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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)

OCALIVA contains the active substance obeticholic acid (farnesoid X-receptor agonist) which helps to improve how your liver works by reducing the production and build up of bile in the liver and also reducing inflammation. 

This medicine is used to treat adult patients with a type of liver disease known as primary biliary cholangitis (also known as primary biliary cirrhosis), either by itself or together with another medicine, ursodeoxycholic acid.


Do not take OCALIVA:

-              if you are allergic to obeticholic acid or any of the other ingredients of this medicine (listed in section 6).

-              if you have a complete blockage of the biliary tract (liver, gall bladder and bile ducts).

 

Warnings and precautions 

Talk to your doctor or pharmacist before taking OCALIVA.

 

If you experience itching that is difficult to tolerate, talk to your doctor.

 

Your doctor will do blood tests to monitor the health of your liver when you start treatment and regularly from there on.  

 

Children and adolescents

This medicine is not for use in children or adolescents.

 

Other medicines and OCALIVA

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

 

In particular, tell your doctor if you are taking so-called bile acid binding resins (cholestyramine, colestipol, colesevelam) used to lower blood cholesterol levels as they may lessen the effect of OCALIVA.  If you take any of these medicines, take OCALIVA at least 4-6 hours before or 4-6 hours after taking bile acid binding resin, giving as much time as possible.  

 

The levels of some medicines such as theophylline (a medicine to help breathing) or tizanidine (a medicine to relieve the stiffness and restriction of muscles) may be increased and need to be monitored by your doctor while taking OCALIVA.  Your doctor may need to monitor how well your blood clots when taking medicines such as warfarin (a medicine to help your blood flow) with OCALIVA. 

 

Pregnancy and breast-feeding

There is little information about the effects of OCALIVA in pregnancy.  As a precautionary measure, you should not take OCALIVA if you are pregnant.

 

It is not known if this medicine passes into human milk.  Your doctor will determine whether you should discontinue breast-feeding or discontinue/abstain from OCALIVA therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for you. 

 

Driving and using machines

This medicine has no or negligible influence on your ability to drive or use machines.


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

 

The recommended dose is one 5 mg film-coated tablet once daily by mouth.

Your doctor may adjust your dose depending on your liver function or if you experience itching that is difficult to tolerate.

 

Depending on your body’s response after 6 months your doctor may increase your dose to 10 mg once daily.  Your doctor will discuss any change of dose with you.

 

You can take OCALIVA with or without food.  If you take bile acid binding resins, take this medicine at least 4-6 hours before or at least 4-6 hours after the bile acid binding resin (see section "Other medicines and OCALIVA").

 

If you take more OCALIVA than you should

If you accidentally take too many tablets, you may experience liver related side effects such as yellowing of the skin.  Contact a doctor or go to a hospital for advice immediately.  

 

If you forget to take OCALIVA

Skip the missed dose and take your next dose when you would normally take it.  Do not take a double dose to make up for a forgotten tablet.

 

If you stop taking OCALIVA

You should continue to take OCALIVA for as long as your doctor tells you to.  Do not stop taking the medicine 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.

 

Tell your doctor or pharmacist if you experience itching of the skin (pruritus) or if the itch gets worse while on this medicine.  In general itching of the skin is a very common side effect that begins within the first month following the start of treatment with OCALIVA and usually becomes less severe over time.

 

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

•              stomach pain

•              feeling tired

 

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

•              thyroid hormone irregularity

•              dizziness

•              fast or irregular heart beat (palpitations)

•              pain in the mouth and throat

•              constipation

•              dry skin, redness of the skin (eczema)

•              rash

•              pain in your joints

•              swelling in the hands and feet

•              fever

 

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse.  This includes any possible side effects not listed in this leaflet. By reporting side effects you can help provide more information on the safety of this medicine.


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 and bottle after “EXP”.  The expiry date refers to the last day of that month.

 

Do not store above 30 °C. 

 

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 obeticholic acid. 

-        OCALIVA 5 mg film-coated tablets: Each film-coated tablet contains 5 mg of obeticholic acid.

-        OCALIVA 10 mg film-coated tablets: Each film-coated tablet contains 10 mg of obeticholic acid.

 

·        The other ingredients are:

-   Tablet core: Microcrystalline cellulose (E460), sodium starch glycolate (Type A), magnesium stearate.

-   Film-coat: Polyvinyl alcohol, part hydrolysed (E1203), titanium dioxide (E171), macrogol 3350 (E1521), talc (E553b), iron oxide yellow (E172).


- OCALIVA 5 mg is a yellow, round film-coated tablet with ‘INT’ on one side and ‘5’ on the other side of the film-coated tablet. - OCALIVA 10 mg is a yellow, triangular film-coated tablet with ‘INT’ on one side and ‘10’ on the other side of the film-coated tablet. Pack sizes 1 bottle with 30 or 100 film-coated tablets. Not all pack sizes may be marketed.

Marketing Authorisation Holder

Intercept Pharma Ltd.

1  Pancras Square

London, N1C 4AG 

United Kingdom

 

Bulk Manufacturer

Piramal Healthcare UK Limited

Whalton Road Morpeth

Northumberland NE61 3YA

United Kingdom

 

Batch ReleaserAlmac Pharma Services Limited

Seagoe Industrial Estate

Portadown

Craigavon

BT63 5UA

United Kingdom


This leaflet was last revised in {03/2018}.
  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 أوكاليفا على المادة الفعَّالة حمض الأوبيتيكوليك (ناهض مستقبل فارنيسويد إكس) والتي تُساعِد في تحسين طريقة عمل كبدك عن طريق تقليل إنتاج ومراكمة العصارة الصفراوية في الكبد وتقليل الالتهاب أيضًا. 

 

يُستَخدَم هذا الدَّواء لعلاج المرضى البالغين المُصابين بأحد أنواع مرض الكبد التي تُعرَف باسم التهاب الأوعية الصفراوية المراري الأوَّلي (يُعرَف أيضًا باسم تليُّف المرارة الأوَّلي)، سواء وحده أو بمصاحبة دواء آخر، حمض الأورسوديوكسيكوليك.

لا تتناول أوكاليفا:

-         إذا كنت تعاني من حساسية تجاه حمض الأوبيتيكوليك أو أي من المكونات الأخرى بهذا الدَّواء (المدرجة بالقسم 6). 

-         إذا كان لديك انسداد كامل للجهاز الصفراوي (الكبد، المرارة، القنوات الصفراوية).

 

تحذيرات واحتياطات 

تحدَّث إلى طبيبك أو الصيدلي الخاص بك قبل تناول أوكاليفا.

 

إذا تعرَّضت لحكة يصعب تحمُّلها، فتحدَّث إلى طبيبك.

 

سيجري لك طبيبك اختبارات الدَّم لمراقبة صحة كبدك عندما تبدأ العلاج وبصفة منتظمة من حينها فصاعدًا.  

 

الأطفال والمراهقون

هذا الدَّواء غير مُخَصص للاستخدام في الأطفال أو المراهقين.

 

تناوُل أوكاليفا مع أدوية أخرى

يُرجى إبلاغ الطبيب أو الصيدلي الخاص بك إذا كنت تتناول أو تناولت مؤخرًا أو قد تتناول أيَّة أدوية أخرى. 

 

على وجه الخصوص، أخبر طبيبك إذا كنت تتناول ما يُسمى براتنجات الارتباط بالحمض الصفراوي (كولستيرامين، الكوليستيبول، كوليسيفيلام) التي تُستَخدَم لخفض مستويات الكولستيرول بالدَّم؛ لأنها قد تُقلل من تأثير أوكاليفا.  إذا كنت تتناول أيًّا من هذه الأدوية، فتناول أوكاليفا قبل أو بعد 4-6 ساعات على الأقل من تناوُل راتنجات الارتباط بالحمض الصفراوي، أو بإعطاء أكبر قدر مُمكِن من الوقت.  

 

قد ترتفع مستويات بعض الأدوية، مثل ثيوفيلين (دواء يُستَخدَم للمساعدة على التَّنفس) أو تيزانيدين (دواء يُستَخدَم لتخفيف تيبُّس العضلات وتقيُّد حركتها) ويستلزم الأمر مراقبتها من قِبَل طبيبك أثناء تناوُل أوكاليفا. قد يحتاج طبيبك إلى مراقبة مدى تجلُّط دمك أثناء تناوُل أدوية مثل وارفارين (دواء يُستَخدَم للمساعدة على تدفُّق الدَّم) مع أوكاليفا. 

 

الحمل والرضاعة الطبيعية

هناك معلومات قليلة بشأن تأثيرات أوكاليفا على الحَمْل.  كإجراء احترازي، يجب عليكِ عدم تناوُل أوكاليفا إذا كنتِ حاملًا.

 

من غير المعروف ما إذا كان هذا الدَّواء يمر إلى لبن الأم أم لا.  سيحدد طبيبكِ ما إذا كان عليكِ التَّوقف عن ممارسة الرضاعة الطبيعيَّة أو التوقُّف/ الامتناع عن العلاج بأوكاليفا مع الأخذ في الاعتبار فائدة الرضاعة الطبيعيَّة للطفل وفائدة العلاج لك. 

 

القيادة واستخدام الآلات

ليس لهذا الدواء تأثير أو هناك تأثير لا يكاد يذكر في القدرة على القيادة واستخدام الآلات.

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تناول دائمًا هذا الدَّواء بالضبط كما أخبرك الطبيب أو الصيدلي الخاص بك.  يُرجى مراجعة الطبيب أو الصيدلي إذا لم تكن متأكدًا تمامًا من كيفية التَّناول.

 

الجرعة المُوصى بها هي قرص واحد مُغلَّف 5 مجم مرَّة واحدة يوميًّا عن طريق الفم.

قد يُعدِّل طبيبك جرعتك بناءً على مدى كفاءة وظائف الكبد لديك أو إذا تعرَّضت لحكة يصعُب تحمُّلها.

 

وفقًا لمدى استجابة جسمك بعد 6 أشهر، قد يُزيد طبيبك جرعتك إلى 10 مجم مرَّة واحدة يوميًّا.  سيناقش معك طبيبك أي تغيير للجرعة.

 

يمكنك تناول أوكاليفا مع الطعام أو دونه.   إذا كنت تتناول راتنجات الارتباط بالحمض الصفراوي فتناول هذا الدَّواء قبل أو بعد 4-6 ساعات على الأقل من تناوُل راتنجات الارتباط بالحمض الصفراوي (انظر قسم: "تناوُل أدوية أخرى مع أوكاليفا").

 

إذا تناولت كمية من أوكاليفا أكثر مما يجب

إذا تناولت كمية كبيرة من الأقراص بطريق الخطأ، فقد تتعرَّض لآثار جانبية متعلقة بالكبد مثل اصفرار الجلد.  اتصل بالطبيب أو اذهب إلى المستشفى؛ للحصول على المشورة فورًا.  

 

إذا أغفلت تناوُل أوكاليفا

تجاوز الجرعة التي أغفلتها وتناول الجرعة التَّالية في الموعد الذي اعتدت تناوُلها فيه.  لا تتناول جرعة مضاعفة لتعويض جرعة أغفلتها.

 

إذا توقفت عن تناول أوكاليفا

استمر في تناول أوكاليفا لطالما يخبرك الطبيب بذلك.  يجب أَلَّا تتوقف عن تناوُل هذا الدواء دون التَّحدث إلى طبيبك أولًا.

 

إذا كانت لديك أية أسئلة إضافية حول استخدام هذا الدَّواء، استشر الطبيب أو الصيدلي الخاص بك.

 

مثله مثل كافة الأدوية، قد يسبب هذا الدَّواء آثارًا جانبية، على الرَّغم من عدم حدوثها لدى الجميع.

 

أخبِر طبيبك أو الصيدلي الخاص بك إذا تعرَّضت لحكة بالجلد أو إذا تفاقمت الحكة أثناء تناوُلك لهذا الدَّواء. وبشكل عام، تُعد الحكة بالجلد أحد الآثار الجانبية الشائعة جدًّا والتي تبدأ في الظهور خلال الشهر الأول بعد بدء العلاج بأوكاليفا وعادةً ما تقل شدتها بمرور الوقت.  

آثار جانبية شائعة جدًّا (قد تُؤثر على أكثر من 1 من بين كل 10 أشخاص):

·         ألم بالمعدة.

·         شعور بالتعب.

 

الآثار الجانبية الشَّائعة (قد تُؤثر في ما يصل إلى 1 من بين كل 10 أشخاص):

·         عدم انتظام هرمون الغدة الدرقية.

·         دوخة.

·         تسارع أو عدم انتظام ضربات القلب (خفقان).

·         ألم في الفم والحلق.

·         إمساك.

·         جفاف الجلد، احمرار في الجلد (الأكزيما).

·         طفح جلدي.

·         ألم في المفاصل.

·         تورُّم اليدين والقدمين.

·         الحمّى.

 

الإبلاغ عن الآثار الجانبية

إذا أُصبت بأية آثار جانبية، فتحدَّث إلى طبيبك أو الصيدلي أو الممرض(ة).ويشمل ذلك أية آثار جانبية مُحتمَلة، غير المُدرجة في هذه النَّشرة.  من خلال إبلاغك عن الآثار الجانبية، يمكنك المساعدة في توفير معلومات إضافية حول أمان استخدام هذا الدَّواء.

يُحفظ هذا الدَّواء بعيدًا عن رؤية ومتناول الأطفال.

 

لا تستخدم هذا الدَّواء بعد تاريخ انتهاء الصلاحية المدون على العبوة الكرتونية وعلى الزجاجة بعد كلمة "EXP".  يُشير تاريخ انتهاء الصلاحية إلى اليوم الأخير من ذلك الشهر.

 

يُحفظ في درجة حرارة لا تزيد عن 30 درجة مئوية.

 

لا تتخلص من الأدوية عن طريق إلقائها في مياه الصرف أو مع المخلفات المنزلية.  استشر الصيدلي الخاص بك عن كيفية التَّخلص من الأدوية التي لم تعد تستخدمها.  سوف تُساعد هذه الإجراءات في الحفاظ على البيئة.

 

 

ما هي محتويات أوكاليفا؟ 

·       المادة الفعالة هي حمض الأوبيتيكوليك.

-      أوكاليفا 5 مجم أقراص مغلفة: يحتوي كل قرص مُغلَّف على 5 مجم من حمض الأوبيتيكوليك.

-      أوكاليفا 10 مجم أقراص مغلفة: يحتوي كل قرص مُغلَّف على 10 مجم من حمض الأوبيتيكوليك.

 

·       المكونات الأخرى هي:

-      محتوى القرص الدَّاخلي: سليلوز فائق التبلور(E460)، جليكولات نشا الصوديوم (النوع "أ")، ستيرات الماغنسيوم.

-      غلاف القرص: كحول متعدد الفينيل، جزء متحلل (E1203)، ثاني أكسيد التيتانيوم (E171)، ماكروجول 3350 (E1521)، تلك (E553b)، أكسيد الحديد الأصفر (E172).

ما هو شكل أوكاليفا؟ وما هي محتويات العبوة؟

-       أوكاليفا 5 مجم هو عبارة عن أقراص مغلَّفة صفراء اللون ودائرية الشكل مطبوع على أحد وجهيها "INT" وعلى الوجه الآخر من القرص المغلف "5".

-       أوكاليفا 10 مجم هو عبارة عن أقراص مغلَّفة صفراء اللون ومثلثية الشَّكل مطبوع على أحد وجهيها "INT" وعلى الوجه الآخر من القرص المغلف "10". 

 

أحجام العبوات

 1زجاجة بها 30 أو 100 قرص مُغلَّف.

 

قد لا يتم تسويق جميع أحجام العبوات.

مالك رخصة التَّسويق

Intercept Pharma Ltd

2 Pancras Square

London, N1C 4AG

United Kingdom

 

جهة التَّصنيع

Piramal Healthcare UK Limited

Whalton Road Morpeth

Northumberland NE61 3YA

United Kingdom

 

Batch Releaser

Almac Pharma Services Limited

Seagoe Industrial Estate

Portadown

Craigavon

BT63 5UA

United Kingdom

تمت آخر مراجعة لهذه النَّشرة في2018-03
 Read this leaflet carefully before you start using this product as it contains important information for you

OCALIVA 5 mg film-coated tablets OCALIVA 10 mg film-coated tablets

OCALIVA 5 mg film coated tablets Each film coated tablet contains 5 mg of obeticholic acid. OCALIVA 10 mg film coated tablets Each film coated tablet contains 10 mg of obeticholic acid. For the full list of excipients, see section 6.1.

Film-coated tablet OCALIVA 5 mg film coated tablets Yellow, 8 mm round tablet debossed with ‘INT’ on one side and ‘5’ on the other side. OCALIVA 10 mg film-coated tablets Yellow, 7.6 mm X 7.4 mm triangular tablet debossed with ‘INT’ on one side and ‘10’ on the other side.

OCALIVA is indicated for the treatment of primary biliary cholangitis (also known as primary biliary cirrhosis) in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA or as monotherapy in adults unable to tolerate UDCA.


Posology

Prior to initiation of treatment with obeticholic acid the patient’s hepatic status must be known.

The starting dose and dosage titration by PBC patient population is shown in Table 1.

Staging/Classification

Non-Cirrhotic or

Child-Pugh Class A

Child-Pugh Class B or C or Decompensated Cirrhotic

Starting Dosage

 

5 mg once daily

5 mg once weekly

Dosage Titration

 

For patients who have not achieved an adequate reduction in alkaline phosphatase (ALP) and/or total bilirubin after 6 months of treatment and the patient is tolerating obeticholic acid, titrate up to 10 mg once daily

For patients who have not achieved an adequate reduction in ALP and/or total bilirubin after 3 months of treatment and the patient is tolerating obeticholic acid, titrate up to 5 mg twice weekly (at least 3 days apart) and subsequently to 10 mg twice weekly (at least 3 days apart) based on response and tolerability

 

Maximum Dosage

10 mg once daily

10 mg twice weekly (at least 3 days apart)

 

 

 

No dose adjustment of concomitant UDCA is required in patients receiving obeticholic acid.

 

Management and dose adjustment for severe pruritus

Management strategies include the addition of bile acid binding resins or antihistamines.

 

For patients experiencing severe intolerability due to pruritus, one or more of the following should be considered:  

 

For Non-Cirrhotic or Child-Pugh Class A patients:

·   Reducing the dosage of obeticholic acid to:

§  5 mg every other day, for patients intolerant to 5 mg once daily

§  5 mg once daily, for patients intolerant to 10 mg once daily

·   Temporarily interrupting obeticholic acid dosing for up to 2 weeks followed by restarting at a reduced dosage. 

·   Continue to increase the dosage to 10 mg once daily, as tolerated, to achieve optimal response.

 

For Child-Pugh Class B or C or Decompensated Cirrhotic patients:

·   Reducing the dosage of obeticholic acid to:

§  5 mg once weekly, for patients intolerant to 5 mg twice weekly

§  10 mg once weekly, for patients intolerant to 10 mg twice weekly

·   Temporarily interrupting obeticholic acid dosing for up to 2 weeks followed by restarting at a reduced dosage if applicable. 

·   Continue to increase the dosage to 10 mg twice weekly, as tolerated, to achieve optimal response.

 

Consider discontinuing treatment with obeticholic acid for patients who continue to experience persistent, intolerable pruritus.

 

Special populations

Patients with hepatic impairment

See table 1 for dose recommendations. Further, see sections 4.4 and 5.2.

 

Elderly (> 65 years)

Limited data exists in elderly patients.  No dose adjustment is required for elderly patients (see section 5.2).

 

Patients with renal impairment

Limited data exists in patients with mild and moderate renal impairment and no data exists in severe renal impairment.  No dose adjustment is required for patients with renal impairment (see section 5.2).

 

Paediatric population

There is no relevant use of obeticholic acid in the paediatric population in the treatment of primary biliary cholangitis (PBC).

 

Method of administration

The tablet should be taken orally with or without food.

 

For patients taking bile acid binding resins, obeticholic acid should be administered at least 4‑6 hours before or 4‑6 hours after taking a bile acid binding resin, or at as great an interval as possible (see section 4.5). 


- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. - Complete biliary obstruction.

Liver related adverse events

Elevations in alanine amino transferase (ALT) and aspartate aminotransferase (AST) have been observed in patients taking obeticholic acid.  Clinical signs and symptoms of hepatic decompensation have also been observed.  These events have occurred as early as within the first month of treatment.  Liver-related adverse events have primarily been observed at doses higher than the maximum recommended dose of 10 mg once daily (see section 4.9). In the post marketing setting, serious liver injury and death have been reported with more frequent dosing of obeticholic acid than recommended in patients with moderate to severe decreases in liver function.

After initiation of therapy, all patients should be monitored for progression of PBC disease with laboratory and clinical assessment to determine whether dosage adjustment is needed. Patients at an increased risk of hepatic decompensation, including those with laboratory evidence of worsening liver function and /or progression to cirrhosis, should be monitored more closely. Dosing frequency should be reduced for patients who progress to advanced disease (i.e. from Child-Pugh Class A to Child-Pugh Class B or C) (see sections 4.2 and 5.2). 

 

Severe pruritus

Severe pruritus was reported in 23% of patients treated with OCALIVA 10 mg arm, 19% of patients in the OCALIVA titration arm, and 7% of patients in the placebo arms.  The median time to onset of severe pruritus was 11, 158, and 75 days for patients in the OCALIVA 10 mg, OCALIVA titration, and placebo arms, respectively.  Management strategies include the addition of bile acid binding resins or antihistamines, dose reduction, reduced dosing frequency, and/or temporary dose interruption (see sections 4.2 and 4.8).


Medicinal products that are affected by obeticholic acid

 

Warfarin

International normalised ratio (INR) is decreased following co‑administration of warfarin and obeticholic acid.  INR should be monitored and the dose of warfarin adjusted, if needed, to maintain the target INR range when co‑administering obeticholic acid and warfarin.

 

Interaction with CYP1A2 substrates with narrow therapeutic index

Obeticholic acid may increase the exposure to concomitant medicinal products that are CYP1A2 substrates.  Therapeutic monitoring of CYP1A2 substrates with narrow therapeutic index (e.g. theophylline and tizanidine) is recommended.

 

Medicinal products that affect obeticholic acid

 

Bile acid binding resins

Bile acid binding resins such as cholestyramine, colestipol, or colesevelam adsorb and reduce bile acid absorption and may reduce efficacy of obeticholic acid.  When concomitant bile acid binding resins are administered, obeticholic acid should be taken at least 4‑6 hours before or 4‑6 hours after taking a bile acid binding resin, or at as great an interval as possible. 


Pregnancy

There are no data on the use of obeticholic acid in pregnant women.  Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).  As a precautionary measure, it is preferable to avoid the use of obeticholic acid during pregnancy.

 

Breast‑feeding

It is unknown whether obeticholic acid is excreted in human milk.  Based on animal studies and intended pharmacology, obeticholic acid is not expected to interfere with breast‑feeding or the growth or development of a breast‑fed child.  A decision should be made whether to discontinue breast‑feeding or to discontinue/abstain from obeticholic acid therapy taking into account the benefit of breast‑feeding for the child and the benefit of therapy for the woman (see section 5.3).

 

Fertility

No fertility data is available in humans.  Animal studies do not indicate any direct or indirect effects on fertility or reproduction (see section 5.3).


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


Summary of the safety profile

The most commonly reported adverse reactions were pruritus (63%) and fatigue (22%).  Adverse reactions leading to discontinuation were 1% in the OCALIVA titration arm and 11% in the OCALIVA 10 mg arm.  The most common adverse reaction leading to discontinuation was pruritus.  The majority of pruritus occurred within the first month of treatment and tended to resolve over time with continued dosing.

 

Tabulated list of adverse reactions

The adverse reactions reported with OCALIVA in the phase III clinical study are listed in the table below by MedDRA system organ class and by frequency.  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), very rare (< 1/10,000) and not known (cannot be estimated from the available data).

 

Table 1.  Frequency of adverse reactions in PBC patients*

System Organ Class

Very common

Common

Endocrine disorders

 

Thyroid function abnormality

Nervous system disorders

 

Dizziness

Cardiac disorders

 

Palpitations

Respiratory, thoracic and mediastinal disorders

 

Oropharyngeal pain

Gastrointestinal disorders

Abdominal pain and discomfort

Constipation

Skin and subcutaneous tissue disorders

Pruritus

Eczema, Rash

Musculoskeletal and connective tissue disorders

 

Arthralgia

General disorders and administration site conditions

Fatigue

Oedema peripheral, Pyrexia

* Adverse reactions are defined as events occurring at a rate of greater than or equal to 5% of patients on obeticholic acid treatment arm and at an incidence greater than or equal to 1% higher than in the placebo treatment arm.

 

Description of selected adverse reactions

 

Pruritus

Approximately 60% of patients had a history of pruritus upon enrollment in the phase III study.  Treatment‑emergent pruritus generally started within the first month following the initiation of treatment.

 

Relative to patients who started on 10 mg once daily in the OCALIVA 10 mg arm, patients in the OCALIVA titration arm had a lower incidence of pruritus (70% and 56% respectively) and a lower discontinuation rate due to pruritus (10% and 1%, respectively).

 

The percentages of patients who required interventions (i.e, dosage adjustments, treatment interruptions, or initiation of antihistamines or bile acid binding resins) were 41% in the OCALIVA 10 mg arm, 34% in the OCALIVA titration group, and 19% in the placebo group.

 

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 the national reporting system listed below

 

To report any side effect(s):

·    Saudi Arabia:

 

 

-   The National Pharmacovigilance and Drug Safety Centre (NPC)

o Fax: +966-11-205-7662

o Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.

o Toll free phone: 8002490000

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

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

 

 

 

·    Other GCC States:

 

 

-   Please contact the relevant competent authority.


The highest single dose exposure of obeticholic acid in healthy volunteers has been at the 500 mg dose. Repeated doses of 250 mg have been administered for 12 consecutive days and some subjects experienced pruritus and reversible transaminase liver elevations.  In PBC patients who received OCALIVA 25 mg once daily (2.5 times the highest recommended dosage) or 50 mg once daily (5 times the highest recommended dosage), a dose‑dependent increase in the incidence of liver‑related adverse reactions (e.g., ascites, primary biliary cholangitis flare, new onset jaundice), and transaminase and bilirubin elevations (up to greater than 3‑times upper limit of normal [ULN]) were reported.  In the case of overdose, patients should be carefully observed and supportive care administered, as appropriate.


Pharmacotherapeutic group:  Bile and liver therapy, Bile acid preparations. ATC code: A05AA04

 

Mechanism of action

Obeticholic acid is a selective and potent agonist for the farnesoid X receptor (FXR), a nuclear receptor expressed at high levels in the liver and intestine.  FXR is thought to be a key regulator of bile acid, inflammatory, fibrotic, and metabolic pathways.  FXR activation decreases the intracellular hepatocyte concentrations of bile acids by suppressing de novo synthesis from cholesterol, as well as, by increasing transport of bile acids out of the hepatocytes.  These mechanisms limit the overall size of the circulating bile acid pool while promoting choleresis, thus reducing hepatic exposure to bile acids.

 

Pharmacodynamic effects

 

Clinical efficacy and safety

A phase III, randomised, double‑blind, placebo‑controlled, parallel‑group, 12‑month study (POISE) evaluated the safety and efficacy of OCALIVA in 216 patients with PBC who were taking UDCA for at least 12 months (stable dose for ≥ 3 months) or who were unable to tolerate UDCA and did not receive UDCA for ≥3 months.  Patients were included in the trial if the alkaline phosphatase (ALP) was greater than or equal to 1.67 times upper limit of normal (ULN) and/or if total bilirubin was greater than 1 x ULN but less 2 x ULN.  Patients were randomised (1:1:1) to receive once daily placebo, OCALIVA 10 mg, or OCALIVA titration (5 mg titrated to 10 mg at 6 months dependent on therapeutic response/tolerability).  The majority (93%) of patients received treatment in combination with UDCA and a small number of patients (7%) unable to tolerate UDCA received placebo, OCALIVA (10 mg) or OCALIVA titration (5 mg to 10 mg) as monotherapy.  ALP and total bilirubin were assessed as categorical variables in the primary composite endpoint, as well as continuous variables over time. 

 

The study population was predominantly female (91%) and white (94%).  The mean age was 56 years, with the majority of patients less than 65 years old.  Mean baseline ALP values ranged from 316 U/L to 327 U/L.  Mean baseline total bilirubin values ranged from 10 μmol/L to 12 μmol/L across treatment arms, with 92% of patients within normal range.

 

Treatment with OCALIVA 10 mg or OCALIVA titration (5 mg to 10 mg) resulted in clinically and statistically significant increases (p < 0.0001) relative to placebo in the number of patients achieving the primary composite endpoint at all study time points (see Table 2).  Responses occurred as early as 2 weeks and were dose dependent (OCALIVA 5 mg compared with 10 mg at 6 months, p=0.0358).

Table 2.  Percentage of PBC patients achieving the primary composite endpointa at month 6 and month 12 with or without UDCAb

 

OCALIVA

10 mgc

(N = 73)

OCALIVA

Titrationc

(N = 70)

Placebo

(N=73)

Month 6

 

 

 

Responders, n (%)

Corresponding 95% CI

37 (51)

39%, 62%

24 (34)

23%, 45%

5 (7)

1%, 13%

p-valued

<0.0001

<0.0001

NA

Month 12

 

 

 

Responders, n (%)

Corresponding 95% CI

35 (48)

36%, 60%

32 (46)

34%, 58%

7 (10)

4%, 19%

p-valued

<0.0001

<0.0001

NA

Components of primary endpointe

ALP less than 1.67-times ULN, n (%)

40 (55)

33 (47)

12 (16)

Decrease in ALP of at least 15%, n (%)

57 (78)

54 (77)

21 (29)

Total bilirubin less than or equal to 1-times ULNf, n (%)

60 (82)

62 (89)

57 (78)

 

 

a Percentage of subjects achieving a response, defined as an ALP less than 1.67‑times the ULN, total bilirubin within the normal range, and an ALP decrease of at least 15%.  Missing values were considered a non‑response. The Fisher’s exact test was used to calculate the 95% Confidence Intervals (Cis).

b In the trial there were 16 patients (7%) who were intolerant and did not receive concomitant UDCA: 6 patients (8%) in the OCALIVA 10 mg arm, 5 patients (7%) in the OCALIVA titration arm, and 5 patients (7%) in the placebo arm.

c Patients were randomized (1:1:1) to receive OCALIVA 10 mg once daily for the entire 12 months of the trial, or OCALIVA titration (5 mg once daily for the initial 6 months, with the option to increase to 10 mg once daily for the last 6 months, if the patient was tolerating OCALIVA but had ALP 1.67-times the ULN or greater, and/or total bilirubin above the ULN, or less than 15% ALP reduction) or placebo. 

dOCALIVA titration and OCALIVA 10 mg versus placebo.  P-values are obtained using the Cochran‑Mantel‑Haenszel General Association test stratified by intolerance to UDCA and pretreatment ALP greater than 3‑times ULN and/or AST greater than 2‑times ULN and/or total bilirubin greater than ULN.

e Response rates were calculated based on the observed case analysis (i.e., [n=observed responder]/[N=Intention to Treat (ITT) population]); percentage of patients with Month 12 values are 86%, 91% and 96% for the OCALIVA 10 mg, OCALIVA titration and placebo arms, respectively.

f The mean baseline total bilirubin value was 0.65 mg/dL, and was within the normal range (i.e., less than or equal to the ULN) in 92% of the enrolled patients.

 

Mean reduction in ALP

Mean reductions in ALP were observed as early as Week 2 and were maintained through Month 12 for patients who were maintained on the same dosage throughout 12 months.  For patients in the OCALIVA titration arm whose OCALIVA dosage was increased from 5 mg once daily to 10 mg once daily, additional reductions in ALP were observed at Month 12 in the majority of patients.

 

Mean reduction in gamma-glutamyl transferase (GGT)

The mean (95% CI) reduction in GGT was 178 (137, 219) U/L in the OCALIVA 10 mg arm, 138 (102, 174) U/L in the OCALIVA titration arm, and 8 (-48, 32) U/L in the placebo arm.

 

Monotherapy

Fifty‑one PBC patients with baseline ALP 1.67‑times ULN or greater and/or total bilirubin greater than ULN were evaluated for a biochemical response to OCALIVA as monotherapy (24 patients received OCALIVA 10 mg once daily and 27 patients received placebo) in a pooled analysis of data from the phase III randomised, double‑blind, placebo‑controlled 12 month study (POISE) and from a randomised, double‑blind, placebo‑controlled, 3‑ month study.  At month 3, 9 (38%) OCALIVA‑treated patients achieved a response to the composite endpoint, compared to 1 (4%) placebo‑treated patient.  The mean (95% CI) reduction in ALP in OCALIVA‑treated patients was 246 (165, 327) U/L compared to an increase of 17 (-7, 42) U/L in the placebo‑treated patients.

 

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with obeticholic acid in all subsets of the paediatric population in PBC (see section 4.2 for information on paediatric use).

 

This medicinal product has been authorised under a so‑called ‘conditional approval’ scheme.  This means that further evidence on this medicinal product is awaited.  The European Medicines Agency will review any new information which may become available at least every year and this SmPC will be updated as necessary.


Absorption

Obeticholic acid is absorbed with peak plasma concentrations (Cmax) occurring at a median time (tmax) of approximately 2 hours.  Co‑administration with food does not alter the extent of absorption of obeticholic acid.

 

Distribution

Human plasma protein binding of obeticholic acid and its conjugates is greater than 99%.  The volume of distribution of obeticholic acid is 618 L.  The volume of distributions of glyco‑ and tauro‑obeticholic acid has not been determined.

 

Biotransformation

Obeticholic acid is conjugated with glycine or taurine in the liver and secreted into bile.  These glycine and taurine conjugates of obeticholic acid are absorbed in the small intestine leading to enterohepatic recirculation.  The conjugates can be deconjugated in the ileum and colon by intestinal microbiota, leading to the conversion to obeticholic acid that can be reabsorbed or excreted in faeces, the principal route of elimination.

 

After daily administration of obeticholic acid, there was accumulation of the glycine and taurine conjugates of obeticholic acid which have in vitro pharmacological activities similar to the parent drug.  The metabolite‑to ‑parent ratios of the glycine and taurine conjugates of obeticholic acid were 13.8 and 12.3, respectively, after daily administration.  An additional third obeticholic acid metabolite, 3‑glucuronide is formed but is considered to have minimal pharmacologic activity.

 

Elimination

After administration of radiolabeled obeticholic acid, greater than 87% is excreted in faeces.  Urinary excretion is less than 3%.

 

Dose/Time proportionality

Following multiple‑dose administration of 5, 10, and 25 mg once daily for 14 days, systemic exposures of obeticholic acid increase dose proportionally.  Exposures of glyco‑ and tauro‑obeticholic acid, and total obeticholic acid increase more than proportionally with dose.

 

Special populations

Elderly

There are limited pharmacokinetic data in elderly patients (≥ 65 years).  Population pharmacokinetic analysis, developed using data from patients up to 65 years old, indicated that age is not expected to significantly influence obeticholic acid clearance from the circulation.

 

Paediatric population

No pharmacokinetic studies were performed with obeticholic acid in patients less than 18 years of age.

 

Gender

Population pharmacokinetic analysis indicated that gender does not influence obeticholic acid pharmacokinetics.

 

Race

Population pharmacokinetic analysis indicated that race is not expected to influence obeticholic acid pharmacokinetics.

 

Renal impairment

Obeticholic acid has minimal renal elimination with less than 3% of the dose recovered in urine.  Based on population pharmacokinetic analysis, renal function did not have a meaningful effect on

the pharmacokinetics of obeticholic acid. 

 

Hepatic impairment

Obeticholic acid is metabolised in the liver and intestines.  The systemic exposure of obeticholic acid, its active conjugates, and endogenous bile acids is increased in patients with moderate and severe hepatic impairment when compared to healthy controls.  Therefore, a modified dose regimen for patients with moderate or severe hepatic impairment is recommended to achieve plasma exposure levels similar to patients with no hepatic impairment (see section 4.2).

 

The impact of mild hepatic impairment (Child‑Pugh Class A) on the pharmacokinetics of obeticholic acid was negligible, therefore, no dose adjustment is necessary for patients with mild hepatic impairment.

 

In subjects with mild, moderate and severe hepatic impairment (Child‑Pugh Class A, B, and C, respectively), mean AUC of total obeticholic acid, the sum of obeticholic acid and its two active conjugates, increased by 1.13‑, 4‑ and 17‑fold, respectively, compared to subjects with normal hepatic function following single‑dose administration of 10 mg obeticholic acid.


Non‑clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to fertility, reproduction and development.  

 

Oral administration of obeticholic acid above the NOAEL to mice, rats, and dogs in pivotal, repeat dose toxicity studies resulted primarily in effects on the hepatobiliary system.  These included increased liver weights, alterations in serum chemistry parameters (ALT, AST, LDH, ALP, GGT, and/or bilirubin), and macroscopic/microscopic alterations.  All changes were reversible with discontinued dosing, and are consistent with and predict the dose‑limiting toxicity in humans (systemic exposure at NOAEL was up to 24‑fold higher than that seen at the maximum recommended human dose).  In a pre- and post-natal toxicity study in rats, the tauro-conjugate of obeticholic acid was found in pups nursing from dams dosed with obeticholic acid


Tablet core

Microcrystalline cellulose (E460)

Sodium starch glycolate (Type A)

Magnesium stearate

 

Tablet coating

Poly(vinyl alcohol), partially hydrolysed (E1203)

Titanium dioxide (E171)

Macrogol 3350 (E1521)

Talc (E553b)

Iron oxide yellow (E172)


Not applicable.


2 years

 Do not store above 30 °C


High‑density polyethylene (HDPE) bottles with a child resistant polypropylene closure and an aluminium foil induction seal.

 

Pack size:  30 or 100 film‑coated tablets.

 

Not all pack sizes may be marketed.


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


Intercept Pharma Ltd. 2 Pancras Square London, N1C 4AG United Kingdom

03/2018
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