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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)

-        Warfarin ZYD® is an anticoagulant drug.” Anti” means against, and” coagulant” refers to blood clotting. An anticoagulant helps reduce clots from forming in the blood.

 

-        Warfarin ZYD® is a narrow therapeutic index drug, which means that there is a narrow margin between too much and too little of the drug. Too much drug may cause you to bleed more. Too little drug may let a harmful clot form.

 

- Warfarin ZYD® is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization.


 

A.    Do not take Warfarin ZYD


Do not take Warfarin ZYD during pregnancy.

 

B.    Take special care with Warfarin ZYD.

·       Talk to your doctor or pharmacist before using Warfarin ZYD if you:

 

o   Have bleeding problems.

o   Fall often.

o   Have liver or kidney problems.

o   Have high blood pressure.

o   Has a heart problem called congestive heart failure?

o   Have diabetes

o   Drink alcohol or have problems with alcohol abuse. Alcohol can affect your WARFARIN dose and should be avoided.

o   Are pregnant or planning to become pregnant. 

o   Are breastfeeding. Warfarin ZYD may increase bleeding in your baby. Talk to your doctor about the best way to feed your baby. If you choose to breastfeed while taking Warfarin ZYD, both you and your baby should be carefully monitored for bleeding problems.

·       Do not make drastic changes in your diet, such as eating large amounts of green, leafy vegetables. The amount of vitamin K in your daily diet may affect therapy with Warfarin ZYD.

·       Avoid intake of cranberry juice or any other cranberry products. Notify your healthcare provider if any of these products are part of your normal diet.

·       Do not attempt to change your weight by dieting, without first checking with your health care provider.

·       Avoid alcohol consumption.

 

C.    Pregnancy & breast-feeding 

 

Spontaneous abortion and still birth are known to occur, and a higher risk of fetal mortality is associated with the use of warfarin. Low birth weight and growth retardation have also been reported. Women of childbearing potential who are candidates for anticoagulant therapy should be carefully evaluated and the indications critically reviewed with the patient. If the patient becomes pregnant while taking this drug, she should be apprised of the potential risks to the fetus, and the possibility of termination of the pregnancy should be discussed in the light of those risks. 

Women who are breast-feeding and anticoagulated with warfarin should be very carefully monitored so that recommended International Normalized Ratio (INR) values are not exceeded. It is prudent to perform coagulation tests on infants at risk for bleeding before advising women taking warfarin to breastfeed.

 

D.    Interactions with this medication

 

Do not start, stop, or change any medicine except on advice of your health care provider. Warfarin ZYD interacts with many different drugs, including aspirin and aspirin-containing ointments and skin creams as well as natural medicines (e.g., bromelains, coenzyme Q10, danshen (Colocasia antiquorum), dong quai (Angelica sinensia), garlic, ginkgo biloba, ginseng and St. John’s wort). Tell your health care provider about any prescription and non-prescription (over-the-counter) drugs that you are taking including occasional use of headache medications.

 


Take Warfarin ZYD exactly the way your health care provider tells you and take it at the same time every day. You can take Warfarin ZYD either with food or on an empty stomach. Your dosage may change from time to time depending on your response to Warfarin ZYD.

A.    If you take more Warfarin ZYD then you should

Use of a large loading dose may increase the incidence of hemorrhagic and other complications, does not offer more rapid protection against thrombi formation, and is not recommended.

B.    If you forget to take Warfarin ZYD

If you miss a dose of Warfarin ZYD, notify your health care provider right away. Take the dose as soon as possible on the same day, but do not take a double dose of Warfarin ZYD the next day to make up for a missed dose.


Your health care provider can tell you about possible side effects of Warfarin ZYD, which include bleeding and allergic reactions. To lower the risk of bleeding, your PT/INR should be kept within a range that is right for you.

 

 

Please contact your health care provider right away if you experience any of the following signs or symptoms of bleeding problems.

 

·       Headache, dizziness, or weakness

·       Bleeding from shaving or other cuts that does not stop

·       Nosebleeds

·       Bleeding of gums when brushing your teeth

·       Coughing up blood

·       Vomiting blood or material that looks like coffee grounds

·       Unusual bruising (black-and-blue marks on your skin) for unknown reasons

·       Pink or dark brown urine

·       Red or black color in your stool

·       More bleeding than usual when you get your menstrual period or unexpected bleeding from the vagina

·       Unusual pain or swelling

 

Serious, but rare, side effects of Warfarin ZYD include skin necrosis (death of skin tissue) and “purple toe syndrome”, either of which may require removal of unhealthy tissue and/or amputation of the affected area. Call your healthcare provider right away if you have pain, color, or temperature change to any area of your body or if you have pain in your toes and they look purple or dark in color. You may need medical care right away. Talk with your health care provider for further information on these side effects.

 

 

Hypersensitivity/allergic reactions are reported infrequently. Signs or symptoms of these reactions may range from mild reactions (rash, itching, hives) to more severe reactions (trouble breathing, throat tightening or constriction, facial swelling, swollen lips or tongue, sudden low blood pressure).

 

 

These are not all of the side effects of Warfarin ZYD. For more information, ask your healthcare provider or pharmacist.

 


Don’t Store Above 30ºC.

Protect from light.

Keep Out of Reach of Children


The active substance is Warfarin Sodium.

 

Warfarin Sodium Tablets USP 1mg

Lactose Monohydrate, Pregelatinized starch Hydroxypropyl Cellulose, Magnesium stearate

D & C Red No. 6 Barium Lake (Lithol Rubin B).   

 

Warfarin Sodium Tablets USP 2mg

Lactose Monohydrate, Pregelatinized starch, Hydroxypropyl Cellulose, Magnesium stearate,

FD & C Blue No. 2 Aluminum Lake (Indigotine) and FD & C Red No. 40 (Allura Red AC) Aluminum Lake.

 

Warfarin Sodium Tablets USP 2.5mg

Lactose Monohydrate, Pregelatinized starch, Hydroxypropyl Cellulose, Magnesium stearate,

D & C Yellow No. 10 Aluminum Lake (Quinoline Yellow WS) and FD & C Blue No. 1

Aluminum Lake (Brilliant Blue FCF).

 

Warfarin Sodium Tablets USP 3mg

Lactose Monohydrate, Pregelatinized starch, Hydroxypropyl Cellulose, Magnesium stearate,

FD & C Yellow No. 6 Aluminum Lake (Sunset Yellow FCF), FD & C Blue No. 2 Aluminum Lake (Indigotine) and FD & C Red No. 40 Aluminum Lake (Allura Red AC).

 

Warfarin Sodium Tablets USP 5mg

Lactose Monohydrate, Pregelatinized starch, Hydroxypropyl Cellulose, Magnesium stearate, FD & C Yellow No. 6 Aluminum Lake (Sunset Yellow FCF).

 

Warfarin Sodium Tablets USP 10mg

Lactose Monohydrate, Pregelatinized starch, Hydroxypropyl Cellulose, Magnesium stearate.

 


Warfarin ZYD 1 mg : Pink, oval, flat, beveled edge, uncoated tablets debossed with the logo of 'WAR', 'l' on one side and bisect on both sides. The tablet should be free of all physical defects. Warfarin ZYD 2 mg: Lavender, oval, flat, beveled edge, uncoated tablets debossed with the logo of 'WAR', '2' on one side and bisect on both sides. The tablet should be free of all physical defects. Warfarin ZYD 2.5 mg : Green, oval, flat, beveled edge, uncoated tablets debossed with the logo of 'WAR', '2.5' on one side and bisect on both sides. The tablet should be free of all physical defects. Warfarin ZYD 3 mg: Tan, oval, flat, beveled edge, uncoated tablets debossed with the logo of 'WAR', '3' on one side and bisect on both sides. The tablet should be free of all physical defects. Warfarin ZYD 5 mg : Peach, oval, flat, beveled edge, uncoated tablets debossed with the logo of 'WAR', '5' on one side and bisect on both sides. The tablet should be free of all physical defects. Warfarin ZYD 10 mg: White to off-white, flat, beveled edge, uncoated tablets debossed with the logo of 'WAR', '10' on one side and bisect on both sides. The tablet should be free of all physical defects. HDPE Pack of 100’s tablets

Marketing Authorization Holder

Zydus Lifesciences Limited

Zydus Corporate Park, Scheme No. 63,

Survey No. 536, Khoraj (Gandhinagar),

Nr. Vaishnodevi Circle, S. G. Highway.

Ahmedabad-382 481. Gujarat. India

 

Manufacturer

Zydus Lifesciences Limited,

Kundaim Industrial Estate, Plot No. 203-213,

Kundaim, Goa - 403 115, INDIA

 


This leaflet was last revised in July 2024.
  نشرة الدواء تحت مراجعة الهيئة العامة للغذاء والدواء (اقرأ هذه النشرة بعناية قبل البدء في استخدام هذا المنتج لأنه يحتوي على معلومات مهمة لك)

-        ورافارين زد واي دي عقار مضاد للتجلط، "مضاد" كلمة تعني معاكس، و"تجلط" يشير إلى تخثر الدم، ويقوم العقار المضاد للتجلط بتقليل تكوّن التخثرات بالدم.

 

-        ورافارين زد واي دي عقار ذو نطاق علاجي ضيق، بمعنى أن هناك فرق صغير بين الجرعة بالغة الإفراط والجرعة بالغة النقص منه، الجرعة بالغة الإفراط تسبب الإفراط في تخثر الدم، والجرعة بالغة النقص قد تسمح بتكوّن تخثر ضار.

 

-        يُستخدم ورافارين زد واي دي (وارفرين صوديوم) في الوقاية و/أو علاج التجلط الوريدي وامتداده، التجلط الرئوي، والرجفان الأذيني مع تكون جلطات.

 

أ‌-       لا تستخدم ورافارين زد واي دي

لا يُستخدم ورافارين زد واي دي أثناء الحمل.

 

 

ب‌-     الاحتياطات عند استعمال ورافارين زد واي دي

 

تحدث مع طبيبك أو الصيدلي قبل استخدم ورافارين زد واي دي إذا كنت تعاني من:

 

o     لديك مشاكل النزيف.

o     ستقع في كثير من الأحيان.

o     وجود مشاكل في الكبد أو الكلى.

o     الإصابة بارتفاع ضغط الدم.

o     هل لديك مشكلة في القلب تسمى قصور القلب الاحتقاني؟

o     مصاب بالسكري

o     شرب الكحول أو لديك مشاكل مع تعاطي الكحول. يمكن أن يؤثر الكحول على جرعة الوارفرين ويجب تجنبها.

o     حامل أو تخططين للحمل.

o     الرضاعة الطبيعية. قد يزيد ورافارين زد واي دي من النزيف لدى طفلك. تحدثي مع طبيبك حول أفضل طريقة لإطعام طفلك. إذا اخترت الرضاعة الطبيعية أثناء تناول ورافارين زد واي دي ، فيجب مراقبتك أنت وطفلك بعناية بحثًا عن مشاكل النزيف.

 

•       لا تقم بإجراء تغييرات جذرية في نظامك الغذائي، مثل تناول كميات كبيرة من الخضار الورقية الخضراء. قد تؤثر كمية فيتامين k في نظامك الغذائي اليومي على العلاج باستخدام ورافارين زد واي دي.

•       تجنب تناول عصير التوت البري أو أي من منتجات التوت البري الأخرى. أخبر مقدم الرعاية الصحية الخاص بك إذا كان أي من هذه المنتجات جزءًا من نظامك الغذائي العادي.

•       لا تحاول تغيير وزنك عن طريق اتباع نظام غذائي، دون مراجعة مقدم الرعاية الصحية الخاص بك أولاً.

•       تجنب استهلاك الكحول.

 

 

 

ت‌-    في حالة الحمل أو التخطيط للحمل

 

من المعروف حدوث الإجهاض التلقائي وولادة جنين ميت، ويرتبط ارتفاع خطر وفاة الجنين باستخدام الوارفرين. كما تم الإبلاغ عن انخفاض الوزن عند الولادة وتأخر النمو. يجب تقييم النساء ذوات القدرة على الإنجاب والمرشحات للعلاج المضاد للتخثر بعناية ومراجعة المؤشرات بشكل نقدي مع المريض. إذا حملت المريضة أثناء تناول هذا الدواء، فيجب إعلامها بالمخاطر المحتملة على الجنين، ويجب مناقشة إمكانية إنهاء الحمل في ضوء تلك المخاطر.

يجب مراقبة النساء المرضعات اللاتي يتناولن مضادات التخثر باستخدام الوارفرين بعناية فائقة حتى لا يتم تجاوز قيم النسبة الدولية المعيارية (INR) الموصى بها. من الحكمة إجراء اختبارات التخثر على الرضع المعرضين لخطر النزيف قبل نصح النساء اللاتي يتناولن الوارفرين أثناء الرضاعة الطبيعية.

 

 

ث‌-    التفاعلات مع هذا الدواء

بلغ موفر الرعاية الصحية لك بكل الأدوية التي تستخدمها، بما في ذلك الأدوية المستخدمة دون وصفة طبية والفيتامينات والمستحضرات العشبية. لا تبدأ أو توقف أو تغير استخدام أي عقار قبل نصيحة موفر الرعاية الصحية لك، ف ورافارين زد واي دي يتفاعل مع العديد من الأدوية المختلفة، بما في ذلك الأسبرين والمراهم المحتوية على الأسبرين وكريمات الجلد، وكذلك الأدوية الطبيعية (مثل: بروميلين، الإنزيم المساعد كيو 10، دانشين (عشبة كولوكيزيا أنتيكورام)، دونج كواي (عشبة أنجليكا سينينسيا)، الثوم، جينكو بيلوبا، جنسنج، ونبتة سانت جون)، بلغ موفر الرعاية الصحية لك بخصوص أي أدوية بوصفة طبية أو بدونها (الأدوية دون وصفة طبية) تستخدمها، بما في ذلك الاستخدام العرَضي لأدوية الصداع. لا تستخدم أدوية أخرى تحتوي على الوارفرين، فالوارفرين هو المكون النشط في عقار ورافارين زد واي دي.

 

 

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استخدم ورافارين زد واي دي بالضبط بحسب الطريقة التي أبلغك بها موفر الرعاية الصحية، واستخدمه في نفس الموعد يومياً، يمكنك استخدام ورافارين زد واي دي إما مع الطعام أو على معدة فارغة، يمكن أن تتغير جرعتك من وقت إلى آخر بحسب استجابتك ل ورافارين زد واي دي.

 

أ‌-       الجرعة الزائدة

استخدام جرعات كبيرة قد يزيد من معدلات حدوث النزيف وغيرها من المضاعفات الأخرى، ولا يقدم حماية أسرع ضد تكوّن الجلطات، ولا يوصى به.

 

ب‌-     الجرعة الفائتة

إذا نسيت إحدى جرعات ورافارين زد واي دي ، بلغي موفر الرعاية الصحية لك فوراً، واستخدمي الجرعة بأسرع ما يمكن في نفس اليوم، ولكن لا تستخدم جرعة مضاعَفة من ورافارين زد واي دي في اليوم التالي لتعويض الجرعة المنسيّة.

 

يمكن لموفر الرعاية الصحية لك أن يخبرك بخصوص الأعراض الجانبية المحتملة مع ورافارين زد واي دي ، وهي تتضمن النزيف وتفاعلات الحساسية، ولتقليل مخاطرة النزيف يجب الحفاظ على نتيجة اختبارات زمن البروثرومبين/ المعدل الدولي المطبوع ضمن الحدود الصحيحة بالنسبة لك.

برجاء الاتصال بموفر الرعاية الصحية لك فوراً إذا مررت بأي من العلامات أو الأعراض التالية أو مشكلات النزيف.

 

•       الصداع، الدوخة، الضعف

•       النزف من الحلاقة أو أي جرح آخر دون توقف

•       النزيف الأنفي

•       نزيف اللّثة عند غسيل الأسنان بالفرشاة

•       السعال المدمم

•       القيء المدمم أو القيء المحتوى على مادة شبيهة بالقهوة.

•       الكدمات غير المعتادة (علامات سوداء وزرقاء بجلدك) لأسباب غير معروفة.

•       تلون البول باللون الوردي أو البني الداكن.

•       تلون البراز باللون الأحمر أو الأسود.

•       النزيف الأكثر من المعتاد مع الدورة الشهرية، أو النزيف المهبلي غير المتوقع

•       الألم أو التورم غير المعتاد

 

هناك أعراض جانبية خطيرة وإن كانت نادرة مع ورافارين زد واي دي تتضمن: التنخر الجلدي (موت النسيج الجلدي)، و"متلازمة إصبع القدم الوردي"، وكل منهما قد يتطلب إزالة الأنسجة غير السليمة صحياً و/أو بتر المنطقة المصابة، اتصل بموفر الرعاية الصحية فوراً إذا شعرت بألم أو تغيرات باللون أو الحرارة بأي من مناطق جسمك، أو إذا شعرت بالألم بأصابع القدم وكانت تبدو بلون وردي أو أسود، فقد تحتاج للرعاية الطبية فوراً. تحدث مع موفر الرعاية الصحية لمزيد من المعلومات بخصوص هذه الأعراض الجانبية.

 

وردت تقارير بخصوص تفاعلات فرط الحساسية/الحساسية النادرة. قد تتراوح أعراض وعلامات هذه التفاعلات بين التفاعلات البسيطة (الطفح الجلدي، الهرش، الشريّ) إلى التفاعلات العنيفة (صعوبة التنفس، شد الحلق أو ضيقه، تورم الوجه، تورم الشفتين أو اللسان، الانخفاض المفاجئ لضغط الدم).

 

هذه ليست جمع الأعراض الجانبية مع ورافارين زد واي دي ، لمزيد من المعلومات قم بسؤال موفر الرعاية الصحية لك أو الصيدلي.

لا تخزنه في درجة حرارة أعلى من 30 درجة مئوية.

يُحفظ بعيداً عن الضوء في علبة محكمة الغلق ومقاومة للضوء.

يحفظ هذا الدواء بعيدًا عن أنظار ومتناول أيدي الأطفال.

 

أ‌-      ما هو ورافارين زد واي دي

 

المادة الفعالة هي ورافارين الصوديوم.

 

أقراص ورافارين الصوديوم 1 ملجم

 

مونوهيدرات اللاكتوز، النشا المجيلتن، هيدروكسي بروبيل السليلوز، ستيرات المغنيسيوم، D & C Red رقم 6 بحيرة الباريوم (ليثول روبين ب).

 

أقراص ورافارين الصوديوم 2 ملجم

مونوهيدرات اللاكتوز، النشا المجيلتن، هيدروكسي بروبيل السليلوز، ستيرات المغنيسيوم، FD & C Blue No. 2 Aluminum Lake (Indigotine) وFD & C Red No. 40 (Allura Red AC) بحيرة الألومنيوم.

 

أقراص ورافارين الصوديوم 2.5 ملجم

مونوهيدرات اللاكتوز، النشا المجيلتن، هيدروكسي بروبيل السليلوز، ستيرات المغنيسيوم، D & C Yellow No. 10 Aluminum Lake (Quinoline Yellow WS) وFD & C Blue No. 1 Aluminum Lake (Brilliant Blue FCF).

 

أقراص ورافارين الصوديوم 3 ملجم

مونوهيدرات اللاكتوز، النشا المجيلتن، هيدروكسي بروبيل السليلوز، ستيرات المغنيسيوم، FD & C Yellow رقم 6 بحيرة الألومنيوم (غروب الشمس الأصفر FCF)، FD & C الأزرق رقم 2 بحيرة الألومنيوم (إنديجوتين) وFD & C الأحمر رقم 40 بحيرة الألومنيوم ( ألورا الأحمر AC).

 

أقراص ورافارين الصوديوم 5 ملجم

مونوهيدرات اللاكتوز، النشا المجيلتن، هيدروكسي بروبيل السليلوز، ستيرات المغنيسيوم، FD & C أصفر رقم 6 بحيرة الألومنيوم (Sunset Yellow FCF).

 

أقراص ورافارين الصوديوم 10 ملجم

مونوهيدرات اللاكتوز، النشا المجيلتن، هيدروكسي بروبيل السليلوز، ستيرات المغنيسيوم.

 

ورافارين زد واي دي 1 ملجم: أقراص وردية، بيضاوية، مسطحة، مشطوفة الحواف، غير مطلية، منقوش عليها شعار "WAR"، "l" على جانب واحد ومنصف على كلا الجانبين. يجب أن يكون الجهاز اللوحي خاليًا من جميع العيوب الجسدية.

 

ورافارين زد واي دي 2 ملجم: أقراص لافندر، بيضاوية، مسطحة، مشطوفة الحواف، غير مطلية، منقوش عليها شعار "WAR"، "2" على جانب واحد ومنصف على كلا الجانبين. يجب أن يكون الجهاز اللوحي خاليًا من جميع العيوب الجسدية.

 

ورافارين زد واي دي 2.5 ملجم: أقراص خضراء، بيضاوية، مسطحة، مشطوفة الحواف، غير مغلفة، محفور عليها شعار "WAR"، "2.5" على جانب واحد ومنصف على كلا الجانبين. يجب أن يكون الجهاز اللوحي خاليًا من جميع العيوب الجسدية.

 

ورافارين زد واي دي 3 ملجم: أقراص بلون أسمر، بيضاوية، مسطحة، مشطوفة الحواف، غير مطلية، منقوش عليها شعار "WAR"، "3" على جانب واحد ومنصف على كلا الجانبين. يجب أن يكون الجهاز اللوحي خاليًا من جميع العيوب الجسدية.

 

ورافارين زد واي دي 5 ملجم: أقراص خوخية، بيضاوية، مسطحة، مشطوفة الحواف، غير مغلفة، محفور عليها شعار "WAR"، "5" على جانب واحد ومنصف على كلا الجانبين. يجب أن يكون الجهاز اللوحي خاليًا من جميع العيوب الجسدية.

 

ورافارين زد واي دي 10 ملجم: أقراص بيضاء إلى بيضاء اللون، مسطحة، مشطوفة، غير مطلية، منقوش عليها شعار "WAR"، "10" على جانب واحد ومنصف على كلا الجانبين. يجب أن يكون الجهاز اللوحي خاليًا من جميع العيوب الجسدية.

 

عبوة HDPE تحتوي على 100 قرص

صاحب ترخيص التسويق

شركة زيدوس لعلوم الحياة المحدودة

Zydus Corporate Park، مخطط رقم 63،

مسح رقم 536، خراج (جانديناجار)،

لا. دائرة فايشنوديفي، طريق S. G. السريع.

أحمد آباد-382481. غوجارات. الهند

 

الشركة الصانعة

زيدوس لعلوم الحياة المحدودة,

منطقة كنديم الصناعية، قطعة رقم 203-213،

 كونديم، جوا - 403115، الهند

تمت مراجعة هذه النشرة آخر مرة في يوليو 2024.
 Read this leaflet carefully before you start using this product as it contains important information for you

Warfarin ZYD® 1 mg Tablet Warfarin ZYD® 2 mg Tablet Warfarin ZYD® 2.5 mg Tablet Warfarin ZYD® 3 mg Tablet Warfarin ZYD® 5 mg Tablet Warfarin ZYD® 10 mg Tablet

Warfarin ZYD® 1 mg Tablet Warfarin Sodium Tablets USP 1 mg Each uncoated tablet contains: Warfarin Sodium USP 1 mg For the full list of excipients, see section 6.1. Warfarin ZYD® 2 mg Tablet Warfarin Sodium Tablets USP 2 mg Each uncoated tablet contains: Warfarin Sodium USP 2 mg For the full list of excipients, see section 6.1. Warfarin ZYD® 2.5 mg Tablet Warfarin Sodium Tablets USP 2.5 mg Each uncoated tablet contains: Warfarin Sodium USP 2.5 mg For the full list of excipients, see section 6.1. Warfarin ZYD® 3 mg Tablet Warfarin Sodium Tablets USP 3 mg Each uncoated tablet contains: Warfarin Sodium USP 3 mg For the full list of excipients, see section 6.1. Warfarin ZYD® 5 mg Tablet Warfarin Sodium Tablets USP 5 mg Each uncoated tablet contains: Warfarin Sodium USP 5 mg For the full list of excipients, see section 6.1. Warfarin ZYD® 10 mg Tablet Warfarin Sodium Tablets USP 10mg Each uncoated tablet contains: Warfarin Sodium USP 10mg For the full list of excipients, see section 6.1.

Warfarin Sodium Tablets USP 1mg: Pink, oval, flat, beveled edge, uncoated tablets debossed with the logo of ‘WAR’, ‘1’ on one side and bisect on both sides. The tablet should be free of all physical defects. Warfarin Sodium Tablets USP 2mg: Lavender, oval, flat, beveled edge, uncoated tablets debossed with the logo of ‘WAR’, ‘2’ on one side and bisect on both sides. The tablet should be free of all physical defects. Warfarin Sodium Tablets USP 2.5mg: Green, oval, flat, beveled edge, uncoated tablets debossed with the logo of ‘WAR’, ‘2.5’ on one side and bisect on both sides. The tablet should be free of all physical defects. Warfarin Sodium Tablets USP 3mg: Tan, oval, flat, beveled edge, uncoated tablets debossed with the logo of ‘WAR’, ‘3’ on one side and bisect on both sides. The tablet should be free of all physical defects. The tablet should be free of all physical defects. Warfarin Sodium Tablets USP 5mg: Peach, oval, flat, beveled edge, uncoated tablets debossed with the logo of ‘WAR’, ‘5’ on one side and bisect on both sides. The tablet should be free of all physical defects. Warfarin Sodium Tablets USP 10mg: White to off white, oval, flat, beveled edge, uncoated tablets debossed with the logo of ‘WAR’, ‘10’ on one side and bisect on both sides. The tablet should be free of all physical defects. The score line is not intended for division of the tablet. The tablet should be swallowed whole.

 

Warfarin ZYD® Tablet is a vitamin K antagonist indicated for:

·       Prophylaxis and treatment of venous thrombosis and its extension, pulmonary embolism (PE).

·       Prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation (AF) and/or cardiac valve replacement

·       Reduction in the risk of death, recurrent myocardial infarction, and thromboembolic events such as stroke or systemic embolization after myocardial infarction.

 


 

Individualized Dosing

The dosage and administration of Warfarin ZYD® Tablet must be individualized for each patient according to the patient's International Normalized Ratio (INR) response to the drug. Adjust the dose based on the patient's INR and the condition being treated. Consult the latest evidence-based clinical practice guidelines regarding the duration and intensity of anticoagulation for the indicated conditions.

 

Recommended Target INR Ranges and Durations for Individual Indications

An INR of greater than 4.0 appears to provide no additional therapeutic benefit in most patients and is associated with a higher risk of bleeding.

 

Venous Thromboembolism (including deep venous thrombosis [DVT] and PE)

 

Adjust the warfarin dose to maintain a target INR of 2.5 (INR range, 2.0 to 3.0) for all treatment durations. The duration of treatment is based on the indication as follows:

·       For patients with a DVT or PE secondary to a transient (reversible) risk factor, treatment with warfarin for 3 months is recommended.

·       For patients with an unprovoked DVT or PE, treatment with warfarin is recommended for at least 3 months. After 3 months of therapy, evaluate the risk-benefit ratio of long-term treatment for the individual patient.

·       For patients with two episodes of unprovoked DVT or PE, long-term treatment with warfarin is recommended. For a patient receiving long-term anticoagulant treatment, periodically reassess the risk-benefit ratio of continuing such treatment in the individual patient.

 

 

Atrial Fibrillation

In patients with non-valvular AF, anticoagulate with warfarin to target INR of 2.5 (range, 2.0 to 3.0).

·       In patients with non-valvular AF that is persistent or paroxysmal and at high risk of stroke (i.e., having any of the following features: prior ischemic stroke, transient ischemic attack, or systemic embolism, or 2 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with warfarin is recommended.

·       In patients with non-valvular AF that is persistent or paroxysmal and at an intermediate risk of ischemic stroke (i.e., having 1 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with warfarin is recommended.

·       For patients with AF and mitral stenosis, long-term anticoagulation with warfarin is recommended.

·       For patients with AF and prosthetic heart valves, long-term anticoagulation with warfarin is recommended; the target INR may be increased, and aspirin added depending on valve type and position, and on patient factors.

 

Mechanical and Bioprosthetic Heart Valves

·       For patients with a bi-leaflet mechanical valve or a Medtronic Hall (Minneapolis, MN) tilting disk valve in the aortic position who are in sinus rhythm and without left atrial enlargement, therapy with warfarin to a target INR of 2.5 (range, 2.0 to 3.0) is recommended.

·       For patients with tilting disk valves and bi-leaflet mechanical valves in the mitral position, therapy with warfarin to a target INR of 3.0 (range, 2.5 to 3.5) is recommended.

·       For patients with caged ball or caged disk valves, therapy with warfarin to a target INR of 3.0 (range, 2.5 to 3.5) is recommended.

·       For patients with a bioprosthetic valve in the mitral position, therapy with warfarin to a target INR of 2.5 (range, 2.0 to 3.0) for the first 3 months after valve insertion is recommended. If additional risk factors for thromboembolism are present (AF, previous thromboembolism, left ventricular dysfunction), a target INR of 2.5 (range, 2.0 to 3.0) is recommended.

 

 

 

Post-Myocardial Infarction

·       For high-risk patients with MI (e.g., those with a large anterior MI, those with significant heart failure, those with intracardiac thrombus visible on transthoracic echocardiography, those with AF, and those with a history of a thromboembolic event), therapy with combined moderate-intensity (INR, 2.0 to 3.0) warfarin plus low-dose aspirin (≤100 mg/day) for at least 3 months after the MI is recommended.

 

Recurrent Systemic Embolism and Other Indications

Oral anticoagulation therapy with warfarin has not been fully evaluated by clinical trials in patients with valvular disease associated with AF, patients with mitral stenosis, and patients with recurrent systemic embolism of unknown etiology. However, a moderate dose regimen (INR 2.0 to 3.0) may be used for these patients.

 

Initial and Maintenance Dosing

The appropriate initial dosing of Warfarin ZYD® Tablet varies widely for different patients. Not all factors responsible for warfarin dose variability are known, and the initial dose is influenced by:

·       Clinical factors including age, race, body weight, sex, concomitant medications, and comorbidities

·       Genetic factors (CYP2C9 and VKORC1 genotypes)

Select the initial dose based on the expected maintenance dose, taking into account the above factors. Modify this dose based on consideration of patient-specific clinical factors. Consider lower initial and maintenance doses for elderly and/or debilitated patients and in Asian patients. Routine use of loading doses is not recommended as this practice may increase haemorrhagic and other complications and does not offer more rapid protection against clot formation.

 

Individualize the duration of therapy for each patient. In general, anticoagulant therapy should be continued until the danger of thrombosis and embolism has passed.

 

Dosing Recommendations without Consideration of Genotype

If the patient's CYP2C9 and VKORC1 genotypes are not known, the initial dose of Warfarin ZYD® Tablet is usually 2 to 5 mg once daily. Determine each patient's dosing needs by close monitoring of the INR response and consideration of the indication being treated. Typical maintenance doses are 2 to 10 mg once daily.

 

Dosing Recommendations with Consideration of Genotype

Table 1 displays three ranges of expected maintenance Warfarin ZYD® Tablet doses observed in subgroups of patients having different combinations of CYP2C9 and VKORC1 gene variants [see Clinical Pharmacology (12.5)]. If the patient's CYP2C9 and/or VKORC1 genotype are known, consider these ranges in choosing the initial dose. Patients with CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3 may require more prolonged time (>2 to 4 weeks) to achieve maximum INR effect for a given dosage regimen than patients without these CYP variants.

 

Table 1: Three Ranges of Expected Maintenance Warfarin ZYD® Tablet Daily Doses Based on CYP2C9 and VKORC1 Genotypes

VKORC1

CYP2C9

 

*1/*1

*1/*2

*1/*3

*2/*2

*2/*3

*3/*3

GG

5–7 mg

5–7 mg

3–4 mg

3–4 mg

3–4 mg

0.5–2 mg

AG

5–7 mg

3–4 mg

3–4 mg

3–4 mg

0.5–2 mg

0.5–2 mg

AA

3–4 mg

3–4 mg

0.5–2 mg

0.5–2 mg

0.5–2 mg

0.5–2 mg

*Ranges are derived from multiple published clinical studies. VKORC1–1639G>A (rs9923231) variant is used in this table. Other co-inherited VKORC1 variants may also be important determinants of warfarin dose.

 

 

Monitoring to Achieve Optimal Anticoagulation

Warfarin ZYD® Tablet has a narrow therapeutic range (index), and its action may be affected by factors such as other drugs and dietary vitamin K. Therefore, anticoagulation must be carefully monitored during Warfarin ZYD® therapy. Determine the INR daily after the administration of the initial dose until INR results stabilize in the therapeutic range. After stabilization, maintain dosing within the therapeutic range by performing periodic INRs.

The frequency of performing INR should be based on the clinical situation but generally acceptable intervals for INR determinations are 1 to 4 weeks. Perform additional INR tests when other warfarin products are interchanged with Warfarin ZYD®, as well as whenever other medications are initiated, discontinued, or taken irregularly. Heparin, a common concomitant drug, increases the INR.

 

Determinations of whole blood clotting and bleeding times are not effective measures for monitoring of Warfarin ZYD® therapy.

 

Renal Impairment

No dosage adjustment is necessary for patients with renal failure. Monitor INR more frequently in patients with compromised renal function to maintain INR within the therapeutic range.

 

Missed Dose

The anticoagulant effect of Warfarin ZYD® Tablet persists beyond 24 hours. If a patient misses a dose of Warfarin ZYD® Tablet at the intended time of day, the patient should take the dose as soon as possible on the same day. The patient should not double the dose the next day to make up for a missed dose.

 

Treatment during Dentistry and Surgery

Some dental or surgical procedures may necessitate the interruption or change in the dose of Warfarin ZYD® Tablet therapy. Consider the benefits and risks when discontinuing Warfarin ZYD® Tablet even for a short period of time. Determine the INR immediately prior to any dental or surgical procedure. In patients undergoing minimally invasive procedures who must be anticoagulated prior to, during, or immediately following these procedures, adjusting the dosage of Warfarin ZYD® Tablet to maintain the INR at the low end of the therapeutic range may safely allow for continued anticoagulation.

 

Conversion from Other Anticoagulants

Heparin

Since the full anticoagulant effect of Warfarin ZYD® Tablet is not achieved for several days, heparin is preferred for initial rapid anticoagulation. During initial therapy with Warfarin ZYD® Tablet, the interference with heparin anticoagulation is of minimal clinical significance. Conversion to Warfarin ZYD® may begin concomitantly with heparin therapy or may be delayed 3 to 6 days. To ensure therapeutic anticoagulation, continue full dose heparin therapy and overlap Warfarin ZYD® therapy with heparin for 4 to 5 days and until Warfarin ZYD® Tablet has produced the desired therapeutic response as determined by INR, at which point heparin may be discontinued.

 

As heparin may affect the INR, patients receiving both heparin and Warfarin ZYD® Tablet should have INR monitoring at least:

·       5 hours after the last intravenous bolus dose of heparin, or

·       4 hours after cessation of a continuous intravenous infusion of heparin, or

·       24 hours after the last subcutaneous heparin injection.

Warfarin ZYD® Tablet may increase the activated partial thromboplastin time (aPTT) test, even in the absence of heparin. A severe elevation (>50 seconds) in aPTT with an INR in the desired range has been identified as an indication of increased risk of postoperative haemorrhage.

 

Other Anticoagulants

Consult the labelling of other anticoagulants for instructions on conversion to Warfarin ZYD® Tablet.

 


Warfarin ZYD® Tablet is contraindicated in: • Pregnancy Warfarin ZYD® Tablet is contraindicated in women who are pregnant except in pregnant women with mechanical heart valves, who are at high risk of thromboembolism. Warfarin ZYD® can cause fatal harm when administered to a pregnant woman. Warfarin ZYD® exposure during pregnancy causes a recognized pattern of major congenital malformations (warfarin embryopathy and fetotoxicity), fetal haemorrhage, and an increased risk of spontaneous abortion and fetal mortality. If Warfarin ZYD® Tablet is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Warfarin ZYD® Tablet is contraindicated in patients with: • Haemorrhagic tendencies or blood dyscrasias • Recent or contemplated surgery of the central nervous system or eye, or traumatic surgery resulting in large open surfaces • Bleeding tendencies associated with: o Active ulceration or overt bleeding of the gastrointestinal, genitourinary, or respiratory tract o Central nervous system haemorrhage o Cerebral aneurysms, dissecting aorta o Pericarditis and pericardial effusions o Bacterial endocarditis • Threatened abortion, eclampsia, and preeclampsia • Unsupervised patients with conditions associated with potential high level of non-compliance • Spinal puncture and other diagnostic or therapeutic procedures with potential for uncontrollable bleeding • Hypersensitivity to warfarin or to any other components of this product (e.g., anaphylaxis) • Major regional or lumbar block anaesthesia • Malignant hypertension

 

Haemorrhage

Warfarin ZYD® Tablet can cause major or fatal bleeding. Bleeding is more likely to occur within the first month. Risk factors for bleeding include high intensity of anticoagulation (INR >4.0), age greater than or equal to 65, history of highly variable INRs, history of gastrointestinal bleeding, hypertension, cerebrovascular disease, anaemia, malignancy, trauma, renal impairment, certain genetic factors. certain concomitant drugs, and long duration of warfarin therapy.

 

Perform regular monitoring of INR in all treated patients. Those at high risk of bleeding may benefit from more frequent INR monitoring, careful dose adjustment to desired INR, and a shortest duration of therapy appropriate for the clinical condition. However, maintenance of INR in the therapeutic range does not eliminate the risk of bleeding.

 

Drugs, dietary changes, and other factors affect INR levels achieved with Warfarin ZYD® Tablet Drugs, dietary changes, and other factors affect INR levels achieved with Warfarin ZYD® therapy. Perform more frequent INR monitoring when starting or stopping other drugs, including botanicals, or when changing dosages of other drugs.

 

Instruct patients about prevention measures to minimize risk of bleeding and to report signs and symptoms of bleeding.

 

Tissue Necrosis

Warfarin ZYD® Tablet can cause necrosis and/or gangrene of skin and other tissues, which is an uncommon but serious risk (<0.1%). Necrosis may be associated with local thrombosis and usually appears within a few days of the start of Warfarin ZYD® Tablet therapy. In severe cases of necrosis, treatment through debridement or amputation of the affected tissue, limb, breast, or penis has been reported.

 

Careful clinical evaluation is required to determine whether necrosis is caused by an underlying disease. Although various treatments have been attempted, no treatment for necrosis has been considered uniformly effective. Discontinue Warfarin ZYD® Tablet therapy if necrosis occurs. Consider alternative drugs if continued anticoagulation therapy is necessary.

 

Calciphylaxis

Warfarin ZYD® Tablet can cause fatal and serious calciphylaxis or calcium uremic arteriolopathy, which has been reported in patients with and without end-stage renal disease. When calciphylaxis is diagnosed in these patients, discontinue Warfarin ZYD® Tablet and treat calciphylaxis as appropriate. Consider alternative anticoagulation therapy.

 

 

Acute Kidney Injury

In patients with altered glomerular integrity or with a history of kidney disease, acute kidney injury may occur with Warfarin ZYD® Tablet, possibly in relation to episodes of excessive anticoagulation and haematuria. More frequent monitoring of anticoagulation is advised in patients with compromised renal function.

 

Systemic Atheroemboli and Cholesterol Microemboli

Anticoagulation therapy with Warfarin ZYD® may enhance the release of atheromatous plaque emboli. Systemic atheroemboli and cholesterol microemboli can present with a variety of signs and symptoms depending on the site of embolization. The most commonly involved visceral organs are the kidneys followed by the pancreas, spleen, and liver. Some cases have progressed to necrosis or death. A distinct syndrome resulting from microemboli to the feet is known as "purple toes syndrome." Discontinue Warfarin ZYD® Tablet therapy if such phenomena are observed. Consider alternative drugs if continued anticoagulation therapy is necessary.

 

 

 

Limb Ischemia, Necrosis, and Gangrene in Patients with HIT and HITTS

Do not use Warfarin ZYD® Tablet as initial therapy in patients with heparin-induced thrombocytopenia (HIT) and with heparin-induced thrombocytopenia with thrombosis syndrome (HITTS). Cases of limb ischemia, necrosis, and gangrene have occurred in patients with HIT and HITTS when heparin treatment was discontinued, and warfarin therapy was started or continued. In some patients, sequelae have included amputation of the involved area and/or death. Treatment with Warfarin ZYD® Tablet may be considered after the platelet count has normalized.

 

Use in Pregnant Women with Mechanical Heart Valves

Warfarin ZYD® Tablet can cause fetal harm when administered to a pregnant woman. While Warfarin ZYD® is contraindicated during pregnancy, the potential benefits of using Warfarin ZYD® Tablet may outweigh the risks for pregnant women with mechanical heart valves at high risk of thromboembolism. In those individual situations, the decision to initiate or continue Warfarin ZYD® should be reviewed with the patient, taking into consideration the specific risks and benefits pertaining to the individual patient's medical situation, as well as the most current medical guidelines. Warfarin ZYD® Tablet exposure during pregnancy causes a recognized pattern of major congenital malformations (warfarin embryopathy and fetotoxicity), fetal haemorrhage, and an increased risk of spontaneous abortion and fetal mortality. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

 

Other Clinical Settings with Increased Risks

In the following clinical settings, the risks of Warfarin ZYD® therapy may be increased:

·       Moderate to severe hepatic impairment

·       Infectious diseases or disturbances of intestinal flora (e.g., sprue, antibiotic therapy)

·       Use of an indwelling catheter

·       Severe to moderate hypertension

·       Deficiency in protein C-mediated anticoagulant response: Warfarin ZYD® reduces the synthesis of the naturally occurring anticoagulants, protein C and protein S. Hereditary or acquired deficiencies of protein C or its cofactor, protein S, have been associated with tissue necrosis following warfarin administration. Concomitant anticoagulation therapy with heparin for 5 to 7 days during initiation of therapy with Warfarin ZYD® may minimize the incidence of tissue necrosis in these patients.

·       Eye surgery: In cataract surgery, Warfarin ZYD® use was associated with a significant increase in minor complications of sharp needle and local anaesthesia block but not associated with potentially sight-threatening operative haemorrhagic complications. As Warfarin ZYD® cessation or reduction may lead to serious thromboembolic complications, the decision to discontinue Warfarin ZYD® before a relatively less invasive and complex eye surgery, such as lens surgery, should be based upon the risks of anticoagulant therapy weighed against the benefits.

·       Polycythaemia vera

·       Vasculitis

·       Diabetes mellitus

 

 

Endogenous Factors Affecting INR

The following factors may be responsible for increased INR response: diarrhoea, hepatic disorders, poor nutritional state, steatorrhea, or vitamin K deficiency.

The following factors may be responsible for decreased INR response: increased vitamin K intake or hereditary warfarin resistance.

 


 

General Information

Drugs may interact with Warfarin ZYD® through pharmacodynamic or pharmacokinetic mechanisms. Pharmacodynamic mechanisms for drug interactions with Warfarin ZYD® are synergism (impaired haemostasis, reduced clotting factor synthesis), competitive antagonism (vitamin K), and alteration of the physiologic control loop for vitamin K metabolism (hereditary resistance). Pharmacokinetic mechanisms for drug interactions with Warfarin ZYD® are mainly enzyme induction, enzyme inhibition, and reduced plasma protein binding. It is important to note that some drugs may interact by more than one mechanism.

 

More frequent INR monitoring should be performed when starting or stopping other drugs, including botanicals, or when changing dosages of other drugs, including drugs intended for short-term use (e.g., antibiotics, antifungals, corticosteroids).

 

Consult the labelling of all concurrently used drugs to obtain further information about interactions with Warfarin ZYD® or adverse reactions pertaining to bleeding.

 

CYP450 Interactions

CYP450 isozymes involved in the metabolism of warfarin include CYP2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. The more potent warfarin S-enantiomer is metabolized by CYP2C9 while the R-enantiomer is metabolized by CYP1A2 and 3A4.

·       Inhibitors of CYP2C9, 1A2, and/or 3A4 have the potential to increase the effect (increase INR) of warfarin by increasing the exposure of warfarin.

·       Inducers of CYP2C9, 1A2, and/or 3A4 have the potential to decrease the effect (decrease INR) of warfarin by decreasing the exposure of warfarin.

Examples of inhibitors and inducers of CYP2C9, 1A2, and 3A4 are below in Table 2; however, this list should not be considered all-inclusive. Consult the labelling of all concurrently used drugs to obtain further information about CYP450 interaction potential. The CYP450 inhibition and induction potential should be considered when starting, stopping, or changing dose of concomitant medications. Closely monitor INR if a concomitant drug is a CYP2C9, 1A2, and/or 3A4 inhibitor or inducer.

 

 

 

 

 

 

Table2: Examples of CYP450 Interactions with Warfarin

Enzyme

Inhibitors

Inducers

 

CYP2C9

amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast

aprepitant, Bosentan, carbamazepine, phenobarbital, rifampin

 

CYP1A2

acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton

montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking

CYP3A4

alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton

armodafinil, amprenavir, aprepitant, Bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

 

Drugs that Increase Bleeding Risk

Examples of drugs known to increase the risk of bleeding are presented in Table below. Because bleeding risk is increased when these drugs are used concomitantly with warfarin, closely monitor patients receiving any such drug with warfarin.

 

Table: Drugs that Can Increase the Risk of Bleeding

Drug Class

Specific Drugs

Anticoagulants

argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin

Antiplatelet Agents

aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine

Nonsteroidal Anti- Inflammatory Agents

celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac

Serotonin Reuptake Inhibitors

citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

 

Antibiotics and Antifungals

There have been reports of changes in INR in patients taking warfarin and antibiotics or antifungals, but clinical pharmacokinetic studies have not shown consistent effects of these agents on plasma concentrations of warfarin.

 

Closely monitor INR when starting or stopping any antibiotic or antifungal in patients taking warfarin.

 

Botanical (Herbal) Products and Foods

More frequent INR monitoring should be performed when starting or stopping botanicals.

 

Few adequate, well-controlled studies evaluating the potential for metabolic and/or pharmacologic interactions between botanicals and Warfarin ZYD® exist. Due to a lack of manufacturing standardization with botanical medicinal preparations, the amount of active ingredients may vary. This could further confound the ability to assess potential interactions and effects on anticoagulation.

 

Some botanicals may cause bleeding events when taken alone (e.g., garlic and Ginkgo biloba) and may have anticoagulant, antiplatelet, and/or fibrinolytic properties. These effects would be expected to be additive to the anticoagulant effects of Warfarin ZYD® Conversely, some botanicals may decrease the effects of Warfarin ZYD® Tablet (e.g., co-enzymeQ10, St. John's wort, ginseng). Some botanicals and foods can interact with Warfarin ZYD® through CYP450 interactions (e.g., echinacea, grapefruit juice, ginkgo, goldenseal, St. John's wort).

 

The amount of vitamin K in food may affect therapy with Warfarin ZYD® Tablet. Advise patients taking Warfarin ZYD® to eat a normal, balanced diet maintaining a consistent amount of vitamin K. Patients taking Warfarin ZYD® Tablet should avoid drastic changes in dietary habits, such as eating large amounts of green leafy vegetables.

 


 

Pregnancy

Risk Summary

Warfarin ZYD® is contraindicated in women who are pregnant except in pregnant women with mechanical heart valves, who are at high risk of thromboembolism, and for whom the benefits of Warfarin ZYD® may outweigh the risks.

 

Warfarin ZYD® Tablet can cause fetal harm. Exposure to warfarin during the first trimester of pregnancy caused a pattern of congenital malformations in about 5% of exposed offspring. Because these data were not collected in adequate and well-controlled studies, this incidence of major birth defects is not an adequate basis for comparison to the estimated incidences in the control group or the U.S. general population and may not reflect the incidences observed in practice. Consider the benefits and risks of Warfarin ZYD® and possible risks to the fetus when prescribing Warfarin ZYD® to a pregnant woman.

 

Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

 

Clinical Considerations

 

Fetal/Neonatal Adverse Reactions

 

In humans, warfarin crosses the placenta, and concentrations in fetal plasma approach the maternal values. Exposure to warfarin during the first trimester of pregnancy caused a pattern of congenital malformations in about 5% of exposed offspring. Warfarin embryopathy is characterized by nasal hypoplasia with or without stippled epiphyses (chondrodysplasia punctata) and growth retardation (including low birth weight). Central nervous system and eye abnormalities have also been reported, including dorsal midline dysplasia characterized by agenesis of the corpus callosum, Dandy-Walker malformation, midline cerebellar atrophy, and ventral midline dysplasia characterized by optic atrophy. Mental retardation, blindness, schizencephaly, microcephaly, hydrocephalus, and other adverse pregnancy outcomes have been reported following warfarin exposure during the second and third trimesters of pregnancy.

 

 

Lactation

 

Risk Summary

 

Warfarin was not present in human milk from mothers treated with warfarin from a limited published study. Because of the potential for serious adverse reactions, including bleeding in a breastfed infant, consider the developmental and health benefits of breastfeeding along with the mother's clinical need for Warfarin ZYD® Tablet and any potential adverse effects on the breastfed infant from Warfarin ZYD® Tablet or from the underlying maternal condition before prescribing Warfarin ZYD® Tablet to a lactating woman.

 

 

Clinical Considerations

Monitor breastfeeding infants for bruising or bleeding.

 

Data

Human Data

Based on published data in 15 nursing mothers, warfarin was not detected in human milk. Among the 15 full-term newborns, 6 nursing infants had documented prothrombin times within the expected range. Prothrombin times were not obtained for the other 9 nursing infants. Effects in premature infants have not been evaluated.

 

Females and Males of Reproductive Potential

Pregnancy Testing

 

Warfarin ZYD® Tablet can cause fetal harm.

Verify the pregnancy status of females of reproductive potential prior to initiating Warfarin ZYD® Tablet therapy.

 

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after the final dose of Warfarin ZYD® Tablet.

 

Paediatric Use

Adequate and well-controlled studies with warfarin sodium have not been conducted in any paediatric population, and the optimum dosing, safety, and efficacy in paediatric patients is unknown. Paediatric use of warfarin sodium is based on adult data and recommendations, and available limited paediatric data from observational studies and patient registries. Paediatric patients administered Warfarin ZYD® should avoid any activity or sport that may result in traumatic injury.

 

The developing haemostatic system in infants and children results in a changing physiology of thrombosis and response to anticoagulants. Dosing of warfarin in the paediatric population varies by patient age, with infants generally having the highest, and adolescents having the lowest milligram per kilogram dose requirements to maintain target INRs. Because of changing warfarin requirements due to age, concomitant medications, diet, and existing medical condition, target INR ranges may be difficult to achieve and maintain in paediatric patients, and more frequent INR determinations are recommended. Bleeding rates varied by patient population and clinical care centre in paediatric observational studies and patient registries.

 

Infants and children receiving vitamin K-supplemented nutrition, including infant formulas, may be resistant to warfarin therapy, while human milk-fed infants may be sensitive to warfarin therapy.

 

Geriatric Use

Of the total number of patients receiving warfarin sodium in controlled clinical trials for which data were available for analysis, 1885 patients (24.4%) were 65 years and older, while 185 patients (2.4%) were 75 years and older. No overall differences in effectiveness or safety were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

 

Patients 60 years or older appear to exhibit greater than expected INR response to the anticoagulant effects of warfarin [see Clinical Pharmacology (12.3)]. Warfarin ZYD® is contraindicated in any unsupervised patient with senility. Conduct more frequent monitoring for bleeding with administration of Warfarin ZYD® to elderly patients in any situation or with any physical condition where added risk of haemorrhage is present. Consider lower initiation and maintenance doses of Warfarin ZYD® in elderly patients.

 

Renal Impairment

Renal clearance is considered to be a minor determinant of anticoagulant response to warfarin. No dosage adjustment is necessary for patients with renal impairment. Instruct patients with renal impairment taking warfarin to monitor their INR more frequently.

 

Hepatic Impairment

Hepatic impairment can potentiate the response to warfarin through impaired synthesis of clotting factors and decreased metabolism of warfarin. Conduct more frequent monitoring for bleeding when using Warfarin ZYD® in these patients.

 

 


 

Not relevant.

 


 

 

 

 

 

MedDRA System organ class

Adverse reaction

Gastrointestinal disorders

Gastrointestinal hemorrhage, rectal hemorrhage, hematemesis; pancreatitis; diarrhea; nausea; vomiting; melaena

Hepatobiliary disorders

Jaundice; hepatic dysfunction

Immune system disorders

Hypersensitivity

Infections and infestations

Fever

Investigations

Unexplained drop in hematocrit; hemoglobin decreased

Nervous system disorders

Cerebral hemorrhage; cerebral subdural hematoma

Renal and urinary disorders

Hematuria, Anticoagulant-related nephropathy (see section 4.4) (Frequency: not known)

Respiratory, thoracic and mediastinal disorders

Hemothorax, epistaxis

Skin and subcutaneous disorders

Rash; alopecia; purpura; 'purple toes' syndrome; erythematous swollen skin patches leading to ecchymosis, infarction and skin necrosis; calciphylaxis

Vascular disorders

Hemorrhage

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

To report any side effect(s):

  • Saudi Arabia:

 

 

- The National Pharmacovigilance Centre (NPC)

o   Toll free phone: 19999

o   E-mail: npc.drug@sfda.gov.sa  

o   Website: https://ade.sfda.gov.sa/

 

 

·   Other GCC States:

 

Please contact the relevant competent authority

 

 

 

 

 

 

 

 

 

 

 

 

 


Signs and Symptoms

Bleeding (e.g., appearance of blood in stools or urine, haematuria, excessive menstrual bleeding, melena, petechiae, excessive bruising or persistent oozing from superficial injuries, unexplained fall in haemoglobin) is a manifestation of excessive anticoagulation.

 

Treatment

The treatment of excessive anticoagulation is based on the level of the INR, the presence or absence of bleeding, and clinical circumstances. Reversal of Warfarin ZYD® anticoagulation may be obtained by discontinuing Warfarin ZYD® therapy and, if necessary, by administration of oral or parenteral vitamin K.

 

The use of vitamin K reduces response to subsequent Warfarin ZYD® therapy and patients may return to a pretreatment thrombotic status following the rapid reversal of a prolonged INR. Resumption of Warfarin ZYD® administration reverses the effect of vitamin K, and a therapeutic INR can again be obtained by careful dosage adjustment. If rapid re-anticoagulation is indicated, heparin may be preferable for initial therapy.

 

Prothrombin complex concentrate (PCC), fresh frozen plasma, or activated Factor VII treatment may be considered if the requirement to reverse the effects of Warfarin ZYD® is urgent. A risk of hepatitis and other viral diseases is associated with the use of blood products; PCC and activated Factor VII are also associated with an increased risk of thrombosis. Therefore, these preparations should be used only in exceptional or life-threatening bleeding episodes secondary to Warfarin ZYD® overdosage.

 

 

 

 

 

 

 

 

 

 

 


Pharmacotherapeutic group: Antithrombotic agent (Vitamin K Antagonist), ATC code: B01AA03

 

Mechanism of Action

Pharmacotherapeutic group: Antithrombotic agent (Vitamin K Antagonist), ATC code: B01A A03

 

Mechanism of action

 

Warfarin is a synthetic anti-coagulant of the coumarin series and acts by inhibiting the synthesis of vitamin K dependent clotting factors, which include Factors II, VII, IX and X, and the anticoagulant proteins C and S. Half-lives of these clotting factors are as follows: Factor II-60 hours, VII-4-6 hours, IX-24 hours, and X-48-72 hours.

 

The half-lives of proteins C and S are approximately 8 hours and 30 hours, respectively.

 

Pharmacodynamics

The resultant in vivo effect is a sequential depression of Factors VII, IX, X and II activities. Vitamin K is an essential cofactor for the post ribosomal synthesis of the vitamin K dependent clotting factors. The vitamin promotes the biosynthesis of γ -carboxyglutamic acid residues in the proteins which are essential for biological activity. Warfarin is thought to interfere with clotting factor synthesis by inhibition of the regeneration of vitamin K1 epoxide. The degree of depression is dependent upon the dosage administered. Therapeutic doses of warfarin decrease the total amount of the active form of each vitamin K dependent clotting factor made by the liver by approximately 30% to 50%.

 

 

Clinical safety and efficacy

 

An anticoagulation effect generally occurs within 24 hours after drug administration. However, peak anticoagulant effect may be delayed 72 to 96 hours. The duration of action of a single dose of racemic warfarin is 2 to 5 days. The effects of warfarin sodium may become more pronounced as the effects of daily maintenance doses overlap.

 

Anticoagulants have no direct effect on an established thrombus, nor do they reverse ischemic tissue damage. However, once a thrombus has occurred, the goal of anticoagulant treatment is to prevent further extension of the formed clot and prevent secondary thromboembolic complications which may result in serious and possibly fatal sequelae.

 

 

 

 

 


Warfarin ZYD® is a racemic mixture of the R- and S-enantiomers of warfarin. The S- enantiomer exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer in humans, but generally has a more rapid clearance.

 

 

Absorption:

There are no differences in the apparent volumes of distribution after intravenous and oral administration of single doses of warfarin solution. Warfarin distributes into a relatively small apparent volume of distribution of about 0.14 liter/kg. A distribution phase lasting 6 to 12 hours is distinguishable after rapid intravenous or oral administration of an aqueous solution. Using a one compartment model, and assuming complete bioavailability, estimates of the volumes of distribution of R- and S-warfarin are similar to each other and to that of the racemate. Concentrations in fetal plasma approach the maternal values, but warfarin has not been found in human milk (see Section 4.6). Approximately 99% of the drug is bound to plasma proteins.

 

Distribution:

Warfarin shows a volume of distribution of about 0.14 L/kg. Approximately 99% of the drug is bound to plasma proteins.

 

Metabolism:

The elimination of warfarin is almost entirely by metabolism. Warfarin is stereo selectively metabolized by hepatic cytochrome P-450 (CYP450) microsomal enzymes to inactive hydroxylated metabolites (predominant route) and by reductases to reduced metabolites (warfarin alcohols) with minimal anticoagulant activity. Identified metabolites of warfarin include dehydrowarfarin, two Dia stereoisomer alcohols, and 4'-, 6-, 7-, 8-, and 10-hydroxywarfarin. The CYP450 isozymes involved in the metabolism of warfarin include CYP2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. CYP2C9, a polymorphic enzyme, is likely to be the principal form of human liver CYP450 that modulates the in vivo anticoagulant activity of warfarin. Patients with one or more variant CYP2C9 alleles have decreased S-warfarin clearance.

 

Excretion:

The terminal half-life of warfarin after a single dose is approximately 1 week; however, the effective half-life ranges from 20 to 60 hours, with a mean of about 40 hours. The clearance of R-warfarin is generally half that of S-warfarin, thus as the volumes of distribution are similar, the half-life of R-warfarin is longer than that of S-warfarin. The half-life of R-warfarin ranges from 37 to 89 hours, while that of S-warfarin ranges from 21 to 43 hours. Studies with radiolabelled drug have demonstrated that up to 92% of the orally administered dose is recovered in urine. Very little warfarin is excreted unchanged in urine. Urinary excretion is in the form of metabolites.

 

 

 

 

 

 


 

 

Warfarin has been shown to be teratogenic in animal studies and has been suspected of causing abnormalities and foetal death when administered during human pregnancy. Warfarin should not be used during pregnancy. No reports of mutagenicity studies involving warfarin have been found in published literature. Warfarin, however, is a long-established drug with an extensive history of clinical use.

 

 


Warfarin Sodium Tablets USP 1mg

Lactose Monohydrate

Pregelatinized starch

Hydroxypropyl Cellulose

Magnesium stearate

D & C Red No. 6 Barium Lake (Lithol Rubin B).

 

Warfarin Sodium Tablets USP 2mg

Lactose Monohydrate,

Pregelatinized starch,

Hydroxypropyl Cellulose,

Magnesium stearate,

FD & C Blue No. 2 Aluminium Lake (Indigotine) and FD & C Red No. 40 (Allura Red AC)

Aluminium Lake.

 

Warfarin Sodium Tablets USP 2.5mg

Lactose Monohydrate,

Pregelatinized starch,

Hydroxypropyl Cellulose,

Magnesium stearate,

D & C Yellow No. 10 Aluminum Lake (Quinoline Yellow WS) and FD & C Blue No. 1

Aluminum Lake (Brilliant Blue FCF).

 

 

 

 

Warfarin Sodium Tablets USP 3mg

Lactose Monohydrate,

Pregelatinised starch,

Hydroxypropyl Cellulose,

Magnesium stearate,

FD & C Yellow No. 6 Aluminium Lake (Sunset Yellow FCF), FD & C Blue No. 2 AluminumLake (Indigotine) and FD & C Red No. 40

Aluminum Lake (Allura Red AC).

 

Warfarin Sodium Tablets USP 5mg

Lactose Monohydrate,

Pregelatinized starch,

Hydroxypropyl Cellulose,

Magnesium stearate,

FD & C Yellow No. 6 Aluminium Lake (Sunset Yellow FCF).

 

Warfarin Sodium Tablets USP 10mg

Lactose Monohydrate,

Pregelatinized starch,

Hydroxypropyl Cellulose,

Magnesium stearate.

 


Not applicable


24 Months

 

Do not store above 30°C.

Protect from Light.

Keep out of reach of children.

 


 

HDPE pack of 100’s

 


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


Zydus Lifesciences Limited Zydus Corporate Park, Scheme No. 63, Survey No. 536, Khoraj (Gandhinagar), Nr. Vaishnodevi Circle, S. G. Highway. Ahmedabad-382 481. Gujarat. India Manufactured by: Zydus Lifesciences Limited, Kundaim Industrial Estate, Plot No. 203-213, Kundaim, Goa - 403 115, INDIA

July 2024.
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