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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)

Devasc contains clopidogrel and belongs to a group of medicines called antiplatelet medicinalproducts. Platelets are very small structures in the blood which clump to gather during blood clotting. By preventing this clumping, antiplatelet medicinal products reduce the chances of blood clots forming (a process called thrombosis).

Devasc is taken by adults to prevent blood clots (thrombi) forming in hardened blood vessels (arteries), a process known as atherothrombosis, which can lead to atherothrombotic e vents (such as stroke, heart attack, or death).

You have been prescribed Devasc to help prevent blood clots and reduce the risk of these severe events because:

- You have a cond itio n of h ardening of art eries (als o known as atherosclerosis), and

 

-   You have previously experienced a heart attack, stroke or have a condition known as peripheral arterial disease, or

-   You have experienced a se vere t ype of chest pain known as ‘unstable angina’ or ‘myocardial infarction’ (heart attack). For the treatment of this condition your doctor may have placed a stent in the blocked or narrowed artery to restore effective blood flow. Yo u sho uld also be give nacetylsalicylic acid (a substance present in many medicines used to relieve pain and lower fever as well as to prevent blood clotting) by your doctor.

-    You have an irregular heartbeat, a condition called ‘atrial fibrillation’, and you cannot take medicines kn own as ‘oral antico agulants’ ( vitamin K antagonists) which prevent new clots from forming and pre vent existing clots from g rowing. You should have been told that ‘oral anticoagulants’are more effective than acetylsalicylic acid or the combined use of Devasc and acetyl salicylic acid for this condi tion. Your doctor should have prescrib ed Devasc plus acetylsali cylic acid if you cannot take ‘oral anticoagulants’ and you do not have a risk of major bleeding.


1.   Do not take Devasc

-   If you are allergic (hypersen sitive) to cl opidogrel or any of t he other ingredients of this medicine (listed in section 6).

-    If you have a medical condition that is currently causing bleeding such as a stomach ulcer or bleeding within the brain.

-  If you suffer from severe liver disease.

If you think any of these appl y to you, or if you are in any doubt at all, consult your doctor before taking Devasc.

 

Warnings and precautions

If any of the situations mentioned below apply to you, you should tell your doctor before taking Devasc:

•  if you have a risk of bleeding such as

-  a medical condition that puts you at risk of internal bleeding (such asa stomach ulcer).

-   a blood disorder that makes you prone to internal bleeding (bleedinginside any tissues, organs or joints of your body).

-  a recent serious injury.

 

-  a recent surgery (including dental).

-  a planned surgery (including dental) in the next seven days.

•   if you have had a clot in an artery of your brain (ischaemic stroke) which occurred within the last seven days.

•  if you have kidney or liver disease.

•  if you have had an allergy or reaction to any medicine used to treat your disease. While you are taking Devasc:

•  You should tell your doctor if a surgery (including dental) is planned.

•   You should also tell your doctor immediately if you develop a medical condition (also known as Thrombotic Thrombocytopenic Purpura or TTP) that includes fever and bruising under the skin that may appear as red pinpoint dots, with or without unexplained extreme tiredness, confusion, yellowing of the skin or eyes (jaundice) (see section 4 ‘Possible side effects’).

•   If you cut or injure yourself, it may take longer than usual for bleeding to stop. This is linked to the way your medicine works as it prevents the ability of blood clots to form. For minor cuts and injuries e.g., cutting yourself, shaving, this is usually of no concern. However, if you are concerned by your bleeding, you should contact your doctor straightaway (see section 4 ‘Possible side effects’).

•  Your doctor may order blood tests.

Children and adolescents

Do not give this medicine to children because it does not work.

Other medicines and Devasc

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription.

Some other medicines may influence the use of Devasc or vice versa. You should specifically tell your doctor if you take

-  medicines that may increase your risk of bleeding such as:

-oral anticoagulants, medicines used to reduce blood clotting,

-a non‑steroidal anti-inflammatory medicine, usually used to treat painful and/or inflammatory conditions of muscle or joints,

-heparin or any other injectable medicine used to reduce blood clotting,

-ticlopidine, other antiplatelet agent,

 

-a selective serotonin reuptake inhibitor (including but not restricted to fluoxetine or fluvoxamine), medicines usually used to treat depression,

-omeprazole or esomeprazole, medicines to treat upset stomach,

-  fluconazole or voriconazole, medicines to treat fungal infections,

-  efavirenz, or other anti-retroviral medicines (used to treat HIV infections),

-  carbamazepine, a medicine to treat some forms of epilepsy,

-  moclobemide, medicine to treat depression,

-  repaglinide, medicine to treat diabetes,

-  paclitaxel, medicine to treat cancer,

-    opioids: while you are treated with clopidogrel, you should inform your doctor before being prescribed any opioid (used to treat severe pain).

If you have experienced severe chest pain (unstable angina or heart attack), you may be prescribed Devasc in combination with acetylsalicylic acid,a substance present in many medicines used to relieve pain and lower fever. An occasional use of acetylsalicylic acid (no more than 1,000 mg in any 24 hour period) should generally not cause a problem, but prolonged use in other circumstances should be discussed with your doctor.

Devasc with food and drink

Devasc may be taken with or without food.

Pregnancy and breast-feeding

It is preferable not to take this product during pregnancy.

If you are pregnant or suspect that you are pregnant, you should tell your doctor or your pharmacist before taking Devasc. If you become pregnant while taking Clopidogrel Tablets 75mg, consult your doctor immediately as it is recommended not to take clopidogrel while you are pregnant.

You should not breast-feed while taking this medicine.

If you are breast-feeding or planning to breast-feed, talk to your doctor before taking this medicine. Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

Devasc is unlikely to affect your ability to drive or to use machines.

 

Devasc contains lactose

If you have been told by your doctor that you have an intolerance to some sugars (e.g. lactose), contact your doctor before taking this medicine.

Devasc contains hydrogenated castor oil

This may cause stomach upset or diarrhoea.


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, including for patients with a condition called ‘atrial fibrillation’ (an irregular heartbeat), is one 75 mg tablet of Clopidogrel Tablets 75mg per day to be taken orally with or without food, and at the same time each day.

If you have experienced severe chest pain (unstable angina or heart attack), your doctor may give you 300 mg of Devasc (1 tablet of 300 mg or 4 tablets of 75 mg) once at the start of treatment. Then, the recommended dose is one 75 mg tablet of Clopidogrel Tablets 75mg per day as described above. You should take Devasc for as long as your doctor continues to prescribe it.

If you take more Devasc than you should

Contact your doctor or the nearest hospital emergency department because of the increased risk of bleeding.

If you forget to take Devasc

If you forget to take a dose of Devasc, but remember within 12 hours of your usual time, take your tablet straightaway and then take your next tablet at the usual time.

If you forget for more than 12 hours, simply take the next single dose at the usual time. Do not take a double dose to make up for a forgotten tablet.

For the 7, 14, 28 and 84 tablets pack sizes, you can check the day on which you last took a tablet of Clopidogrel Tablets 75mg by referring to the calendar printed on the blister.

If you stop taking Devasc

Do not stop the treatment unless your doctor tells you so. Contact your doctor or pharmacist before stopping.

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.

Contact your doctor immediately if you experience:

-   fever, signs of infection or extreme tiredness. These may be due to rare decrease of some blood cells.

-   signs of liver problems such as yellowing of the skin and/or the eyes (jaundice), whether or not associated with bleeding which appears under the skin as red pinpoint dots and/or confusion (see section 2 ‘Warnings and precautions’).

-   swelling in the mouth or skin disorders such as rashes and itching, blisters of the skin. These may be the signs of an allergic reaction..

The most common side effect reported with Devasc is bleeding.

Bleeding may occur as bleeding in the stomach or bowels, bruising, haematoma (unusual bleeding or bruising under the skin), nose bleed, blood in the urine. In a small number of cases, bleeding in the eye, inside the head, the lung or the joints has also been reported.

If you experience prolonged bleeding when taking Devasc

If you cut or injure yourself, it may take longer than usual for bleeding to stop. This is linked to the way your medicine works as it prevents the ability of blood clots to form. For minor cuts and injuries e.g., cutting yourself, shaving, this is usually of no concern. However, if you are concerned by your bleeding, you should contact your doctor straightaway (see section 2 ‘Warnings and precautions’).

Other side effects include:

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

Diarrhoea, abdominal pain, indigestion or heartburn. Uncommon side effects (may affect up to 1 in 100 people):

Headache, stomach ulcer, vomiting, nausea, constipation, excessive gas in stomach or intestines, rashes, itching, dizziness, sensation of tingling and numbness.

Rare side effect (may affect up to 1 in 1000 people):

Vertigo, enlarged breasts in males.

Very rare side effects (may affect up to 1 in 10,000 people):

Jaundice; severe abdominal pain with or without back pain; fever, breathing difficulties sometimes associated with cough; generalised allergic reactions (for example, overall sensation of heat with sudden general discomfort until fainting); swelling in the mouth; blisters of the skin; skin allergy;

 

sore mouth (stomatitis); decrease in blood pressure; confusion; hallucinations; joint pain; muscular pain; changes in taste or loss of taste of food.

Side effects with frequency not known (frequency cannot be estimated from the available data): Hypersensitivity reactions with chest or abdominal pain, persistent low blood sugar symptoms. In addition, your doctor may identify changes in your blood or urine test results.

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. You can also report side effects directly (see details below). By reporting side effects you can help provide more information on the safety of this medicine.

•  Saudi Arabia:

 
 Text Box: The National Pharmacovigilance and Drug Safety Centre (NPC) o SFDA Call Center: 19999
o	E-mail:npc.drug@sfda.gov.sa

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

 

 

o Other GCC States:

Please contact the relevant competent authority


Store below 30°C.

•  Store in the original package in order to protect from moisture.

•  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 pack after EXP. The expiry date refers to the last day of the 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 protect the environment.


What Devasc contains

Each  film-coated  Tablets      contains Clopidogrel Hydrogen Sulfate equivalent to 75mg of Clopidogrel.

 

The other ingredients Lactose Monohydrate, Cellulose Microcrystalline, Low substituted Hydroxy propyl cellulose, Crospovidone, Mannitol, Silica colloidal anhydrous, Macrogol, Hydrogenated Castor oil, Opadry II Pink 33K84976.


Pink, round, bevel edged, biconvex film coated tablets plain on both sides Not all pack sizes may be marketed. How supplied: Devasc are supplied in Blister pack. Devasc Box of 30 blister Tablets (3x10’s).

Saudi Amarox Industrial Company Aljameah Street, Malaz quarter,

Riyadh 11441, Saudi Arabia

Tel: +966 11 477 2215

Manufacturers

Hetero Labs Limted Unit-V


09/2022
  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 ديفاسك على المادة الفعالة كلوبيدوجريل والتي تنتمي إلى مجموعة من الأدوية تسمى المنتجات الطبية المضادة للصفيحات. الصفائح الدموية هي هياكل صغيرة جدًا في الدم تتكتل لتتجمع أثناء تخثر الدم. تقلل المنتجات الطبية المضادة للصفيحات من فرص تكوين جلطات الدم من خلال منع تكتل الصفائح الدموية (وهي عملية تسمى تجلط الدم).

يستخدم ديفاسك في البالغين لمنع تجلط الدم (الجلطات) في الأوعية الدموية المتصلبة (الشرايين) ، وهي عملية تعرف باسم تجلط الشرايين ، والتي يمكن أن تؤدي إلى أحداث التخثر العصيدي (مثل السكتة الدماغية أو النوبة القلبية أو الموت).

لقد تم وصف ديفاسك لك للمساعدة في منع تجلط الدم وتقليل مخاطر هذه الأحداث الشديدة للأسباب التالية:

-      إذا كان لديك حالة تصلب الشرايين ، و عانيت سابقًا من نوبة قلبية أو سكتة دماغية أو لديك حالة تعرف باسم مرض الشرايين المحيطية ، أو عانيت مسبقا من نوع من آلام الصدر المعروفة باسم "الذبحة الصدرية غير المستقرة" أو "احتشاء عضلة القلب" (النوبة القلبية). لعلاج هذه الحالة ، قد يكون طبيبك قد وضع دعامة في الشريان المسدود أو الضيق لاستعادة تدفق الدم بفاعلية. يمكنك أيضًا إعطاء حمض اسيتيل ساليسيليك (مادة موجودة في العديد من الأدوية المستخدمة لتخفيف الألم وخفض الحمى وكذلك لمنع تخثر الدم) من قبل طبيبك.

-      إذا كان لديك عدم انتظام في ضربات القلب ، وهي حالة تسمى "الرجفان الأذيني" ، ولا يمكنك تناول أدوية مثل "مضادات التخثر الفموية" (مضادات فيتامين ك) التي تمنع تكوين الجلطات الجديدة و تمنع الجلطات الموجودة من الزيادة. يجب أن يكون قد تم إخبارك أن "مضادات التخثر الفموية" أكثر فعالية لهذه الحالة من حمض أسيتيل الساليسيليك أو الاستخدام المشترك لـ ديفاسك وحمض أسيتيل الساليسيليك. يجب أن يصف طبيبك دواء ديفاسك بالإضافة إلى حمض أسيتيل ساليسيليك إذا لم تستطع تناول "مضادات التخثر الفموية" ولم يكن لديك خطر حدوث نزيف حاد.

لا تتناول ديفاسك

-        إذا كنت تعاني من حساسية (فرط الحساسية) تجاه كلوبيدوجريل أو أي من المكونات الأخرى لهذا الدواء (المُدرجة في القسم 6).

-        إذا كنت تعاني من حالة طبية تسبب حاليًا نزيفًا مثل قرحة في المعدة أو نزيف داخل المخ.

-        إذا كنت تعاني من مرض كبدي حاد.

إذا كنت تعتقد أن أيًا من هذه الحالات تتطابق لحالتك ، أو إذا كان لديك أي شك على الإطلاق ، فاستشر طبيبك قبل تناول ديفاسك.

 

التحزيرات والإحتياطات

إذا كانت أي من الحالات المذكورة أدناه تنطبق عليك ، يجب أن تخبر طبيبك قبل تناول ديفاسك:

·       إذا كان لديك خطر حدوث نزيف مثل

-        حالة طبية تعرضك لخطر النزيف الداخلي (مثل قرحة المعدة).

-        اضطراب في الدم يجعلك عرضة لنزيف داخلي (نزيف داخل أي أنسجة أو أعضاء أو مفاصل في جسمك).

-        إصابة خطيرة حديثة.

-        جراحة حديثة (بما في ذلك جراحة الأسنان).

-        عملية جراحية مخططة (بما في ذلك جراحة الأسنان) في الأيام السبعة المقبلة.

·       إذا كان لديك جلطة في أحد شرايين الدماغ (سكتة إقفارية) والتي حدثت خلال الأيام السبعة الماضية.

·       إذا كنت تعاني من أمراض الكلى أو الكبد.

·       إذا كان لديك حساسية أو رد فعل تجاه أي دواء يستخدم لعلاج مرضك.

أثناء تناول ديفاسك:

·       يجب أن تخبر طبيبك إذا كنت تخطط لإجراء عملية جراحية (بما في ذلك جراحة الأسنان).

·       يجب عليك أيضًا إخبار طبيبك على الفور إذا كنت تعاني من حالة طبية (تُعرف أيضًا باسم فرفرية نقص الصفيحات التخثرية)و التي تشمل الحمى والكدمات تحت الجلد التي قد تظهر على شكل نقاط حمراء دقيقة ، مع أو بدون تعب شديد غير مبرر ، والارتباك ، والاصفرار في الجلد أو العينين (اليرقان) (انظر القسم 4 "الآثار الجانبية المحتملة").

·       إذا جُرِحت أو جرحت نفسك ، فقد يستغرق الأمر وقتًا أطول من المعتاد حتى يتوقف النزيف. يرتبط هذا بالطريقة التي يعمل بها دوائك لأنه يمنع قدرة الجلطات الدموية على التكون. بالنسبة للجروح والإصابات الطفيفة ، مثل جرح نفسك أو الحلاقة ، لا داعي للقلق عادةً. ومع ذلك ، إذا كنت قلقًا بشأن النزيف ، فيجب عليك الاتصال بطبيبك على الفور (انظر القسم 4 "الآثار الجانبية المحتملة").

·       قد يطلب طبيبك إجراء فحوصات الدم.

الأطفال والمراهقون

لا يتم استخدام هذا الدواء للأطفال لعدم الفائدة منه.

تناول الأدوية الأخرى و ديفاسك

أخبر طبيبك أو الصيدلي إذا كنت تتناول أو تناولت مؤخرًا أو قد تتناول أي أدوية أخرى ، بما في ذلك الأدوية التي تم الحصول عليها بدون وصفة طبية.

قد تؤثر بعض الأدوية الأخرى على استخدام ديفاسك أو العكس.

يجب أن تخبر طبيبك على وجه التحديد إذا كنت تتناول

-        الأدوية التي قد تزيد من خطر إصابتك بالنزيف مثل:

مضادات التخثر الفموية ، الأدوية المستخدمة لتقليل تخثر الدم

-        دواء غير ستيرويدي مضاد للالتهابات ، يستخدم عادة لعلاج الحالات المؤلمة و / أو الالتهابية للعضلات أو المفاصل ،

-        الهيبارين أو أي دواء آخر عن طريق الحقن يستخدم لتقليل تخثر الدم.

-        تيكلوبيدين ، عامل آخر مضاد للصفيحات

-        مثبط انتقائي لاسترداد السيروتونين (بما في ذلك على سبيل المثال لا الحصر فلوكستين أو فلوفوكسامين) ، الأدوية المستخدمة عادة لعلاج الاكتئاب ،

-        أوميبرازول أو إيزوميبرازول ، أدوية لعلاج اضطراب المعدة.

-        فلوكونازول أو فوريكونازول ، أدوية لعلاج الالتهابات الفطرية

-        إيفافيرينز ، أو أدوية أخرى مضادة للفيروسات القهقرية (تستخدم لعلاج عدوى فيروس نقص المناعة البشرية) ،

-        كاربامازيبين دواء لعلاج بعض أشكال الصرع.

-        موكلوبميد ، دواء لعلاج الاكتئاب

-        ريباجلينيد ، دواء لعلاج مرض السكري

-        باكليتاكسيل دواء لعلاج السرطان

-        المواد الأفيونية: أثناء علاجك بالكلوبيدوجريل ، يجب عليك إبلاغ طبيبك قبل وصف أي مادة أفيونية (تستخدم لعلاج الآلام الشديدة).

إذا كنت تعاني من ألم شديد في الصدر (ذبحة صدرية غير مستقرة أو نوبة قلبية) ، فقد يتم وصف ديفاسك لك مع حمض أسيتيل الساليسيليك ، وهي مادة موجودة في العديد من الأدوية المستخدمة لتخفيف الألم وخفض الحمى. يجب ألا يسبب الاستخدام العرضي لحمض أسيتيل الساليسيليك (لا يزيد عن 1000 ملغم في أي فترة 24 ساعة) مشكلة بشكل عام ، ولكن يجب مناقشة الاستخدام المطول في ظروف أخرى مع طبيبك.

تناول ديفاسك مع الطعام والشراب

يمكن تناول ديفاسك مع أو بدون طعام.

الحمل والرضاعة

يفضل عدم تناول هذا المنتج أثناء الحمل.

إذا كنت حاملاً أو تشك في أنك حامل ، يجب أن تخبر طبيبك أو الصيدلي قبل تناول ديفاسك. إذا أصبحت حاملاً أثناء تناول أقراص كلوبيدوجريل 75 ملغم ، فاستشيري طبيبك على الفور حيث يوصي بعدم تناول عقار كلوبيدوجريل أثناء الحمل.

يجب عدم الإرضاع أثناء تناول هذا الدواء.

إذا كنت ترضعين رضاعة طبيعية أو تخططين للإرضاع ، تحدثي إلى طبيبك قبل تناول هذا الدواء.

اسأل طبيبك أو الصيدلي للحصول على المشورة قبل تناول أي دواء.

 القيادة واستخدام الألات

 من غير المحتمل أن يؤثر ديفاسك على قدرتك على القيادة أو استخدام الآلات.

محتوي ديفاسك من اللاكتوز

إذا أخبرك طبيبك أنك لا تتحمل بعض السكريات (مثل اللاكتوز) ، فاتصل بطبيبك قبل تناول هذا الدواء.

يحتوي ديفاسك على زيت الخروع المهدرج

 هذا قد يسبب اضطراب في المعدة أو الإسهال.

https://localhost:44358/Dashboard

احرص دائمًا على تناول هذا الدواء كما أخبرك طبيبك أو الصيدلي تماما.

استشر طبيبك أو الصيدلي إذا لم تكن متأكدًا.

الجرعة الموصى بها ، بما في ذلك المرضى الذين يعانون من حالة تسمى "الرجفان الأذيني" (عدم انتظام ضربات القلب) ، هي قرص واحد 75 ملغم من أقراص كلوبيدوجريل 75 ملغم يوميًا يتم تناولها عن طريق الفم مع الطعام أو بدونه ، وفي نفس الوقت كل يوم.

إذا عانيت من ألم شديد في الصدر (ذبحة صدرية غير مستقرة أو نوبة قلبية) ، فقد يعطيك طبيبك 300 ملغم من ديفاسك (قرص واحد من 300 ملغم أو 4 أقراص من 75 مجم) مرة واحدة في بداية العلاج. بعد ذلك ، الجرعة الموصى بها هي قرص واحد 75 ملغم من أقراص كلوبيدوجريل 75 ملغم يوميًا كما هو موضح أعلاه.

يجب أن تستمر في تتناول ديفاسك طالما استمر طبيبك في وصفه.

إذا تناولت ديفاسك أكثر مما ينبغي

اتصل بطبيبك أو أقرب قسم طوارئ في المستشفى بسبب زيادة خطر النزيف.

إذا نسيت أن تتناول ديفاسك

إذا نسيت تناول جرعة من ديفاسك ، ولكن تذكرت في غضون 12 ساعة من وقتك المعتاد ، تناول القرص على الفور ثم تناول القرص التالي في الوقت المعتاد.

إذا نسيت لأكثر من 12 ساعة ، ببساطة تناول الجرعة المفردة التالية في الوقت المعتاد. لا تتناول جرعة مضاعفة لتعويض قرص منسي.

بالنسبة لعبوات ذات أحجام 7 و 14 و 28 و 84 قرصًا ، يمكنك التحقق من اليوم الذي تناولت فيه آخر مرة قرصًا من أقراص كلوبيدوجريل 75 ملغم بالرجوع إلى التقويم المطبوع على الشريط.

إذا توقفت عن تناول ديفاسك

لا تتوقف عن العلاج إلا إذا أخبرك طبيبك بذلك. اتصل بطبيبك أو الصيدلي قبل التوقف.

إذا كان لديك أي أسئلة أخرى حول استخدام هذا الدواء ، اسأل طبيبك أو الصيدلي .

1.      الآثار الجانبية المحتملة

مثل جميع الأدوية ، يمكن أن يسبب هذا الدواء آثارًا جانبية ، على الرغم من عدم حدوثها لدى الجميع.

اتصل بطبيبك على الفور إذا واجهت:

-        حمى ، علامات عدوى أو تعب شديد. قد يكون هذا بسبب انخفاض نادر في بعض خلايا الدم.

-        علامات تدل على مشاكل في الكبد مثل اصفرار الجلد و / أو العينين (اليرقان) ، سواء كانت مرتبطة بالنزيف الذي يظهر تحت الجلد على شكل نقاط حمراء و / أو ارتباك (انظر القسم 2 "التحذيرات والاحتياطات").

-        انتفاخ في الفم أو اضطرابات جلدية مثل الطفح الجلدي والحكة وظهور تقرحات في الجلد. قد تكون هذه علامات رد فعل تحسسي .

التأثير الجانبي الأكثر شيوعًا الذي تم الإبلاغ عنه مع ديفاسك هو النزيف.

قد يحدث النزيف كنزيف في المعدة أو الأمعاء ، كدمات ، ورم دموي (نزيف غير عادي أو كدمات تحت الجلد) ، نزيف الأنف ، دم في البول. في عدد قليل من الحالات ، تم الإبلاغ أيضًا عن نزيف في العين أو داخل الرأس أو الرئة أو المفاصل.

إذا كنت تعاني من نزيف طويل الأمد عند تناول ديفاسك

إذا جُرِحت أو جرحت نفسك ، فقد يستغرق الأمر وقتًا أطول من المعتاد حتى يتوقف النزيف. يرتبط هذا بالطريقة التي يعمل بها دوائك لأنه يمنع قدرة الجلطات الدموية على التكون. بالنسبة للجروح والإصابات الطفيفة ، مثل جرح نفسك أو الحلاقة ، لا داعي للقلق عادةً. ومع ذلك ، إذا كنت قلقًا بشأن النزيف ، فيجب عليك الاتصال بطبيبك على الفور (انظر القسم 2 "التحذيرات والاحتياطات").

تشمل الآثار الجانبية الأخرى:

أعراض جانبية شائعة (قد تظهر على 1 من كل 10 أشخاص):

الإسهال وآلام البطن وعسر الهضم أو الحموضة المعوية.

أعراض جانبية غير شائعة (قد تظهر على 1 من كل 100 شخص):

صداع ، قرحة في المعدة ، قيء ، غثيان ، إمساك ، غازات مفرطة في المعدة أو الأمعاء ، طفح جلدي ، حكة ، دوار ، إحساس بالوخز والتنميل.

أعراض جانبية نادرة (قد تظهر على 1 من بين 1000 شخص):

الدوار وتضخم الثديين عند الذكور.

أعراض جانبية نادرة جدًا (قد تظهر على 1 من بين 10000 شخص):

اليرقان؛ آلام شديدة في البطن مع أو بدون آلام الظهر ؛ الحمى وصعوبات التنفس المرتبطة أحيانًا بالسعال ؛ ردود الفعل التحسسية العامة (على سبيل المثال ، الإحساس العام بالحرارة مع عدم الراحة العامة المفاجئة حتى الإغماء) ؛ تورم في الفم. بثور الجلد. حساسية الجلد؛ قرحة الفم (التهاب الفم) ؛ انخفاض في ضغط الدم. ارتباك؛ الهلوسة. ألم المفاصل؛ ألم عضلي؛ تغيرات في طعم أو فقدان طعم الطعام.

أعراض جانبية ذات شيوع غير معروف (لا يمكن تقدير شيوعها من البيانات المتاحة):

تفاعلات فرط الحساسية مع ألم في الصدر أو البطن ، أعراض انخفاض سكر الدم المستمرة.

بالإضافة إلى ذلك ، قد يحدد طبيبك التغيرات في نتائج اختبار الدم أو البول.

 التبليغ عن الأعراض الجانبية

 إذا زادت حدة أي من هذه الأعراض الجانبية ، أو لاحظت ظهور أعراض جانبية غير ما تم ذكره في هذه النشرة ، يرجى إبلاغ الطبيب المعالج أو الصيدلي. وهذا يشمل أي آثار جانبية محتملة غير مدرجة في هذه النشرة. يمكنك أيضا الإبلاغ عن الآثار الجانبية مباشرة (انظر التفاصيل أدناه). بالإبلاغ عن الآثار الجانبية يمكنك المساعدة في توفير مزيد من المعلومات حول أمان هذا الدواء.

Text Box: للإبلاغ عن الأعراض الجانبية
-	المملكة العربية السعودية
-	المركز الوطني للتيقظ والسلامة الدوائية
o	مركز الاتصال بالهيئة العامة للغذاء والدواء: 19999 
o	البريد الإلكتروني: npc.drug@sfda.gov.sa
o	الموقع الإلكتروني: www.sfda.gov.sa/npc

دول مجلس التعاون الخليجي الأخرى:

 يرجى الاتصال بالسلطة الصحية المختصة.

·        يحفظ في درجة حرارة أقل من 30 درجة مئوية.

·       يجب التخزين في العلبة الأصلية لحمايته من الرطوبة.

·       احفظ هذا الدواء بعيدًا عن رؤية ومتناول أيدي الأطفال.

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

·       لا تتخلص من الأدوية في مياه الصرف الصحي أو النفايات المنزلية. اسأل الصيدلي عن كيفية التخلص من الأدوية التي لم تعد تستخدمها. ستساعد هذه الإجراءات في حماية البيئة.

المادة الفعالة لديفاسك أقراص

تحتوي كل قرص مُغلّف على كلوبيدوجريل ثنائي الكبريتات ما يعادل 75 ملغم من كلوبيدوجريل.

المكونات الأخرى: اللاكتوز أحادي الهيدرات ، السليلوز دقيق التبلور ، الهيدروكسي بروبيل السليلوز ، كروسبوفيدون ، مانيتول ، السيليكا الغروية اللامائية ، ماكروغول ، زيت الخروع المهدرج ، أوبادري II الوردي 33K84976

كيف يبدو ديفاسك ومحتويات العبوة

 أقراص مستديرة مغلفة بطبقه رقيقة ذات اللون الوردي ، مشطوفة الحواف ، محدبة من الجانبين ملساء من كلا الجانبين قد ، لا يتم تسويق جميع أحجام العبوات.

 كيف تتوفر:

 يتم توفير ديفاسك في عبوة بها شرائط .عبوة ديفاسك تحتوي على 30 قرص (3 x10)

شركة أماروكس السعودية للصناعة

شارع الجامعة – الملز – الرياض 11441

المملكة العربية السعودية.

تليفون: + 966 114772215

07/2021
 Read this leaflet carefully before you start using this product as it contains important information for you

Devasc (Clopidogrel Tablets 75mg)

Devasc (Clopidogrel Tablets 75mg) Each film-coated tablet contains Clopidogrel hydrogen sulphate Ph.Eur equivalent to 75mg of Clopidogrel. Excipients with known effect: Each film-coated tablet contains 3 mg of lactose and 3.3 mg of hydrogenated castor oil.

Devasc (Clopidogrel Tablets 75mg) Pink, round, bevel edged, biconvex, film coated tablets imprinted in black color with "I2" on one side and plain on other side.

Secondary prevention of atherothrombotic events Clopidogrel is indicated in:

•  Adult patients suffering from myocardial infarction (from a few days until less than 35 days),ischaemic stroke (from 7 days until less than 6 months) or established peripheral arterial disease.

•  Adult patients suffering from acute coronary syndrome:

-                      Non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction), including patients undergoing a stent placement following percutaneous coronary intervention, in combination with acetylsalicylic acid (ASA).

-                      ST segment elevation acute myocardial infarction, in combination with ASA in medically treated patients eligible for thrombolytic therapy.

Prevention of atherothrombotic and thromboembolic events in atrial fibrillation

Module-1

In adult patients with atrial fibrillation who have at least one risk factor for vascular events, are not suitable for treatment with Vitamin K antagonists (VKA) and who have a low bleeding risk, Clopidogrel is indicated in combination with ASA for the prevention of atherothrombotic and thromboembolic events, including stroke.

For further information please refer to section 5.1.


• Adults and elderly 

Clopidogrel Tablets 75mg

Clopidogrel should be given as a single daily dose of 75 mg.

In patients suffering from acute coronary syndrome:

-                      Non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction):

Clopidogrel treatment should be initiated with a single 300-mg loading dose and then continued at 75 mg once a day (with acetylsalicylic acid (ASA) 75 mg-325 mg daily). Since higher doses of ASA were associated with higher bleeding risk it is recommended that the dose of ASA should not be higher than 100 mg. The optimal duration of treatment has not been formally established. Clinical trial data support use up to 12 months, and the maximum benefit was seen at 3 months (see section 5.1).

-                      ST segment elevation acute myocardial infarction: Clopidogrel should be given as a single daily dose of 75 mg initiated with a 300-mg loading dose in combination with ASA and with or without thrombolytic. For patients over 75 years of age Clopidogrel should be initiated without a loading dose. Combined therapy should be started as early as possible after symptoms start and continued for at least four weeks. The benefit of the combination of Clopidogrel with ASA beyond four weeks has not been studied in this setting (see section 5.1).

In patients with trial should be given as a single daily dose of 75mg. ASA(75-100mg daily)should be initiated and continued in combination with Clopidogrel (see section 5.1).

If a dose is missed:

-                      Within less than 12 hours after regular scheduled time: patients should take the dose immediately and then take the next dose at the regular scheduled time.

-                      For more than 12 hours: patients should take the next dose at the regular scheduled time and should not double the dose.

•  Paediatric population

Clopidogrel should not be used in children because of efficacy concerns (see section 5.1).

•  Renal impairment

Therapeutic experience is limited in patients with renal impairment (see section 4.4).

•  Hepatic impairment

Therapeutic experience is limited in patients with moderate hepatic disease who may have bleeding diatheses (see section 4.4).
Method of administration

For oral use

It may be given with or without food.


• Hypersensitivity to the active substance or to any of the excipients listed in section 2 or section 6.1. • Severe hepatic impairment. • Active pathological bleeding such as peptic ulcer or intracranial haemorrhage.

Bleeding and haematological disorders

Due to the risk of bleeding and haematological adverse reactions, blood cell count determination and/or other appropriate testing should be promptly considered whenever clinical symptoms suggestive of bleeding arise during the course of treatment (see section 4.8). As with other antiplatelet agents, clopidogrel should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or other pathological conditions and in patients receiving treatment with ASA, heparin, glycoprotein IIb/IIIa inhibitors or non-steroidal antiinflammatory drugs (NSAIDs) including Cox-2 inhibitors, or selective serotonin reuptake inhibitors (SSRIs), or other medicinal products associated with bleeding risk such as pentoxifylline (see section 4.5). Patients should be followed carefully for any signs of bleeding including occult bleeding, especially during the first weeks of treatment and/or after invasive cardiac procedures or surgery. The concomitant administration of Clopidogrel with oral anticoagulants is not recommended since it may increase the intensity of bleedings (see section 4.5).

If a patient is to undergo elective surgery and antiplatelet effect is temporarily not desirable, Clopidogrel should be discontinued 7 days prior to surgery. Patients should inform physicians and dentists that they are taking Clopidogrel before any surgery is scheduled and before any new medicinal product is taken. Clopidogrel prolongs bleeding time and should be used with caution in patients who have lesions with a propensity to bleed (particularly gastrointestinal and intraocular).

Patients should be told that it might take longer than usual to stop bleeding when they take Clopidogrel (alone or in combination with ASA), and that they should report any unusual bleeding (site or duration) to their physician.

Thrombotic Thrombocytopenic Purpura (TTP) has been reported very rarely following the use of Clopidogrel, sometimes after a short exposure. It is characterised by thrombocytopenia and microangiopathic haemolytic anaemia associated with either neurological findings, renal dysfunction or fever. TTP is a potentially fatal condition requiring prompt treatment including plasmapheresis
Acquired haemophilia

Acquired haemophilia has been reported following use of Clopidogrel. In cases of confirmed isolated activated Partial Thromboplastin Time (aPTT) prolongation with or without bleeding, acquired haemophilia should be considered. Patients with a confirmed diagnosis of acquired haemophilia should be managed and treated by specialists, and Clopidogrel should be discontinued.

Recent ischaemic stroke

In view of the lack of data, Clopidogrel cannot be recommended during the first 7 days after acute ischaemic stroke.

Cytochrome P450 2C19 (CYP2C19)

Pharmacogenetics: In patients who are poor CYP2C19 metabolisers, Clopidogrel at recommended doses forms less of the active metabolite of Clopidogrel and has a smaller effect on platelet function. Tests are available to identify a patient's CYP2C19 genotype.

Since Clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of medicinal products that inhibit the activity of this enzyme would be expected to result in reduced drug levels of the active metabolite of Clopidogrel. The clinical relevance of this interaction is uncertain. As a precaution concomitant use of strong or moderate CYP2C19 inhibitors should be discouraged (see section 4.5 for a list of CYP2C19 inhibitors, see also section 5.2).

CYP2C8 substrates

Caution is required in patients treated concomitantly with Clopidogrel and CYP2C8 substrate medicinal products (see section 4.5).
Cross-reactions among thienopyridines

Patients should be evaluated for history of hypersensitivity to thienopyridines (such as Clopidogrel, ticlopidine,prasugrel) since cross-reactivity among thienopyridines has been reported (see section 4.8). Thienopyridines may cause mild to severe allergic reactions such as rash, angioedema, or haematological cross-reactions such as thrombocytopenia and neutropenia. Patients who had developed a previous allergic reaction and/or haematological reaction to one thienopyridine may have an increased risk of developing the same or another reaction to another thienopyridine. Monitoring for signs of hypersensitivity in patients with a known allergy to thienopyridines is advised.

Renal impairment

Therapeutic experience with Clopidogrel is limited in patients with renal impairment. Therefore

Clopidogrel should be used with caution in these patients (see section 4.2).

Hepatic impairment

Experience is limited in patients with moderate hepatic disease who may have bleeding diatheses. Clopidogrel should therefore be used with caution in this population (see section 4.2).
Excipients

Plavix contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains hydrogenated castor oil which may cause stomach upset and diarrhoea.  


Medicinal products associated with bleeding risk: There is an increased risk of bleeding due to the potential additive effect. The concomitant administration of medicinal products associated with bleeding risk should be undertaken with caution (see section 4.4).

Oral anticoagulants: the concomitant administration of Clopidogrel with oral anticoagulants is not recommended since it may increase the intensity of bleedings (see section 4.4). Although the administration of Clopidogrel 75 mg/day did not modify the pharmacokinetics of S-warfarin or International Normalised Ratio (INR) in patients receiving long-term warfarin therapy, coadministration of Clopidogrel with warfarin increases the risk of bleeding because of independent effects on haemostasis.

Glycoprotein IIb/IIIa inhibitors: clopidogrel should be used with caution in patients who receive concomitant glycoprotein IIb/IIIa inhibitors (see section 4.4).

Acetylsalicylic acid (ASA): ASA did not modify the clopidogrel-mediated inhibition of ADPinduced platelet aggregation, but clopidogrel potentiated the effect of ASA on collagen-induced platelet aggregation. However, concomitant administration of 500 mg of ASA twice a day for one day did not significantly increase the prolongation of bleeding time induced by clopidogrel intake. A pharmacodynamic interaction between clopidogrel and acetylsalicylic acid is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution (see section 4.4). However, clopidogrel and ASA have been administered together for up to one year (see section 5.1).

Heparin: in a clinical study conducted in healthy subjects, clopidogrel did not necessitate modification of the heparin dose or alter the effect of heparin on coagulation. Co-administration of heparin had no effect on the inhibition of platelet aggregation induced by clopidogrel. A pharmacodynamic interaction between clopidogrel and heparin is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution (see section 4.4).

Thrombolytics: the safety of the concomitant administration of clopidogrel, fibrin or non-fibrin specific thrombolytic agents and heparins was assessed in patients with acute myocardial infarction. The incidence of clinically significant bleeding was similar to that observed when thrombolytic agents and heparin are coadministered with ASA (see section 4.8)

NSAIDs: in a clinical study conducted in healthy volunteers, the concomitant administration of clopidogrel and naproxen increased occult gastrointestinal blood loss. However, due to the lack of interaction studies with other NSAIDs it is presently unclear whether there is an increased risk of gastrointestinal bleeding with all NSAIDs. Consequently, NSAIDs including Cox-2 inhibitors and clopidogrel should be co-administered with caution (see section 4.4).

SSRIs: since SSRIs affect platelet activation and increase the risk of bleeding, the concomitant administration of SSRIs with clopidogrel should be undertaken with caution

Other concomitant therapy: Since clopidogrel is metabolised to its active metabolite partly by

CYP2C19, use of medicinal products that inhibit the activity of this enzyme would be expected to result in reduced drug levels of the active metabolite of clopidogrel. The clinical relevance of this interaction is uncertain. As a precaution concomitant use of strong or moderate CYP2C19 inhibitors should be discouraged (see sections 4.4 and 5.2).

Medicinal products that are strong or moderate CYP2C19 inhibitors include, for example, omeprazole and esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, carbamazepine, and efavirenz.
Proton Pump Inhibitors (PPI):

Omeprazole 80 mg once daily administered either at the same time as clopidogrel or with 12 hours between the administrations of the two drugs decreased the exposure of the active metabolite by 45% (loading dose) and 40% (maintenance dose). The decrease was associated with a 39% (loading dose) and 21% (maintenance dose) reduction of inhibition of platelet aggregation. Esomeprazole is expected to give a similar interaction with clopidogrel.

Inconsistent data on the clinical implications of this pharmacokinetic (PK)/pharmacodynamic (PD) interaction in terms of major cardiovascular events have been reported from both observational and clinical studies. As a precaution, concomitant use of omeprazole or esomeprazole should be discouraged (see section 4.4).

Less pronounced reductions of metabolite exposure has been observed with pantoprazole or lansoprazole.

The plasma concentrations of the active metabolite was 20% reduced (loading dose) and 14% reduced (maintenance dose) during concomitant treatment with pantoprazole 80 mg once daily. This was associated with a reduction of the mean inhibition of platelet aggregation by 15% and 11%, respectively. These results indicate that clopidogrel can be administered with pantoprazole.

There is no evidence that other medicinal products that reduce stomach acid such as H2 blockers or antacids interfere with antiplatelet activity of clopidogrel.

Other medicinal products: A number of other clinical studies have been conducted with clopidogrel and other concomitant medicinal products to investigate the potential for pharmacodynamic and pharmacokinetic interactions. No clinically significant pharmacodynamic interactions were observed when clopidogrel was coadministered with atenolol, nifedipine, or both atenolol and nifedipine. Furthermore, the pharmacodynamic activity of clopidogrel was not significantly influenced by the co-administration of phenobarbital or oestrogen.

The pharmacokinetics of digoxin or theophylline were not modified by the co-administration of clopidogrel. Antacids did not modify the extent of clopidogrel absorption.

Data from the CAPRIE study indicate that phenytoin and tolbutamide which are metabolised by CYP2C9 can be safely co-administered with clopidogrel.

CYP2C8 substrate medicinal products: Clopidogrel has been shown to increase repaglinide exposure in healthy volunteers. In vitro studies have shown the increase in repaglinide exposure is due to inhibition of CYP2C8 by the glucuronide metabolite of clopidogrel. Due to the risk of increased plasma concentrations, concomitant administration of clopidogrel and drugs primarily cleared by CYP2C8 metabolism (e.g., repaglinide, paclitaxel) should be undertaken with caution (see section 4.4).

Apart from the specific medicinal product interaction information described above, interaction studies with clopidogrel and some medicinal products commonly administered in patients with atherothrombotic disease have not been performed. However, patients entered into clinical trials with clopidogrel received a variety of concomitant medicinal products including diuretics, beta blockers, ACEI, calcium antagonists, cholesterol lowering agents, coronary vasodilators, antidiabetic agents (including insulin), antiepileptic agents and GPIIb/IIIa antagonists without evidence of clinically significant adverse interactions.

As with other oral P2Y12 inhibitors, co-administration of opioid agonists has the potential to delay and reduce the absorption of clopidogrel presumably because of slowed gastric emptying. The clinical relevance is unknown. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring coadministration of morphine or other opioid agonists.


As no clinical data on exposure to clopidogrel during pregnancy are available, it is preferable not to use clopidogrel during pregnancy as a precautionary measure.

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3).

Breast-feeding

It is unknown whether clopidogrel is excreted in human breast milk. Animal studies have shown excretion of clopidogrel in breast milk. As a precautionary measure, breast-feeding should not be continued during.

Clopidogrel was not shown to alter fertility in animal studies.


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


Summary of the safety profile 

Clopidogrel has been evaluated for safety in more than 44,000 patients who have participated in clinical studies, including over 12,000 patients treated for 1 year or more. Overall, clopidogrel 75 mg/day was comparable to ASA 325 mg/day in CAPRIE regardless of age, gender and race. The clinically relevant adverse reactions observed in the CAPRIE, CURE, CLARITY, COMMIT and ACTIVE-A studies are discussed below. In addition to clinical studies experience, adverse reactions have been spontaneously reported.

Bleeding is the most common reaction reported both in clinical studies as well as in postmarketing experience where it was mostly reported during the first month of treatment.

In CAPRIE, in patients treated with either clopidogrel or ASA, the overall incidence of any bleeding was 9.3%. The incidence of severe cases was similar for clopidogrel and ASA.

In CURE, there was no excess in major bleeds with clopidogrel plus ASA within 7 days after coronary bypass graft surgery in patients who stopped therapy more than five days prior to surgery. In patients who remained on therapy within five days of bypass graft surgery, the event rate was 9.6% for clopidogrel plus ASA, and 6.3% for placebo plus ASA.

In CLARITY, there was an overall increase in bleeding in the clopidogrel plus ASA group vs. the placebo plus ASA group .The incidence of major bleeding was similar between groups. This was consistent across subgroups of patients defined by baseline characteristics, and type of fibrinolytic or heparin therapy.

In COMMIT, the overall rate of non cerebral major bleeding or cerebral bleeding was low and similar in both groups.

In ACTIVE-A, the rate of major bleeding was greater in the clopidogrel + ASA group than in the placebo + ASA group (6.7% versus 4.3%). Major bleeding was mostly of extra cranial origin in both groups (5.3% in the clopidogrel + ASA group; 3.5% in the placebo +ASA group), mainly from the gastrointestinal tract (3.5% vs. 1.8%). There was an excess of intracranial bleeding in the clopidogrel + ASA treatment group compared to the placebo + ASA group (1.4% versus 0.8%, respectively). There was no statistically significant difference in the rates of fatal bleeding (1.1% in the clopidogrel + ASA group and 0.7% in the placebo +ASA group) and haemorrhagic stroke (0.8% and 0.6%, respectively) between groups.
Tabulated list of adverse reactions

Adverse reactions that occurred either during clinical studies or that were spontaneously reported are presented in the table below. Their frequency is defined using the following conventions: 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 system organ class, adverse reactions are presented in order of decreasing seriousness.

 

 

System          Organ

Class

Common

Uncommon

Rare

 

Very rare, not known*

Blood and the lymphatic system

disorders

 

Thrombocytopenia, leucopenia, eosinophilia

Neutropenia, including neutropenia

severe

Thrombotic

thrombocytopenic purpura (TTP) (see section 4.4), aplastic anaemia,

pancytopenia,

agranulocytosis,         severe thrombocytopenia, granulocytopenia, anaemia

Cardiac disorders

 

 

 

 

Kounis                    syndrome

(vasospastic allergic angina

/allergic myocardial infarction) in the

context           of         a hypersensitivity            reaction due to clopidogrel*

 

Immune       system

disorders

 

 

 

 

Serum sickness, anaphylactoid reactions, cross-reactive drug hypersensitivity among thienopyridines

(such as ticlopidine,

prasugrel) (see section 4.4)*, insulin autoimmune syndrome, which can lead to severe hypoglycemia, particularly in patients with

HLA DRA4 subtype (more frequent in the Japanese population)*

Psychiatric disorders

 

 

 

 

Hallucinations, confusion

Nervous       system

disorders

 

Intracranial bleeding (some cases were reported with fatal outcome), headache, paraesthesia, dizziness

 

Taste disturbances, ageusia

Eye disorders

 

Eye                  bleeding

(conjunctival, ocular, retinal)

 

 

Ear and labyrinth

 

 

Vertigo

 

 

disorders

 

 

 

 

Vascular disorders

Haematoma

 

 

 

Serious haemorrhage, haemorrhage of operative wound, vasculitis,

hypotension

Respiratory,

  thoracic            and

mediastinal disorders

Epistaxis

 

 

 

Respiratory tract bleeding (haemoptysis, pulmonary haemorrhage),

bronchospasm,            interstitial pneumonitis, eosinophilic pneumonia

Gastrointestinal disorders

Gastrointestinal haemorrhage, diarrhoea, abdominal pain, dyspepsia

Gastric duodenal

gastritis, nausea, flatulence

ulcer      and

ulcer, vomiting, constipation,

Retroperitoneal haemorrhage

  Gastrointestinal              and

retroperitoneal

haemorrhage with fatal outcome, pancreatitis, colitis (including ulcerative or lymphocytic colitis), stomatitis

Hepato-biliary disorders

 

 

 

Acute liver failure, hepatitis, abnormal liver

function test

  Skin                  and

subcutaneous tissue disorders

Bruising

Rash, pruritus, skin bleeding (purpura)

 

Bullous dermatitis (toxic

Epidermal necrolysis,

  Stevens                   Johnson

Syndrome, erythema multiforme, acute generalised exanthematous

 

 

 

 

 

 

 

pustulosis (AGEP)), angioedema, drug-induced hypersensitivity syndrome, drug rash with eosinophilia and systemic symptoms

(DRESS),                       rash

erythematous or exfoliative,     urticaria, eczema, lichen planus

Reproductive systems and breast disorders

 

 

 

 

Gynaecomastia

 

Musculoskeletal connective tissue and bone disorders

 

 

 

 

 

Musculo-skeletal bleeding (haemarthrosis), arthritis, arthralgia, myalgia

Renal and urinary disorders

 

 

Haematuria

 

 

Glomerulonephritis blood creatinine increased

 

General disorders and administration site conditions

Bleeding puncture site

at

 

 

 

Fever 

Investigations

 

 

Bleeding

time

 

 

 

 

 

prolonged,

neutrophil

 

 

 

 

 

count

decreased,

 

 

 

 

 

platelet

count

 

 

 

 

 

decreased

 

 

* Information related to clopidogrel with frequency “not known”.

Reporting of suspected adverse Reactions

 If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects    not listed in this leaflet. You can also report side effects directly (see details below). By reporting side affects; you can help provide more information on the safety of this medicine.

Saudi Arabia:

The National Pharmacovigilance and Drug Safety Centre (NPC)
o SFDA Call Center: 19999
o E-mail:npc.drug@sfda.gov.sa
o Website:https://ade.sfda.gov.sa/

o Other GCC States:
Please contact the relevant competent authority.


Overdose following clopidogrel administration may lead to prolonged bleeding time and subsequent bleeding complications. Appropriate therapy should be considered if bleedings are observed.

No antidote to the pharmacological activity of clopidogrel has been found. If prompt correction of prolonged bleeding time is required, platelet transfusion may reverse the effects of clopidogrel.


Pharmacotherapeutic group: platelet aggregation inhibitors excl. heparin, ATC Code: B01AC-04.

Mechanism of action

Clopidogrel is a prodrug, one of whose metabolites is an inhibitor of platelet aggregation. Clopidogrel must be metabolised by CYP450 enzymes to produce the active metabolite that inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. Due to the irreversible binding, platelets exposed are affected for the remainder of their lifespan (approximately 7-10 days) and recovery of normal platelet function occurs at a rate consistent with platelet turnover. Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of platelet activation by released ADP.

Because the active metabolite is formed by CYP450 enzymes, some of which are polymorphic or subject to inhibition by other medicinal products, not all patients will have adequate platelet inhibition.

Pharmacodynamic effects

Repeated doses of 75 mg per day produced substantial inhibition of ADP-induced platelet aggregation from the first day; this increased progressively and reached steady state between Day 3 and Day 7. At steady state, the average inhibition level observed with a dose of 75 mg per day was between 40% and 60%. Platelet aggregation and bleeding time gradually returned to baseline values, generally within 5 days after treatment was discontinued.

Clinical efficacy and safety

The safety and efficacy of clopidogrel have been evaluated in 5 double-blind studies involving over 88,000 patients: the CAPRIE study, a comparison of clopidogrel to ASA, and the CURE, CLARITY, COMMIT and ACTIVE-A studies comparing clopidogrel to placebo, both medicinal products given in combination with ASA and other standard therapy.

Recent myocardial infarction (MI), recent stroke or established peripheral arterial disease

The CAPRIE study included 19,185 patients with atherothrombosis as manifested by recent myocardial infarction (<35 days), recent ischaemic stroke (between 7 days and 6 months) or established peripheral arterial disease (PAD). Patients were randomised to clopidogrel 75 mg/day or ASA 325 mg/day, and were followed for 1 to 3 years. In the myocardial infarction subgroup, most of the patients received ASA for the first few days following the acute myocardial infarction.

 [95% CI: 0.2 to 16.4]; p=0.045), which corresponds, for every 1,000 patients treated for 2 years, to 10 [CI: 0 to 20] additional patients being prevented from experiencing a new ischaemic event. Analysis of total mortality as a secondary endpoint did not show any significant difference between clopidogrel (5.8%) and ASA (6.0%).

In a subgroup analysis by qualifying condition (myocardial infarction, ischaemic stroke, and PAD) the benefit appeared to be strongest (achieving statistical significance at p=0.003) in patients enrolled due to PAD (especially those who also had a history of myocardial infarction) (RRR = 23.7%; CI: 8.9 to 36.2) and weaker (not significantly different from ASA) in stroke patients (RRR = 7.3%; CI: -5.7 to 18.7 [p=0.258]). In patients who were enrolled in the trial on the sole basis of a recent myocardial infarction, clopidogrel was numerically inferior, but not statistically different from ASA (RRR = -4.0%; CI: -22.5 to 11.7 [p=0.639]). In addition, a subgroup analysis by age suggested that the benefit of clopidogrel in patients over 75 years was less than that observed in patients ≤75 years.

Since the CAPRIE trial was not powered to evaluate efficacy of individual subgroups, it is not clear whether the differences in relative risk reduction across qualifying conditions are real, or a result of chance.

Acute coronary syndrome

The CURE study included 12,562 patients with non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction), and presenting within 24 hours of onset of the most recent episode of chest pain or symptoms consistent with ischaemia. Patients were required to have either ECG changes compatible with new ischaemia or elevated cardiac enzymes or troponin I or T to at least twice the upper limit of normal. Patients were randomised to clopidogrel (300 mg loading dose followed by 75 mg/day, N=6,259) or placebo (N=6,303), both given in combination with ASA (75-325 mg once daily) and other standard therapies. Patients were treated for up to one year. In CURE, 823 (6.6%) patients received concomitant GPIIb/IIIa receptor antagonist therapy. Heparins were administered in more than 90% of the patients and the relative rate of bleeding between clopidogrel and placebo was not significantly affected by the concomitant heparin therapy.

The number of patients experiencing the primary endpoint [cardiovascular (CV) death, myocardial infarction (MI), or stroke] was 582 (9.3%) in the clopidogrel-treated group and 719 (11.4%) in the placebo-treated group, a 20% relative risk reduction (95% CI of 10%-28%; p=0.00009) for the clopidogrel-treated group (17% relative risk reduction when patients were treated conservatively, 29% when they underwent percutaneous transluminal coronary angioplasty (PTCA) with or without stent and 10% when they underwent coronary artery bypass graft (CABG)). New cardiovascular events (primary endpoint) were prevented, with relative risk reductions of 22% (CI: 8.6, 33.4), 32% (CI: 12.8, 46.4), 4% (CI: -26.9, 26.7), 6% (CI: -33.5, 34.3) and 14% (CI:-31.6, 44.2), during the 0-1, 1-3, 3-6, 6-9 and 9-12 month study intervals, respectively. Thus, beyond 3 months of treatment, the benefit observed in the clopidogrel + ASA group was not further increased, whereas the risk of haemorrhage persisted (see section 4.4).

The use of clopidogrel in CURE was associated with a decrease in the need of thrombolytic therapy (RRR = 43.3%; CI: 24.3%, 57.5%) and GPIIb/IIIa inhibitors (RRR = 18.2%; CI: 6.5%,

28.3%).

The number of patients experiencing the co-primary endpoint (CV death, MI, stroke or refractory ischaemia) was 1,035 (16.5%) in the clopidogrel-treated group and 1,187 (18.8%) in the placebotreated group, a 14% relative risk reduction (95% CI of 6%-21%, p=0.0005) for the clopidogreltreated group. This benefit was mostly driven by the statistically significant reduction in the incidence of MI [287 (4.6%) in the clopidogrel treated group and 363 (5.8%) in the placebo treated group]. There was no observed effect on the rate of rehospitalisation for unstable angina. The results obtained in populations with different characteristics (e.g. unstable angina or non-Qwave MI, low to high risk levels, diabetes, need for revascularisation, age, gender, etc.) were consistent with the results of the primary analysis. In particular, in a post-hoc analysis in 2,172 patients (17% of the total CURE population) who underwent stent placement (Stent-CURE), the data showed that clopidogrel compared to placebo, demonstrated a significant RRR of 26.2% favouring Clopidogrel for the co-primary endpoint (CV death, MI stock )and also significant RRR of 23.9% for the second co-primary end point. 

The benefits observed with Clopidogrel were independent of other acute and long-term cardiovascular therapies (such as heparin/LMWH, GPIIb/IIIa antagonists, lipid lowering medicinal products, beta blockers, and ACE-inhibitors). The efficacy of Clopidogrel was observed independently of the dose of ASA (75-325 mg once daily).

In patients with acute ST-segment elevation MI, safety and efficacy of Clopidogrel have been evaluated in 2randomised, placebo-controlled, double-blind studies, CLARITY and COMMIT.

The CLARITY trial included 3,491 patients presenting within 12 hours of the onset of a ST elevation MI and planned for thrombolytic therapy. Patients received clopidogrel (300 mg loading dose, followed by 75 mg/day, n=1,752) or placebo (n=1,739), both in combination with ASA (150 to 325 mg as a loading dose, followed by 75 to 162 mg/day), a fibrinolytic agent and, when appropriate, heparin. The patients were followed for 30 days. The primary endpoint was the occurrence of the composite of an occluded infarct-related artery on the predischarge angiogram, or death or recurrent MI before coronary angiography. For patients who did not undergo angiography, the primary endpoint was death or recurrent myocardial infarction by Day 8 or by hospital discharge. The patient population included 19.7% women and 29.2% patients ≥ 65 years. A total of 99.7% of patients received fibrinolytics (fibrin specific: 68.7%, non-fibrin specific: 31.1%), 89.5% heparin, 78.7% beta blockers, 54.7% ACE inhibitors and 63% statins. Fifteen percent (15.0%) of patients in the clopidogrel group and 21.7% in the placebo group reached the primary endpoint, representing an absolute reduction of 6.7% and a 36 % odds reduction in favor of clopidogrel (95% CI: 24, 47%; p < 0.001), mainly related to a reduction in occluded infarct-related arteries. This benefit was consistent across all prespecified subgroups including patients' age and gender, infarct location, and type of fibrinolytic or heparin used.

The 2x2 factorial design COMMIT trial included 45,852 patients presenting within 24 hours of the onset of the symptoms of suspected MI with supporting ECG abnormalities (i.e. ST elevation, ST depression or left bundlebranch block). Patients received clopidogrel (75 mg/day, n=22,961) or placebo (n=22,891), in combination with ASA (162 mg/day), for 28 days or until hospital discharge. The co-primary endpoints were death from any cause and the first occurrence of re-infarction, stroke or death. The population included 27.8% women, 58.4% patients ≥ 60 years (26% ≥ 70 years) and 54.5% patients who received fibrinolytics. Clopidogrel significantly reduced the relative risk of death from any cause by 7% (p=0.029), and the relative risk of the combination of re-infarction, stroke or death by 9% (p=0.002), representing an absolute reduction of 0.5% and 0.9%, respectively. This benefit was consistent across age, gender and with or without fibrinolytics, and was observed as early as 24 hours.

De-escalation of P2Y Inhibitor Agents in ACS

Switching from a more potent P2Y receptor inhibitor to clopidogrel in association with aspirin after acute phase in ACS has been evaluated in two randomized investigator-sponsored studies (ISS) - TOPIC and TROPICAL-ACS - with clinical outcome data.

The clinical benefit provided by the more potent P2Y inhibitors, ticagrelor and prasugrel, in their pivotal studies is related to a significant reduction in recurrent ischaemic events (including acute and sub acute stent thrombosis (ST), myocardial infarction (MI), and urgent revascularization). Although the ischaemic benefit was consistent throughout the first year, greater reduction in ischaemic recurrence after ACS was observed during the initial days following the treatment initiation. In contrast, post-hoc analyses demonstrated statistically significant increases in the

bleeding risk with the more potent P2Y inhibitors, occurring predominantly during the maintenance phase, after the first month post-ACS. TOPIC and TROPICAL-ACS were designed to study how to mitigate the bleeding events while maintaining efficacy.TOPIC (Timing Of Platelet Inhibition after acute Coronary syndrome)

This randomized, open-label trial included ACS patients requiring PCI. Patients on aspirin and a more potent P2Y blocker and without adverse event at one month were assigned to switch to fixed-dose aspirin plus

Overall, 645 of 646 patients with STEMI or NSTEMI or unstable angina were analyzed (deescalated DAPT (n=322); unchanged DAPT (n=323)). Follow-up at one year was performed for 316 patients (98.1%) in the deescalated DAPT group and 318 patients (98.5%) in the unchanged DAPT group. The median follow-up for both groups was 359 days. The characteristics of the studied cohort were similar in the 2 groups.

The primary outcome, a composite of cardiovascular death, stroke, urgent revascularization, and

BARC (Bleeding Academic Research Consortium) bleeding ≥2 at 1 year post ACS, occurred in 43 patients (13.4%) in the de-escalated DAPT group and in 85 patients (26.3%) in the unchanged DAPT group (p<0.01). This statistically significant difference was mainly driven by fewer bleeding events, with no difference reported in ischaemic endpoints (p=0.36), while BARC ≥2 bleeding occurred less frequently in the de-escalated DAPT group (4.0%) versus 14.9% in the unchanged DAPT group (p<0.01). Bleeding events defined as all BARC occurred in 30 patients (9.3%) in the de-escalated DAPT group and in 76 patients (23.5%) in the unchanged DAPT group (p<0.01).

TROPICAL-ACS (Testing Responsiveness to Platelet Inhibition on Chronic Antiplatelet Treatment for Acute Coronary Syndromes)

This randomized, open-label trial included 2,610 biomarker-positive ACS patients after successful PCI. Patients were randomized to receive either prasugrel 5 or 10 mg/d (Days 0-14)

(n=1306), or prasugrel 5 or 10

mg/d (Days 0-7) then de-escalated to clopidogrel 75 mg/d (Days 8-14) (n=1304), in combination with ASA (<100 mg/day). At Day 14, platelet function testing (PFT) was performed. The prasugrel-only patients were continued on prasugrel for 11.5 months.

The de-escalated patients underwent high platelet reactivity (HPR) testing. If HPR≥46 units, the patients were escalated back to prasugrel 5 or 10 mg/d for 11.5 months; if HPR<46 units, the patients continued on clopidogrel 75 mg/d for 11.5 months. Therefore, the guided de-escalation arm had patients on either Prasugrel (40%) or clopidogrel (60%). All patients were continued on aspirin and were followed for one year.

The primary endpoint (the combined incidence of CV death, MI, stroke and BARC bleeding grade ≥2 at 12 months) was met showing non-inferiority. Ninety five patients (7%) in the guided de-escalation group and 118 patients (9%) in the control group (p non-inferiority=0.0004) had an event. The guided de-escalation did not result in an increased combined risk of ischemic events (2.5% in the de-escalation group vs 3.2% in the control group; p non-inferiority=0.0115), nor in the key secondary endpoint of BARC bleeding ≥2 ((5%) in the de-escalation group versus 6% in the control group (p=0.23)). The cumulative incidence of all bleeding events(BARC class 1 to 5) was 9% (114 events) in the guided de-escalation group versus 11% (137 events) in the control group (p=0.14).

Atrial fibrillation

The ACTIVE-W and ACTIVE-A studies, separate trials in the ACTIVE program, included patients with atrial fibrillation (AF) who had at least one risk factor for vascular events. Based on enrollment criteria, physicians enrolled patients in ACTIVE-W if they were candidates for vitamin K antagonist (VKA) therapy (such as warfarin). The ACTIVE-A study included patients who could not receive VKA therapy because they were unable or unwilling to receive the treatment.

The ACTIVE-W study demonstrated that anticoagulant treatment with vitamin K antagonists was more effective than with clopidogrel and ASA.

The ACTIVE-A study (N=7,554) was a multicenter, randomized, double-blind, placebocontrolled study which compared clopidogrel 75 mg/day + ASA (N=3,772) to placebo + ASA (N=3,782). The recommended dose for ASA was 75 to 100 mg/day. Patients were treated for up to 5 years.

Patients randomized in the ACTIVE program were those presenting with documented AF, i.e., either permanent AF or at least 2 episodes of intermittent AF in the past 6 months, and had at least one of the following risk factors: age ≥75 years or age 55 to 74 years and either diabetes mellitus requiring drug therapy, or documented previous MI or documented coronary artery disease; treated for systemic hypertension; prior

The major exclusion criteria for patients were documented peptic ulcer disease within the previous 6 months; prior intracerebral hemorrhage; significant thrombocytopenia (platelet count < 50 x 10 /l); requirement for clopidogrel or oral anticoagulants (OAC); or intolerance to any of the two compounds.

Seventy-three percent (73%) of patients enrolled into the ACTIVE-A study were unable to take VKA due to physician assessment, inability to comply with INR (international normalised ratio) monitoring, predisposition to falling or head trauma, or specific risk of bleeding; for 26% of the patients, the physician's decision was based on the patient's unwillingness to take VKA.

The patient population included 41.8 % women. The mean age was 71 years, 41.6% of patients were ≥75 years. A total of 23.0% of patients received anti-arrhythmics, 52.1% beta-blockers, 54.6% ACE inhibitors, and 25.4% statins.

The number of patients who reached the primary endpoint (time to first occurrence of stroke, MI, non-CNS systemic embolism or vascular death) was 832 (22.1%) in the group treated with clopidogrel + ASA and 924 (24.4%) in the placebo + ASA group (relative risk reduction of 11.1%; 95% CI of 2.4% to 19.1%; p=0.013), primarily due to a large reduction in the incidence of strokes. Strokes occurred in 296 (7.8%) patients receiving clopidogrel + ASA and 408 (10.8%) patients receiving placebo + ASA (relative risk reduction, 28.4%; 95% CI, 16.8% to

38.3%; p=0.00001).

Paediatric population

In a dose escalation study of 86 neonates or infants up to 24 months of age at risk for thrombosis (PICOLO), clopidogrel was evaluated at consecutive doses of 0.01, 0.1 and 0.2 mg/kg in neonates and infants and 0.15 mg/kg only in neonates. The dose of 0.2 mg/kg achieved the mean percent inhibition of 49.3% (5 μM ADP induced platelet aggregation) which was comparable to that of adults taking Plavix 75 mg/day.

In a randomised, double-blind, parallel-group study (CLARINET), 906 paediatric patients (neonates and infants) with cyanotic congenital heart disease palliated with a systemic-topulmonary arterial shunt were randomised to receive Clopidogrel 0.2 mg/kg (n=467) or placebo (n=439) along with concomitant background therapy up to the time of second stage surgery. The mean time between shunt palliation and first administration of study medicinal product was 20 days. Approximately 88% of patients received concomitant ASA (range of 1 to 23 mg/kg/day). There was no significant difference between groups in the primary composite endpoint of death, shunt thrombosis or cardiac-related intervention prior to 120 days of age following an event considered of thrombotic nature (89 [19.1%] for the Clopidogrel group and 90 [20.5%] for the placebo group) (see section 4.2). Bleeding was the most frequently reported adverse reaction in both Clopidogrel and placebo groups; however, there was no significant difference in the bleeding rate between groups. In the long-term safety follow-up of this study, 26 patients with the shunt still in place at one year of age received Clopidogrel up to 18 months of age. No new safety concerns were noted during this long-term follow-up.

The CLARINET and the PICOLO trials were conducted using a constituted solution of clopidogrel. In a relative bioavailability study in adults, the constituted solution of clopidogrel showed a similar extent and slightly higher rate of absorption of the main circulating (inactive) metabolite compared to the authorised tablet.

  


Absorption

After single and repeated oral doses of 75 mg per day, clopidogrel is rapidly absorbed. Mean peak plasma levels of unchanged clopidogrel (approximately 2.2-2.5 ng/ml after a single 75 mg oral dose) occurred approximately 45 minutes after dosing. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites.

Distribution

Clopidogrel and the main circulating (inactive) metabolite bind reversibly in vitro to human plasma proteins (98% and 94% respectively. The bindings is no saturable in vitro over a wide concentration range 

Biotransformation:

Clopidogrel is extensively metabolised by the liver. In vitro and in vivo, clopidogrel is metabolised according to two main metabolic pathways: one mediated by esterases and leading to hydrolysis into its inactive carboxylic acid derivative (85% of circulating metabolites), and one mediated by multiple cytochromes P450. Clopidogrel is first metabolised to a 2-oxoclopidogrel intermediate metabolite. Subsequent metabolism of the 2-oxoclopidogrel intermediate metabolite results in formation of the active metabolite, a thiol derivative of clopidogrel. The active metabolite is formed mostly by CYP2C19 with contributions from several other CYP enzymes, including CYP1A2, CYP2B6 and CYP3A4. The active thiol metabolite which has been isolated in vitro, binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation. 

The C of the active metabolite is twice as high following a single 300-mg clopidogrel loading dose as it is after four days of 75-mg maintenance dose. C occurs approximately 30 to 60 minutes after dosing.
Elimination

Following an oral dose of C-labelled clopidogrel in man, approximately 50% was excreted in the urine and approximately 46% in the faeces in the 120-hour interval after dosing. After a single oral dose of 75 mg, clopidogrel has a half-life of approximately 6 hours. The elimination half-life of the main circulating (inactive) metabolite was 8 hours after single and repeated administration.


Pharmacogenetics

CYP2C19 is involved in the formation of both the active metabolite and the 2-oxo-clopidogrel intermediate metabolite. Clopidogrel active metabolite pharmacokinetics and antiplatelet effects, as measured by ex vivo platelet aggregation assays, differ according to CYP2C19 genotype.

The CYP2C19*1 allele corresponds to fully functional metabolism while the CYP2C19*2 and CYP2C19*3 alleles are nonfunctional. The CYP2C19*2 and CYP2C19*3 alleles account for the majority of reduced function alleles in Caucasian (85%) and Asian (99%) poor metabolisers. Other alleles associated with absent or reduced metabolism are less frequent and include CYP2C19*4, *5, *6, *7, and *8. A patient with poor metaboliser status will possess two loss-offunction alleles as defined above. Published frequencies for the poor CYP2C19 metaboliser genotypes are approximately 2% for Caucasians, 4% for Blacks and 14% for Chinese. Tests are available to determine a patient's CYP2C19 genotype.

A crossover study in 40 healthy subjects, 10 each in the four CYP2C19 metaboliser groups (ultrarapid, extensive, intermediate and poor), evaluated pharmacokinetic and antiplatelet responses using 300 mg followed by 75 mg/day and 600 mg followed by 150 mg/day, each for a total of 5 days (steady state). No substantial differences in active metabolite exposure and mean inhibition of platelet aggregation (IPA) were observed between ultrarapid, extensive and intermediate metabolisers. In poor metabolisers, active metabolite exposure was decreased by 63-71% compared to extensive metabolisers. After the 300 mg/75 mg dose regimen, antiplatelet responses were decreased in the poor metabolisers with mean IPA (5 μM ADP) of 24%(24 hours) and 37% (Day 5) as compared to IPA of 39% (24 hours) and 58% (Day 5) in the extensive metabolisers and 37% (24 hours) and 60% (Day 5) in the intermediate metabolisers. When poor metabolisers received the 600 mg/150 mg regimen, active metabolite exposure was greater than with the 300 mg/75 mg regimen. In addition, IPA was 32% (24 hours) and 61% (Day 5), which were greater than in the poor metabolisers receiving the 300 mg/75 mg regimen, and were similar to the other CYP2C19 metaboliser groups receiving the 300 mg/75 mg regimen. An appropriate dose regimen for this patient population has not been established in clinical outcome trials. 

Consistent with the above results, in a meta-analysis including 6 studies of 335 clopidogreltreated subjects at steady state, it was shown that active metabolite exposure was decreased by 28% for intermediate metabolisers, and 72% for poor metabolisers while platelet aggregation inhibition (5 μM ADP) was decreased with differences in IPA of 5.9% and 21.4%, respectively, when compared to extensive metabolisers.

The influence of CYP2C19 genotype on clinical outcomes in patients treated with clopidogrel has not been evaluated in prospective, randomised, controlled trials. There have been a number of retrospective analyses, however, to evaluate this effect in patients treated with clopidogrel for whom there are genotyping results In TRITON-TIMI 38 and 3 of the cohort studies (Collet, Sibbing, Giusti) the combined group of patients with either intermediate or poor metaboliser status had a higher rate of cardiovascular events (death, myocardial infarction, and stroke) or stent thrombosis compared to extensive metabolisers.

In CHARISMA and one cohort study (Simon), an increased event rate was observed only in poor metabolisers when compared to extensive metabolisers.

In CURE, CLARITY, ACTIVE-A and one of the cohort studies (Trenk), no increased event rate was observed based on metaboliser status.

None of these analyses were adequately sized to detect differences in outcome in poor metabolisers.

Special populations

The pharmacokinetics of the active metabolite of clopidogrel is not known in these special populations.

Renal impairment

After repeated doses of 75 mg clopidogrel per day in subjects with severe renal disease (creatinine clearance from 5 to 15 ml/min), inhibition of ADP-induced platelet aggregation was lower (25%) than that observed in healthy subjects, however, the prolongation of bleeding time was similar to that seen in healthy subjects receiving 75 mg of clopidogrel per day. In addition, clinical tolerance was good in all patients.

Hepatic impairment

After repeated doses of 75 mg clopidogrel per day for 10 days in patients with severe hepatic impairment, inhibition of ADP-induced platelet aggregation was similar to that observed in healthy subjects. The mean bleeding time prolongation was also similar in the two groups.

Race

The prevalence of CYP2C19 alleles that result in intermediate and poor CYP2C19 metabolism differs according to race/ethnicity (see Pharmacogenetics). From literature, limited data in Asian populations are available to assess the clinical implication of genotyping of this CYP on clinical outcome events.


During non-clinical studies in rat and baboon, the most frequently observed effects were liver changes. These occurred at doses representing at least 25 times the exposure seen in humans receiving the clinical dose of 75 mg/day and were a consequence of an effect on hepatic metabolising enzymes. No effect on hepatic metabolising enzymes was observed in humans receiving clopidogrel at the therapeutic dose.

At very high doses, a poor gastric tolerability (gastritis, gastric erosions and/or vomiting) of clopidogrel was also reported in rat and baboon.

There was no evidence of carcinogenic effect when clopidogrel was administered for 78 weeks to mice and 104 weeks to rats when given at doses up to 77 mg/kg per day (representing at least 25 times the exposure seen in humans receiving the clinical dose of 75 mg/day).

Clopidogrel has been tested in a range of in vitro and in vivo genotoxicity studies, and showed no genotoxic activity.
Clopidogrel was found to have no effect on the fertility of male and female rats and was not teratogenic in either rats or rabbits. When given to lactating rats, clopidogrel caused a slight delay in the development of the off spring. Specific pharmacokinetic studies performed with radiolabelled clopidogrel have shown that the parent compound or its metabolites are excreted in the milk. Consequently, a direct effect (slight toxicity), or an indirect effect (low palatability) cannot be excluded.


The other ingredients are: Lactose Monohydrate, Cellulose Microcrystalline, Low substituted Hydroxy Propyl cellulose, Crospovidone, Mannitol, Silica colloidal anhydrous, Macrogol, Hydrogenated Castor oil. 

Film coating composition: HPMC 2910/Hypromellose 6 cP (E464), Lactose Monohydrate,

Titanium Dioxide(E171), Triacetin, Iron oxide red (E172).


NA


36 months

Store below 30ºC


Clopigen 75 tablets are supplied in Blister pack.

Box of 30 blistered tablets (3x10’s).


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


Saudi Amarox Industrial Company Aljameah Street, Malaz quarter, Riyadh 11441 Saudi Arabia Module-1 Tel: +966 11 477 2215 Manufacture: Hetero Lab Unit V, Hyderabad, India

08/09/2022
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