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DIFICLIR is an antibiotic which contains the active substance fidaxomicin.
DIFICLIR film-coated tablets are used in adults, adolescents and children with a body weight of at least 12.5 kg to treat infections of the lining of the colon (large intestine) with certain bacteria called Clostridium difficile. This serious illness can result in painful, severe diarrhoea.
DIFICLIR works by killing the bacteria that cause the infection and helps to reduce the associated diarrhoea.
- If you are allergic to fidaxomicin or any of the other ingredients of this medicine (listed in section 6).
Warnings and precautions
Talk to your doctor or pharmacist before taking DIFICLIR.
If you feel that you might have a severe allergic reaction such as trouble breathing (dyspnea), swelling of the face or throat (angioedema), severe rash, severe itching (pruritus) or severe hives (urticaria), stop taking DIFICLIR and seek medical advice urgently from your doctor, pharmacist or at your local hospital emergency department (see section 4).
If you are allergic to macrolides (a class of antibiotics), ask your doctor for advice before using this medicine. Your doctor will tell you whether this medicine is suitable for you.
If you have kidney or liver problems, ask your doctor for advice before using this medicine. Your doctor will tell you whether this medicine is suitable for you.
If, next to your infection of the large intestine, you also have an inflammation of the intestines (inflammatory bowel disease), ask your doctor for advice before using this medicine. Your doctor will tell you whether this medicine is suitable for you.
There are limited data available on the use of fidaxomicin in severe cases of the disease (e.g. pseudomembranous colitis). Your doctor will know whether your disease falls in the severe categories and will tell you whether this medicine is suitable for you.
Children and adolescents
Do not give this medicine to children with a body weight below 12.5 kg, because these children require a reduced dose. For appropriate dosing in these patients, DIFICLIR granules for oral suspension may be used.
Other medicines and DIFICLIR
Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines.
DIFICLIR blood levels can be affected by other medicines you take, and blood levels of other medicines can be affected by taking DIFICLIR. Examples of such medicines are:
- cyclosporin (a medicine used to dampen down the body’s immune reactions, used e.g., after an organ or bone marrow transplant, for psoriasis or eczema, or for rheumatoid arthritis or nephrotic syndrome)
- ketoconazole (a medicine used to treat fungal infections)
- erythromycin (a medicine used to treat ear, nose, throat, chest and skin infections)
- clarithromycin (a medicine used to treat chest infections, throat and sinus infections, skin and tissue infections and Helicobacter pylori infections associated with duodenal or stomach ulcer)
- verapamil (a medicine used to treat high blood pressure or to prevent chest pain attacks, or used following a heart attack to prevent another one)
- dronedarone and amiodarone (medicines used to control the heartbeat)
- dabigatran etexilat (a medicine used to prevent the formation of blood clots after hip or knee replacement surgery)
You should not use DIFICLIR in combination with one of these medicines, unless your doctor tells you otherwise. If you use one of these medicines, please ask your doctor for advice before taking this medicine.
Pregnancy and breast-feeding
You should not take DIFICLIR if you are pregnant, unless your doctor tells you otherwise. This is because it is not known whether fidaxomicin can harm your baby.
If you are pregnant or think you may be pregnant, ask your doctor or pharmacist for advice before taking this medicine.
It is not known whether fidaxomicin passes into breast milk, but it is not expected to do so.
If you are breastfeeding, ask your doctor or pharmacist for advice before taking this medicine.
Driving and using machines
DIFICLIR is not expected to affect your ability to drive, use tools or machines.
DIFICLIR contains sodium
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.
Always take this medicine exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.
The standard dosing for patients weighing at least 12.5 kg is one tablet (200 mg) twice daily (one tablet every 12 hours) for 10 days (see scheme 1 below).
It is possible that your doctor has prescribed an alternate dosing. The recommendation for an alternate dosing is twice daily administration for days 1-5. Do not take a tablet on day 6, then once daily every other day for days 7-25 (see also scheme 2 below).
Scheme 1 - Standard dosing
DAY | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 |
Morning | 200 mg | 200 mg | 200 mg | 200 mg | 200 mg | 200 mg | 200 mg | 200 mg | 200 mg | 200 mg |
Evening | 200 mg | 200 mg | 200 mg | 200 mg | 200 mg | 200 mg | 200 mg | 200 mg | 200 mg | 200 mg |
Scheme 2 - Alternate dosing
DAY | 1 | 2 | 3 | 4 | 5 |
| |||||
Morning | 200 mg | 200 mg | 200 mg | 200 mg | 200 mg |
| |||||
Evening | 200 mg | 200 mg | 200 mg | 200 mg | 200 mg |
| |||||
DAY | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 | |
| - | 200 mg | - | 200 mg | - | 200 mg | - | 200 mg | - | 200 mg | |
DAY | 16 | 17 | 18 | 19 | 20 | 21 | 22 | 23 | 24 | 25 | |
| - | 200 mg | - | 200 mg | - | 200 mg | - | 200 mg | - | 200 mg | |
200 mg - DIFICLIR 200 mg film-coated tablet
- No tablet
Swallow the tablets whole with a glass of water. You can take DIFICLIR before, during or after meals.
If you take more DIFICLIR than you should
If you have taken more tablets than you should have, talk to a doctor. Take the medicine pack with you so the doctor knows what you have taken.
If you forget to take DIFICLIR
Take the tablet as soon as you remember, unless it is time for the next dose. In that case, skip the missed dose. Do not take a double dose to make up for a forgotten dose.
If you stop taking DIFICLIR
Do not stop taking DIFICLIR, unless your doctor has advised you to do so.
Keep taking this medicine until the course is finished, even if you feel better.
If you stop taking this medicine too soon, the infection may come back.
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.
A severe allergic reaction may occur, including trouble breathing (dyspnea), swelling of the face or throat (angioedema), severe rash or severe itching (pruritus) (see section 2). If such reaction occurs, stop taking DIFICLIR and seek medical advice urgently from your doctor, pharmacist or at your local hospital emergency department.
The most common side effects (may affect up to 1 in 10 people) are:
- vomiting,
- nausea
- constipation.
Other possible side effects are the following:
Uncommon side effects (may affect up to 1 in 100 people)
- decreased appetite
- dizziness, headache
- dry mouth, altered taste (dysgeusia)
- bloated feeling, wind (flatulence)
- rash, itching (pruritus)
Not known side effects (frequency cannot be estimated from the available data)
- swelling of the face and throat (angioedema), trouble breathing (dyspnea)
Additional side effects in children and adolescents
- hives
Store below 30ºC.
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 after “EXP”. The expiry date refers to the last day of that month.
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 fidaxomicin. Each film-coated tablet contains 200 mg of fidaxomicin.
- The other ingredients are:
Tablet core: microcrystalline cellulose, pregelatinised starch, hydroxypropyl cellulose, butylated hydroxytoluene, sodium starch glycolate and magnesium stearate
Coating: polyvinyl alcohol, titanium dioxide (E 171), talc, polyethylene glycol and lecithin (soy)
Marketing Authorisation Holder
Tillotts Pharma GmbH
Warmbacher Strasse 80
79618 Rheinfelden
Germany
Manufacturer of the final product
Patheon, Inc. (TRO)
2100 Syntex Court
Mississauga, Ontario, L5N 7K9
Canada
Manufacturer responsible for batch release
Tillotts Pharma AG
Hauptstrasse 27
4417 Ziefen
Switzerland
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.
To report any side effect(s):
· Saudi Arabia:
· The National Pharmacovigilance Centre (NPC): - SFDA Call Center: 19999 - E-mail: npc.drug@sfda.gov.sa - Website: https://ade.sfda.gov.sa/ |
· Other GCC states:
- Please contact the relevant competent authority. |
Council of Arab Health Ministers
This is a Medicament - A medicament is a product which affects your health, and its consumption contrary to instructions is dangerous for you. - Follow strictly the doctor’s prescription, the method of use and the instructions of the pharmacist who sold the medicament. - The doctor and the pharmacist are experts in medicine, their benefits and risks. - Do not by yourself interrupt the period of treatment prescribed for you. - Do not repeat the same prescription without consulting your doctor. - Keep all medicaments out of reach of children.
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Council of Arab Health Ministers
Union of Arab Pharmacists
يعتبر "ديفيكلير" بمثابة مضاد حيوي يحتوي على مادة فيداكسوميسين الفعالة.
يُستخدم ديفيكلير الأقراص المغلفة لدى البالغين والأطفال الذين لديهم وزن على الأقل 12.5 كجم لعلاج عدوى بطانة القولون (الأمعاء الغليظة) ببكتيريا معينة يطلق عليها اسم المَطثِيّةُ العَسيرة (بكتيريا لاهوائية
عصوية الشكل) لدى البالغين. وقد يؤدي هذا المرض الخطير إلى حدوث إسهال مؤلم شديد. ويعمل هذا الدواء من خلال القضاء على البكتيريا التي تسبب العدوى ويساعد في تقليل حدوث الإسهال المصاحب.
لا تتناول ديفيكلير
-إ ذا كنت تعاني من حساسية تجاه مادة فيداكسوميسين أو غيرها من المكونات الأخرى التي يحتوي عليها هذا الدواء (مدرجة في القسم رقم6 ).
التحذيرات والاحتياطات
ينبغي التحدث إلى الطبيب أو الصيدلي قبل تناول ديفيكلير.
في حالة التعرض لرد فعل ناتج عن الحساسية الشديدة مثل اضطراب التنفس (ضيق التنفس)، وانتفاخ الوجه أو الحلق (الوذمةالوعائية)، والطفح الحاد، الحكة الحادة (الحكة) أو خلايا شديدة (الشرى) ينبغي التوقف عن تناول ديفيكلير، وطلب الاستشارة الطبية من الطبيب أو الصيدلي
أو قسم الطوارئ لدى المستشفى المحلى على الفور (انظر قسم 4 ) .
إذا لديك حساسية على المكروليدات (فئة من المضادات الحيوية)، استشر طبيبك قبل استعمال هذا الدواء. وسوف يخبرك الطبيب ما إذا كان هذا الدواء مناسبًا لك أم لا.
إذا كنت تعاني من مشكلات في الكلى أو الكبد؛ فينبغي استشارة الطبيب قبل استعمال هذا الدواء. وسوف يخبرك الطبيب ما إذا كان هذا الدواء مناسبًا لك أم لا.
إذا تعرضت أيضا للإصابة بالتهاب الأمعاء (مرض التهاب الأمعاء) بعد إصابة بالتهابات الأمعاء الغليظة، فينبغي استشارة الطبيب قبل استعمال هذا الدواء. وسوف يخبرك الطبيب ما إذا كان هذا الدواء مناسبًا لك أم لا.
هناك محدودية في البيانات المتاحة حول استعمال فيداكسوميسين في الحالات الخطيرة للمرض (على سبيل المثال التهاب القولون الغشائي الكاذب) وسيتعرف الطبيب على إذا ما كان مرضك يندرج ضمن الفئات الحادة أم لا، وسوف يخبرك ما إذا كان هذا الدواء مناسبًا لك أم لا.
الأطفال والمراهقون
لا تعطي هذا الدواء للأطفال الذين يقل وزنهم عن 12.5 كجم، لأن هؤلاء الأطفال يحتاجون إلى جرعة مخفضة. للحصول على الجرعات المناسبة لهؤلاء المرضى، يمكن استخدام حبيبات ديفيكلير المعلقة عن طريق الفم.
الأدوية الأخرى وديفيكلير
ينبغي إخبار الطبيب أو الصيدلي إذا كنت تتناول أدوية أخرى حالياً أو تناولتها مؤخراً أو كان هناك إمكانية لتناولها لاحقاً.
يمكن أن تتأثر مستويات الدم لديفيكلير باستخدام الأدوية الأخرى، ويمكن لمستويات الدم للأدوية الأخرى أن تتأثر باستخدام ديفيكلير.
وتتضمن أمثلة هذه الأدوية:
- سيكلوسبورين (دواء يُستخدم لتقليل تفاعلات الجسم المناعية، فُيستعمل على سبيل المثال بعد زراعة عضو أو نخاع عظمي، أو لعلاج الصدفية أو الأكزيما، أو لعلاج التهاب المفاصل الروماتويدي أو المتلازمة الكلوي)
- كيتوكونازول (دواء يستخدم لعلاج العدوى الفطرية)
- إريثروميسين (دواء يستخدم لعلاج عدوى الأذن والأنف والحلق والصدر والجلد)
- كلاريثروميسين (دواء يستخدم لعلاج عدوى الصدر والحلق والجيوب الأنفية والجلد والأنسجة وعدوى الملوية البوابية المصاحبة لقرحة الاثنى عشر أو قرحة المعدة)
- فيراباميل (دواء يُستخدم لعلاج ارتفاع ضغط الدم أو لمنع نوبات ألم الصدر، أو يُستخدم عقب التعرض لنوبة قلبية لمنع حدوث نوبة أخرى)
- درونيدارون وأميودارون (أدوية تُستخدم للتحكم في ضربات القلب)
- دابيجتران إيتيكسيلت (دواء يُستخدم لمنع تكون جلطات الدم بعد جراحة استبدال الورك أو الركبة)
لا ينبغي استخدام ديفيكلير بمصاحبة أحد هذه الأدوية ما لم يخبرك الطبيب بخلاف ذلك. وإذا كنت تستخدم أحد هذه الأدوية، فُيرجى استشارة الطبيب قبل تناول هذا الدواء.
الحمل والرضاعة الطبيعية
لا ينبغي تناول ديفيكلير أثناء الحمل ما لم يذكر الطبيب خلاف ذلك.
وهذا نظراً لأنه ليس من المعروف إذا ما كان فيداكسوميسين له تأثير على الجنين أم لا.
ينبغي استشارة الطبيب أو الصيدلي قبل تناول هذا الدواء في حالة الحمل أو الاعتقاد بحدوث حمل.
ليس من المعروف ما إذا كان فيداكسوميسين ينتقل إلى لبن الثدي أم لا، لكن ليس من المتوقع حدوث ذلك.
وفي حالة الرضاعة الطبيعية، ينبغي استشارة الطبيب أو الصيدلي قبل تناول هذا الدواء.
القيادة واستعمال الآلات
لا يتوقع أن يكون لدواء ديفيكلير تأثير على القدرة على القيادة واستعمال الأدوات والآلات.
ديفيكلير يحتوي على الصوديوم
يحتوي هذا الدواء على أقل من 1 مليمول صوديوم (23 ملغ) لكل قرص، وهذا يعني أنه “خالي من الصوديوم” بشكل أساسي.
ينبغي تناول هذا الدواء كما أخبرك الطبيب تما ًما. وفي حالة التردد، ينبغي مراجعة الطبيب أو الصيدلي.
الجرعة الجرعة القياسية للمرضى الذين لا يقل وزنهم عن 12.5 كجم هي قرص واحد ( 200ملجم) مرتين يوميًا (قرص واحد كل 12ساعة) لمدة 10أيام. (انظر الجدول 1 أدناه).
من الممكن أن يكون طبيبك قد وصف لك جرعات بديلة. التوصية بالجرعات البديلة هي تناوله مرتين يوميًا لمدة 1-5 أيام. لا تتناول قرصًا في اليوم السادس، ثم تناوله مرة واحدة يوميًا كل يومين لمدة الأيام من 7 إلى 25 (انظر أيضًا الجدول 2 أدناه).
الجدول 1 - الجرعات القياسية
يوم | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 |
الصباح | 200 ملجم | 200 ملجم | 200 ملجم | 200 ملجم | 200 ملجم | 200 ملجم | 200 ملجم | 200 ملجم | 200 ملجم | 200 ملجم |
المساء | 200 ملجم | 200 ملجم | 200 ملجم | 200 ملجم | 200 ملجم | 200 ملجم | 200 ملجم | 200 ملجم | 200 ملجم | 200 ملجم |
الجدول 2 - الجرعات البديلة
يوم | 1 | 2 | 3 | 4 | 5 |
| ||||
الصباح | 200 ملجم | 200 ملجم | 200 ملجم | 200 ملجم | 200 ملجم |
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المساء | 200 ملجم | 200 ملجم | 200 ملجم | 200 ملجم | 200 ملجم |
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يوم | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 |
| - | 200 ملجم | - | 200 ملجم | - | 200 ملجم | - | 200 ملجم | - | 200 ملجم |
يوم | 16 | 17 | 18 | 19 | 20 | 21 | 22 | 23 | 24 | 25 |
| - | 200 ملجم | - | 200 ملجم | - | 200 ملجم | - | 200 ملجم | - | 200 ملجم |
قم بابتلاع القرص كاملاً مع شرب كوب من الماء. يمكن تناول ديفيكلير قبل الوجبات أو أثناءها أو بعدها.
في حالة تناول جرعات زائدة من ديفيكلير
إذا تناولت أقرا ًصا أكثر من المطلوب، ينبغي التحدث إلى الطبيب. وينبغي اصطحاب علبة الدواء ليتعرف الطبيب على ما تم تناوله.
في حالة نسيان تناول ديفيكلير
قم بتناول القرص بأسرع ما يمكن عند التذكر، إلا إذا حان موعد تناول الجرعة التالية. في تلك الحالة، يمكن تخطى الجرعة الفائتة.
لاينبغي تناول جرعة مزدوجة لتعويض الجرعة المنسية.
في حالة التوقف عن تناول ديفيكلير
لا ينبغي التوقف عن تناول ديفيكلير إلا بأمر الطبيب.
ينبغي مواصلة تناول هذا الدواء حتى انتهاء المقرر العلاجي حتى ولو شعرت بتحسن.
في حالة التوقف عن تناول الدواء في فترة مبكرة جدًا من العلاج، ربما يؤدي هذا لعودة العدوى.
في حالة وجود استفسارات إضافية حول الاستخدام، ينبغي سؤال الطبيب أو الصيدلي.
مثل جميع الأدوية يمكن أن يتسبب هذا الدواء في حدوث آثار جانبية، إلا أنها لا تحدث لجميع الأفراد.
قد يحدث رد فعل ناتج عن الحساسية الشديدة، بما يشمل اضطراب التنفس (ضيق التنفس)، وانتفاخ الوجه أو الحلق (الوذمة الوعائية)، والطفح الحاد أو الحكة الحادة (الحكة) (انظر قسم .(2إذا تعرضت لردود الأفعال هذه، فينبغي التوقف عن تناول ديفيكلير، وطلب الاستشارة الطبية من الطبيب أو الصيدلي أو قسم الطوارئ لدى المستشفى المحلى على الفور (انظر قسم4).
تضمنت الآثار الجانبية الأكثر شيو ًعا (يمكن أن تؤثر على 1من كل 10أفراد):
- القيء
- الغثيان
- الإمساك.
وتتضمن الآثار الجانبية المحتملة الأخرى ما يلي:
الآثار الجانبية غير الشائعة (يمكن أن تصيب 1من بين كل 100فرد)
- قلة الشهية
- الدوار، الصداع
- جفاف الفم، تغير المذاق (خلل الذوق)
- الشعور بالانتفاخ، الريح (امتلاء البطن بالغازات)
- الطفح، الحكة (الحكة)
الآثار الجانبية غير المعلومة (لا يمكن تقدير مدى التكرار من البيانات المتوفرة حالياً)
- انتفاخ الوجه والحلق (الوذمة الوعائية)، اضطرابات التنفس (ضيق التنفس)
آثار جانبية إضافية عند الأطفال والمراهقين
- خلايا النحل
يُخزن في درجة حرارة أقل من 30درجة مئوية.
ينبغي الاحتفاظ بهذا الدواء بعيدًا عن بصر ومتناول الأطفال.
لا ينبغي استعمال الدواء بعد تاريخ انتهاء الصلاحية المدوّن على العبوة الكرتونية بعد كلمة "تاريخ انتهاء الصلاحية". يشير تاريخ إنتهاء الصلاحية إلى آخر يوم في ذلك الشهر.
لا ينبغي التخلص من أي أدوية عبر الفضلات السائلة أو مخلفات المنزل. وينبغي سؤال الصيدلي حول كيفية التخلص من الأدوية غير المستخدمة. فالقيام بهذه الإجراءات يساعد في حماية البيئة.
المادة الفعالة هي فيداكسوميسين. يحتوي كل قرص مغلف على 200ملجم فيداكسوميسين.
-تتضمن المكونات الأخرى:
قلب القرص: سيللوز بلوري مكروي، نشا مجلتن مسبقاً، هيدروكسي بروبيل السيللوز، بوتيلاتد هيدروكسي تولين، جليكولات
نشا الصوديوم وستيرات المغنسيوم.
التغليف: كحول عديد الفاينيل، ثاني أكسيد التيتانيم (E 171)التلك، جليكول بولي إثيلين والليستين (الصويا) .
أقراص ديفيكلير 200ملجم المغلفة هي أقراص كبسولية الشكل ذات لون بين الأبيض والأبيض المائل للصفرة مكتوب على أحد
جانبيها " FDX " وعلى الجانب الآخر " 200".
ديفيكلير متوفر على هيئة:
1 × 100بثور جرعة وحدة مثقوبة من الألومنيوم/ قرص مغلف من الألومنيوم
1 × 20بثور جرعة وحدات مثقوبة من الألومنيوم/ قرص مغلف من الألومنيوم
قد لا يتم تسويق جميع أحجام العلب.
الجهة الحاملة لتصريح تسويق المنتج
Tillotts Pharma GmbH
Warmbacher Strasse 80
79618 Rheinfelden
ألمانيا
الشركة المصنعة للمنتج النهائي
Patheon، Inc. (TRO)
2100 Syntex Court
Mississauga, Ontario, L5N 7K9
كندا
الشركة المسؤولة عن ٳصدار رقم التشغيلة
Tillotts Pharma AG
Hauptstrasse 27
4417 Ziefen
سويسرا
للابلاغ حول الأعراض الجانبية التي قد تحدث يرجى التواصل عبر العناوين التالية:
المملكة العربية السعودية:
- المركز الوطني للتيقظ الدوائي (NPC) مركز اتصال الهيئة العامة للغذاء والدواء: 19999 البريد الإلكتروني: npc.drug@sfda.gov.sa الموقع الإلكتروني : https://ade.sfda.gov.sa/ |
·دول الخليج الأخرى:
- الرجاء الاتصال بالجهات الوطنية في كل دولة |
مجلس وزراء الصحة العرب:
إن هذا دواء |
مجلس وزراء الصحة العرب
واتحاد الصيادلة العرب
DIFICLIR is indicated for the treatment of Clostridium difficile infections (CDI) also known as C. difficile-associated diarrhoea (CDAD) in adult and paediatric patients with a body weight of at least 12.5 kg (see section 4.2 and 5.1).
Consideration should be given to official guidelines on the appropriate use of antibacterial agents.
Posology
Adults
· Standard dosing
The recommended dose is 200 mg (one tablet) administered twice daily (once every 12 hours) for 10 days (see section 5.1).
· Extended-pulsed dosing
DIFICLIR 200 mg tablets administered twice daily for days 1-5 (no intake of a tablet on day 6) then once daily on alternate days for days 7-25 (see section 5.1).
If a dose has been forgotten, the missed dose should be taken as soon as possible or, if it's nearly time for the next dose, the tablet should be skipped altogether.
Special populations
Elderly population
No dose adjustment is considered necessary (see section 5.2)
Renal impairment
No dose adjustment is considered necessary. Due to the limited clinical data in this population, DIFICLIR should be used with caution in patients with severe renal impairment (see sections 4.4 and 5.2).
Hepatic impairment
No dose adjustment is considered necessary. Due to the limited clinical data in this population, DIFICLIR should be used with caution in patients with moderate to severe hepatic impairment (see sections 4.4 and 5.2).
Paediatric population
The recommended dose in paediatric patients weighing at least 12.5 kg and able to swallow whole tablets, is 200 mg administered twice daily (once every 12 hours) for 10 days.
Method of administration:
DIFICLIR is intended for oral use.
DIFICLIR should be administered whole with water.
DIFICLIR can be taken with or without food.
Hypersensitivity reactions
Hypersensitivity reactions including severe angioedema have been reported (see section 4.8). If a severe allergic reaction occurs during treatment with DIFICLIR, the medicinal product should be discontinued and appropriate measures taken.
Some patients with hypersensitivity reactions reported a history of allergy to macrolides. Fidaxomicin should be used with caution in patients with a known macrolides allergy.
Renal and hepatic impairment
Due to limited clinical data, fidaxomicin should be used with caution in patients with severe renal impairment or moderate to severe hepatic impairment (see section 5.2).
Pseudomembranous colitis, fulminant or life threatening CDI
Due to limited clinical data, fidaxomicin should be used with caution in patients with pseudomembranous colitis, fulminant or life threatening CDI.
Co-administration of potent P-glycoprotein inhibitors
Co-administration of potent P-glycoprotein inhibitors such as cyclosporine, ketoconazole, erythromycin, clarithromycin, verapamil, dronedarone and amiodarone is not recommended (see sections 4.5 and 5.2). In case fidaxomicin is administered concomitantly with potent P-glycoprotein inhibitors, caution is advised.
Paediatric population
Only one paediatric patient below 6 months of age has been exposed to fidaxomicin in clinical trials. Therefore, patients below 6 months of age should be treated with caution.
Testing for C.difficile colonization or toxin is not recommended in children younger that 1 year due to high rate of asymptomatic colonization unless severe diarrhea is present in infants with risk factors for stasis such as Hirschsprung disease, operated anal atresia or other severe motility disorders. Alternative aetiologies should always se sought and C.difficile enterocolitis be proven.
Effect of P-gp inhibitors on fidaxomicin
Fidaxomicin is a substrate of P-gp. Co-administration of single doses of the P-gp inhibitor cyclosporine A and fidaxomicin in healthy volunteers, resulted in a 4- and 2-fold increase in fidaxomicin Cmax and AUC, respectively and in a 9.5 and 4-fold increase in Cmax and AUC, respectively, of the main active metabolite OP-1118. As the clinical relevance of this increase in exposure is unclear, co-administration of potent inhibitors of P-gp, such as cyclosporine, ketoconazole, erythromycin, clarithromycin, verapamil, dronedarone and amiodarone is not recommended (see section 4.4 and 5.2).
Effect of fidaxomicin on P-gp substrates
Fidaxomicin may be a mild to moderate inhibitor of intestinal P-gp.
Fidaxomicin (200 mg twice daily) had a small but not clinically relevant effect on digoxin exposure. However, a larger effect on P-gp substrates with lower bioavailability more sensitive to intestinal P-gp inhibition such as dabigatran etexilat cannot be excluded.
Effect of fidaxomicin on other transporters
Fidaxomicin does not have a clinically significant effect on the exposure of rosuvastatin, a substrate for the transporters OATP2B1 and BCRP. Co-administration of 200 mg fidaxomicin twice daily with a single dose of 10 mg rosuvastatin to healthy subjects did not have a clinically significant effect on the AUCinf of rosuvastatin.
Paediatric population
Interaction studies have only been performed in adults.
Pregnancy
There are no data available form the use of fidaxomicin in pregnant woman. Animal studies did not indicate direct or indirect harmful effects with respect to reproductive toxicity. As a precautionary measure, it is preferable to avoid the use of fidaxomicin during pregnancy.
Breast-feeding
It is unknown whether fidaxomicin and its metabolites are excreted in human milk. Although no effects on the breastfed newborns/infants are anticipated since the systemic exposure to fidaxomicin is low, a risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from DIFICLIR therapy, taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.
Fertility
Fidaxomicin had no effects on fertility when evaluated in rats (see section 5.3).
DIFICLIR has no or negligible influence on the ability to drive and use machines.
Summary of the safety profile
The most common adverse reactions are vomiting (1.2%), nausea (2.7%) and constipation (1.2%).
Tabulated summary of adverse reactions
Table 1 displays adverse reactions associated with twice daily administration of fidaxomicin in the treatment of C. difficile infection, reported in at least two patients, presented by system organ class.
The frequency of adverse reactions is 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), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 1: Summary of adverse reactions by MedDRA system organ class
MedDRA system organ class | Common | Uncommon | Frequency not known |
Immune system disorders
|
| rash, pruritus | hypersensitivity reactions (angioedema, dyspnea)
|
Metabolism and nutrition disorders |
| decreased appetite |
|
Nervous system disorders |
| dizziness, headache, dysgeusia |
|
Gastrointestinal disorders | vomiting, nausea, constipation | abdominal distention, flatulence, dry mouth |
|
Description of selected adverse reactions
Acute hypersensitivity reactions, such as angioedema and dyspnea, have been reported during post-marketing (see section 4.3 and 4.4).
Paediatric population
The safety and efficacy of fidaxomicin has been evaluated in 136 patients from birth to less than 18 years of age. Frequency, type and severity of adverse reactions in children are expected to be the same as in adults. In addition to the ADR shown in table, two cases or urticaria were reported.
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.
To report any side effect (s):
· Saudi Arabia:
The National Pharmacovigilance Centre (NPC) · SFDA Call Center: 19999 · E-Mail: npc.drug@sfda.gov.sa · Website: https://ade.sfda.gov.sa/
|
· Other GCC states:
- Please contact the relevant competent authority.
|
No adverse reactions for acute overdose have been reported during clinical studies or from post-marketing data. However, the potential for adverse reactions cannot be ruled out and general supportive measures are recommended.
Pharmacotherapeutic group: Antidiarrheals, intestinal antiinflammatory/antiinfective agents, antibiotics, ATC code: A07AA12
Mechanism of action
Fidaxomicin is an antibiotic belonging to the macrocyclic class of antibacterials.
Fidaxomicin is bactericidal and inhibits RNA synthesis by bacterial RNA polymerase. It interferes with RNA polymerase at a distinct site from that of rifamycins. Inhibition of the Clostridial RNA polymerase occurs at a concentration 20-fold lower than that for the E. coli enzyme (1 μM vs. 20 μM), partly explaining the significant specificity of fidaxomicin activity. Fidaxomicin has been shown to inhibit C. difficile sporulation in vitro.
Pharmacokinetic/Pharmacodynamic (PK/PD) relationship
Fidaxomicin is a locally acting drug. As a topical agent, systemic PK/PD relationships cannot be established, however in vitro data show fidaxomicin to have time-dependent bactericidal activity and suggest time over MIC may be the parameter most predicative of clinical efficacy.
Breakpoints
Fidaxomicin is a topically acting drug that cannot be used to treat systemic infections; therefore the establishment of a clinical breakpoint is not relevant. The epidemiological cut-off value for fidaxomicin and C. difficile, distinguishing the wild-type population from isolates with acquired resistance traits, is ≥1.0 mg/L.
Antimicrobial spectrum
Fidaxomicin is a narrow spectrum antimicrobial drug with bactericidal activity against C. difficile. Fidaxomicin has an MIC90 of 0.25 mg/L versus C. difficile, and its main metabolite, OP-1118, has an MIC90 of 8 mg/L. Gram negative organisms are intrinsically not susceptible to fidaxomicin.
Effect on the intestinal flora
Studies have demonstrated that fidaxomicin treatment did not affect Bacteroides concentrations or other major components of the microbiota in the faeces of CDI patients.
Mechanism of resistance
There are no known transferable elements that confer resistance to fidaxomicin. Also no cross- resistance has been discovered with any other antibiotic class including β-lactams, macrolides, metronidazole, quinolones, rifampin, and vancomycin. Specific mutations of RNA polymerase are associated with reduced susceptibility to fidaxomicin.
Clinical efficacy
The efficacy of fidaxomicin was evaluated in two pivotal, randomized, double blind Phase 3 studies (Study 003 and 004). Fidaxomicin was compared with orally administered vancomycin. The primary end point was clinical cure assessed after 12 days.
Non-inferiority of fidaxomicin compared with vancomycin was demonstrated in both studies (see Table 2).
Table 2 Combined results of studies 003 and 004
Per Protocol (PP) | Fidaxomicin | Vancomycin | 95% Confidence | |
Clinical Cure | 91.9% | 90.2% | (-1.8, 5.3) | |
modified Intent-to-Treat (mITT) | Fidaxomicin | Vancomycin | 95% Confidence | |
Clinical Cure | 87.9% | 86.2% | (-2.3, 5.7) |
*for treatment difference
The rate of recurrence in the 30 days following treatment was assessed as a secondary endpoint. The rate of recurrence (including relapses) was significantly lower with fidaxomicin (14.1% versus 26.0% with a 95% CI of [-16.8%, -6.8%]), however these trials were not prospectively designed to prove prevention of reinfection with a new strain.
Description of the patient population in clinical trials in adults
In the two pivotal clinical trials of patients with CDI, 47.9% (479/999) of patients (per protocol population) were ≥65 years of age and 27.5% (275/999) of patients were treated with concomitant antibiotics during the study period. Twenty-four percent of patients met at least one of the following three criteria at baseline for scoring severity: body temperature >38.5°C, leukocyte count >15,000, or creatinine value ≥1.5 mg/dl. Patients with fulminant colitis and patients with multiple episodes (defined as more than one prior episode within the previous 3 months) of CDI were excluded in the studies.
Trial with the extended-pulse fidaxomicin dosing (EXTEND)
EXTEND was a randomised, open-label study that compared extended-pulse fidaxomicin dosing with orally administered vancomycin. The primary endpoint was sustained clinical cure 30 days after end of treatment (Day 55 for fidaxomicin, day 40 for vancomycin). The sustained clinical cure 30 days after end of treatment was significantly higher for fidaxomicin vs. vancomycin (see Table 1).
Table 1 Results of EXTEND study
modified Intent-to-Treat | Fidaxomicin | Vancomycin | 95% Confidence |
Clinical cure 30 days after end of treatment | 70.1% | 59.2% | (1.0, 20.7) |
*for treatment difference
Description of the patient population in extended-pulse fidaxomicin dosing trial
The trial was conducted with adults aged 60 years and older. The median age of the patients was 75. 72% (257/356) received other antibiotics within the last 90 days. 36.5% had a severe infection.
Paediatric population
The safety and efficacy of fidaxomicin in paediatric patients from birth to less than 18 years of age was investigated in a multicentre, investigator-blind, randomised, parallel group study where 148 patients were randomised to either fidaxomicin or vancomycin in a 2:1 ratio. A total of 30, 49, 40 and 29 patients were randomised in the age groups of birth to < 2 years, 2 to < 6 years, 6 to < 12 years and 12 to < 18 years, respectively. Confirmed clinical response 2 days after end of treatment was similar between the fidaxomicin and vancomycin group (77.6% vs 70.5% with a point difference of 7.5% and 95% CI for the difference of [-7.4%, 23.9%]). The rate of recurrence 30 days after end of treatment was numerically lower with fidaxomicin (11.8% vs 29.0%), but the rate difference is not statistically significant (point difference of -15.8% and 95% CI for the difference of [-34.5%, 0.5%]). Both treatments had a similar safety profile.
Absorption
The bioavailability in humans is unknown. In healthy adults, Cmax is approximately 9.88 ng/ml and AUC0-t is 69.5 ng•hr/ml following administration of 200 mg fidaxomicin, with a Tmax of 1.75 hours. In CDI patients, average peak plasma levels of fidaxomicin and its main metabolite OP-1118 tend to be 2- to 6-fold higher than in healthy adults. There was very limited accumulation of fidaxomicin or OP-1118 in plasma following administration of 200 mg fidaxomicin every 12 hours for 10 days.
Cmax for fidaxomicin and OP-1118 in plasma were 22% and 33% lower following a high fat meal vs fasting, but the extent of exposure (AUC0-t) was equivalent.
Fidaxomicin and the metabolite OP-1118 are substrates of P-gp.
In vitro studies showed that fidaxomicin and the metabolite OP-1118 are inhibitors of the transporters BCRP, MRP2 and OATP2B1, but were not found to be substrates. Under conditions of clinical use, fidaxomicin has no clinically relevant effect on the exposure of rosuvastatin, a substrate for OATP2B1 and BCRP (see section 4.5). The clinical relevance of MRP2 inhibition is not yet known.
Distribution
The volume of distribution in humans is unknown, due to very limited absorption of fidaxomicin. Biotransformation
No extensive analysis of metabolites in plasma has been performed, due to low levels of systemic absorption of fidaxomicin. A main metabolite, OP-1118, is formed through hydrolysis of the isobutyryl ester. In vitro metabolism studies showed that the formation of OP-1118 is not dependent on CYP450 enzymes. This metabolite also shows antimicrobial activity (see section 5.1).
Fidaxomicin does not induce or inhibit CYP450 enzymes in vitro.
Elimination
Following a single dose of 200 mg fidaxomicin, the majority of the administered dose (over 92%) was recovered in the stool as fidaxomicin or its metabolite OP-1118 (66%). The main elimination pathways of systemically available fidaxomicin have not been characterized. Elimination through urine is negligible (<1%). Only very low levels of OP-1118 and no fidaxomicin was detectable in human urine. The half life of fidaxomicin is approximately 8-10 h.
Special populations
Elderly
Plasma levels appear to be elevated in the elderly (age ≥ 65 years). Fidaxomicin and OP-1118 levels were approximately 2 times higher in patients ≥ 65 years compared to patients < 65 years. This difference is not considered clinically relevant.
Paediatric population
After administration of film-coated tablets, the mean (SD) plasma levels in the paediatric patients from 6 to less than 18 years was 48.53 (69.85) ng/ml and 143.63 (286.31) ng/ml for fidaxomicin and its main metabolite OP-1118, respectively, at 1 to 5 hours postdose.
Inflammatory bowel disease
Data from an open label, single arm study in adult CDI patients with concomitant inflammatory bowel disease (IBD) indicated no major difference in plasma concentrations of fidaxomicin or its main metabolite OP-1118 in patients with IBD as compared with patients without IBD in other studies. The maximum fidaxomicin and OP‑1118 plasma levels in CDI patients with concomitant IBD were within the range of levels found in CDI patients without IBD.
Hepatic impairment
Limited data from patients with an active history of chronic hepatic cirrhosis in the Phase 3 studies showed that median plasma levels of fidaxomicin and OP-1118 may be approximately 2- and 3-fold higher, respectively, than in non-cirrhotic patients.
Renal impairment
Limited data suggest that there is no major difference in plasma concentration of fidaxomicin or
OP-1118 between patients with reduced renal function (creatinine clearance < 50 ml/min) and patients with normal renal function (creatinine clearance ≥ 50 ml/min).
Gender, weight and race
Limited data suggest that gender, weight and race do not have any major influence on the plasma concentration of fidaxomicin or OP-1118.
Nonclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeat dose toxicity, genotoxicity, and reproductive toxicity.
Reproductive and fertility parameters showed no statistically significant differences in rats treated with fidaxomicin at doses up to 6.3 mg/kg/day (intravenous).
No target organs for toxicity were observed in juvenile animals, and no important potential risks have been observed in the nonclinical studies that might be relevant for paediatric patients.
Core tablets:
Microcrystalline cellulose
Pregelatinised starch (maize)
Hydroxypropyl cellulose
Butylated hydroxytoluene
Sodium starch glycolate
Magnesium stearate
Coating:
Polyvinyl alcohol
Titanium dioxide (E171)
Talc
Polyethylene glycol
Lecithin (soy)
Not applicable.
Keep out of the reach of children.
Store below 30°C.
100 x 1 film-coated tablet in alu/alu perforated unit dose blisters.
20 x 1 film-coated tablet in alu/alu perforated unit dose blisters.
Not all pack sizes may be marketed.
Any unused product or waste material should be disposed of in accordance with local requirements.
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