتئابية.

إذا أُصبت بإسهال شديد أو غثيان أو قيء، فعليك استشارة طبيبك.

 

الأطفال والمراهقون

لم يخضع أبريميلاست للدراسة على الأطفال والمراهقين، لذلك لا يوصى باستخدامه للأطفال والمراهقين الذين تبلغ أعمارهم 17 عاماً وأقل.

 

الأدوية الأخرى وأبريڤا

أخبر طبيبك أو الصيدلي إذا كنت تأخذ، أخذت مؤخراً، أو قد تأخذ أية أدوية أخرى. يشمل ذلك الأدوية التي حصلت عليها بدون وصفة طبية والأدوية العشبية. ذلك لأن أبريڤا قد يؤثر على طريقة عمل بعض الأدوية الأخرى. وبعض الأدوية الأخرى قد تؤثر أيضاً على طريقة عمل أبريڤا.

أبلغ طبيبك أو الصيدلي قبل تناول أبريڤا إذا كنت تتناول أيّاً من الأدوية التالية على وجه الخصوص:

· ريفامبيسين - وهو مضاد حيوي يستخدم في علاج مرض السل

· فينيتوين وفينوباربيتال وكاربامازيبين - وهي أدوية تستخدم في علاج النوبات أو الصرع

· نبتة سانت جونز - وهو دواء عشبي لعلاج القلق الخفيف والاكتئاب. 

 

الحمل والرضاعة

يتوافر القليل من المعلومات حول آثار أبريميلاست على الحمل. يجب ألا تصبحي حاملاً أثناء العلاج بهذا الدواء، ويجب اتباع وسيلة فعّالة من وسائل منع الحمل أثناء العلاج بأبريڤا. من غير المعروف إذا ما كان هذا الدواء يصل إلى حليب الثدي أم لا. يجب ألا تستخدمي أبريڤا أثناء الرضاعة الطبيعية.

أخبري طبيبك إذا كنت تعتقدين أنك حاملاً أو تخططين للحمل أو إذا كنتِ مرضعاً أو تخططين لذلك.

 

تأثير أبريڤا على القيادة واستخدام الآلات  

ليس لأبريڤا أي تأثير على القدرة على القيادة واستخدام الآلات.

 

يحتوي أبريڤا على لاكتوز أحادي الماء

يحتوي أبريڤا على لاكتوز (نوع من السكر). إذا أخبرك طبيبك أنك لا يمكن أن تتحمل بعض السكريات، أو تهضمها، فاستشره قبل تناول هذا الدواء.

https://localhost:44358/Dashboard

قم دائماً بتناول هذا الدواء كما وصفه لك طبيبك تماماً. تأكد من طبيبك أو الصيدلي إذا كانت لديك أية استفسارات.

 

الجرعة المطلوبة

•  عند بدء تناول أبريڤا للمرة الأولى، ستستلم "عبوة بدء" تحتوي على جميع الجرعات كما هو مدرج في الجدول أدناه.

•  "عبوة البدء" تم توسيمها بوضوح لتضمن أنك تأخذ القرص الصحيح في الوقت الصحيح.

•  سيبدأ علاجك بتناول جرعة أقل، وسيتم زيادتها تدريجياً على مدار الأيام الستة الأولى من العلاج.

•  سوف تحتوي "عبوة البدء" أيضاً على أقراص كافية لثمانية أيام أخرى بالجرعة الموصى بها (تتراوح الأيام بين 7 أيام إلى 14 يوماً).

•  الجرعة الموصى بها من أبريڤا هي 30 ملغم مرتين يومياً بعد اكتمال مرحلة المعايرة، حيث تقسم إلى جرعة 30 ملغم في الصباح، وجرعة أخرى واحدة 30 ملغم في المساء، بفارق 12 ساعة تقريباً بين كل منهما مع الأكل أو بدونه.

•  هذه جرعة إجمالية يومية من 60 ملغم. بنهاية اليوم السادس ستكون قد وصلت إلى الجرعة الموصى بها.

بمجرد الوصول إلى الجرعة الموصى بها، ستتناول فقط القرص ذي تركيز 30 ملغم في عبواتك الموصوفة لك. ستحتاج للمرور بمرحلة زيادة الجرعة هذه تدريجياً لمرة واحدة فقط حتى وإن أعدت بدء تناول العلاج.

اليوم

الجرعة الصباحية

الجرعة المسائية

إجمالي الجرعة اليومية

اليوم الأول

10 ملغم (باللون الأحمر)

لا تتناول جرعة

10 ملغم

اليوم الثاني

10 ملغم (باللون الأحمر)

10 ملغم (باللون الأحمر)

20 ملغم

اليوم الثالث

10 ملغم (باللون الأحمر)

20 ملغم (باللون الأبيض)

30 ملغم

اليوم الرابع

20 ملغم (باللون الأبيض)

20 ملغم (باللون الأبيض)

40 ملغم

اليوم الخامس

20 ملغم (باللون الأبيض)

30 ملغم (باللون الوردي)

50 ملغم

اليوم السادس وما بعده

30 ملغم (باللون الوردي)

30 ملغم (باللون الوردي)

60 ملغم

 

الأشخاص الذين يعانون من مشاكل بالكلى

إذا كنت تعاني من مشاكل شديدة في الكلى، فحينها تكون الجرعة الموصى بها من أبريڤا هي 30 ملغم مرة واحدة يومياً (جرعة صباحية). سيتحدث إليك طبيبك بشأن كيفية زيادة جرعتك عند بدء تناول أبريڤا للمرة الأولى.

 

موعد وطريقة تناول أبريڤا

•  ابتلع الأقراص بالكامل، يفضل مع الماء.

•  يمكنك تناول الأقراص مع الطعام أو بدونه.

•  تناول أبريڤا في الوقت ذاته يومياً، بحيث تتناول قرصاً واحداً في الصباح، وقرصاً واحداً في المساء.

•  إذا لم تتحسن حالتك بعد مرور ستة أشهر من العلاج، فعليك استشارة طبيبك.

 

إذا تناولت جرعة زائدة من أبريڤا

إذا تناولت جرعة زائدة من أبريڤا، فاستشر طبيباً أو توجه إلى مستشفى على الفور. خذ معك عبوة الدواء وهذه النشرة.

 

إذا نسيت تناول أبريڤا

•  إذا نسيت تناول جرعة من أبريڤا، فتناولها فور تذكرها. وإذا كان الوقت قريباً لوقت تناول جرعتك التالية، فتجاوز الجرعة المنسية. وتناول الجرعة التالية في وقتك المعتاد.

•  لا تقم بتناول جرعة مضاعفة للتعويض عن الجرعة المنسية.

 

إذا توقفت عن تناول أبريڤا

•  يجب عليك الاستمرار بتناول أبريڤا حتى يخبرك الطبيب بالتوقف عن تناوله.

•  لا تتوقف عن تناول أبريڤا بدون استشارة طبيبك أولاً.

إذا كان لديك أية أسئلة إضافية حول استخدام هذا الدواء، يرجى استشارة الطبيب أو الصيدلي.

مثل جميع الأدوية، قد يسبب هذا الدواء آثاراً جانبيةً، إلا أنه ليس بالضرورة أن تحدث لدى جميع مستخدمي هذا الدواء.

بعض الآثار الجانبية قد تكون خطيرة. تم الإبلاغ عن حالات غير شائعة من التفكير والسلوك الانتحاري (بما فيها الانتحار). يرجى إخبار طبيبك على الفور بأي مشاعر اكتئاب أو أفكار انتحارية أو سلوك انتحاري قد تراودك. قد تعاني أيضاً من أرق (شائع)، أو حالة مزاجية اكتئابية (شائعة).

 

آثار جانبية شائعة جداً (قد تؤثر على أكثر من 1 من كل 10 أشخاص)

•  إسهال

•  غثيان

 

آثار جانبية شائعة (قد تؤثر على ما يصل إلى 1 من كل 10 أشخاص)

•  سعال

•  ألم في الظهر

•  قيء

•  شعور بالإرهاق

•  ألم في المعدة

•  فقدان الشهية

•  حركات متكررة في الأمعاء

•  صعوبة في النوم (أرق)

•  عسر الهضم، أو حرقة المعدة

•  نوبات صداع أو نوبات صداع نصفي أو نوبات صداع التوتر

•  حالات عدوى الجهاز التنفسي العلوي، مثل البرد وسيلان الأنف والتهاب الجيوب الأنفية

•  التهاب الأنابيب في رئتيك وتورمها (الشعب الهوائية)

•  نزلات البرد الشائعة (التهاب البلعوم الأنفي)

•  اكتئاب

 

آثار جانبية غير شائعة (قد تؤثر على ما يصل إلى 1 من كل 100 شخص)

•  طفح جلدي

•  شرى (أرتيكاريا)

•  فقدان الوزن

•  رد فعل تحسسي

•  نزف في الأمعاء أو في المعدة

•  فكر أو سلوك انتحاري

 

آثار جانبية غير معروفة (لا يمكن تقدير التكرار من البيانات المتاحة):

•  رد فعل تحسسي شديد (قد يشمل تورم الوجه أو الشفتين أو الفم أو اللسان أو الحلق الذي قد يؤدي لصعوبة في التنفس أو البلع) 

إذا كنت تبلغ من العمر 65 عاماً أو أكثر، فقد تكون أكثر عرضة لمضاعفات مثل الإسهال الشديد والغثيان والقيء.

تحدث إلى طبيبك أو الصيدلي، إذا عانيت من أي آثار جانبية. بما فيها الآثار التي لم يتم ذكرها في هذه النشرة.

احفظ هذا الدواء بعيداً عن مرأى ومتناول الأطفال.

لا يحفظ عند درجة حرارة أعلى من 30° مئوية.

يحفظ داخل العبوة الأصلية.

لا تستخدم هذا الدواء بعد تاريخ انتهاء الصلاحية المذكور على العبوة الخارجية. يشير تاريخ الانتهاء إلى اليوم الأخير من ذلك الشهر.

لا تستخدم هذا الدواء إذا لاحظت أي علامات تلف واضحة عليه.

لا تتخلص من الأدوية عن طريق مياه الصرف الصحي أو النفايات المنزلية. اسأل الصيدلي عن كيفية التخلص من الأدوية التي لم تعد بحاجة إليها. اتبع هذه الإجراءات للحفاظ على سلامة البيئة.

ما هي محتويات أبريڤا

المادة الفعّالة هي أبريميلاست. يحتوي كل قرص مغطى بطبقة رقيقة من أبريڤا 10 ملغم، 20 ملغم أو 30 ملغم أقراص مغطاة بطبقة رقيقة على 10 ملغم، 20 ملغم أو 30 ملغم أبريميلاست على التوالي.

المواد الأخرى المستخدمة في التركيبة التصنيعية هي سيلليلوز بلوري مكروي، لاكتوز أحادي الماء، كروس كارميللوز الصوديوم، ثنائي أكسيد السيليكون الغروي، ستيرات المغنيسيوم، أوبادري II 85F250081 أحمر (في أقراص 10 ملغم فقط)، أوبادري II 85F28751 أبيض (في أقراص 20 ملغم فقط) وأوبادري II 85F240174 وردي (في أقراص 30 ملغم فقط).

أبريڤا 10 ملغم أقراص مغطاة بطبقة رقيقة هي عبارة عن أقراص لونها أحمر بيضاوية الشكل مغطاة بطبقة رقيقة منقوش على أحد جانبيها "A" و"10" على الجانب الآخر معبأة في عبوات من الألومينيوم/كلوريد متعدد الڤينيل/أكلار.

أبريڤا 20 ملغم أقراص مغطاة بطبقة رقيقة هي عبارة عن أقراص لونها أبيض بيضاوية الشكل مغطاة بطبقة رقيقة منقوش على أحد جانبيها "A" و"20" على الجانب الآخر معبأة في عبوات من الألومينيوم/كلوريد متعدد الڤينيل/أكلار.

أبريڤا 30 ملغم أقراص مغطاة بطبقة رقيقة هي عبارة عن أقراص لونها وردي بيضاوية الشكل مغطاة بطبقة رقيقة منقوش على أحد جانبيها "A" و"30" على الجانب الآخر معبأة في عبوات من الألومينيوم/كلوريد متعدد الڤينيل/أكلار.

أحجام العبوات:

· عبوة البدء: 28 قرص مغطى بطبقة رقيقة: 4 (10 ملغم) أقراص مغطاة بطبقة رقيقة، 4 (20 ملغم) أقراص مغطاة بطبقة رقيقة و20 (30 ملغم) قرص مغطى بطبقة رقيقة.

العبوة الاعتيادية: 60 (30 ملغم) قرص مغطى بطبقة رقيقة.

اسم وعنوان مالك رخصة التسويق

شركة الجزيرة للصناعات الدوائية
طريق الخرج
صندوق بريد 106229
الرياض 11666، المملكة العربية السعودية

هاتف: 8107023 (11-966) +، 2142472 (11-966) +
فاكس: 2078170 (11-966) +
البريد الإلكتروني: jpimedical@hikma.com

 

الشركة المصنعة

شركة الجزيرة للصناعات الدوائية
طريق الخرج
صندوق بريد 106229
الرياض 11666، المملكة العربية السعودية

هاتف: 8107023 (11-966) +، 2142472 (11-966) +
فاكس: 2078170 (11-966) +
البريد الإلكتروني: jpimedical@hikma.com

تمت مراجعة هذه النشرة بتاريخ 12/2019؛ رقم النسخة SA1.0.
 Read this leaflet carefully before you start using this product as it contains important information for you

Apriva 10 mg Film-coated Tablets Apriva 20 mg Film-coated Tablets Apriva 30 mg Film-coated Tablets

Apriva 10 mg Film-coated Tablets Each film-coated tablet contains 10 mg apremilast. Excipient with known effect: Lactose monohydrate. Each film-coated tablet contains 43.67 mg lactose monohydrate. Apriva 20 mg Film-coated Tablets Each film-coated tablet contains 20 mg apremilast. Excipient with known effect: Lactose monohydrate. Each film-coated tablet contains 87.34 mg lactose monohydrate. Apriva 30 mg Film-coated Tablets Each film-coated tablet contains 30 mg apremilast. Excipient with known effect: Lactose monohydrate. Each film-coated tablet contains 131.0 mg lactose monohydrate. For the full list of excipients, see section 6.1.

Apriva 10 mg Film-coated Tablets Film-coated tablets. Red elliptical shaped film-coated tablet embossed with “A” on one side and “10” on the other side. Apriva 20 mg Film-coated Tablets Film-coated tablets. White elliptical shaped film-coated tablet embossed with “A” on one side and 20 on the other side. Apriva 30 mg Film-coated Tablets Film-coated tablets. Pink oval shaped film-coated tablet embossed with “A” on one side and 30 on the other side.

Psoriatic arthritis

Apriva, alone or in combination with Disease Modifying Antirheumatic Drugs (DMARDs), is indicated for the treatment of active psoriatic arthritis (PsA) in adult patients who have had an inadequate response or who have been intolerant to a prior DMARD therapy (see section 5.1).

 

Psoriasis

Apriva is indicated for the treatment of moderate to severe chronic plaque psoriasis in adult patients who failed to respond to or who have a contraindication to, or are intolerant to other systemic therapy including cyclosporine, methotrexate or psoralen and ultraviolet-A light (PUVA).


Treatment with Apriva should be initiated by specialists experienced in the diagnosis and treatment of psoriasis or psoriatic arthritis.

 

Posology

The recommended dose of apremilast is 30 mg twice daily taken orally, morning and evening, approximately 12 hours apart, with no food restrictions. An initial titration schedule is required as shown below in Table 1. No re-titration is required after initial titration.

 

Table 1: Dose titration schedule

Day 1

Day2

Day 3

Day 4

Day 5

Day 6 & thereafter

AM

AM

PM

AM

PM

AM

PM

AM

PM

AM

PM

10 mg

10 mg

10 mg

10 mg

20 mg

20 mg

20 mg

20 mg

30 mg

30 mg

30 mg

 

If patients miss a dose, the next dose should be taken as soon as possible. If it is close to the time for their next dose, the missed dose should not be taken and the next dose should be taken at the regular time.

During pivotal trials the greatest improvement was observed within the first 24 weeks of treatment. If a patient shows no evidence of therapeutic benefit after 24 weeks, treatment should be reconsidered. The patient's response to treatment should be evaluated on a regular basis.

 

Special populations

Elderly patients

No dose adjustment is required for this patient population (see sections 4.8 and 5.2).

 

Patients with renal impairment

No dose adjustment is needed in patients with mild and moderate renal impairment. The dose of apremilast should be reduced to 30 mg once daily in patients with severe renal impairment (creatinine clearance of less than 30 ml per minute estimated by the Cockcroft-Gault equation). For initial dose titration in this group, it is recommended that apremilast be titrated using only the AM schedule listed in Table 1 and the PM doses be skipped (see section 5.2).

 

Patients with hepatic impairment

No dose adjustment is necessary for patients with hepatic impairment (see section 5.2).

 

Paediatric population

The safety and efficacy of apremilast in children aged 0 to 17 years have not been established. No data are available.

Method of administration

Apriva is for oral use. The film-coated tablets should be swallowed whole, and can be taken either with or without food.


Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Pregnancy (see section 4.6).

Diarrhoea, Nausea, and Vomiting

There have been post-marketing reports of severe diarrhoea, nausea, and vomiting associated with the use of apremilast. Most events occurred within the first few weeks of treatment. In some cases, patients were hospitalized. Patients 65 years of age or older may be at a higher risk of complications. If patients develop severe diarrhoea, nausea, or vomiting, discontinuation of treatment with apremilast may be necessary.

 

Psychiatric disorders

Apremilast is associated with an increased risk of psychiatric disorders such as insomnia and depression. Instances of suicidal ideation and behaviour, including suicide, have been observed in patients with or without history of depression (see section 4.8). The risks and benefits of starting or continuing treatment with apremilast should be carefully assessed if patients report previous or existing psychiatric symptoms or if concomitant treatment with other medicinal products likely to cause psychiatric events is intended. Patients and caregivers should be instructed to notify the prescriber of any changes in behaviour or mood and of any suicidal ideation. If patients suffered from new or worsening psychiatric symptoms, or suicidal ideation or suicidal attempt is identified, it is recommended to discontinue treatment with apremilast.

 

Severe renal impairment

Apriva should be dose reduced to 30 mg once daily in patients with severe renal impairment (see sections 4.2 and 5.2).

 

Underweight patients

Patients who are underweight at the start of treatment should have their body weight monitored regularly. In the event of unexplained and clinically significant weight loss, these patients should be evaluated by a medical practitioner and discontinuation of treatment should be considered.

 

Apriva contains lactose monohydrate

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.


Co-administration of strong cytochrome P450 3A4 (CYP3A4) enzyme inducer, rifampicin, resulted in a reduction of systemic exposure of apremilast, which may result in a loss of efficacy of apremilast. Therefore, the use of strong CYP3A4 enzyme inducers (e.g. rifampicin, phenobarbital, carbamazepine, phenytoin and St. John's Wort) with apremilast is not recommended. Co-administration of apremilast with multiple doses of rifampicin resulted in a decrease in apremilast area-under-the-concentration time curve (AUC) and maximum serum concentration (Cmax) by approximately 72% and 43%, respectively. Apremilast exposure is decreased when administered concomitantly with strong inducers of CYP3A4 (e.g. rifampicin) and may result in reduced clinical response.

In clinical studies, apremilast has been administered concomitantly with topical therapy (including corticosteroids, coal tar shampoo and salicylic acid scalp preparations) and UVB phototherapy.

There was no clinically meaningful drug-drug interaction between ketoconazole and apremilast. Apremilast can be co-administered with a potent CYP3A4 inhibitor such as ketoconazole.

There was no pharmacokinetic drug-drug interaction between apremilast and methotrexate in psoriatic arthritis patients. Apremilast can be co-administered with methotrexate.

There was no pharmacokinetic drug-drug interaction between apremilast and oral contraceptives containing ethinyl estradiol and norgestimate. Apremilast can be co-administered with oral contraceptives.


Women of childbearing potential

Pregnancy should be excluded before treatment can be initiated. Women of childbearing potential should use an effective method of contraception to prevent pregnancy during treatment.

 

Pregnancy

Pregnancy Category C.

There are limited data about the use of apremilast in pregnant women.

Apremilast is contraindicated during pregnancy. Effects of apremilast on pregnancy included embryofetal loss in mice and monkeys, and reduced fetal weights and delayed ossification in mice at doses higher than the currently recommended highest human dose. No such effects were observed when exposure in animals was at 1.3-fold the clinical exposure (see section 5.3).

 

Breast-feeding

Apremilast was detected in milk of lactating mice (see section 5.3). It is not known whether apremilast, or its metabolites, are excreted in human milk. A risk to the breastfed infant cannot be excluded, therefore apremilast should not be used during breast-feeding.

 

Fertility

No fertility data is available in humans. In animal studies in mice, no adverse effects on fertility were observed in males at exposure levels 3-fold clinical exposure and in females at exposure levels 1-fold clinical exposure. For pre-clinical fertility data see section 5.3.


Apremilast has no or negligible influence on the ability to drive and use machines.


Summary of the safety profile

The most commonly reported adverse reactions in Phase III clinical studies have been gastrointestinal (GI) disorders including diarrhoea (15.7%) and nausea (13.9%). These GI adverse reactions were mostly mild to moderate in severity, with 0.3% of diarrhoea and 0.3% of nausea reported as being severe. These adverse reactions generally occurred within the first 2 weeks of treatment and usually resolved within 4 weeks. The other most commonly reported adverse reactions included upper respiratory tract infections (8.4%), headache (7.9%), and tension headache (7.2%). Overall, most adverse reactions were considered to be mild or moderate in severity.

The most common adverse reactions leading to discontinuation during the first 16 weeks of treatment were diarrhoea (1.7%), and nausea (1.5%). The overall incidence of serious adverse reactions was low and did not indicate any specific system organ involvement.

Hypersensitivity reactions were uncommonly observed in apremilast clinical studies (see section 4.3).

 

Tabulated list of adverse reactions

The adverse reactions observed in patients treated with apremilast are listed below by system organ class (SOC) and frequency for all adverse reactions. Within each SOC and frequency grouping, adverse reactions are presented in order of decreasing seriousness.

The adverse drug reactions were determined based on data from the apremilast clinical development programme. The frequencies of adverse drug reactions are those reported in the apremilast arms of the four Phase III studies in PsA (n = 1945) or the two Phase III studies in PSOR (n=1184) (highest frequency from either data pool is represented in Table 2).

Frequencies are defined as: 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); not known (cannot be estimated from the available data).

 

Table 2: Summary of adverse reactions in psoriatic arthritis (PsA) and/or psoriasis (PSOR)

System Organ Class

Frequency

Adverse reaction

 
 

Infections and infestations

Common

Bronchitis

 

Upper respiratory tract infection

 

Nasopharyngitis*

 

Immune system disorders

Uncommon

Hypersensitivity

 

Metabolism and nutrition disorders

Common

Decreased appetite*

 

Psychiatric disorders

Common

Insomnia

Depression

 

Uncommon

Suicidal ideation and behaviour #

 

Nervous system disorders

Common

Migraine*

 

Tension headache*

 

Headache*

 

Respiratory, thoracic, and mediastinal disorders

Common

Cough

 

Gastrointestinal disorders

Very Common

Diarrhoea*

 

Nausea*

 

Common

Vomiting*

 

Dyspepsia

 

Frequent bowel movements

 

Upper abdominal pain *

 

Gastroesophageal reflux disease

 

Uncommon

Gastrointestinal haemorrhage

 

Skin and subcutaneous tissue disorders

Uncommon

Rash

Urticaria

 

Not known

Angioedema

 

Musculoskeletal and connective tissue disorders

Common

Back pain*

 

General disorders and administrative site conditions

Common

Fatigue

 

Investigations

Uncommon

Weight decrease

 

*At least one of these adverse reactions was reported as serious

Description of selected adverse reactions

# In clinical studies and post-marketing experience, uncommon cases of suicidal ideation and behaviour, were reported, while completed suicide was reported post-marketing. Patients and caregivers should be instructed to notify the prescriber of any suicidal ideation (see also section 4.4).

 

Body weight loss

Patient weight was measured routinely in clinical studies. The mean observed weight loss in patients treated for up to 52 weeks with apremilast was 1.99 kg. A total of 14.3% of patients receiving apremilast had observed weight loss between 5-10% while 5.7% of the patients receiving apremilast had observed weight loss greater than 10%. None of these patients had overt clinical consequences resulting from weight loss. A total of 0.1% of patients treated with apremilast discontinued due to adverse reaction of weight decreased.

Please see additional warning in section 4.4 for patients who are underweight at beginning of treatment.

 

Special populations

Elderly patients

From post-marketing experience, elderly patients ≥ 65 years of age may be at a higher risk of complications of severe diarrhea, nausea and vomiting (see section 4.4).

 

Patients with hepatic impairment

The safety of apremilast was not evaluated in PsA or PSOR patients with hepatic impairment.

 

Patients with renal impairment

In the PsA or PSOR clinical studies, the safety profile observed in patients with mild renal impairment was comparable to patients with normal renal function. The safety of apremilast was not evaluated in PsA or PSOR patients with moderate or severe renal impairment in the clinical studies.

 

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

•    Saudi Arabia

The National Pharmacovigilance Center (NPC)

Fax: + (966-11) 2057662

Call NPC at: + (966-11) 2038222, Exts: 2317-2356-2340.

SFDA Call Center: 19999

e-mail: npc.drug@sfda.gov.sa

Website: https://ade.sfda.gov.sa/

•    Other GCC States

Please contact the relevant competent authority

 


Apremilast was studied in healthy subjects at a maximum total daily dose of 100 mg (given as 50 mg BID) for 4.5 days without evidence of dose limiting toxicities. In case of an overdose, it is recommended that the patient is monitored for any signs or symptoms of adverse effects and appropriate symptomatic treatment is instituted. In the event of overdose, symptomatic and supportive care is advised.


Pharmacotherapeutic group: Immunosupressants, selective immunosuppressants, ATC code: L04AA32

 

Mechanism of action

Apremilast, an oral small-molecule inhibitor of phosphodiesterase 4 (PDE4), works intracellularly to modulate a network of pro-inflammatory and anti-inflammatory mediators. PDE4 is a cyclic adenosine monophosphate (cAMP)-specific PDE and the dominant PDE in inflammatory cells.

PDE4 inhibition elevates intracellular cAMP levels, which in turn down-regulates the inflammatory response by modulating the expression of TNF-α, IL-23, IL-17 and other inflammatory cytokines. Cyclic AMP also modulates levels of anti-inflammatory cytokines such as IL-10. These pro- and anti-inflammatory mediators have been implicated in psoriatic arthritis and psoriasis.

 

Pharmacodynamic effects

In clinical studies in patients with psoriatic arthritis, apremilast significantly modulated, but did not fully inhibit, plasma protein levels of IL-1α, IL-6, IL-8, MCP-1, MIP-1β, MMP-3, and TNF-α. After 40 weeks of treatment with apremilast, there was a decrease in plasma protein levels of IL-17 and IL-23, and an increase in IL-10. In clinical trials in patients with psoriasis, apremilast decreased lesional skin epidermal thickness, inflammatory cell infiltration, and expression of pro-inflammatory genes, including those for inducible nitric oxide synthase (iNOS), IL-12/IL-23p40, IL-17A, IL-22 and IL-8.

Apremilast administered at doses of up to 50 mg BID did not prolong the QT interval in healthy subjects.

 

Clinical trials experience

Psoriatic Arthritis

The safety and efficacy of apremilast were evaluated in 3 multi-center, randomized, double-blind, placebo-controlled studies (Studies PALACE 1, PALACE 2, and PALACE 3) of similar design in adult patients with active PsA (≥ 3 swollen joints and ≥ 3 tender joints) despite prior treatment with small molecule or biologic DMARDs. A total of 1493 patients were randomised and treated with either placebo, apremilast 20 mg or apremilast 30 mg given orally twice daily.

Patients in these studies had a diagnosis of PsA for at least 6 months. One qualifying psoriatic skin lesion (at least 2 cm in diameter) was also required in PALACE 3. Apremilast was used as a monotherapy (34.8%) or in combination with stable doses of small molecule DMARDs (65.2%).

Patients received apremilast in combination with one or more of the following: methotrexate (MTX, ≤ 25 mg/week, 54.5%), sulfasalazine (SSZ, ≤ 2 g/day, 9.0%), and leflunomide (LEF; ≤ 20 mg/day, 7.4%). Concomitant treatment with biologic DMARDs, including TNF blockers, was not allowed. Patients with each subtype of PsA were enrolled in the 3 studies, including symmetric polyarthritis (62.0%), asymmetric oligoarthritis (26.9%), distal interphalangeal (DIP) joint arthritis (6.2%), arthritis mutilans (2.7%), and predominant spondylitis (2.1%). Patients with pre-existing enthesopathy (63%) or pre-existing dactylitis (42%) were enrolled. A total of 76.4% of patients were previously treated with only small-molecule DMARDs and 22.4% of patients were previously treated with biologic DMARDs, which includes 7.8% who had a therapeutic failure with a prior biologic DMARD. The median duration of PsA disease was 5 years.

Based on the study design, patients whose tender and swollen joint counts had not improved by at least 20% were considered non-responders at Week 16. Placebo patients who were considered non-responders were re-randomized 1:1 in a blinded fashion to either apremilast 20 mg twice daily or 30 mg twice daily. At Week 24, all remaining placebo-treated patients were switched to either apremilast 20 or 30 mg BID. Following 52 weeks of treatment, patients could continue on open label apremilast 20 mg or 30 mg within the long-term extension of the PALACE 1, PALACE 2, and PALACE 3 studies for a total duration of treatment up to 5 years (260 weeks).

The primary endpoint was the percentage of patients achieving American College of Rheumatology (ACR) 20 response at Week 16.

Treatment with apremilast resulted in significant improvements in the signs and symptoms of PsA, as assessed by the ACR 20 response criteria compared to placebo at Weeks 16. The proportion of patients with ACR 20/50/70 (responses in Studies PALACE 1, PALACE 2 and PALACE 3, and the pooled data for studies PALACE 1, PALACE 2 and PALACE 3) for apremilast 30 mg twice daily at Week 16 are shown in Table 3. ACR 20/50/70 responses were maintained at Week 24.

Among patients who were initially randomized to apremilast 30 mg twice daily treatment, ACR 20/50/70 response rates were maintained through Week 52 in the pooled Studies PALACE 1, PALACE 2 and PALACE 3 (Figure 1).

 

Table 3: Proportion of patients with ACR responses in studies PALACE 1, PALACE 2 and PALACE 3 and pooled studies at Week 16

 

PALACE 1

PALACE 2

PALACE 3

POOLED

Na

Placebo

+/-

DMARDs N=168

Apremilast 30 mg BID

+/-

DMARDs N=168

Placebo

+/-

DMARDs N=159

Apremilast 30 mg BID

+/-

DMARDs N=162

Placebo

+/-

DMARDs N=169

Apremilast 30 mg BID

+/-

DMARDs N=167

Placebo

+/-

DMARDs N=496

Apremilast 30 mg BID

+/-

DMARDs N=497

ACR 20a

        

Week 16

19.0%

38.1%**

18.9%

32.1%*

18.3%

40.7%**

18.8%

37.0%**

ACR 50

        

Week 16

6.0%

16.1%*

5.0%

10.5%

8.3%

15.0%

6.5%

13.9%**

ACR 70

        

Week 16

1.2%

4.2%

0.6%

1.2%

2.4%

3.6%

1.4%

3.0%

*p ≤ 0.01 for apremilast vs. placebo.

**p ≤ 0.001 for apremilast vs. placebo

N is the number of patients as randomized and treated.

 

Figure 1: Proportion of ACR 20/50/70 responders through Week 52 in the pooled analysis of studies PALACE 1, PALACE 2 and PALACE 3 (NRI*)

*NRI: None responder imputation. Subjects who discontinued early prior to the time point and subjects who did not have sufficient data for a definitive determination of response status at the time point are counted as non-responders.

Among 497 patients initially randomized to apremilast 30 mg twice daily, 375 (75%) patients were still on this treatment on Week 52. In these patients, ACR 20/50/70 responses at Week 52 were of 57%, 25%, and 11% respectively. Among 497 patients initially randomized to apremilast 30 mg twice daily, 375 (75%) patients entered the long term extension studies, and of these, 221 patients (59%) were still on this treatment at Week 260. ACR responses were maintained in the long-term open label extension studies for up to 5 years.

Responses observed in the apremilast treated group were similar in patients receiving and not receiving concomitant DMARDs, including MTX. Patients previously treated with DMARDs or biologics who received apremilast achieved a greater ACR 20 response at Week 16 than patients receiving placebo.

Similar ACR responses were observed in patients with different PsA subtypes, including DIP. The number of patients with arthritis mutilans and predominant spondylitis subtypes was too small to allow meaningful assessment.

In PALACE 1, PALACE 2 and PALACE 3, improvements in Disease Activity Scale (DAS) 28 C-reactive protein (CRP) and in the proportion of patients achieving a modified PsA response criteria (PsARC) were greater in the apremilast group, compared to placebo at Week 16 (nominal p-value p< 0.0004, p-value ≤0.0017, respectively). These improvements were maintained at Week 24. Among patients who remained on the apremilast treatment to which they were randomized at study start, DAS28(CRP) score and PsARC response were maintained through Week 52.

At Weeks 16 and 24 improvements in parameters of peripheral activity characteristic of psoriatic arthritis (e.g. number of swollen joints, number of painful/tender joints, dactylitis and enthesitis) and in the skin manifestations of psoriasis were seen in the apremilast-treated patients. Among patients who remained on the apremilast treatment to which they were randomized at study start, these improvements were maintained through Week 52.

The clinical responses were maintained in the same parameters of peripheral activity and in the skin manifestations of psoriasis in the open-label extension studies for up to 5 years of treatment.

 

Physical function and health-related quality of life

Apremilast-treated patients demonstrated statistically significant improvement in physical function, as assessed by the disability index of the health assessment questionnaire (HAQ-DI) change from baseline, compared to placebo at Weeks 16 in PALACE 1, PALACE 2 and PALACE 3 and in the pooled studies Improvement in HAQ-DI scores was maintained at Week 24.

Among patients who were initially randomized to apremilast 30 mg twice daily treatment, the change from baseline in the HAQ-DI score at week 52 was -0.333 in the apremilast 30 mg twice daily group in a pooled analysis of the open label phase of studies PALACE 1, PALACE 2 and PALACE 3.

In studies PALACE 1, PALACE 2 and PALACE 3, significant improvements were demonstrated in health-related quality of life, as measured by the changes from baseline in the physical functioning (PF) domain of the Short Form Health Survey version 2 (SF-36v2), and in the Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-fatigue) scores in patients treated with apremilast compared to placebo at Weeks 16 and 24. Among patients who remained on the apremilast treatment, to which they were initially randomized at study start, improvement in physical function and FACIT- fatigue was maintained through Week 52.

Improved physical function as assessed by the HAQ-DI and the SF36v2PF domain, and the FACIT-fatigue scores were maintained in the open-label extension studies for up to 5 years of treatment.

 

Psoriasis

The safety and efficacy of apremilast were evaluated in two multicenter, randomized, double-blind, placebo-controlled studies (Studies ESTEEM 1 and ESTEEM 2) which enrolled a total of 1257 patients with moderate to severe plaque psoriasis who had a body surface area (BSA) involvement of ≥ 10%, Psoriasis Area and Severity Index (PASI) score ≥ 12, static Physician Global Assessment (sPGA) of ≥ 3 (moderate or severe), and who were candidates for phototherapy or systemic therapy.

These studies had a similar design through Week 32. In both studies, patients were randomized 2:1 to apremilast 30 mg BID or placebo for 16 weeks (placebo-controlled phase) and from Weeks 16-32, all patients received apremilast 30 mg BID (maintenance phase). During the Randomized Treatment Withdrawal Phase (Weeks 32-52), patients originally randomized to apremilast who achieved at least a 75% reduction in their PASI score (PASI-75) (ESTEEM 1) or a 50% reduction in their PASI score (PASI-50) (ESTEEM 2) were re-randomized at Week 32 to either placebo or apremilast 30 mg BID. Patients who were re-randomized to placebo and who lost PASI-75 response (ESTEEM 1) or lost 50% of the PASI improvement at Week 32 compared to baseline (ESTEEM 2) were retreated with apremilast 30 mg BID. Patients who did not achieve the designated PASI response by Week 32, or who were initially randomized to placebo, remained on apremilast until Week 52. The use of low potency topical corticosteroids on the face, axillae, and groin, coal tar shampoo and/or salicylic acid scalp preparations was permitted throughout the studies. In addition, at Week 32, subjects who did not achieve a PASI-75 response in ESTEEM 1, or a PASI-50 response in ESTEEM 2, were permitted to use topical psoriasis therapies and/or phototherapy in addition to apremilast 30 mg BID treatment.

Following 52 weeks of treatment, patients could continue on open-label apremilast 30mg within the long-term extension of the ESTEEM 1 and ESTEEM 2 studies for a total duration of treatment up to 5 years (260 weeks).

In both studies, the primary endpoint was the proportion of patients who achieved PASI-75 at Week 16. The major secondary endpoint was the proportion of patients who achieved a sPGA score of clear (0) or almost clear (1) at Week 16.

The mean baseline PASI score was 19.07 (median 16.80), and the proportion of patients with sPGA score of 3 (moderate) and 4 (severe) at baseline was 70.0% and 29.8%, respectively with a mean baseline BSA involvement of 25.19% (median 21.0%). Approximately 30% of all patients had received prior phototherapy and 54% had received prior conventional systemic and/or biologic therapy for the treatment of psoriasis (including treatment failures), with 37% receiving prior conventional systemic therapy and 30% receiving prior biologic therapy. Approximately one-third of patients had not received prior phototherapy, conventional systemic or biologic therapy. A total of 18% of patients had a history of psoriatic arthritis.

The proportion of patients achieving PASI-50, -75 and -90 responses, and sPGA score of clear (0) or almost clear (1), are presented in Table 4 below. Treatment with apremilast resulted in significant improvement in moderate to severe plaque psoriasis as demonstrated by the proportion of patients with PASI-75 response at Week 16, compared to placebo. Clinical improvement measured by sPGA, PASI-50 and PASI-90 responses were also demonstrated at Week 16. In addition, apremilast demonstrated a treatment benefit across multiple manifestations of psoriasis including pruritus, nail disease, scalp involvement and quality of life measures.

 

Table 4: Clinical response at week 16 in studies ESTEEM 1 and ESTEEM 2 (FAS a, LOCFb)

 

ESTEEM 1

ESTEEM 2

Placebo

30 mg BID APR*

Placebo

30 mg BID APR*

N

282

562

137

274

PASIc 75, n (%)

15 (5.3)

186 (33.1)

8 (5.8)

79 (28.8)

sPGAd of Clear or

Almost Clear, n (%)

11 (3.9)

122 (21.7)

6 (4.4)

56 (20.4)

PASI 50, n (%)

48 (17.0)

330 (58.7)

27 (19.7)

152 (55.5)

PASI 90, n (%)

1 (0.4)

55 (9.8)

2 (1.5)

24 (8.8)

Percent Change BSAe (%)

mean± SD

- 6.9

± 38.95

- 47.8

± 38.48

- 6.1

± 47.57

-48.4

± 40.78

Change in Pruritus VASf (mm), mean± SD

- 7.3

± 27.08

- 31.5

± 32.43

- 12.2

± 30.94

- 33.5

±35.46

Change in DLQIg, mean± SD

- 2.1

± 5.69

- 6.6

± 6.66

-2.8

± 7.22

-6.7

± 6.95

Change in SF-36 MCS h, mean± SD

- 1.02

± 9.161

2.39

± 9.504

0.00

±10.498

2.58

± 10.129

*p< 0.0001 for apremilast vs placebo, except for ESTEEM 2 PASI 90 and Change in SF-36 MCS where p=0.0042 and p=0.0078, respectively.

a FAS = Full Analysis Set

b LOCF= Last Observation Carried forward

c PASI = Psoriasis Area and Severity Index

d sPGA = Static Physician Global Assessment

e BSA = Body Surface Area

VAS = Visual Analog Scale; 0 = best, 100 = worst

g DLQI = Dermatology Life Quality Index; 0 = best, 30 = worst

h SF-36 MCS = Medical Outcome Study Short Form 36-Item Health Survey, Mental Component Summary

 

The clinical benefit of apremilast was demonstrated across multiple subgroups defined by baseline demographics and baseline clinical disease characteristics (including psoriasis disease duration and patients with a history of psoriatic arthritis). The clinical benefit of apremilast was also demonstrated regardless of prior psoriasis medication usage and response to prior psoriasis treatments. Similar response rates were observed across all weight ranges.

Response to apremilast was rapid, with significantly greater improvements in the signs and symptoms of psoriasis, including PASI, skin discomfort/pain and pruritus, compared to placebo by Week 2. In general, PASI responses were achieved by Week 16 and were maintained through Week 32.

In both studies, the mean percent improvement in PASI from baseline remained stable during the Randomized Treatment Withdrawal Phase for patients re-randomized to apremilast at Week 32 (Table 5).

 

Table 5: Persistence of effect among subjects randomized to APR 30 BID at Week 0 and re-randomized to APR 30 BID at Week 32 to Week 52

 

Time Point

ESTEEM 1

ESTEEM 2

 

Patients who achieved PASI-75 at Week 32

Patients who achieved PASI-50 at Week 32

 
 

Percent Change in PASI from baseline, mean (%) ± SDa

Week 16

-77.7 ± 20.30

-69.7 ± 24.23

 

Week 32

-88 ± 8.30

-76.7 ± 13.42

 

Week 52

-80.5 ± 12.60

-74.4 ± 18.91

 

Change in DLQI from baseline, mean± SDa

Week 16

-8.3 ± 6.26

-7.8 ± 6.41

 

Week 32

-8.9 ± 6.68

-7.7 ± 5.92

 

Week 52

-7.8 ± 5.75

-7.5 ± 6.27

 

Proportion of subjects with Scalp Psoriasis PGA (ScPGA) 0 or 1, n/N (%)b

Week 16

40/48 (83.3)

21/37 (56.8)

 

Week 32

39/48 (81.3)

27/37 (73.0)

 

Week 52

35/48 (72.9)

20/37 (54.1)

 

Includes subjects re-randomized to APR 30 BID at Week 32 with a baseline value and a post-baseline value at the evaluated study week.

bN is based on subjects with moderate or greater scalp psoriasis at baseline who were re-randomized to APR 30 BID at Week 32. Subjects with missing data were counted as nonresponders.

 

In Study ESTEEM 1, approximately 61% of patients re-randomized to apremilast at Week 32 had a PASI-75 response at Week 52. Of the patients with at least a PASI-75 response who were re-randomized to placebo at Week 32 during a Randomized Treatment Withdrawal Phase, 11.7% were PASI-75 responders at Week 52. The median time to loss of PASI-75 response among the patients re-randomized to placebo was 5.1 weeks.

In Study ESTEEM 2, approximately 80.3% of patients re-randomized to apremilast at Week 32 had a PASI-50 response at Week 52. Of the patients with at least a PASI-50 response who were re-randomized to placebo at Week 32, 24.2% were PASI-50 responders at Week 52. The median time to loss of 50% of their Week 32 PASI improvement was 12.4 weeks.

After randomized withdrawal from therapy at Week 32, approximately 70% of patients in Study ESTEEM 1, and 65.6% of patients in Study ESTEEM 2, regained PASI-75 (ESTEEM 1) or PASI-50 (ESTEEM 2) responses after re-initiation of apremilast treatment. Due to the study design the duration of re-treatment was variable, and ranged from 2.6 to 22.1 weeks.

In Study ESTEEM 1, patients randomized to apremilast at the start of the study who did not achieve a PASI-75 response at Week 32 were permitted to use concomitant topical therapies and/or UVB phototherapy between Weeks 32 to 52. Of these patients, 12% achieved a PASI-75 response at Week 52 with apremilast plus topical and/or phototherapy treatment.

In Studies ESTEEM 1 and ESTEEM 2, significant improvements (reductions) in nail psoriasis, as measured by the mean percent change in Nail Psoriasis Severity Index (NAPSI) from baseline, were observed in patients receiving apremilast compared to placebo-treated patients at Week 16 (p< 0.0001 and p=0.0052, respectively). Further improvements in nail psoriasis were observed at Week 32 in patients continuously treated with apremilast.

In Studies ESTEEM 1 and ESTEEM 2, significant improvements in scalp psoriasis of at least moderate severity (≥3), measured by the proportion of patients achieving Scalp Psoriasis Physician's Global Assessment (ScPGA) of clear (0) or minimal (1) at Week 16, were observed in patients receiving apremilast compared to placebo-treated patients (p< 0.0001 for both studies). The improvements were generally maintained in subjects who were re-randomized to apremilast at Week 32 through Week 52 (Table 5).

In Studies ESTEEM 1 and ESTEEM 2, significant improvements in quality of life as measured by the Dermatology Life Quality Index (DLQI) and the SF-36v2MCS were demonstrated in patients receiving apremilast compared with placebo-treated patients (Table 4). Improvements in DLQI were maintained through Week 52 in subjects who were re-randomized to apremilast at Week 32 (Table 5). In addition, in Study ESTEEM 1, significant improvement in the Work Limitations Questionnaire (WLQ-25) Index was achieved in patients receiving apremilast compared to placebo.

Among 832 patients initially randomized to apremilast 30 mg twice daily, 443 patients (53%) entered the open-label extension studies of ESTEEM 1 and ESTEEM 2, and of these 115 patients (26%) were still on treatment at week 260. For patients who remained on apremilast in the open label extension of ESTEEM 1 and ESTEEM 2 studies, improvements were generally maintained in PASI score, affected BSA, itch, nail and quality of life measures for up to 5 years.

The long-term safety of apremilast 30 mg twice daily in patients with psoriatic arthritis and psoriasis was assessed for a total duration of treatment up to 5 years. Long-term experience in open-label extension studies with apremilast was generally comparable to the 52-week studies.


Absorption

Apremilast is well absorbed with an absolute oral bioavailability of approximately 73%, with peak plasma concentrations (Cmax) occurring at a median time (tmax) of approximately 2.5 hours. Apremilast pharmacokinetics are linear, with a dose-proportional increase in systemic exposure in the dose range of 10 to 100 mg daily. Accumulation is minimal when apremilast is administered once daily and approximately 53% in healthy subjects and 68% in patients with psoriasis when administered twice daily. Co-administration with food does not alter the bioavailability therefore, apremilast can be administered with or without food.

 

Distribution

Human plasma protein binding of apremilast is approximately 68%. The mean apparent volume of distribution (Vd) is 87 L, indicative of extravascular distribution.

 

Biotransformation

Apremilast is extensively metabolised by both CYP and non-CYP mediated pathways including oxidation, hydrolysis, and conjugation, suggesting inhibition of a single clearance pathway is not likely to cause a marked drug-drug interaction. Oxidative metabolism of apremilast is primarily mediated by CYP3A4, with minor contributions from CYP1A2 and CYP2A6. Apremilast is the major circulating component following oral administration. Apremilast undergoes extensive metabolism with only 3% and 7% of the administered parent compound recovered in urine and faeces, respectively. The major circulating inactive metabolite is the glucuronide conjugate of O-demethylated apremilast (M12). Consistent with apremilast being a substrate of CYP3A4, apremilast exposure is decreased when administered concomitantly with rifampicin, a strong inducer of CYP3A4.

In vitro, apremilast is not an inhibitor or inducer of cytochrome P450 enzymes. Hence, apremilast co-administered with substrates of CYP enzymes is unlikely to affect the clearance and exposure of active substances that are metabolised by CYP enzymes.

In vitro, apremilast is a substrate, and a weak inhibitor of P-glycoprotein (IC50>50µM), however clinically relevant drug interactions mediated via P-gp are not expected to occur.

In vitro, apremilast has little to no inhibitory effect (IC50>10µM) on Organic Anion Transporter (OAT)1 and OAT3, Organic Cation Transporter (OCT)2, Organic Anion Transporting Polypeptide (OATP)1B1 and OATP1B3, or breast cancer resistance protein (BCRP) and is not a substrate for these transporters. Hence, clinically relevant drug-drug interactions are unlikely when apremilast is co-administered with drugs that are substrates or inhibitors of these transporters.

 

Elimination

The plasma clearance of apremilast is on average about 10 L/hr in healthy subjects, with a terminal elimination half-life of approximately 9 hours. Following oral administration of radiolabelled apremilast, about 58% and 39% of the radioactivity is recovered in urine and faeces, respectively, with about 3% and 7% of the radioactive dose recovered as apremilast in urine and faeces, respectively.

 

Elderly patients

Apremilast was studied in young and elderly healthy subjects. The exposure in elderly subjects (65 to 85 years of age) is about 13% higher in AUC and about 6% higher in Cmax for apremilast than that in young subjects (18 to 55 years of age). There is limited pharmacokinetic data in subjects over 75 years of age in clinical trials. No dosage adjustment is necessary for elderly patients.

 

Renal impairment

There is no meaningful difference in the PK of apremilast between mild or moderate renal impaired subjects and matched healthy subjects (N=8 each). The results support that no dose adjustment is needed in patients with mild and moderate renal impairment. Reduce apremilast dose to 30 mg once daily in patients with severe renal impairment (eGFR less than 30 ml/min/1.73 m2 or CLcr < 30 ml/min). In 8 subjects with severe renal impairment to whom a single dose of 30 mg apremilast was administered, the AUC and Cmax of apremilast increased by approximately 89% and 42%, respectively.

 

Hepatic impairment

The pharmacokinetics of apremilast and its major metabolite M12 are not affected by moderate or severe hepatic impairment. No dose adjustment is necessary for patients with hepatic impairment.


Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology and repeated dose toxicity. There is no evidence for immunotoxic, dermal irritation, or phototoxic potential.

 

Fertility and early embryonic development

In a male mouse fertility study, apremilast at oral dosages of 1, 10, 25, and 50 mg/kg/day produced no effects on male fertility; the no observed adverse effect level (NOAEL) for male fertility was greater than 50 mg/kg/day 3-fold clinical exposure).

In a combined female mouse fertility and embryo-fetal developmental toxicity study with oral dosages of 10, 20, 40, and 80 mg/kg/day, a prolongation of oestrous cycles and increased time to mating were observed at 20 mg/kg/day and above; despite this, all mice mated and pregnancy rates were unaffected. The no observed effect level (NOEL) for female fertility was 10 mg/kg/day (1.0-fold clinical exposure).

 

Embryo-fetal development

In a combined female mouse fertility and embryo-fetal developmental toxicity study with oral dosages of 10, 20, 40, and 80 mg/kg/day, absolute and/or relative heart weights of maternal animals were increased at 20, 40, and 80 mg/kg/day. Increased numbers of early resorptions and reduced numbers of ossified tarsals were observed at 20, 40, and 80 mg/kg/day. Reduced fetal weights and retarded ossification of the supraoccipital bone of the skull were observed at 40 and 80 mg/kg/day. The maternal and developmental NOEL in the mouse was 10 mg/kg/day (1.3-fold clinical exposure).

In a monkey embryo-fetal developmental toxicity study, oral dosages of 20, 50, 200, and 1000 mg/kg/day resulted in a dose-related increase in prenatal loss (abortions) at dosages of 50 mg/kg/day and above; no test article-related effect in prenatal loss was observed at 20 mg/kg/day (1.4-fold clinical exposure).

 

Pre- and post-natal development

In a pre- and postnatal study, apremilast was administered orally to pregnant female mice at dosages of 10, 80 and 300 mg/kg/day from gestation day (GD) 6 to Day 20 of lactation.

Reductions in maternal body weight and weight gain, and one death associated with difficulty in delivering pups were observed at 300 mg/kg/day. Physical signs of maternal toxicity associated with delivering pups were also observed in one mouse at each of 80 and 300 mg/kg/day.

Increased peri- and postnatal pup deaths and reduced pup body weights during the first week of lactation were observed at ≥ 80 mg/kg/day (≥ 4.0-fold clinical exposure). There were no apremilast-related effects on duration of pregnancy, number of pregnant mice at the end of the gestation period, number of mice that delivered a litter, or any developmental effects in the pups beyond postnatal day 7. It is likely that pup developmental effects observed during the first week of the postnatal period were related to the apremilast-related pup toxicity (decreased pup weight and viability) and/or lack of maternal care (higher incidence of no milk in the stomach of pups). All developmental effects were observed during the first week of the postnatal period; no apremilast-related effects were seen during the remaining pre- and post-weaning periods, including sexual maturation, behavioural, mating, fertility and uterine parameters. The NOEL in the mouse for maternal toxicity and F1 generation was 10 mg/kg/day (1.3-fold clinical AUC).

 

Carcinogenicity studies

Carcinogenicity studies in mice and rats showed no evidence of carcinogenicity related to treatment with apremilast.

 

Genotoxicity studies

Apremilast is not genotoxic. Apremilast did not induce mutations in an Ames assay or chromosome aberrations in cultured human peripheral blood lymphocytes in the presence or absence of metabolic activation. Apremilast was not clastogenic in an in vivo mouse micronucleus assay at doses up to 2000 mg/kg/day.

 

Other studies

There is no evidence for immunotoxic, dermal irritation, or phototoxic potential.


Apriva 10 mg Film-coated Tablets

-   Microcrystalline cellulose

-   Lactose monohydrate

-   Croscarmellose sodium

-   Colloidal silicon dioxide

-   Magnesium stearate

-   Opadry II 85F250081 Red in (Apriva 10 mg Film-coated Tablets)

-   Opadry II 85F28751 White (Apriva 20 mg Film-coated Tablets)

-   Opadry II 85F240174 Pink (Apriva 20 mg Film-coated Tablets)


Not applicable.


24 months.

Do not store above 30°C.

Store in the original package.


ALU/PVC/ACLAR Pack.

Pack sizes:

Starter pack: 28 film-coated tablets: 4 (10 mg) film-coated tablets, 4 (20 mg) film-coated tablets and 20 (30 mg) film-coated tablets.


Any unused medicinal product or waste material should be disposed of in accordance with local requirements.


Jazeera Pharmaceutical Industries Al-Kharj Road P.O. BOX 106229 Riyadh 11666, Saudi Arabia Tel: + (966-11) 8107023, + (966-11) 2142472 Fax: + (966-11) 2078170 e-mail: jpimedical@hikma.com

03 September 2019
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