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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)

ABODEX contains a medicine called abiraterone acetate. It is used to treat prostate cancer in adult

men that has spread to other parts of the body. ABODEX stops your body from making testosterone;

this can slow the growth of prostate cancer.

When ABODEX is prescribed for the early stage of disease where it is still responding to hormone

therapy, it is used with a treatment that lowers testosterone (androgen deprivation therapy).

When you take this medicine, your doctor will also prescribe another medicine called prednisone or

prednisolone. This is to lower your chances of getting high blood pressure, having too much water in

your body (fluid retention) or having reduced levels of a chemical known as potassium in your blood.


Do not take ABODEX if:

-  you are allergic to abiraterone acetate or any of the other ingredients of this medicine (listed

in section 6(

-  you are a woman, especially if pregnant. ABODEX is for use in male patients only.

-  you have severe liver damage.

-  in combination with Ra-223 (which is used to treat prostate cancer).

 

Do not take this medicine if any of the above apply to you. If you are not sure, talk to your doctor or

pharmacist before taking this medicine.

 

Warnings and precautions

Talk to your doctor or pharmacist before taking this medicine:

 - if you have liver problems

 - if you have been told you have high blood pressure or heart failure or low blood potassium (low

blood potassium may increase the risk of heart rhythm problems

 - if you have had other heart or blood vessel problems

-  if you have an irregular or rapid heart rate

-  if you have shortness of breath

-  if you have gained weight rapidly

-  if you have swelling in the feet, ankles, or legs

-  if you have taken a medicine known as ketoconazole in the past for prostate cancer

-  about the need to take this medicine with prednisone or prednisolone

 - about possible effects on your bones

 - if you have high blood sugar.

Tell your doctor if you have been told you have any heart or blood vessel conditions, including heart

rhythm problems (arrhythmia) or are being treated with medicines for these conditions.

 

Tell your doctor if you have yellowing of the skin or eyes, darkening of the urine, or severe nausea or

vomiting, as these could be signs or symptoms of liver problems. Rarely, failure of the liver to

function (called acute liver failure) may occur, which can lead to death.

 

Decrease in red blood cells, reduced sex drive (libido), muscle weakness and/or muscle pain may

occur.

ABODEX must not be given in combination with Ra-223 due to a possible increase in the risk of bone

fracture or death.

If you plan to take Ra-223 following treatment with ABODEX and prednisone/prednisolone, you must

wait 5 days before starting treatment with Ra-223.

If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before taking

this medicine.

 

Blood monitoring

ABODEX may affect your liver, and you may not have any symptoms. When you are taking this

medicine, your doctor will check your blood periodically to look for any effects on your liver.

 

Children and adolescents

This medicine is not for use in children and adolescents. If ABODEX is accidentally ingested by a

child or adolescent, go to the hospital immediately and take the package leaflet with you to show to

the emergency doctors.

 

Other medicines and ABODEX

Ask your doctor or pharmacist for advice before taking any medicine.

 

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other

medicines. This is important because ABODEX may increase the effects of a number of medicines

including heart medicines, tranquilisers, herbal medicines (e.g., St John’s wort) and others. Your

doctor may want to change the dose of these medicines. Also, some medicines may increase or

decrease the effects of ABODEX. This may lead to side effects or to ABODEX not working as well as it should.

Androgen deprivation treatment may increase the risk of heart rhythm problems. Tell your doctor if

you are receiving medicine

-          used to treat heart rhythm problems (e.g. quinidine, procainamide, amiodarone and sotalol); known to increase the risk of heart rhythm problems [e.g. methadone (used for pain relief and

-          part of drug addiction detoxification), moxifloxacin (an antibiotic), antipsychotics (used for serious mental illnesses)]

Tell your doctor if you are taking any of the medicines listed above.

 

ABODEX with food

-          This medicine must not be taken with food (see section 3, “Taking this medicine”).

-          Taking ABODEX with food may cause side effects.

 

 

Pregnancy and breast-feeding

ABODEX is not for use in women.

-          This medicine may cause harm to the unborn child if it is taken by women who are pregnant.

-          If you are having sex with a woman who can become pregnant, use a condom and another effective birth control method.

-          If you are having sex with a pregnant woman, use a condom to protect the unborn child.

 

Driving and using machines

This medicine is not likely to affect your being able to drive and use any tools or machines.

 

ABODEX contains lactose

-          ABODEX contains lactose (a type of sugar). If you have been told by your doctor that you have an intolerance to some sugars, contact 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

The recommended dose is 1,000 mg (two tablets) once a day.

Taking this medicine

-          Take this medicine by mouth.

-          Do not take ABODEX with food.

-          Take ABODEX at least one hour before or at least two hours after eating (see section 2, ABODEX with food”)

-          Swallow the tablets whole with water.

-          Do not break the tablets.

-          ABODEX is taken with a medicine called prednisone or prednisolone. Take the prednisone or prednisolone exactly as your doctor has told you.

-          You need to take prednisone or prednisolone every day while you are taking ABODEX.

-          The amount of prednisone or prednisolone you take may need to change if you have a medical emergency. Your doctor will tell you if you need to change the amount of prednisone or prednisolone you take. Do not stop taking prednisone or prednisolone unless your doctor tells you to.

Your doctor may also prescribe other medicines while you are taking ABODEX and prednisone or

prednisolone.

 

If you take more ABODEX than you should

If you take more than you should, talk to your doctor or go to a hospital immediately.

If you forget to take ABODEX

-          If you forget to take ABODEX or prednisone or prednisolone, take your usual dose the following day.

-          If you forget to take ABODEX or prednisone or prednisolone for more than one day, talk to your doctor without delay.

If you stop taking ABODEX

Do not stop taking ABODEX or prednisone or prednisolone unless your doctor tells you to.

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.

Stop taking ABODEX and see a doctor immediately if you notice any of the following:

-          Muscle weakness, muscle twitches or a pounding heart beat (palpitations). These may be signs that the level of potassium in your blood is low.

Other side effects include:

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

Fluid in your legs or feet, low blood potassium, liver function test increases, high blood pressure,

urinary tract infection, diarrhea.

Common (may affect up to 1 in 10 people):

High fat levels in your blood, chest pain, irregular heart beat (atrial fibrillation), heart failure, rapid

heart rate, severe infections called sepsis, bone fractures, indigestion, blood in urine, rash.

Uncommon (may affect up to 1 in 100 people):

Adrenal gland problems (related to salt and water problems), abnormal heart rhythm (arrhythmia),

muscle weakness and/or muscle pain.

Rare (may affect up to 1 in 1,000 people):

Lung irritation (also called allergic alveolitis).

Failure of the liver to function (also called acute liver failure).

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

Heart attack, changes in ECG - electrocardiogram (QT prolongation).

 

Bone loss may occur in men treated for prostate cancer. ABODEX in combination with prednisone or

prednisolone may increase bone loss.


-          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 carton, cardboard wallet, and the blister. The expiry date refers to the last day of that month.

-          Do not store above 30ºC.

-          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 to protect the environment.


The active substance is abiraterone acetate. Each film-coated tablet contains 250 mg

abiraterone acetate.

Abiraterone Acetate Tablets also contain the following inactive ingredients

The other ingredients Lactose monohydrate, Microcrystalline cellulose , Croscarmellose

sodium, Povidone K 30, Sodium laurylsulfate, Colloidal silicon dioxide and Magnesium stearate


White to off-white, oval shaped tablets, debossed with “ABR” on one side and “250" on other side. Pack: 120’s HDPE container pack.

MS Pharma Saudi,

Riyadh, Kingdome Saudi Arabia.

info-ksa@mspharma.com

Manufacturer by:

Msn laboratories private limited- India for MS Pharma-Saudi.


June-2020 SPM190539
  نشرة الدواء تحت مراجعة الهيئة العامة للغذاء والدواء (اقرأ هذه النشرة بعناية قبل البدء في استخدام هذا المنتج لأنه يحتوي على معلومات مهمة لك)

يحتوي دواء ابوديكس على مادة دوائية تسمى أبيراتيرون أسيتيت. يستخدم هذا الدواء في علاج سرطان البروستاتا في الرجال البالغين الذي انتشر إلى أماكن أخرى من الجسم.

. يعمل دواء ابوديكس على منع الجسم من تصنيع هرمون التستوستيرون؛

مما قد يبطء من معدل نمو سرطان البروستاتا.

عندما يُوصف دواء ابوديكس في الحالات المبكرة من السرطان التي لم تزل تستجب للعلاج الهرموني، فإنه يُستخدم مع دواء يعمل على خفض مستوى هرمون التستوستيرون (العلاج بإنقاص مستويات الأندروجين).

أثناء تناول هذا الدواء فإن الطبيب سيصف دواء آخر يسمى بريدنيزون أو بريدنيزيلون. وذلك من أجل التقليل من فرص الإصابة بارتفاع ضغط الدم أو احتباس كمية كبيرة من الماء في الجسم أو نقص مستويات بعض العناصر الكيميائية في الدم مثل البوتاسيوم. 

لا تتناول ابوديكس في الحالات الآتية:

- إذا كنت تعاني من حساسية مفرطة لمادة أبيراتيرون أسيتيت أو لأي مكونات أخرى في هذا الدواء (من المكونات المذكورة في الفقرة 6).

في حالة السيدات، خاصة الحوامل منهن.  يُستخدم هذا الدواء في المرضى الرجال البالغين فقط.

إذا كنت تعاني من مشاكل حادة في الكبد.

إذا كنت تتناول معه دواء Ra-223 (الذي يستخدم في علاج سرطان البروستاتا).

لا تتناول هذا الدواء إذا كان ينطبق عليك أي مما سبق ذكره بالأعلى. يجب التواصل مع الطبيب أو الصيدلي قبل تناول هذا الدواء إذا كنت غير متأكد من أي مما سبق.

 

التحذيرات والاحتياطات

استشر الطبيب أو الصيدلي قبل تناول هذا الدواء في الحالات التالية:

 إذا كنت تعاني من مشاكل في الكبد.

 إذا سبق وأخبرك الأطباء أنك تعاني من ارتفاع ضغط الدم أو قصور في القلب أو انخفاض مستوى البوتاسيوم في الدم (حيث أن نقص مستوى البوتاسيوم في الدم قد يزيد من خطورة إصابتك باضطراب في نظم كهربية القلب).

 إذا كنت قد عانيت من مشاكل أخرى في القلب أو الأوعية الدموية. 

إذا كنت تعاني من عدم انتظام أو سرعة في ضربات القلب.

إذا كنت تعاني من قصر في النفس.

إذا لاحظت زيادة سريعة في الوزن.

إذا كنت تعاني من تورم في القدم أو الكاحل أو الساق.

إذا تناولت في السابق دواء معروف باسم كيتوكونازول من أجل علاج سرطان البروستاتا.

إذا كنت في حاجة لتناول دواء بريدنيزون أو بريدنيزيلون مع هذا الدواء.

 الأعراض الجانبية المحتملة في العظام.

 إذا كنت تعاني من ارتفاع مستوى السكر في الدم.

أخبر الطبيب إذا كنت تعاني من أي مشاكل في القلب أو الأوعية الدموية، بما في ذلك مشاكل اضطراب نظم كهربية القلب أو إذا كنت تتناول أدوية لعلاج هذه الحالات.

أخبر الطبيب إذا كنت تعاني من اصفرار في الجلد أو العين أو تحول البول للون الغامق أو الشعور الحاد بالغثيان أو القيء، لأن هذه الأعراض أو العلامات قد تعني وجود مشاكل في الكبد.

. ونادرا ما يحدث فشل كبدي (الفشل الكبدي الحاد)، والذي قد يؤدي إلى الوفاة.

قد يحدث نقص في عدد كرات الدم الحمراء وفي الرغبة الجنسية وضعف في العضلات و / أو ألم في العضلات.

يجب ألا يُعطى هذا الدواء مع دواء Ra-223 بسبب الزيادة المحتملة لخطر الإصابة بكسر في العظام أو الوفاة.

إذا كنت تنوي تناول دواء Ra-223 بعد العلاج بدواء ابوديكس ودواء بريدنيزون / بريدنيزيلون، فيجب أن تنتظر 5 أيام قبل البدء في تناول دواء Ra-223.

يجب استشارة الطبيب أو الصيدليّ قبل أخذ هذا الدواء في حالة عدم تأكدك إن كانت أي من هذه الأمور تنطبق عليك.

متابعة فحوصات الدم

قد يؤثر دواء ابوديكس على الكبد، وقد لا تظهر عليك أية أعراض.  .

سيقوم الطبيب بإجراء فحوصات دورية للدم عند تناولك هذا الدواء للبحث عن أي آثار على الكبد.

الأطفال والمراهقون

هذا الدواء لا يستخدم في الأطفال والمراهقين. إذا تم ابتلاع دواء ابوديكس بطريق الخطأ من قبل طفل أو مراهق، فتوجه إلى المستشفى على الفور وأحضر معك النشرة الدوائية للعبوة لعرضها على أطباء الطوارئ.

 

تناول أدوية أخرى مع دواء ابوديكس

يجب استشارة الطبيب أو الصيدلي قبل تناول أي دواء.

يجب عليك إخبار الطبيب أو الصيدليّ إذا كنت تتناول أدوية أو تناولت مؤخرًا بعض الأدوية أو تنوي تناول أي دواء آخر.

يعد ذلك مهما لأن دواء ابوديكس قد يزيد من تأثيرات بعض الأدوية بما في ذلك أدوية القلب والمهدئات والأعشاب الطبية (مثل نبتة سانت جونز ) وأدوية أخرى.

قد يحتاج الطبيب أن يغير جرعة الدواء الخاصة بك. وأيضا؛ فإن بعض الأدوية قد تؤثر على فاعلية الدواء بالزيادة أو بالنقصان.

. وذلك قد يؤدي إلى ظهور أعراض جانبية أو عدم فاعلية الدواء كما ينبغي.

قد تزيد الأدوية المثبطة للأندروجينات من مخاطر الإصابة بمشاكل في نظم كهربية القلب. .

-         يجب إبلاغ الطبيب إذا كنت تتناول أدوية تستخدم في علاج مشاكل نظم كهربية القلب (مثل؛ كوينيدين، بروكينامايد، أميودارون، سوتالول) أو أدوية معروف أنها تزيد من مخاطر الإصابة بمشاكل في نظم كهربية القلب (مثل دواء ميثادون (يستخدم في علاج الألم وكجزء من علاج الإدمان) ودواء موكسيفلوكساسين (مضاد حيوي) أو الأدوية المضادة للذهان (تستخدم في علاج حالات المرض العقلي الشديدة))

يرجى استشارة الطبيب إذا كنت تتناول أي من الأدوية المذكورة بالأعلى.

تناول دواء ابوديكس مع الطعام

-         يجب تجنب تناول هذا الدواء مع الطعام (يرجى الاطلاع على الفقرة 3 "طريقة تناول هذا الدواء").

-         تناول دواء ابوديكس مع الطعام قد يتسبب في ظهور أعراض جانبية.

الحمل والرضاعة الطبيعية

لا يستخدم دواء ابوديكس في السيدات.

-         قد يشكل هذا الدواء ضررا على الجنين إذا تم تناوله من قبل الأم الحامل.

-         إذا كنت تمارس علاقة حميمية مع امرأة يمكن أن تصبح حاملا، فيجب استخدام واقي ذكري أو أي طريقة أخرى فعالة في منع الحمل.

-         إذا كنت تمارس علاقة حميمية مع امرأة حامل، فيجب  استخدام واقي ذكري من أجل حماية الجنين

 

القيادة واستخدام الآلات

من غير المحتمل أن يؤثر هذا الدواء على قدرتك على القيادة واستخدام أي أدوات أو آلات.

 

يحتوي ابوديكس على اللاكتوز

-          يحتوي ابوديكس على اللاكتوز (نوع من أنواع السكر). ينبغي استشارة الطبيب قبل تناول هذا الدواء إذا كان قد سبق وأخبرك الطبيب بعدم قدرتك على تحمل بعض أنواع السكر.

https://localhost:44358/Dashboard

يجب عليك تناول هذا الدواء وفقًا لتعليمات الطبيب. يرجى استشارة الطبيب أو الصيدليّ قبل أخذ هذا الدواء إذا كان لديك أية شكوك.

الجرعة المُوصى بها

الجرعة الموصى بها هي 1000 ملغم (قرصين) تؤخذ مرة في اليوم.

طريقة تناول هذا الدواء

-         تناول هذا الدواء عبر الفم.

-         لا تتناول دواء ابوديكس مع الطعام.

-         تناول دواء ابوديكس قبل ساعة على الأقل من تناول الطعام أو بعد ساعتين على الأقل من الانتهاء من الطعام (يرجى الاطلاع على الفقرة 2 "تناول دواء ابوديكس مع الطعام").

-         قم ببلع القرص بأكمله باستخدام الماء.

-         لا تقم بكسر أقراص الدواء.

-         يؤخذ دواء ابوديكس مع دواء آخر يسمى بريدنيزون أو بريدنيزولون. يجب عليك تناول  دواء بريدنيزون أو بريدنيزولون وفقًا لتعليمات الطبيب.

-         يجب تناول دواء بريدنيزون أو بريدنيزولون يوميا أثناء علاجك بهذا الدواء.

-         قد يحتاج الطبيب إلى تغيير جرعة دواء بريدنيزون أو بريدنيزولون إذا كنت تعاني من حالة طبية طارئة. سيخبرك الطبيب إذا كنت في حاجة إلى تغير جرعة هذه الأدوية. لا تتوقف عن تناول دواء بريدنيزون أو بريدنيزولون إلا إذا أخبرك الطبيب بذلك.

قد يصف الطبيب أيضا بعض الأدوية الأخرى أثناء تناولك دواء ابوديكس  ودواء بريدنيزون أو بريدنيزولون.

إذا تناولت جرعات من دواء ابوديكس أكثر من الموصى بها

يجب الإسراع في إبلاغ الطبيب أو التوجه إلى المستشفى إذا تناولت جرعات من الدواء أكثر من الموصى بها.

إذا نسيت تناول دواء ابوديكس

-         إذا نسيت تناول دواء ابوديكس أو بريدنيزون أو بريدنيزولون، فعليك بتناول جرعتك الطبيعية في اليوم التالي.

-         إذا نسيت تناول دواء ابوديكس أو بريدنيزون أو بريدنيزولون لأكثر من يوم، فيجب استشارة الطبيب في أسرع وقت.

إذا توقفت عن تناول دواء ابوديكس

لا تتوقف عن تناول دواء ابوديكس أو بريدنيزون أو بريدنيزولون إلا إذا أخبرك الطبيب بذلك.

يرجى استشارة الطبيب أو الصيدلي إذا كانت لديك أية أسئلة إضافية فيما يتعلق بتناول هذا الدواء.

مثل كافة الأدوية، فإن هذا الدواء يمكن أن يتسبب في ظهور بعض الأعراض جانبية، وعلى الرغم من ذلك فإنها لا تظهر على جميع المرضى.

يجب التوقف عن تناول هذا الدواء  مع التوجه الفوري إلى الطبيب إذا لاحظت أي من هذه الأعراض الجانبية الآتية:

-         ضعف في العضلات أو ارتعاش لا إرادي في العضلات أو خفقان القلب. قد تكون هذه الأعراض علامات لانخفاض مستوى البوتاسيوم في الدم.

أعراض جانبية أخرى:

الأعراض الجانبية المألوفة جدا (قد تؤثر في أكثر من 1 من بين 10 أشخاص):

تجمع سوائل في القدم أو الساق، نقص مستوى البوتاسيوم في الدم، زيادة إنزيمات الكبد، ارتفاع ضغط الدم،

عدوى في الجهاز البولي/ إسهال.

الأعراض الجانبية المألوفة (تؤثر في 1 من بين 10 أشخاص):

ارتفاع مستوى الدهون في الدم، ألم في الصدر، عدم انتظام في ضربات القلب (رجفان أذيني)، فشل / قصور قلبي، سرعة ضربات القلب، عدوى شديدة تسمى تجرثم دموي، كسر في العظام، عسر هضم، نزول دم في البول، ظهور طفح جلدي.

الأعراض الجانبية غير المألوفة (تؤثر في أقل من 1 بين 100 شخص):

مشاكل في الغدة الكظرية (مشاكل لها علاقة باحتباس الملح والماء في الجسم)، مشاكل في نظم ضربات القلب (اختلال كهربية القلب)،

ضعف في العضلات و / أو ألم في العضلات.

الأعراض الجانبية النادرة (تؤثر في 1 من بين  1,000 شخص):

تهيج رئوي (يسمى أيضا؛ التهاب الحويصلات الهوائية التحسسي).

فشل في وظائف الكبد (يسمى أيضا؛ فشل كبدي حاد).

الأعراض الجانبية غير المعروفة (لا يمكن تحديد نسبة تكرارها من البيانات المتاحة):

سكتة قلبية، تغيرات معينة في مخطط رسم كهربية القلب (إطالة الفترة QT).

قد يحدث فقدان في الكثافة العظمية في الرجال الذين يعالجون من سرطان البروستاتا. قد يعمل تناول دواء ابوديكس مع بريدنيزون أو بريدنيزيلون على زيادة ضعف العظام.

-         يُحفظ الدواء بعيدا عن متناول الأطفال.

-         لا تستخدم الدواء بعد مرور تاريخ انتهاء الصلاحية الموضح على العبوة والشريط. يشير تاريخ انتهاء الصلاحية إلى اليوم الأخير في الشهر.

-         يحفظ في درجة حرارة لا تتجاوز 30 درجة مئوية .

-         لا تقم بإلقاء أية أدوية في مياه الصرف أو في النفايات المنزلية. وبدلاً عن ذلك قم باستشارة الصيدلي عن كيفية التخلص الآمن من الأدوية التي لم تعد بحاجة إليها. ستساعد هذه الإجراءات في المحافظة على البيئة.

- المادة الفعالة: أبيراتيرون أسيتيت. يحتوي كل قرص مغلف على 250 ملغم

أبيراتيرون أسيتيت.

كما يحتوي القرص أيضا على هذه المواد غير النشطة:

باقي المكونات: لاكتوز أحادي الهيدرات، سليلوز دقيق البلورات ، كروس كارميلوز الصوديوم،

بوفيدون K 30، لوريل سلفات الصوديوم، ثاني أكسيد السيليكون الغروي، استيارات الماغنيسيوم.

قراص بيضاوية الشكل لها لون يميل بين الأبيض والأبيض المصفر، ومنقوش على أحد جوانبها "ABR" وعلى الجانب الآخر "250".

العبوة: عبوة من البولي إيثيلين عالي الكثافة.

إم إس فارما السعودية

الرياض ، المملكة العربية السعودية .

    info-ksa@mspharma.com

 

صنعت بواسطة  

إم إس إن المختبرات الخاصة المحدودة – الهند لصالح إم إس فارما – المملكة العربية السعودية

يونيو-2020 SPM190539
 Read this leaflet carefully before you start using this product as it contains important information for you

Abodex 250 mg Tablets.

Each film coated tablet contains Abiraterone acetate USP 250 mg Excipients with known effect Product contains lactose. For the full list of excipients, see section 6.1.

Tablet White to off-white, oval shaped tablets, debossed with “ABR” on one side and “250" on other side.

Abiraterone Acetate is indicated with prednisone or prednisolone for:

•         The treatment of newly diagnosed high risk metastatic hormone sensitive prostate cancer (mHSPC) in adult men in combination with androgen deprivation therapy (ADT) (see section 5.1).

•         The treatment of metastatic castration resistant prostate cancer (mCRPC) in adult men who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated (see section 5.1).

•         The treatment of mCRPC in adult men whose disease has progressed on or after a docetaxel-based chemotherapy regimen.


This medicinal product should be prescribed by an appropriate healthcare professional.

 

Posology

The recommended dose is 1,000 mg (four 250 mg tablets) as a single daily dose that must not be taken with food (see “Method of administration” below). Taking the tablets with food increases systemic exposure to abiraterone (see sections 4.5 and 5.2).

 

Dosage of prednisone or prednisolone

For mHSPC, Abiraterone Acetate is used with 5 mg prednisone or prednisolone daily.

For mCRPC, Abiraterone Acetate is used with 10 mg prednisone or prednisolone daily.

 

Medical castration with luteinising hormone releasing hormone (LHRH) analogue should be continued during treatment in patients not surgically castrated.

Recommended monitoring

Serum transaminases should be measured prior to starting treatment, every two weeks for the first three months of treatment and monthly thereafter. Blood pressure, serum potassium and fluid retention should be monitored monthly. However, patients with a significant risk for congestive heart failure should be monitored every 2 weeks for the first three months of treatment and monthly thereafter (see section 4.4).

 

In patients with pre-existing hypokalaemia or those that develop hypokalaemia whilst being treated with Abiraterone Acetate, consider maintaining the patient's potassium level at ≥ 4.0 mM.

 

For patients who develop Grade ≥ 3 toxicities including hypertension, hypokalaemia, oedema and other nonmineralocorticoid toxicities, treatment should be withheld, and appropriate medical management should be instituted. Treatment with Abiraterone Acetate should not be reinitiated until symptoms of the toxicity have resolved to Grade 1 or baseline.

 

In the event of a missed daily dose of either Abiraterone Acetate, prednisone or prednisolone, treatment should be resumed the following day with the usual daily dose.

 

 

Hepatotoxicity

For patients who develop hepatotoxicity during treatment (alanine aminotransferase [ALT] increases or aspartate aminotransferase [AST] increases above 5 times the upper limit of normal [ULN]), treatment should be withheld immediately (see section 4.4). Re-treatment following return of liver function tests to the patient's baseline may be given at a reduced dose of 500 mg (one tablet) once daily. For patients being re-treated, serum transaminases should be monitored at a minimum of every two weeks for three months and monthly thereafter. If hepatotoxicity recurs at the reduced dose of 500 mg daily, treatment should be discontinued.

 

If patients develop severe hepatotoxicity (ALT or AST 20 times the ULN) anytime while on therapy, treatment should be discontinued, and patients should not be re-treated.

 

Hepatic impairment

No dose adjustment is necessary for patients with pre-existing mild hepatic impairment, Child-Pugh Class A.

Moderate hepatic impairment (Child-Pugh Class B) has been shown to increase the systemic exposure to abiraterone by approximately four-fold following single oral doses of abiraterone acetate 1,000 mg (see section 5.2). There are no data on the clinical safety and efficacy of multiple doses of abiraterone acetate when administered to patients with moderate or severe hepatic impairment (Child-Pugh Class B or C). No dose adjustment can be predicted. The use of Abiraterone Acetate should be cautiously assessed in patients with moderate hepatic impairment, in whom the benefit clearly should outweigh the possible risk (see sections 4.2 and 5.2). Abiraterone Acetate should not be used in patients with severe hepatic impairment (see sections 4.3, 4.4 and 5.2).

Renal impairment

No dose adjustment is necessary for patients with renal impairment (see section 5.2). However, there is no clinical experience in patients with prostate cancer and severe renal impairment. Caution is advised in these patients (see section 4.4).

Paediatric population

There is no relevant use of Abiraterone Acetate in the paediatric population.

Method of administration

Abiraterone Acetate is for oral use.

The tablets should be taken at least two hours after eating and no food should be eaten for at least one hour after taking the tablets. These should be swallowed whole with water.


- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. - Women who are or may potentially be pregnant (see section 4.6). - Severe hepatic impairment [Child-Pugh Class C (see sections 4.2, 4.4 and 5.2)]. - Abodex with prednisone or prednisolone is contraindicated in combination with Ra-223.

Hypertension, hypokalaemia, fluid retention and cardiac failure due to mineralocorticoid excess

 

Abiraterone Acetate may cause hypertension, hypokalaemia and fluid retention (see section 4.8) as aconsequence of increased mineralocorticoid levels resulting from CYP17 inhibition (see section 5.1). Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in incidence and severity of these adverse reactions. Caution is required in treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalaemia (e.g., those on cardiac glycosides), or fluid retention (e.g., those with heart failure, severe or unstable angina pectoris, recent myocardial infarction or ventricular arrhythmia and those with severe renal impairment).

 

Abiraterone Acetate should be used with caution in patients with a history of cardiovascular disease. The Phase 3 studies conducted with Abiraterone Acetate excluded patients with uncontrolled hypertension, clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or New York Heart Association Class (NYHA) III or IV heart failure (study 301) or Class II to IV heart failure (studies 3011 and 302) or cardiac ejection fraction measurement of < 50%. In studies 3011 and 302, patients with

atrial fibrillation, or other cardiac arrhythmia requiring medical therapy were excluded. Safety in patients with left ventricular ejection fraction (LVEF) < 50% or NYHA Class III or IV heart failure (in study 301) or NYHA Class II to IV heart failure (in studies 3011 and 302) was not established (see sections 4.8 and 5.1).

 

Before treating patients with a significant risk for congestive heart failure (e.g.a history of cardiac failure, uncontrolled hypertension, or cardiac events such as ischaemic heart disease), consider obtaining an assessment of cardiac function (e.g. echocardiogram). Before treatment with Abiraterone Acetate, cardiac failure should be treated and cardiac function optimised. Hypertension, hypokalaemia and fluid retention should be corrected and controlled. During treatment, blood pressure, serum potassium, fluid retention (weight gain, peripheral oedema), and other signs and symptoms of congestive heart failure should be monitored every 2 weeks for 3 months, then monthly thereafter and abnormalities corrected. QT prolongation has been observed in patients experiencing hypokalaemia in association with Abiraterone Acetate treatment. Assess cardiac function as clinically indicated, institute appropriate management and consider discontinuation of this treatment if there is a clinically significant decrease in cardiac function (see section 4.2).

 

Hepatotoxicity and hepatic impairment

Marked increases in liver enzymes leading to treatment discontinuation or dose modification occurred in controlled clinical studies (see section 4.8). Serum transaminase levels should be measured prior to starting treatment, every two weeks for the first three months of treatment, and monthly thereafter. If clinical symptoms or signs suggestive of hepatotoxicity develop, serum transaminases should be measured immediately. If at any time the ALT or AST rises above 5 times the ULN, treatment should be interrupted immediately, and liver function closely monitored. Retreatment may take place only after return of liver function tests to the patient's baseline and at a

reduced dose level (see section 4.2).

If patients develop severe hepatotoxicity (ALT or AST 20 times the ULN) anytime while on therapy, treatment should be discontinued, and patients should not be re-treated.

Patients with active or symptomatic viral hepatitis were excluded from clinical trials; thus, there are no data to support the use of Abiraterone Acetate in this population.

There are no data on the clinical safety and efficacy of multiple doses of abiraterone acetate when administered to patients with moderate or severe hepatic impairment (Child-Pugh Class B or C). The use of Abiraterone Acetate should be cautiously assessed in patients with moderate hepatic impairment, in whom the benefit clearly should outweigh the possible risk (see sections 4.2 and 5.2). Abiraterone Acetate should not be used in patients with severe hepatic impairment (see

sections 4.2, 4.3 and 5.2).

 

There have been rare post-marketing reports of acute liver failure and hepatitis fulminant, some with fatal outcome (see section 4.8).

Corticosteroid withdrawal and coverage of stress situations

Caution is advised and monitoring for adrenocortical insufficiency should occur if patients are withdrawn from prednisone or prednisolone. If Abiraterone Acetate is continued after corticosteroids are withdrawn, patients should be monitored for symptoms of mineralocorticoid excess (see information above).

 

In patients on prednisone or prednisolone who are subjected to unusual stress, an increased dose of

corticosteroids may be indicated before, during and after the stressful situation.

 

Bone density

Decreased bone density may occur in men with metastatic advanced prostate cancer. The use of Abiraterone Acetate in combination with a glucocorticoid could increase this effect.

 

Prior use of ketoconazole

Lower rates of response might be expected in patients previously treated with ketoconazole for prostate cancer.

 

Hyperglycemia

The use of glucocorticoids could increase hyperglycemia; therefore blood sugar should be measured frequently in patients with diabetes.

 

Use with chemotherapy

The safety and efficacy of concomitant use of Abiraterone Acetate with cytotoxic chemotherapy has not been established (see section 5.1).

 

Intolerance to excipients

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. This medicinal product also contains more than 1.18 mmol (or 27 mg) sodium per dose of two tablets. To be taken into consideration by patients on a controlled sodium diet.

 

Potential risks

Anaemia and sexual dysfunction may occur in men with metastatic prostate cancer including those undergoing treatment with Abiraterone Acetate.

 

Skeletal muscle effects

Cases of myopathy have been reported in patients treated with Abiraterone Acetate. Some patients had rhabdomyolysis with renal failure. Most cases developed within the first month of treatment and recovered after Abiraterone Acetate withdrawal. Caution is recommended in patients concomitantly treated with medicinal products known to be associated with myopathy/ rhabdomyolysis.

 

 

Interactions with other medicinal products

Strong inducers of CYP3A4 during treatment are to be avoided unless there is no therapeutic alternative, due to risk of decreased exposure to abiraterone (see section 4.5).

 

Combination of abiraterone and prednisone/prednisolone with Ra-223

 

Treatment with abiraterone and prednisone/prednisolone in combination with Ra-223 is contraindicated (see section 4.3) due to an increased risk of fractures and a trend for increased mortality among asymptomatic or mildly symptomatic prostate cancer patients as observed in clinical trials.

 

It is recommended that subsequent treatment with Ra-223 is not initiated for at least 5 days after the last administration of ZYTIGA in combination with prednisone/prednisolone.


 

Effect of food on abiraterone acetate

 

Administration with food significantly increases the absorption of abiraterone acetate. The efficacy and safety when given with food have not been established therefore this medicinal product must not be taken with food (see sections 4.2 and 5.2)

Interactions with other medicinal products

Potential for other medicinal products to affect abiraterone exposures

In a clinical pharmacokinetic interaction study of healthy subjects pretreated with a strong CYP3A4 inducer rifampicin, 600 mg daily for 6 days followed by a single dose of abiraterone acetate 1,000 mg, the mean plasma AUC∞ of abiraterone was decreased by 55%.

Strong inducers of CYP3A4 (e.g., phenytoin, carbamazepine, rifampicin, rifabutin, rifapentine, phenobarbital, St John's wort [Hypericum perforatum]) during treatment are to be avoided, unless there is no therapeutic alternative.

 

In a separate clinical pharmacokinetic interaction study of healthy subjects, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone.

 

Potential to affect exposures to other medicinal products

Abiraterone is an inhibitor of the hepatic drug-metabolising enzymes CYP2D6 and CYP2C8.

 

In a study to determine the effects of abiraterone acetate (plus prednisone) on a single dose of the CYP2D6 substrate dextromethorphan, the systemic exposure (AUC) of dextromethorphan was increased approximately 2.9 fold. The AUC24 for dextrorphan, the active metabolite of dextromethorphan, increased approximately 33%.

 

Caution is advised when administering with medicinal products activated by or metabolised by CYP2D6, particularly with medicinal products that have a narrow therapeutic index. Dose reduction of medicinal products with a narrow therapeutic index that are metabolised by CYP2D6 should be considered. Examples of medicinal products metabolised by CYP2D6 include metoprolol, propranolol, desipramine, venlafaxine, haloperidol, risperidone, propafenone, flecainide, codeine, oxycodone and tramadol (the latter three medicinal products requiring CYP2D6 to form their active

analgesic metabolites).

 

In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone was increased by 46% and the AUCs for M-III and M-IV, the active metabolites of pioglitazone, each decreased by 10% when pioglitazone was given together with a single dose of 1,000 mg abiraterone acetate. Although these results indicate that no clinically meaningful increases in exposure are expected when Abiraterone Acetate is combined with medicinal products that are predominantly eliminated by CYP2C8, patients should be monitored for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly.

 

In vitro, the major metabolites abiraterone sulphate and N-oxide abiraterone sulphate were shown to inhibit the hepatic uptake transporter OATP1B1 and as a consequence it may increase the concentrations of medicinal products eliminated by OATP1B1. There are no clinical data available to confirm transporter based interaction.

 

Use with products known to prolong QT interval

Since androgen deprivation treatment may prolong the QT interval, caution is advised when administering Abiraterone Acetate with medicinal products known to prolong the QT interval or medicinal products able to induce torsades de pointes such as class IA (e.g. Quinidine, isopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, moxifloxacin, antipsychotics, etc.

 

Use with Spironolactone

Spironolactone binds to the androgen receptor and may increase prostate specific antigen (PSA) levels. Use with Abiraterone Acetate is not recommended (see section 5.1).


Women of childbearing potential

There are no human data on the use of Abiraterone Acetate in pregnancy and this medicinal product is not for use in women of childbearing potential.

 

Contraception in males and females

It is not known whether abiraterone or its metabolites are present in semen. A condom is required if the patient is engaged in sexual activity with a pregnant woman. If the patient is engaged in sex with a woman of childbearing potential, a condom is required along with another effective contraceptive method. Studies in animals have shown reproductive toxicity (see section 5.3).

 

Pregnancy

Abiraterone Acetate is not for use in women and is contraindicated in women who are or may potentially be pregnant (see section 4.3 and 5.3).

 

Breast-feeding

Abiraterone Acetate is not for use in women.

 

Fertility

Abiraterone affected fertility in male and female rats, but these effects were fully reversible (see section 5.3).


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


 

Summary of the safety profile

In an analysis of adverse reactions of composite Phase 3 studies with Abiraterone Acetate, adverse reactions that were observed in ≥10% of patients were peripheral oedema, hypokalaemia, hypertension urinary tract infection, and alanine aminotransferase increased and/or aspartate aminotransferase increased.

Other important adverse reactions include, cardiac disorders, hepatotoxicity, fractures, and allergic alveolitis.

Abiraterone Acetate may cause hypertension, hypokalaemia and fluid retention as a

pharmacodynamic consequence of its mechanism of action. In Phase 3 studies, anticipated mineralocorticoid adverse reactions were seen more commonly in patients treated with abiraterone acetate than in patients treated with placebo: hypokalaemia 18% vs.8%, hypertension 22% vs. 16% and fluid retention (peripheral oedema) 23% vs. 17%, respectively. In patients treated with abiraterone acetate, CTCAE (version 4.0) Grades 3 and 4 hypokalaemia were observed in 6% and 2% of patients, CTCAE (version 4.0) Grades 3 and 4 hypertension were observed in 8% and 5% of patients, and fluid retention (peripheral oedema) Grades 3 and 4 were observed in 1% and 1% of

patients, respectively. Mineralocorticoid reactions generally were able to be successfully managed medically. Concomitant use of a corticosteroid reduces the incidence and severity of these adverse reactions (see section 4.4).

Tabulated list of adverse reactions

In studies of patients with metastatic advanced prostate cancer who were using an LHRH analogue, or were previously treated with orchiectomy, Abiraterone Acetate was administered at a dose of 1,000 mg daily in combination with low dose prednisone or prednisolone (either 5 or 10 mg daily depending on the indication).

 

Adverse reactions observed during clinical studies and post-marketing experience are listed below by frequency category. Frequency categories are defined as follows: 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) and not known (frequency cannot be estimated from the available data).

 

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

 

Table 1: Adverse reactions identified in clinical studies and post-marketing

System organ class

Adverse reactions and frequency

Infections and infestations

Very common: Urinary tract infection

 

Common: sepsis

Endocrine disorders

Uncommon: adrenal insufficiency

Metabolism and nutrition disorders

Very common: hypokalaemia

 

Common: hypertriglyceridaemia

Cardiac disorders

Common: cardiac failure*, angina pectoris, atrial fibrillation, tachycardia

 

Uncommon: other arrythmias

 

Not known: myocardial infection, QT prolongation (see section 4.4 and 4.5)

Vascular disorders

Very common: hypertension

Respiratory, thoracic and mediastinal disorders

Rare: allergic alveolitis a

Gastrointestinal disorders

Very common: diarrhea

Common: dyspepsia

Hepatobiliary disorders

               Very common: alanine aminotransferase increased and/or aspartate aminotransferase increased b

 

Rare: hepatitis fulminant, acute hepatic failure

Skin and subcutaneous tissue disorders

Common: rash

Musculoskeletal and connective tissue disorders

Uncommon: myopathy, rhabdomyolysis

Renal and urinary disorders

Common: haematuria

General disorders and administration site conditions

Very common: oedema peripheral

Injury, poisoning and procedural complications

Common: fractures**

 

 

* Cardiac failure also includes congestive heart failure, left ventricular dysfunction and ejection fraction decreased

** Fractures includes osteoporosis and all fractures with the exception of pathological fractures

a Spontaneous reports from post-marketing experience

b Alanine aminotransferase increased and/or aspartate aminotransferase increased includes ALT increased, AST increased, and hepatic function abnormal.

 

The following CTCAE (version 4.0) Grade 3 adverse reactions occurred in patients treated with abiraterone acetate: hypokalaemia 5%; urinary tract infection 2%; alanine aminotransferase increased and/or aspartate aminotransferase increased 4%; hypertension 6%; fractures 2%; peripheral oedema, cardiac failure, and atrial fibrillation 1% each. CTCAE (version 4.0) Grade 3 hypertriglyceridaemia and angina pectoris occurred in < 1% of patients. CTCAE (version 4.0) Grade 4 urinary tract infection, alanine aminotransferase increased and/or aspartate aminotransferase increased, hypokalemia, cardiac failure, atrial fibrillation, and fractures occurred in < 1% of patients.

 

A higher incidence of hypertension and hypokalemia was observed in the hormone sensitive population (study 3011). Hypertension was reported in 36.7% of patients in the hormone sensitive population (study 3011) compared to 11.8% and 20.2% in studies 301 and 302, respectively. Hypokalemia was observed in 20.4% of patients in the hormone sensitive population (study 3011) compared to 19.2% and 14.9% in 301 and 302, respectively).

The incidence and severity of adverse events was higher in the subgroup of patients with baseline ECOG2 performance status grade and also in elderly patients (≥75 years).

 

 

Description of selected adverse reactions

 

Cardiovascular reactions

The three Phase 3 studies excluded patients with uncontrolled hypertension, clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or NYHA Class III or IV heart failure (study 301) or Class II to IV heart failure (studies 3011 and 302) or cardiac ejection fraction measurement of < 50%. All patients enrolled (both active and placebo-treated patients) were concomitantly treated with androgen deprivation therapy, predominantly with the use of LHRH analogues, which has been associated with diabetes, myocardial infarction, cerebrovascular accident and sudden cardiac death.The incidence of cardiovascular adverse reactions in the Phase 3 studies in patients taking abiraterone acetate versus patients taking placebo were as follows: atrial fibrillation 2.6% vs. 2.0%, tachycardia 1.9% vs. 1.0%, angina pectoris 1.7% vs. 0.8%, cardiac failure 0.7% vs. 0.2%, and arrhythmia 0.7% vs. 0.5%.

 

Hepatotoxicity

Hepatotoxicity with elevated ALT, AST and total bilirubin has been reported in patients treated with abiraterone acetate. Across Phase 3 clinical studies, hepatotoxicity grades 3 and 4 (e.g., ALT or AST increases of > 5 x ULN or bilirubin increases > 1.5 x ULN) were reported in approximately 6% of patients who received abiraterone acetate, typically during the first 3 months after starting treatment. In Study 3011, grade 3 or 4 hepatotoxicity was observed in 8.4% of patients treated with Abiraterone Acetate. Ten patients who received Abiraterone Acetate were discontinued because of hepatotoxicity; two had Grade 2 hepatotoxicity, six had Grade 3 hepatotoxicity, and two had Grade

4 hepatotoxicity. No patient died of hepatotoxicity in Study 3011. In the Phase 3 clinical studies, patients whose baseline ALT or AST were elevated were more likely to experience liver function test elevations than those beginning with normal values. When elevations of either ALT or AST > 5 x ULN, or elevations in bilirubin > 3 x ULN were observed, abiraterone acetate was withheld or discontinued. In two instances marked increases in liver function tests occurred (see section 4.4). These two patients with normal baseline hepatic function, experienced ALT or AST elevations 15 to 40 x ULN and bilirubin elevations 2 to 6 x ULN. Upon discontinuation of treatment, both patients

had normalisation of their liver function tests and one patient was re-treated without recurrence of the elevations. In study 302, Grade 3 or 4 ALT or AST elevations were observed in 35 (6.5%) patients treated with abiraterone acetate. Aminotransferase elevations resolved in all but 3 patients (2 with new multiple liver metastases and 1 with AST elevation approximately 3 weeks after the last dose of abiraterone acetate). In Phase 3 clinical studies, treatment discontinuations due to ALT and AST increases or abnormal hepatic function were reported in 1.1% of patients treated with

abiraterone acetate and 0.6% of patients treated with placebo; no deaths were reported due to hepatotoxicity events.

 

In clinical trials, the risk for hepatotoxicity was mitigated by exclusion of patients with baseline hepatitis or significant abnormalities of liver function tests. In the 3011 trial, patients with baseline ALT and AST > 2.5 X ULN, bilirubin > 1.5 X ULN or those with active or symptomatic viral hepatitis or chronic liver disease; ascites or bleeding disorders secondary to hepatic dysfunction were excluded. In the 301 trial, patients with baseline ALT and AST ≥ 2.5 x ULN in the absence of liver metastases and > 5 x ULN in the presence of liver metastases were excluded. In the 302 trial, patients with liver metastases were not eligible and patients with baseline ALT and AST ≥ 2.5 x

ULN were excluded. Abnormal liver function tests developing in patients participating in clinical trials were vigorously managed by requiring treatment interruption and permitting re-treatment only after return of liver function tests to the patient's baseline (see section 4.2). Patients with elevations of ALT or AST > 20 x ULN were not re-treated. The safety of re-treatment in such patients is unknown. The mechanism for hepatotoxicity is not understood.

 

 

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.

 

To report any side effect(s):

 

- The National Pharmacovigilance and Drug Safety Centre (NPC):

·         Fax: +966-11-205-7662

·         Toll free phone: 19999

·         E-mail: npc.drug@sfda.gov.sa

·         Website: www.sfda.gov.sa/npc

 

 

 

 

 

 

 


Human experience of overdose with Abiraterone Acetate is limited.

There is no specific antidote. In the event of an overdose, administration should be withheld, and general supportive measures undertaken, including monitoring for arrhythmias, hypokalaemia and for signs and symptoms of fluid retention. Liver function also should be assessed.


Pharmacotherapeutic group: endocrine therapy, other hormone antagonists and related agents, ATC code: L02BX03

Mechanism of action

Abiraterone acetate (Abiraterone Acetate Tablets) is converted in vivo to abiraterone, an androgen biosynthesis inhibitor. Specifically, abiraterone selectively inhibits the enzyme 17α hydroxylase/ C17,20-lyase (CYP17). This enzyme is expressed in and is required for androgen biosynthesis in testicular, adrenal and prostatic tumour tissues. CYP17 catalyses the conversion of pregnenolone and progesterone into testosterone precursors, DHEA and androstenedione, respectively, by 17α- hydroxylation and cleavage of the C17,20 bond. CYP17 inhibition also results in increased mineralocorticoid production by the adrenals (see section 4.4).

 

Androgen-sensitive prostatic carcinoma responds to treatment that decreases androgen levels. Androgen deprivation therapies, such as treatment with LHRH analogues or orchiectomy, decrease androgen production in the testes but do not affect androgen production by the adrenals or in the tumour. Treatment with Abiraterone Acetate decreases serum testosterone to undetectable levels (using commercial assays) when given with LHRH analogues (or orchiectomy).

Pharmacodynamic effects

Abiraterone Acetate decreases serum testosterone and other androgens to levels lower than those achieved by the use of LHRH analogues alone or by orchiectomy. This results from the selective inhibition of the CYP17 enzyme required for androgen biosynthesis. PSA serves as a biomarker in patients with prostate cancer. In a Phase 3 clinical study of patients who failed prior chemotherapy with taxanes, 38% of patients treated with abiraterone acetate, versus 10% of patients treated with placebo, had at least a 50% decline from baseline in PSA levels.

 

Clinical efficacy and safety

Efficacy was established in three randomised placebo-controlled multicentre Phase 3 clinical studies (studies 3011, 302 and 301) of patients with mHSPC and mCRPC. Study 3011 enrolled patients who were newly diagnosed (within 3 months of randomization) mHSPC who had high-risk prognostic factors. High-risk prognosis was defined as having at least 2 of the following 3 risk factors: (1) Gleason score of ≥8; (2) presence of 3 or more lesions on bone scan; (3) presence of measurable visceral (excluding lymph node disease) metastasis. In the active arm, Abiraterone

Acetate was administered at a dose of 1000 mg daily in combination with low dose prednisone 5 mg once daily in addition to ADT (LHRH agonist or orchiectomy), which was the standard of care treatment. Patients in the control arm received ADT and placebos for both Abiraterone Acetate and prednisone. Study 302 enrolled docetaxel naïve patients; whereas, study 301 enrolled patients who had received prior docetaxel. Patients were using an LHRH analogue or were previously treated with orchiectomy. In the active treatment arm, Abiraterone Acetate was administered at a dose of

1,000 mg daily in combination with low dose prednisone or prednisolone 5 mg twice daily. Control patients received placebo and low dose prednisone or prednisolone 5 mg twice daily.

 

Changes in PSA serum concentration independently do not always predict clinical benefit. Therefore, in all studies it was recommended that patients be maintained on their study treatments until discontinuation criteria were met as specified below for each study.

 In all studies spironolactone use was not allowed as spironolactone binds to the androgen receptor and may increase PSA levels.

 

Study 3011 (patients with newly diagnosed high risk mHSPC)

In Study 3011, (n=1199) the median age of enrolled patients was 67 years. The number of patients treated with Abiraterone Acetate by racial group was Caucasian 832 (69.4%), Asian 246 (20.5%), Black or African American 25 (2.1%), other 80 (6.7%), unknown/not reported 13 (1.1%), and American Indian or Alaska Native 3 (0.3%). The ECOG performance status was 0 or 1 for 97% of patients. Patients with known brain metastasis, uncontrolled hypertension, significant heart disease, or NYHA Class II-IV heart failure were excluded. Patients that were treated with prior pharmacotherapy, radiation therapy, or surgery for metastatic prostate cancer were excluded with

the exception of up to 3 months of ADT or 1 course of palliative radiation or surgical therapy to treat symptoms resulting from metastatic disease. Co-primary efficacy endpoints were overall survival (OS) and radiographic progression-free survival (rPFS). The median baseline pain score, as measured by the Brief Pain Inventory Short Form (BPI-SF) was 2.0 in both the treatment and Placebo groups. In addition to the co-primary endpoint measures, benefit was also assessed using time to skeletal-related event (SRE), time to subsequent therapy for prostate cancer, time to initiation of chemotherapy, time to pain progression, and time to PSA progression. Treatment

continued until disease progression, withdrawal of consent, the occurrence of unacceptable toxicity, or death.

 

Radiographic progression-free survival was defined as the time from randomization to the occurrence of radiographic progression or death from any cause. Radiographic progression included progression by bone scan (according to modified PCWG2) or progression of soft tissue lesions by CT or MRI (according to RECIST 1.1).

A significant difference in rPFS between treatment groups was observed (see Table 2 and Figure 1).

 

Table 2: Radiographic Progression-Free Survival - Stratified Analysis; Intent-to-treat Population (Study PCR3011)

 

Table 2: Radiographic Progression-Free Survival - Stratified Analysis; Intent-to-treat Population (Study PCR3011)

 

AA-P

Placebo

Subjects randomized

597

602

Event

239 (40.0%)

354 (58.8%)

Censored

358 (60.0%)

248 (41.2%)

Time to Event (months)

 

 

Median (95% CI)

33.02 (29.57, NE)

14.78 (14.69, 18.27)

Range

(0.0+, 41.0+)

(0.0+, 40.6+)

P value a

< 0.0001

 

Hazard ratio (95% CI) b

0.466 (0.394, 0.550)

 

 

Note: += censored observation, NE=not estimable. The radiographic progression and death are considered in defining the rPFS event. AA-P= subjects who received abiraterone acetate and prednisone.

a p value is from a log-rank test stratified by ECOG PS score (0/1 or 2) and visceral lesion (absent or present).

b Hazard ratio is from stratified proportional hazards model. Hazard ratio <1 favors AA-P.

 

Figure 1: Kaplan-Meier Plot of Radiographic Progression-free Survival; Intent-to-treat Population (StudyPCR3011)

 

 

 

A statistically significant improvement in OS in favor of AA-P plus ADT was observed with a 38% reduction in the risk of death compared to Placebo plus ADT (HR=0.621; 95% CI: 0.509, 0.756; p<0.0001, crossing the pre-specified boundary for OS at Interim Analysis 1 of 0.010 (see Table 3 and Figure 2).

 

Table 3: Overall Survival, Stratified Analysis; Intent-to-treat Population (Study PCR3011)

 

AA-P

Placebo

Subjects randomized

597

602

Event

169 (28.3 %)

237 (39.4%)

Censored

428 (71.7 %)

365 (60.6%)

Overall Survival (months)

 

 

Median (95% CI)

NE (NE, NE)

34.73 (33.05, NE)

Range

(0.1+, 43.5+)

(1.4+, 43.5+)

P value a

< 0.0001

 

Hazard ratio (95% CI) b

0.621 (0.509, 0.756)

 

 

Note: += censored observation, NE=not estimable. AA-P= subjects who received abiraterone acetate and prednisone.

a p value is from a log-rank test stratified by ECOG PS score (0/1 or 2) and visceral lesion (absent or present).

b Hazard ratio is from stratified proportional hazards model. Hazard ratio <1 favors AA-P.

 

 

 

Figure 2: Kaplan-Meier Plot of Overall Survival; Intent-to-treat Population (Study

PCR3011)

 

 

 

Subgroup analyses consistently favor treatment with Abiraterone Acetate. The treatment effect of AA-P on rPFS and OS across the pre-specified subgroups was favorable and consistent with the overall study population, except for the subgroup of ECOG score of 2 where no trend towards benefit was observed, however the small sample size (n=40) limits drawing any meaningful conclusion.

 

In addition to the observed improvements in overall survival and rPFS, benefit was demonstrated for Abiraterone Acetate vs. Placebo treatment in all prospectively-defined secondary endpoint measures as follows:

 

Time to skeletal-related event (SRE): There was a 30% reduction in the risk of skeletal-related events (HR = 0.703; 95% CI: [0.539, 0.916], p = 0.0086). The median time to SRE has not been reached for the Abiraterone Acetate or placebo study arm.

 

Time to PSA progression based on PCWG2 criteria: The median time to PSA progression was 33.2 months for patients receiving Abiraterone Acetate and 7.4 months for patients receiving placebo (HR = 0.299; 95% CI: [0.255, 0.352], p <0.0001).

 

Time to subsequent therapy: The median time to subsequent therapy at the time of interim analysis was not reached for patients receiving Abiraterone Acetate and was 21.6 months for patients receiving placebo (HR = 0.415; 95% CI: [0.346, 0.497], p <0.0001).

 

Time to initiation of chemotherapy: The median time to initiation of chemotherapy was not reached for patients receiving Abiraterone Acetate and was 38.9 months for patients receiving placebo (HR= 0.443; 95% CI: [0.349, 0.561], p < 0.0001).

 

Time to pain progression: The median time to pain progression was not reached for patients receiving Abiraterone Acetate and was 16.6 months for patients receiving placebo (HR = 0.695; 95% CI: [0.583, 0.829], p <0.0001).

 

The majority of exploratory endpoints favored treatment with abiraterone acetate and prednisone (AA-P) over Placebo.

 

Study 302 (chemotherapy naïve patients)

This study enrolled chemotherapy naïve patients who were asymptomatic or mildly symptomatic and for whom chemotherapy was not yet clinically indicated. A score of 0-1 on Brief Pain Inventory-Short Form (BPI-SF) worst pain in last 24 hours was considered asymptomatic, and a score of 2-3 was considered mildly symptomatic.

 

In study 302, (n = 1,088) the median age of enrolled patients was 71 years for patients treated with Abiraterone Acetate plus prednisone or prednisolone and 70 years for patients treated with placebo plus prednisone or prednisolone. The number of patients treated with Abiraterone Acetate by racial group was Caucasian 520 (95.4%), Black 15 (2.8%), Asian 4 (0.7%) and other 6 (1.1%). The Eastern Cooperative Oncology Group (ECOG) performance status was 0 for 76% of patients, and 1 for 24% of patients in both arms. Fifty percent of patients had only bone metastases, an additional 31% of patients had bone and soft tissue or lymph node metastases and 19% of patients had only

soft tissue or lymph node metastases. Patients with visceral metastases were excluded. Co-primary efficacy endpoints were overall survival and radiographic progression-free survival (rPFS). In addition to the co-primary endpoint measures, benefit was also assessed using time to opiate use for cancer pain, time to initiation of cytotoxic chemotherapy, time to deterioration in ECOG performance score by ≥ 1 point and time to PSA progression based on Prostate Cancer Working Group-2 (PCWG2) criteria. Study treatments were discontinued at the time of unequivocal clinical progression. Treatments could also be discontinued at the time of confirmed radiographic

progression at the discretion of the investigator.

Radiographic progression free survival (rPFS) was assessed with the use of sequential imaging studies as defined by PCWG2 criteria (for bone lesions) and modified Response Evaluation Criteria In Solid Tumors (RECIST) criteria (for soft tissue lesions). Analysis of rPFS utilised centrallyreviewed radiographic assessment of progression.

At the planned rPFS analysis there were 401 events, 150 (28%) of patients treated with Abiraterone Acetate and 251 (46%) of patients treated with placebo had radiographic evidence of progression or had died. A significant difference in rPFS between treatment groups was observed (see Table 4 and Figure 3).

 

Table 4: Study 302: Radiographic progression-free survival of patients treated with either ZYTIGA or placebo in combination with prednisone or prednisolone plus LHRH analogues or prior orchiectomy

 

AA-P

(N=456)

Placebo

(N=542)

Radiographic progression-free survival (rPFS)

 

 

Progression or death

150 (28%)

251 (46%)

Median rPFS in months

(95% CI)

Not reached

(11.66; NE)

8.3

(8.12; 8.4)

p-value*

< 0.0001

Hazard ratio** (95% CI)

0.425 (0.347; 0.522)

 

 

NE = Not estimated

* p-value is derived from a log-rank test stratified by baseline ECOG score (0 or 1)

** Hazard ratio < 1 favours Abiraterone Acetate

 

Figure 3: Kaplan Meier curves of radiographic progression-free survival in patients treated with either Abiraterone Acetate or placebo in combination with prednisone or prednisolone plus LHRH analogues or prior orchiectomy

 

 

However, subject data continued to be collected through the date of the second interim analysis of Overall survival (OS). The investigator radiographic review of rPFS performed as a follow up sensitivity analysis is presented in Table 5 and Figure 4.

 

Six hundred and seven (607) subjects had radiographic progression or died: 271 (50%) in the abiraterone acetate group and 336 (62%) in the placebo group. Treatment with abiraterone acetate decreased the risk of radiographic progression or death by 47% compared with placebo (HR = 0.530; 95% CI: [0.451; 0.623], p < 0.0001). The median rPFS was 16.5 months in the abiraterone acetate group and 8.3 months in the placebo group.

 

Table 5: Study 302: Radiographic progression-free survival of patients treated with either ZYTIGA or placebo in combination with prednisone or prednisolone plus LHRH analogues or prior orchiectomy (At second interim analysis of OS-Investigator Review)

 

AA-P

(N=546)

Placebo

(N=542)

Radiographic progression-free survival (rPFS)

 

 

Progression or death

271 (50%)

336 (62%)

Median rPFS in months

(95% CI)

16.5

(13.80; 16.79)

8.3

(8.05; 9.43)

p-value*

< 0.0001

Hazard ratio**

(95% CI)

0.530 (0.451; 0.623)

 

 

* p-value is derived from a log-rank test stratified by baseline ECOG score (0 or 1)

** Hazard ratio < 1 favours Abiraterone Acetate

 

Figure 4: Kaplan Meier curves of radiographic progression-free survival in patients treated with either Abiraterone Acetate or placebo in combination with prednisone or prednisolone plus LHRH analogues or prior orchiectomy (At second interim analysis of OS-Investigator Review)

 

 

A planned interim analysis (IA) for OS was conducted after 333 deaths were observed. The study was unblinded based on the magnitude of clinical benefit observed and patients in the placebo group were offered treatment with Abiraterone Acetate. Overall survival was longer for Abiraterone Acetate than placebo with a 25% reduction in risk of death (HR = 0.752; 95% CI: [0.606; 0.934], p= 0.0097), but OS was not mature and interim results did not meet the pre-specified stopping boundary for statistical significance (see Table 4). Survival continued to be followed after this IA.

The planned final analysis for OS was conducted after 741 deaths were observed (median follow up of 49 months). Sixtyfive percent (354 of 546) of patients treated with Abiraterone Acetate, compared with 71% (387 of 542) of patients treated with placebo, had died. A statistically significant OS benefit in favour of the Abiraterone Acetate-treated group was demonstrated with a 19.4% reduction in risk of death (HR = 0.806; 95% CI: [0.697; 0.931], p = 0.0033) and an improvement in median OS of 4.4 months (Abiraterone Acetate 34.7 months, placebo 30.3 months) (see Table 6 and Figure 5). This improvement was demonstrated even though 44% of patients in the placebo arm received Abiraterone Acetate as subsequent therapy.

 

Table 6: Study 302: Overall survival of patients treated with either ZYTIGA or placebo in combination with prednisone or prednisolone plus LHRH analogues or prior orchiectomy

 

AA-P

(N=546)

Placebo

(N=542)

Interim survival analysis

 

 

Death (%)

147 (27%)

186 (34%)

Median Survival (months)

(95% CI)

Not reached

(NE; NE)

27.2

(25.95; NE)

p-value*

< 0.0097

Hazard ratio**

(95% CI)

0.752 (0.606; 0.934)

 

Final survival analysis

 

Deaths

354 (65%)

387 (71%)

Median overall Survival in months

(95% CI)

34.7 (32.7; 36.8)

 

30.3 (28.7; 33.3)

p-value*

< 0.0033

Hazard ratio**

(95% CI)

0.806 (0.697; 0.931)

 

 

NE = Not Estimated

* p-value is derived from a log-rank test stratified by baseline ECOG score (0 or 1)

** Hazard ratio < 1 favours Abiraterone Acetate

 

Figure 5: Kaplan Meier survival curves of patients treated with either Abiraterone Acetate or placebo in combination with prednisone or prednisolone plus LHRH analogues or prior orchiectomy, final analysis

 

 

 

In addition to the observed improvements in overall survival and rPFS, benefit was demonstrated for Abiraterone Acetate vs. Placebo treatment in all secondary endpoint measures as follows:

 

Time to PSA progression based on PCWG2 criteria: The median time to PSA progression was 11.1 months for patients receiving Abiraterone Acetate and 5.6 months for patients receiving placebo (HR = 0.488; 95% CI: [0.420; 0.568], p < 0.0001). The time to PSA progression was approximately doubled with Abiraterone Acetate treatment (HR = 0.488). The proportion of subjects with a confirmed PSA response was greater in the Abiraterone Acetate group than in the placebo group (62% vs. 24%; p < 0.0001). In subjects with measurable soft tissue disease, significantly increased numbers of complete and partial tumor responses were seen with Abiraterone Acetate treatment.

 

Time to opiate use for cancer pain: The median time to opiate use for prostate cancer pain at the time of final analysis was 33.4 months for patients receiving Abiraterone Acetate and was 23.4 months for patients receiving placebo (HR = 0.721; 95% CI: [0.614; 0.846], p < 0.0001).

 

Time to initiation of cytotoxic chemotherapy: The median time to initiation of cytotoxic

chemotherapy was 25.2 months for patients receiving Abiraterone Acetate and 16.8 months for patients receiving placebo (HR = 0.580; 95% CI: [0.487; 0.691], p < 0.0001).

 

Time to deterioration in ECOG performance score by ≥ 1 point: The median time to deterioration in ECOG performance score by ≥ 1 point was 12.3 months for patients receiving Abiraterone Acetate and 10.9 months for patients receiving placebo (HR = 0.821; 95% CI: [0.714; 0.943], p = 0.0053).

 

The following study endpoints demonstrated a statistically significant advantage in favour of Abiraterone Acetate treatment:

 

Objective response: Objective response was defined as the proportion of subjects with measurable disease achieving a complete or partial response according to RECIST criteria (baseline lymph node size was required to be ≥ 2 cm to be considered a target lesion). The proportion of subjects with measurable disease at baseline who had an objective response was 36% in the Abiraterone Acetate group and 16% in the placebo group (p < 0.0001).

 

Pain: Treatment with Abiraterone Acetate significantly reduced the risk of average pain intensity progression by 18% compared with placebo (p = 0.0490). The median time to progression was 26.7 months in the Abiraterone Acetate group and 18.4 months in the placebo group.

 

Time to degradation in the FACT-P (Total Score): Treatment with Abiraterone Acetate decreased the risk of FACT-P (Total Score) degradation by 22% compared with placebo (p = 0.0028). The median time to degradation in FACT-P (Total Score) was 12.7 months in the Abiraterone Acetate group and 8.3 months in the placebo group.

Study 301 (patients who had received prior chemotherapy)

 

Study 301 enrolled patients who had received prior docetaxel. Patients were not required to show disease progression on docetaxel, as toxicity from this chemotherapy may have led to discontinuation.

 

Patients were maintained on study treatments until there was PSA progression (confirmed 25% increase over the patient's baseline/nadir) together with protocol-defined radiographic progression and symptomatic or clinical progression. Patients with prior ketoconazole treatment for prostate cancer were excluded from this study. The primary efficacy endpoint was overall survival.

 

The median age of enrolled patients was 69 years (range 39-95). The number of patients treated with Abiraterone Acetate by racial group was Caucasian 737 (93.2%), Black 28 (3.5%), Asian 11 (1.4%) and other 14 (1.8%). Eleven percent of patients enrolled had an ECOG performance score of 2; 70% had radiographic evidence of disease progression with or without PSA progression; 70% had received one prior cytotoxic chemotherapy and 30% received two. Liver metastasis was

present in 11% of patients treated with Abiraterone Acetate.

 

In a planned analysis conducted after 552 deaths were observed, 42% (333 of 797) of patients treated with Abiraterone Acetate compared with 55% (219 of 398) of patients treated with placebo, had died. A statistically significant improvement in median overall survival was seen in patients treated with Abiraterone Acetate (see Table 7).

 

 

Table 7: Overall survival of patients treated with either ZYTIGA or placebo in combination with prednisone or prednisolone plus LHRH analogues or prior orchiectomy

 

AA-P

(N=546)

Placebo

(N=542)

Primary survival analysis

 

 

Death (%)

333 (42%)

219 (55%)

Median Survival (months)

(95% CI)

14.8 (14.1; 15.4)

10.9 (10.2; 12.0)

p-value*

< 0.0001

Hazard ratio**

(95% CI)

0.646 (0.543; 0.768)

 

Updated survival analysis

 

Deaths

501 (63%)

274 (69%)

Median Survival in months

(95% CI)

15.8 (14.8;17.0)

 

11.2 (10.4; 13.1)

Hazard ratio**

(95% CI)

0.740 (0.638, 0.859)

 

 

a p-value is derived from a log-rank test stratified by ECOG performance status score (0-1 vs. 2), pain score (absent vs. present), number of prior chemotherapy regimens (1 vs. 2), and type of disease progression (PSA only vs. radiographic).

b Hazard ratio is derived from a stratified proportional hazards model. Hazard ratio < 1 favours Abiraterone Acetate

 

At all evaluation time points after the initial few months of treatment, a higher proportion of patients treated with Abiraterone Acetate remained alive, compared with the proportion of patients treated with placebo (see Figure 6).

 

Figure 6: Kaplan Meier survival curves of patients treated with either Abiraterone Acetate or placebo in combination with prednisone or prednisolone plus LHRH analogues or prior orchiectomy

 

 

Subgroup survival analyses showed a consistent survival benefit for treatment with Abiraterone Acetate (see Figure 7).

 

Figure 7: Overall survival by subgroup: hazard ratio and 95% confidence interval

 

AA = Abiraterone Acetate; BPI = Brief Pain Inventory; C.I. = confidence interval; ECOG = Eastern Cooperative Oncology Group performance score; HR = hazard ratio; NE = not evaluable.

 

In addition to the observed improvement in overall survival, all secondary study endpoints favoured Abiraterone Acetate and were statistically significant after adjusting for multiple testing as follows:

 

Patients receiving Abiraterone Acetate demonstrated a significantly higher total PSA response rate (defined as a ≥ 50% reduction from baseline), compared with patients receiving placebo, 38% vs.10%, p < 0.0001.

 

The median time to PSA progression was 10.2 months for patients treated with Abiraterone Acetate and 6.6 months for patients treated with placebo (HR = 0.580; 95% CI: [0.462; 0.728], p < 0.0001).

 

The median radiographic progression-free survival was 5.6 months for patients treated with Abiraterone Acetate and 3.6 months for patients who received placebo (HR = 0.673; 95% CI: [0.585; 0.776], p < 0.0001).

 

Pain

The proportion of patients with pain palliation was statistically significantly higher in the

Abiraterone Acetate group than in the placebo group (44% vs. 27%, p = 0.0002). A responder for pain palliation was defined as a patient who experienced at least a 30% reduction from baseline in the BPI-SF worst pain intensity score over the last 24 hours without any increase in analgesic usage score observed at two consecutive evaluations four weeks apart. Only patients with a baseline pain score of ≥ 4 and at least one post-baseline pain score were analysed (N = 512) for pain palliation.

 

A lower proportion of patients treated with Abiraterone Acetate had pain progression compared to patients taking placebo at 6 (22% vs. 28%), 12 (30% vs. 38%) and 18 months (35% vs. 46%). Pain progression was defined as an increase from baseline of ≥ 30% in the BPI-SF worst pain intensity score over the previous 24 hours without a decrease in analgesic usage score observed at two consecutive visits, or an increase of ≥ 30% in analgesic usage score observed at two consecutive visits. The time to pain progression at the 25th percentile was 7.4 months in the Abiraterone Acetate

group, versus 4.7 months in the placebo group.

 

Skeletal-related events

A lower proportion of patients in the Abiraterone Acetate group had skeletal-related events compared with the placebo group at 6 months (18% vs. 28%), 12 months (30% vs. 40%), and 18 months (35% vs. 40%). The time to first skeletal-related event at the 25th percentile in the Abiraterone Acetate group was twice that of the control group at 9.9 months versus 4.9 months. A skeletal-related event was defined as a pathological fracture, spinal cord compression, palliative radiation to bone, or surgery to bone.

 

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Abiraterone Acetate in all subsets of the paediatric population in advanced prostate cancer. See section 4.2 for information on paediatric use.


Following administration of abiraterone acetate, the pharmacokinetics of abiraterone and abiraterone acetate have been studied in healthy subjects, patients with metastatic advanced prostate cancer and subjects without cancer with hepatic or renal impairment. Abiraterone acetate is rapidly converted in vivo to abiraterone, an androgen biosynthesis inhibitor (see section 5.1).

 

Absorption

Following oral administration of abiraterone acetate in the fasting state, the time to reach maximum plasma abiraterone concentration is approximately 2 hours.

 

Administration of abiraterone acetate with food, compared with administration in a fasted state, results in up to a 10-fold (AUC) and up to a 17-fold (Cmax) increase in mean systemic exposure of abiraterone, depending on the fat content of the meal. Given the normal variation in the content and composition of meals, taking Abiraterone Acetate with meals has the potential to result in highly variable exposures. Therefore, Abiraterone Acetate must not be taken with food. It should be taken at least two hours after eating and no food should be eaten for at least one hour after taking

Abiraterone Acetate. The tablets should be swallowed whole with water (see section 4.2).

 

Distribution

The plasma protein binding of 14C-abiraterone in human plasma is 99.8%. The apparent volume of distribution is approximately 5,630 l, suggesting that abiraterone extensively distributes to peripheral tissues.

 

Biotransformation

Following oral administration of 14C-abiraterone acetate as capsules, abiraterone acetate is hydrolysed to abiraterone, which then undergoes metabolism including sulphation, hydroxylation and oxidation primarily in the liver. The majority of circulating radioactivity (approximately 92%) is found in the form of metabolites of abiraterone. Of 15 detectable metabolites, 2 main metabolites, abiraterone sulphate and N-oxide abiraterone sulphate, each represents approximately 43% of total radioactivity.

 

Elimination

The mean half-life of abiraterone in plasma is approximately 15 hours based on data from healthy subjects. Following oral administration of 14C-abiraterone acetate 1,000 mg, approximately 88% of the radioactive dose is recovered in faeces and approximately 5% in urine. The major compounds present in faeces are unchanged abiraterone acetate and abiraterone (approximately 55% and 22% of the administered dose, respectively).

Hepatic impairment

The pharmacokinetics of abiraterone acetate was examined in subjects with pre-existing mild or moderate hepatic impairment (Child-Pugh Class A and B, respectively) and in healthy control subjects. Systemic exposure to abiraterone after a single oral 1,000 mg dose increased by approximately 11% and 260% in subjects with mild and moderate preexisting hepatic impairment, respectively. The mean half-life of abiraterone is prolonged to approximately 18 hours in subjects with mild hepatic impairment and to approximately 19 hours in subjects with moderate hepatic impairment.

 

In another trial, the pharmacokinetics of abiraterone were examined in subjects with pre-existing severe (n = 8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normal hepatic function. The AUC to abiraterone increased by approximately 600% and the fraction of free drug increased by 80% in subjects with severe hepatic impairment compared to subjects with normal hepatic function.

 

No dose adjustment is necessary for patients with pre-existing mild hepatic impairment.

 

The use of abiraterone acetate should be cautiously assessed in patients with moderate hepatic impairment in whom the benefit clearly should outweigh the possible risk (see sections 4.2 and 4.4). abiraterone acetate should not be used in patients with severe hepatic impairment (see sections 4.2, 4.3 and 4.4).

 

For patients who develop hepatotoxicity during treatment, suspension of treatment and dose adjustment may be required (see sections 4.2 and 4.4).

 

Renal impairment

The pharmacokinetics of abiraterone acetate was compared in patients with end-stage renal disease on a stable haemodialysis schedule versus matched control subjects with normal renal function. Systemic exposure to abiraterone after a single oral 1,000 mg dose did not increase in subjects with end-stage renal disease on dialysis. Administration in patients with renal impairment, including severe renal impairment, does not require dose reduction (see section 4.2). However, there is no clinical experience in patients with prostate cancer and severe renal impairment. Caution is advised in these patients.


In all animal toxicity studies, circulating testosterone levels were significantly reduced. As a result, reduction in organ weights and morphological and/or histopathological changes in the reproductive organs, and the adrenal, pituitary and mammary glands were observed. All changes showed complete or partial reversibility. The changes in the reproductive organs and androgen-sensitive organs are consistent with the pharmacology of abiraterone. All treatment-related hormonal changes reversed or were shown to be resolving after a 4-week recovery period.

 

In fertility studies in both male and female rats, abiraterone acetate reduced fertility, which was completely reversible in 4 to 16 weeks after abiraterone acetate was stopped.

 

In a developmental toxicity study in the rat, abiraterone acetate affected pregnancy including reduced foetal weight and survival. Effects on the external genitalia were observed though abiraterone acetate was not teratogenic.

 

In these fertility and developmental toxicity studies performed in the rat, all effects were related to the pharmacological activity of abiraterone.

 

Aside from reproductive organ changes seen in all animal toxicology studies, non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. Abiraterone acetate was not carcinogenic in a 6-month study in the transgenic (Tg.rasH2) mouse. In a 24- month carcinogenicity study in the rat,abiraterone acetate increased the incidence of interstitial cell neoplasms in the testes. This finding is

considered related to the pharmacological action of abiraterone and rat specific. Abiraterone acetate was not carcinogenic in female rats.

The active substance, abiraterone, shows an environmental risk for the aquatic environment,especially to fish.


Lactose monohydrate, Microcrystalline cellulose PH 101, Croscarmellose sodium, Povidone K 30,

Sodium laurylsulfate, Colloidal silicon dioxide Magnesium stearate and Purified Water.


NA


24 months

Do not store above 30؛C.


120’s HDPE container.


Based on its mechanism of action, this medicinal product may harm a developing foetus; therefore, women who are pregnant or may be pregnant should not handle it without protection, e.g., gloves. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. This medicinal product may pose a risk to the aquatic environment (see section 5.3).


MS Pharma Saudi, Riyadh, Kingdome Saudi Arabia. medical-ksa@mspharma.com

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