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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)

Eliquis contains the active substance apixaban and belongs to a group of medicines called anticoagulants. This medicine helps to prevent blood clots from forming by blocking Factor Xa, which is an important component of blood clotting.

 

Eliquis is used in adults:

-             to prevent blood clots (deep vein thrombosis [DVT]) from forming after hip or knee replacement operations. After an operation to the hip or knee you may be at a higher risk of developing blood clots in your leg veins. This can cause the legs to swell, with or without pain. If a blood clot travels from your leg to your lungs, it can block blood flow causing breathlessness, with or without chest pain. This condition (pulmonary embolism) can be life-threatening and requires immediate medical attention.

 

-             to prevent a blood clot from forming in the heart in patients with an irregular heart beat (atrial fibrillation) and at least one additional risk factor. Blood clots may break off and travel to the brain and lead to a stroke or to other organs and prevent normal blood flow to that organ (also known as a systemic embolism). A stroke can be life-threatening and requires immediate medical attention.

 

-             to treat blood clots in the veins of your legs (deep vein thrombosis) and in the blood vessels of your lungs (pulmonary embolism), and to prevent blood clots from re-occurring in the blood vessels of your legs and/or lungs.


Do not take Eliquis if:

-             you are allergic to apixaban or any of the other ingredients of this medicine (listed in section 6);

-             you are bleeding excessively;

-             you have a disease in an organ of the body that increases the risk of serious bleeding (such as an active or a recent ulcer of your stomach or bowel, recent bleeding in your brain);

-             you have a liver disease which leads to increased risk of bleeding (hepatic coagulopathy);

-             you are taking medicines to prevent blood clotting (e.g., warfarin, rivaroxaban, dabigatran or heparin), except when changing anticoagulant treatment, while having a venous or arterial line and you get heparin through this line to keep it open, or if a tube is inserted into your blood vessel (catheter ablation) to treat an irregular heartbeat (arrhythmia).

 

Warnings and precautions

Talk to your doctor, pharmacist or nurse before you take this medicine if you have any of the following:

-             an increased risk of bleeding, such as:

-             bleeding disorders, including conditions resulting in reduced platelet activity;

-             very high blood pressure, not controlled by medical treatment;

-             you are older than 75 years;

-             you weigh 60 kg or less;

-             a severe kidney disease or if you are on dialysis;

-             a liver problem or a history of liver problems;

-             This medicine will be used with caution in patients with signs of altered liver function.

-             had a tube (catheter) or an injection into your spinal column (for anaesthesia or pain reduction), your doctor will tell you to take this medicine 5 hours or more after catheter removal;

-             if you have a prosthetic heart valve;

-             if your doctor determines that your blood pressure is unstable or another treatment or surgical procedure to remove the blood clot from your lungs is planned.

 

Take special care with Eliquis

-             if you know that you have a disease called antiphospholipid syndrome (a disorder of the immune system that causes an increased risk of blood clots), tell your doctor who will decide if the treatment may need to be changed.

 

If you need to have surgery or a procedure which may cause bleeding, your doctor might ask you to temporarily stop taking this medicine for a short while. If you are not sure whether a procedure may cause bleeding ask your doctor.

 

Children and adolescents

This medicine is not recommended in children and adolescents under 18 years of age.

 

Other medicines and Eliquis

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

 

Some medicines may increase the effects of Eliquis and some may decrease its effects. Your doctor will decide, if you should be treated with Eliquis when taking these medicines and how closely you should be monitored.

 

The following medicines may increase the effects of Eliquis and increase the chance for unwanted bleeding:

-             some medicines for fungal infections (e.g., ketoconazole, etc.);

-             some antiviral medicines for HIV / AIDS (e.g., ritonavir);

-             other medicines that are used to reduce blood clotting (e.g., enoxaparin, etc.);

-             anti-inflammatory or pain medicines (e.g., acetylsalicylic acid or naproxen). Especially, if you are older than 75 years and are taking acetylsalicylic acid, you may have an increased chance of bleeding;

-             medicines for high blood pressure or heart problems (e.g., diltiazem);

-             antidepressant medicines called selective serotonin re-uptake inhibitors or serotonin norepinephrine re-uptake inhibitors.

 

The following medicines may reduce the ability of Eliquis to help prevent blood clots from forming:

-             medicines to prevent epilepsy or seizures (e.g., phenytoin, etc.);

-             St John’s Wort (a herbal supplement used for depression);

-             medicines to treat tuberculosis or other infections (e.g., rifampicin).

 

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor, pharmacist or nurse for advice before taking this medicine.

 

The effects of Eliquis on pregnancy and the unborn child are not known. You should not take this medicine if you are pregnant. Contact your doctor immediately if you become pregnant while taking this medicine.

 

It is not known if Eliquis passes into human breast milk. Ask your doctor, pharmacist or nurse for advice before taking this medicine while breast-feeding. They will advise you whether to stop breast-feeding or to stop/not start taking this medicine.

 

Driving and using machines

Eliquis has not been shown to impair your ability to drive or use machines.

 

Eliquis contains lactose (a type of sugar) and sodium

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

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially "sodium-free".


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

 

Dose

Swallow the tablet with a drink of water. Eliquis can be taken with or without food.

Try to take the tablets at the same times every day to have the best treatment effect.

 

If you have difficulty swallowing the tablet whole, talk to your doctor about other ways to take Eliquis. The tablet may be crushed and mixed with water, or 5% glucose in water, or apple juice or apple puree, immediately before you take it.

 

Instructions for crushing:

·            Crush the tablets with a pestle and mortar.

·            Transfer all the powder carefully into a suitable container then mix the powder with a little e.g., 30 mL (2 tablespoons), water or one of the other liquids mentioned above to make a mixture.

·            Swallow the mixture.

·            Rinse the pestle and mortar you used for crushing the tablet and the container, with a little water or one of the other liquids (e.g., 30 mL), and swallow the rinse.

 

If necessary, your doctor may also give you the crushed Eliquis tablet mixed in 60 mL of water or 5% glucose in water, through a nasogastric tube.

 

Take Eliquis as recommended for the following:

 

To prevent blood clots from forming after hip or knee replacement operations.

The recommended dose is one tablet of Eliquis 2.5 mg twice a day. For example, one in the morning and one in the evening.

You should take the first tablet 12 to 24 hours after your operation.

 

If you have had a major hip operation you will usually take the tablets for 32 to38 days.

If you have had a major knee operation you will usually take the tablets for 10 to 14 days.

 

To prevent a blood clot from forming in the heart in patients with an irregular heart beat and at least one additional risk factor.

The recommended dose is one tablet of Eliquis 5 mg twice a day.

 

The recommended dose is one tablet of Eliquis 2.5 mg twice a day if:

-                  you have severely reduced kidney function;

-                 two or more of the following apply to you:

-             your blood test results suggest poor kidney function (value of serum creatinine is 1.5 mg/dL (133 micromole/L) or greater) ;

-             you are 80 years old or older;

-             your weight is 60 kg or lower.

 

The recommended dose is one tablet twice a day, for example, one in the morning and one in the evening. Your doctor will decide how long you must continue treatment for.

 

To treat blood clots in the veins of your legs and blood clots in the blood vessels of your lungs

The recommended dose is two tablets of Eliquis 5 mg twice a day for the first 7 days, for example, two in the morning and two in the evening.

After 7 days the recommended dose is one tablet of Eliquis 5 mg twice a day, for example, one in the morning and one in the evening.

 

For preventing blood clots from re-occurring following completion of 6 months of treatment

The recommended dose is one tablet of Eliquis 2.5 mg twice a day for example, one in the morning and one in the evening.

Your doctor will decide how long you must continue treatment for.

 

Your doctor might change your anticoagulant treatment as follows:

 

-             Changing from Eliquis to anticoagulant medicines

Stop taking Eliquis. Start treatment with the anticoagulant medicines (for example heparin) at the time you would have taken the next tablet.

 

-             Changing from anticoagulant medicines to Eliquis

Stop taking the anticoagulant medicines. Start treatment with Eliquis at the time you would have had the next dose of anticoagulant medicine, then continue as normal.

 

-             Changing from treatment with anticoagulant containing vitamin K antagonist (e.g., warfarin) to Eliquis

Stop taking the medicine containing a vitamin K antagonist. Your doctor needs to do blood‑measurements and instruct you when to start taking Eliquis.

 

-             Changing from Eliquis to anticoagulant treatment containing vitamin K antagonist (e.g., warfarin).

If your doctor tells you that you have to start taking the medicine containing a vitamin K antagonist, continue to take Eliquis for at least 2 days after your first dose of the medicine containing a vitamin K antagonist. Your doctor needs to do blood-measurements and instruct you when to stop taking Eliquis.

 

Patients undergoing cardioversion

If your abnormal heartbeat needs to be restored to normal by a procedure called cardioversion, take this medicine at the times your doctor tells you, to prevent blood clots in blood vessels in your brain and other blood vessels in your body.

 

If you take more Eliquis than you should

Tell your doctor immediately if you have taken more than the prescribed dose of this medicine. Take the medicine pack with you, even if there are no tablets left.

 

If you take more Eliquis than recommended, you may have an increased risk of bleeding. If bleeding occurs, surgery, blood transfusions, or other treatments that may reverse anti-factor Xa activity may be required.

 

If you forget to take Eliquis

-             Take the dose as soon as you remember and:

-             take the next dose of Eliquis at the usual time

-             then continue as normal.

 

If you are not sure what to do or have missed more than one dose, ask your doctor, pharmacist or nurse.

 

If you stop taking Eliquis

Do not stop taking this medicine without talking to your doctor first, because the risk of developing a blood clot could be higher if you stop treatment too early.

 

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.


 

Like all medicines, this medicine can cause side effects, although not everybody gets them. Eliquis can be given for three different medical conditions. The known side effects and how frequently they occur for each of these medical conditions may differ and are listed separately below. For these conditions, the most common general side effect of this medicine is bleeding which may be potentially life threatening and require immediate medical attention.

 

The following side effects are known if you take Eliquis to prevent blood clots from forming after hip or knee replacement operations.

 

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

-             Anaemia which may cause tiredness or paleness;

-             Bleeding including:

-             bruising and swelling;

-             Nausea (feeling sick).

 

Uncommon side effects (may affect up to 1 in 100 people)

-             Reduced number of platelets in your blood (which can affect clotting) ;

-             Bleeding:

-             occurring after your operation including bruising and swelling, blood or liquid leaking from the surgical wound/incision (wound secretion) or injection site;

-             in your stomach, bowel or bright/red blood in the stools;

-             blood in the urine;

-             from your nose;

-             from the vagina;

-             Low blood pressure which may make you feel faint or have a quickened heartbeat;

-             Blood tests may show:

-             abnormal liver function;

-             an increase in some liver enzymes;

-             an increase in bilirubin, a breakdown product of red blood cells, which can cause yellowing of the skin and eyes;

-             Itching.

 

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

-             Allergic reactions (hypersensitivity) which may cause: swelling of the face, lips, mouth, tongue and/or throat and difficulty breathing. Contact your doctor immediately if you experience any of these symptoms.

-             Bleeding:

-             into a muscle;

-             in your eyes;

-             from your gums and blood in your spit when coughing;

-             from your rectum;

-             Hair loss.

 

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

-             Bleeding:

-             in your brain or in your spinal column;

-             in your lungs or your throat;

-             in your mouth;

-             into your abdomen or space behind your abdominal cavity;

-             from a haemorrhoid;

-             tests showing blood in the stools or in the urine;

-        Skin rash which may form blisters and looks like small targets (central dark spots surrounded by a paler area, with a dark ring around the edge) (erythema multiforme);

-             Blood vessel inflammation (vasculitis) which may result in skin rash or pointed, flat, red, round spots under the skin's surface or bruising.

 

The following side effects are known if you take Eliquis to prevent a blood clot from forming in the heart in patients with an irregular heart beat and at least one additional risk factor.

 

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

-        Bleeding including:

-             in your eyes;

-             in your stomach or bowel;

-             from your rectum;

-             blood in the urine;

-             from your nose;

-             from your gums;

-             bruising and swelling;

-             Anaemia which may cause tiredness or paleness;

-             Low blood pressure which may make you feel faint or have a quickened heartbeat;

-             Nausea (feeling sick);

-             Blood tests may show:

-             an increase in gamma-glutamyltransferase (GGT).

 

Uncommon side effects (may affect up to 1 in 100 people)

-        Bleeding:

-             in your brain or in your spinal column;

-             in your mouth or blood in your spit when coughing;

-             into your abdomen, or from the vagina;

-             bright/red blood in the stools;

-             bleeding occurring after your operation including bruising and swelling, blood or liquid leaking from the surgical wound/incision (wound secretion) or injection site;

-             from a haemorrhoid;

-             tests showing blood in the stools or in the urine;

-             Reduced number of platelets in your blood (which can affect clotting) ;

-             Blood tests may show:

-             abnormal liver function;

-             an increase in some liver enzymes;

-             an increase in bilirubin, a breakdown product of red blood cells, which can cause yellowing of the skin and eyes;

-             Skin rash;

-             Itching;

-             Hair loss;

-             Allergic reactions (hypersensitivity) which may cause: swelling of the face, lips, mouth, tongue and/or throat and difficulty breathing. Contact your doctor immediately if you experience any of these symptoms.

 

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

-        Bleeding:

-             in your lungs or your throat;

-             into the space behind your abdominal cavity;

-             into a muscle.

 

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

-        Skin rash which may form blisters and looks like small targets (central dark spots surrounded by a paler area, with a dark ring around the edge) (erythema multiforme).

 

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

-             Blood vessel inflammation (vasculitis) which may result in skin rash or pointed, flat, red, round spots under the skin's surface or bruising.

 

The following side effects are known if you take Eliquis to treat or prevent re-occurrence of blood clots in the veins of your legs and blood clots in the blood vessels of your lungs.

 

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

-        Bleeding including:

-             from your nose;

-             from your gums;

-             blood in the urine;

-             bruising and swelling;

-             in your stomach, your bowel, from your rectum;

-             in your mouth;

-             from the vagina;

-             Anaemia which may cause tiredness or paleness;

-             Reduced number of platelets in your blood (which can affect clotting) ;

-             Nausea (feeling sick) ;

-             Skin rash;

-             Blood tests may show:

-             an increase in gamma-glutamyltransferase (GGT) or alanine aminotransferase (ALT).

 

Uncommon side effects (may affect up to 1 in 100 people)

-        Low blood pressure which may make you feel faint or have a quickened heartbeat

-        Bleeding:

-             in your eyes;

-             in your mouth or blood in your spit when coughing;

-             bright/red blood in the stools;

-             tests showing blood in the stools or in the urine;

-             bleeding occurring after your operation including bruising and swelling, blood or liquid leaking from the surgical wound/incision (wound secretion) or injection site;

-             from a haemorrhoid;

-             into a muscle;

-        Itching;

-        Hair loss;

-        Allergic reactions (hypersensitivity) which may cause: swelling of the face, lips, mouth, tongue and/or throat and difficulty breathing. Contact your doctor immediately if you experience any of these symptoms.

-             Blood tests may show:

-             abnormal liver function;

-             an increase in some liver enzymes;

-             an increase in bilirubin, a breakdown product of red blood cells, which can cause yellowing of the skin and eyes.

 

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

Bleeding:

-             in your brain or in your spinal column;

-             in your lungs.

 

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

-        Bleeding:

-             into your abdomen or the space behind your abdominal cavity.

-             Skin rash which may form blisters and looks like small targets (central dark spots surrounded by a paler area, with a dark ring around the edge) (erythema multiforme);

-             Blood vessel inflammation (vasculitis) which may result in skin rash or pointed, flat, red, round spots under the skin's surface or bruising.

 

Reporting of side effects

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

 

To Report side effects

 

·       Saudi Arabia:

 

National Pharmacovigilance Center ( NPC )

 

·       Call center: 19999

·       E-mail: npc.drug@sfda.gov.sa

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

 

·       Other GCC States

 

-   Please contact the relevant competent authority.


Keep this medicine out of the sight and reach of children.

 

Do not store above 30 ° C.

Do not use this medicine after the expiry date which is stated on the carton and on the blister after EXP. The expiry date refers to the last day of that month.

 

This medicine does not require any special storage conditions.

 

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

 


•             The active substance is apixaban. Each tablet contains 2.5 mg of apixaban.

•             The other ingredients are:

-             Tablet core: lactose anhydrous (see section 2 “Eliquis contains lactose (a type of sugar) and sodium”), microcrystalline cellulose, croscarmellose sodium (see section 2 “Eliquis contains lactose (a type of sugar) and sodium”), sodium laurilsulfate, magnesium stearate (E470b);

-             Film coat: lactose monohydrate (see section 2 “Eliquis contains lactose (a type of sugar) and sodium”), hypromellose (E464), titanium dioxide (E171), triacetin, yellow iron oxide (E172).


The film-coated tablets are yellow, round (diameter of 5.95 mm) and marked with “893” on one side and “2½” on the other side. - They come in blisters in cartons of 10, 20 ,60, 168 and 200 film-coated tablets. - Unit dose blisters in cartons of 60x1 and 100x1 film-coated tablets for delivery in hospitals are also available. Not all pack sizes may be marketed. Patient Alert Card: handling information Inside the Eliquis pack together with the package leaflet you will find a Patient Alert Card or your doctor might give you a similar card. This Patient Alert Card includes information that will be helpful to you and alert other doctors that you are taking Eliquis. You should keep this card with you at all times. 1. Take the card. 2. Separate your language as needed (this is facilitated by the perforated edges)). 3. Complete the following sections or ask your doctor to do it: - Name: - Birth Date: - Indication: - Dose : ........mg twice daily - Doctor's Name: - Doctor's telephone: 4. Fold the card and keep it with you at all times

Bristol-Myers Squibb / Pfizer EEIG, Ireland

 

Manufacturer

 

Pfizer Ireland Pharmaceuticals, Newbridge, Ireland
 

Packaging & Release By

Pfizer Manufacturing Deutschland GmbH, Freiburg, Germany

 


February 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 إليكويس على المادة الفعالة أبيكسابان وينتمي إلى مجموعة من الأدوية تسمى مضادات التجلط. يساعد هذا الدواء على منع تكون جلطات الدم عن طريق إعاقة العامل العاشر أ، وهو عنصر مهم من عناصر تجلط الدم.

 

يُستخدم إليكويس مع البالغين:

- لمنع جلطات الدم (الخثار الوريدي العميق [DVT]) من التكون بعد عمليات تغير مفصل الحوض أو الركبة. بعد إجراء عملية جراحية في الحوض أو الركبة، يمكن أن تكون معرضًا لخطر أكبر لتكوّن جلطات الدم في أوردة ساقيك. يمكن لهذا أن يسبب تورم الساقين، المصحوب أو غير المصحوب بألم. إذا انتقلت الجلطة الدموية من ساقك إلى رئتيك، يمكنها منع تدفق الدم مما يتسبب في حدوث حالة من ضيق التنفس، مصحوبة أو غير مصحوبة بألم في الصدر. يمكن لهذه الحالة (جلطة بالشريان الرئوي) أن تكون مهددة للحياة، ولذا فهي تتطلب رعاية طبية فورية.

 

- لمنع تكون جلطات الدم في القلب لدى المرضى المصابين بعدم انتظام نبضات القلب (الذبذبه الاذينيه) وعامل خطر إضافي واحد على الأقل. قد تتكسر جلطات الدم وتنتقل إلى الدماغ مما يؤدي إلى الإصابة بالسكتة الدماغية أو قد تنتقل إلى عضو آخر وتمنع التدفق الطبيعي للدم إلى هذا العضو (وهو ما يُعرف أيضًا بجلطات بالدورة الدموية). يمكن أن تكون السكتة الدماغية مهددة للحياة، ولذا فهي تتطلب رعاية طبية فورية.

 

-  لعلاج جلطات الدم في أوردة ساقيك (الخثار الوريدي العميق) وفي الأوعية الدموية برئتيك (جلطة بالشريان الرئوي) ولمنع الجلطات الدموية من التكون مرةً أخرى في الأوعية الدموية لساقيك و/أو رئتيك.

 

 

أ - موانع استعمال إليكويس

- إذا كنت مصابًا بالحساسية تجاه أبيكسابان أو أي مكون آخر من مكونات هذا الدواء (المدرجة في القسم ٦)؛

- إذا كنت تعاني من نزيف مفرط؛

- إذا كنت تعاني من مرض في أحد أعضاء الجسم يسبب زيادة خطر الإصابة بنزيف خطير (مثل قرحة حديثة أو نشطة بمعدتك أو أمعائك أو نزيف حديث بالدماغ

- إذا كنت تعاني من مرض بالكبد يؤدي إلى زيادة خطر النزيف (اعتلال تجلطي كبدي)؛

- إذا كنت تتناول أدوية لمنع تجلط الدم (مثل وارفارين أو ريفاروكسابان أو دابيجاتران أو هيبارين)، باستثناء عند تغيير العلاج المضاد للتجلط، أو أثناء تركيب جهاز وريدي او شرياني مركزي وتلقي هيبارين عبر هذا الخط للحفاظ عليه مفتوحًا، أو إذا تم إدخال أنبوب في أحد أوعيتك الدموية (استئصال بالقثطرة) لعلاج نبضات القلب غير المنتظمة (اضطراب ضربات القلب).

 

ب – الاحتياطات عند استعمال إليكويس

تحدث إلى طبيبك أو الصيدلي أو الممرضة قبل أن تتناول هذا الدواء إذا كنت تعاني من أي مما يلي:

- خطر زائد لحدوث نزيف، مثل:

n      اضطرابات النزيف، بما في ذلك الحالات التي تؤدي إلى انخفاض نشاط الصفائح الدموية؛

n      ارتفاع شديد بضغط الدم ، الذي لا يتم التحكم فيه بالعلاج الطبي؛

n      إذا كنت تبلغ من العمر أكثر من ٧٥ عامًا؛

n      إذا كنت تزن ٦۰ كلجم أو أقل؛

- مرض شديد بالكلى أو إذا كنت تخضع للغسيل الكلوي؛

- مرض بالكبد أو تاريخ من الإصابة بمرض في الكبد؛

 يجب استخدام هذا الدواء مع توخي الحذر في المرضى الذين يُظهرون علامات لتغير وظائف الكبد.

- وجود أنبوب (قسطره) أو حقن داخل عمودك الفقري (للتخدير أو تخفيف الألم)، سيخبرك طبيبك بأن عليك تناول هذا الدواء بعد مرور ٥ ساعات أو أكثر على نزع  القسطره؛

- إذا كانت لديك صمامات قلب اصطناعية؛

- إذا قرر طبيبك أن ضغط دمك غير مستقر أو في حالة التخطيط لعلاج آخر أو لإجراء جراحي للتخلص من جلطة الدم برئتيك.

 

توخ الحذر بشكل خاص عند استعمال إليكويس

-        إذا كنت تعرف أن لديك مرضًا يسمى متلازمة أضداد الشحميات الفسفورية (اضطراب في الجهاز المناعي يسبب زيادة خطر الإصابة بجلطات الدم)، أخبر طبيبك الذي سيقرر إذا ما كان العلاج قد يحتاج إلى تغيير.

 

إذا كنت تحتاج إلى جراحة أو إجراء طبي قد يتسبب في حدوث نزيف، فقد يطلب منك الطبيب التوقف المؤقت عن تناول هذا الدواء لفترة قصيرة. إذا لم تكن متأكدًا مما إذا كان الإجراء سيتسبب في وجود نزيف أم لا؛ فاسأل طبيبك.

 

الأطفال والمراهقون

لا ينصح باستخدام هذا الدواء لعلاج الأطفال والمراهقين تحت سن ۱٨ عامًا.

 

ج – التداخلات الدوائية من أخذ هذا المستحضر مع أي أدوية أخرى أو أعشاب أو مكملات غذائية

أخبر طبيبك أو الصيدلي أو الممرضة إذا كنت تتناول أو تناولت حديثًا أو قد تتناول أي أدوية أخرى.

 

فقد تزيد بعض الأدوية من تأثير إليكويس والبعض الآخر قد يقلل من هذا التأثير. سوف يقرر طبيبك إذا ما كان يمكن علاجك باستخدام إليكويس عند تناولك لهذه الأدوية أم لا وإلى أي مدى تنبغي متابعتك عن كثب.

 

يمكن أن تزيد الأدوية التالية من تأثير إليكويس وقد تزيد من فرصة حدوث نزيف غير مرغوب فيه:

- بعض الأدوية الخاصة بحالات العدوى الفطرية (مثل كيتوكونازول، إلخ.)؛

- بعض مضادات الفيروسات المستخدمة لعلاج فيروس نقص المناعة البشرية (HIV)/الإيدز (مثل، ريتونافير)؛

- الأدوية الأخرى المُستخدمة لمنع تجلط الدم (مثل إينوكسابارين، إلخ.)؛

- الأدوية المضادة للالتهابات أو الآلام (مثل حمض الأسيتيل ساليسيليك أو نابروكسين). بشكل خاص إذا كنت أكبر من ٧٥ عامًا وتتناول حمض أسيتيل ساليسيليك، فقد تكون فرصة إصابتك بالنزيف أكبر؛

- الأدوية الخاصة بعلاج ضغط الدم المرتفع أو امراض القلب (مثل ديلتيازيم)؛

- الأدوية المضادة للاكتئاب التي تسمى مثبطات إعادة امتصاص السيروتونين الانتقائية أو مثبطات إعادة امتصاص النورإبينفرين والسيروتونين.

 

 

 

قد تقلل الأدوية التالية من قدرة إليكويس على المساعدة في منع تكون جلطات الدم:

- الأدوية المستخدمة لمنع الإصابة بالصرع أو النوبات (مثل فينيتوين، إلخ.)؛

- نبتة سانت جون (مكمل عشبي يُستخدم لعلاج الاكتئاب)؛

- الأدوية المستخدمة لعلاج الدرن أوحالات العدوى الأخرى (مثل ريفامبيسين).

 

د - الحمل والرضاعة

إذا كنت حاملًا أو ترضعين رضاعة طبيعية، أو تعتقدين أنك ربما تكونين حاملًا أو تخططين للحمل، فاستشيري طبيبكِ أو الصيدلي أو الممرضة قبل تناول هذا الدواء.

 

آثار إليكويس على الحمل والجنين غير معروفة. ينبغي عليكِ عدم تناول هذا الدواء أثناء الحمل. اتصلي بطبيبكِ فورًا إذا أصبحت حاملًا أثناء تناول هذا الدواء.

 

لم تتم معرفة إذا ما كان إليكويس يمر في لبن الثدي في البشر. استشيري طبيبك أو الصيدلي أو الممرضة قبل تناول هذا الدواء أثناء الرضاعة الطبيعية. سوف ينصحونكِ بالتوقف عن الرضاعة الطبيعية أو بالتوقف/عدم البدء في تناول هذا الدواء.

 

هـ - تأثير إليكويس على القيادة واستخدام الآلات

لم يثبت أن إليكويس يضعف من قدرتك على القيادة أو استخدام الآلات.

 

و – معلومات هامة حول بعض مكونات إليكويس

يحتوي إليكويس على اللاكتوز (وهو نوع من السكر) والصوديوم

إذا أخبرك طبيبك أنك مصاب بعدم تحمل لبعض السكريات، فاتصل به قبل تناول هذا الدواء.

يحتوي هذا الدواء على أقل من ۱ مليمول من الصوديوم (۲۳ ملجم) لكل قرص، أي أنه يُعد "خاليًا من الصوديوم" بشكل أساسي.

 

 

https://localhost:44358/Dashboard

 

احرص دومًا على تناول هذا الدواء تمامًا كما أخبرك طبيبك أو الصيدلي. استشر طبيبك أو الصيدلي أو الممرضة إذا كنت غير متأكد.

 

الجرعة

ابتلع القرص مع شرب بعض الماء. يمكن تناول إليكويس مع الطعام أو دونه.

حاول أن تتناول الأقراص في الأوقات نفسها كل يوم للحصول على أفضل تأثير للعلاج.

 

إذا كنت تواجه صعوبة في ابتلاع القرص كاملًا، فتحدث مع طبيبك حول الطرق الأخرى لتناول إليكويس. يمكن سحق القرص وخلطه مع الماء أو مع محلول جلوكوز بنسبة ٥ ٪ في الماء أو مع عصير تفاح أو هريس التفاح، وذلك قبل تناوله مباشرةً.

 

تعليمات لسحق الأقراص:

  • اسحق الأقراص باستخدام مدق ووعاء.
  • انقل المسحوق بأكمله بحذر إلى داخل حاوية ملائمة ثم اخلط المسحوق مع كمية صغيرة من الماء، على سبيل المثال ۳۰ مل (ملعقتان كبيرتان)، أو من أحد السوائل الأخرى المذكورة أعلاه لعمل خليط.
  • ابتلع الخليط.
  • اشطف المدق والوعاء اللذين استخدمتهما لسحق القرص واشطف الحاوية بقليل من الماء أو أحد السوائل الأخرى (بمقدار ۳۰ مل على سبيل المثال)، وابتلع الخليط الناتج عن الشطف.

 

إذا لزم الأمر، قد يعطيك طبيبك أيضًا قرص إليكويس المسحوق مخلوطًا مع ٦۰ مل من الماء أو محلول جلوكوز بتركيز ٥ ٪ في الماء، عن طريق أنبوب أنفي معدي.

 

تناول إليكويس بالطريقة الموصى بها من أجل ما يلي:

 

لمنع تكون جلطات الدم بعد عمليات تغير مفصل الحوض  أو الركبة.

الجرعة الموصى بها هي قرص واحد من إليكويس2,5 ملجم مرتين يوميًا. على سبيل المثال، قرص صباحًا وقرص مساءً.

ينبغي أن تتناول القرص الأول بعد ۱۲ إلى ۲٤ ساعة من خضوعك للعملية.

 

إذا كنت قد خضعت لعملية جراحية كبيرة في الحوض فسوف تتناول الأقراص غالبًا لمدة ۳۲ إلى ۳٨ يومًا.

إذا كنت قد خضعت لعملية جراحية كبيرة في الركبة فسوف تتناول الأقراص غالبًا لمدة ۱۰ أيام إلى ۱٤ يومًا.

 

منع تكون جلطات الدم في القلب لدى المرضى المصابين بعدم انتظام نبضات القلب وعامل خطر واحد إضافي على الأقل.

الجرعة الموصى بها هي قرص واحد من إليكويس ٥ ملجم مرتين يوميًا.

 

الجرعة الموصى بها هي قرص واحد من إليكويس ٢.٥ ملجم مرتين يوميًا، في حالة:

-         إصابتك بقصور شديدة بوظائف الكلي؛

-        وجود حالتين أو أكثر مما يلي عليك:

-        نتائج فحوصات الدم الخاصة بك تفيد بوجود قصور بوظائف كلى (قيمة كرياتينين المصل ١.٥ ملجم /ديسيلتر (۱۳۳ ميكرومول/لتر) أو أعلى)؛

-        أن يكون سنك ٨۰ عامًا أو أكبر؛

-        أن يكون وزنك ٦۰ كلجم أو أقل.

 

الجرعة الموصى بها هي قرص واحد مرتين يوميًا، على سبيل المثال، قرص صباحًا وقرص مساءً. سيقرر طبيبك المدة اللازمة لعلاجك.

 

لعلاج جلطات الدم في أوردة ساقيك وجلطات الدم في الأوعية الدموية برئتيك( جلطة بالشريان الرئوي)

الجرعة الموصى بها هي قرصان من إليكويس ٥ ملجم مرتين يوميًا خلال الأيام الـ٧ الأولى، على سبيل المثال، قرصان صباحًا وقرصان مساءً.

بعد ٧ أيام تكون الجرعة الموصى بها قرصًا واحدًا من إليكويس ٥ ملجم مرتين يوميًا، على سبيل المثال، قرص صباحًا وقرص مساءً.

 

لمنع تكرار الإصابة بجلطات الدم بعد استكمال العلاج لمدة ٦ أشهر

الجرعة الموصى بها هي قرص واحد من إليكويس ٢.٥ ملجم مرتين يوميًا، على سبيل المثال، قرص صباحًا وقرص مساءً.

سيقرر طبيبك المدة اللازمة لعلاجك.

 

قد يقوم طبيبك بتغيير العلاج المضاد للتجلط الخاص بك كما يلي:

 

- التغيير من إليكويس إلى الأدوية المضادة للتجلط

توقف عن تناول إليكويس. ابدأ العلاج باستخدام الأدوية المضادة للتجلط (مثل هيبارين) في الوقت الذي كان من المفترض أن تتناول فيه القرص التالي.

 

- التغيير من الأدوية المضادة للتجلط إلى إليكويس

توقف عن تناول الأدوية المضادة للتجلط. ابدأ العلاج باستخدام إليكويس في الوقت المحدد الذي كان من المفترض أن تتناول فيه الجرعة التالية من الدواء المضاد للتجلط، ثم تابع بشكل طبيعي.

 

- التغيير من العلاج بالأدوية المضادة للتجلط التي تحتوي على ضاد فيتامين K (مثل وارفارين) إلى إليكويس

توقف عن تناول الدواء الذي يحتوي على ضاد فيتامين K. يجب أن يقوم الطبيب بإجراء تحاليل للدم وإرشادك حول موعد بدء تناول إليكويس.

 

- التغيير من إليكويس إلى الأدوية المضادة للتجلط التي تحتوي على ضاد فيتامين K (مثل وارفارين).

إذا أخبرك طبيبك بضرورة البدء في تناول دواء يحتوي على ضاد فيتامين K، فتابع تناول إليكويس لمدة يومين على الأقل بعد أول جرعة من الدواء الذي يحتوي على ضاد فيتامين K. يجب أن يقوم الطبيب بإجراء تحاليل للدم وإرشادك حول موعد التوقف عن تناول إليكويس.

 

المرضى الذين يخضعون لتقويم ضربات القلب

إذا كانت نبضات قلبك غير الطبيعية بحاجة إلى استعادة طبيعتها عن طريق إجراء يسمى تقويم ضربات القلب، تناول هذا الدواء في الأوقات التي يخبرك بها طبيبك لمنع تجلط الدم في الأوعية الدموية في الدماغ والأوعية الدموية الأخرى في جسمك.

 

 

 

أ – الجرعة الزائدة من إليكويس

أخبر طبيبك على الفور إذا كنت قد تناولت أكثر من الجرعة الموصوفة من هذا الدواء. خذ عبوة الدواء معك، حتى وإن لم يتبق فيها أي أقراص.

 

إذا أخذت جرعة إليكويس أكبر من الموصى بها، فقد تعرض نفسك لزيادة خطر النزيف. في حالة حدوث نزيف، قد تكون هناك حاجة لإجراء عملية جراحية أو نقل الدم أو علاجات أخرى قد تعكس نشاط مضادات العامل العاشر أ.

 

ب – نسيان تناول جرعة إليكويس

-تناول الجرعة بمجرد أن تتذكر، و:

-  تناول الجرعة التالية من إليكويس في الوقت المعتاد

-  ثم استمر كالمعتاد.

 

إذا كنت غير متأكد مما يجب القيام به أو أنه قد فاتتك أكثر من جرعة واحدة، فاسأل طبيبك أو الصيدلي أو الممرضة.

 

ج – التوقف عن تناول إليكويس

لا تتوقف عن تناول هذا الدواء دون التحدث مع طبيبك أولًا، لأن خطر الإصابة بتجلط الدم قد يكون أعلى إذا قمت بإيقاف العلاج أبكر من اللازم.

 

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

كما هو الحال بالنسبة لجميع الأدوية، قد يسبب هذا الدواء أعراضًا جانبية، غير أنها لا تصيب الجميع. يمكن إعطاء إليكويس لعلاج ثلاث حالات طبية مختلفة. قد تختلف الأعراض الجانبية المعروفة ومعدل تكرار ظهورها لهذه الحالات الطبية، وهي مدرجة بشكل منفصل أدناه. بالنسبة لهذه الحالات، يعتبر العرض الجانبي الأكثر شيوعًا لهذا الدواء هو النزيف الذي قد يكون مهددًا للحياة ويتطلب العناية الطبية الفورية.

 

الأعراض الجانبية التالية معروفة إذا تناولت إليكويس لمنع تكون جلطات الدم بعد عمليات استبدال الورك أو الركبة.

 

الأعراض الجانبية الشائعة (قد تؤثر على ما يصل إلى شخص واحد بين كل ۱۰ أشخاص)

- فقر الدم مما قد يسبب الإرهاق أو الشحوب؛

- حالات نزيف بما في ذلك:

            - التكدم والتورم؛

- الغثيان (الشعور بالرغبة في التقيؤ).

 

الأعراض الجانبية غير الشائعة (قد تؤثر على ما يصل إلى شخص واحد من بين كل ۱۰۰ شخص)

- انخفاض عدد الصفائح الدموية في دمك (مما يمكن أن يؤثر في عملية تجلط الدم)؛

- حالات نزيف:

- يحدث بعد عمليتك بما في ذلك التكدم والتورم أو تسرب الدم أو السوائل من الجرح/الشق الجراحي (إفرازات من الجرح) أو موضع الحقن؛

- في المعدة أو الأمعاء أو وجود دم أحمر/زاهي اللون في البراز؛

            - دم في البول؛

- من أنفك؛

- من المهبل؛

- ضغط الدم المنخفض الذي يمكن أن يجعلك تشعر بالضعف أو يتسبب في حدوث تسارع في ضربات القلب؛

- يمكن أن تُظهر فحوصات الدم ما يلي:

            -  قصور في وظائف كبد؛

            - ارتفاع في بعض إنزيمات الكبد؛

         - ارتفاع في البيليروبين، وهو أحد نواتج تحلل خلايا الدم الحمراء، الأمر الذي يمكن أن يتسبب في اصفرار الجلد والعينين؛

- الحكة.

 

الأعراض الجانبية النادرة (قد تؤثر على ما يصل إلى شخص واحد بين كل ۱۰۰۰ شخص)

- تفاعلات الحساسية (فرط الحساسية) والتي قد تسبب: تورم في الوجه و/أو الشفتين و/أو الفم و/أو اللسان و/أو الحلق وصعوبة في التنفس. اتصل بطبيبك على الفور إذا تعرضت لأي من الأعراض التالية.

- حالات نزيف:

            - في إحدى العضلات؛

            - نزيف في عينيك؛

            - نزيف من لثتك ووجود دم في البصاق أثناء السعال؛

- نزيف من مستقيمك؛

- تساقط الشعر.

 

أعراض جانبية معدل تكرارها غير معروف (لا يمكن تقدير معدل التكرار من البيانات المتاحة)

- حالات نزيف:

-         نزيف في دماغك أو في عمودك الفقري؛

-         نزيف في رئتيك أو حلقك؛

-         نزيف في فمك؛

-         نزيف في بطنك أو في المساحة الموجودة خلف تجويفك البطني؛

-         نزيف من البواسير؛

-         اختبارات تظهر وجود دم في البراز أو البول؛

-        طفح جلدي قد يشكل بثورًا ويظهر في صورة حبوب صغيرة الحجم (بقع داكنة في المنتصف محاطة بمساحة أفتح لونًا مع وجود حلقة داكنة محيطة بالحافة) (الاحمرار الجلدي عديد الأشكال)؛

-        التهاب الأوعية الدموية (التهاب وعائي) الذي قد يؤدي إلى ظهور طفح جلدي، أو تكدم، أو بقع بارزة، مسطحة، حمراء، دائرية تحت سطح الجلد.

 

الأعراض الجانبية التالية معروفة في حالة تناول إليكويس لمنع تكون تجلطات الدم في القلب لدى المرضى المصابين بعدم انتظام نبضات القلب وبعامل خطر واحد إضافي على الأقل.

 

الأعراض الجانبية الشائعة (قد تؤثر على ما يصل إلى شخص واحد بين كل ۱۰ أشخاص)

-           حالات نزيف بما في ذلك:

- نزيف في عينيك؛

- نزيف في معدتك أو أمعائك؛

- نزيف من المستقيم؛

            - وجود دم في البول؛

- نزيف من أنفك؛

- نزيف من لثتك؛

- التكدم والتورم؛

- فقر الدم الذي قد يسبب التعب أو الشحوب؛

- ضغط الدم المنخفض الذي قد يجعلك تشعر بالإغماء أو أن ضربات قلبك سريعة؛

- الغثيان (الشعور برغبة في التقيؤ)؛

- قد تُظهر فحوصات الدم:

                   - زيادة في إنزيم جاما جلوتاميل ترانسفيراز (GGT).

الأعراض الجانبية غير الشائعة (قد تؤثر على ما يصل إلى شخص واحد من بين كل ۱۰۰ شخص)

-         حالات نزيف:

-         نزيف في دماغك أو في عمودك الفقري؛

-         نزيف في فمك أو وجود دم في البصاق أثناء السعال؛

-         نزيف في بطنك أو من المهبل؛

-         وجود دم زاهي اللون /أحمر في البراز؛

-         نزيف يحدث بعد عمليتك بما في ذلك التكدم والتورم أو تسرب الدم أو أي سائل آخر من الجرح/الشق الجراحي (إفرازات الجروح) أو موضع الحقن؛

-         نزيف من البواسير؛

-         اختبارات تظهر وجود دم في البراز أو في البول؛

- انخفاض عدد الصفائح الدموية في دمك (مما يمكن أن يؤثر على التجلط)؛

- قد تظهر فحوصات الدم:

-         اعتلال في وظائف الكبد؛

-         ارتفاع في بعض إنزيمات الكبد؛

-         زيادة في البيليروبين، وهو مادة ناتجة عن تحلل خلايا الدم الحمراء، مما يمكن أن يسبب اصفرار الجلد والعينين؛

- الطفح الجلدي؛

- الحكة؛

- تساقط الشعر؛

 

- تفاعلات الحساسية (فرط الحساسية) والتي قد تسبب: تورم في الوجه و/أو الشفتين و/أو الفم و/أو اللسان و/أو الحلق وصعوبة في التنفس. اتصل بطبيبك على الفور إذا تعرضت لأي من الأعراض التالية.

 

الأعراض الجانبية النادرة (قد تؤثر على ما يصل إلى شخص واحد بين كل ۱۰۰۰ شخص)

-         حالات نزيف:

- نزيف في رئتيك أو حلقك؛

- في المساحة الموجودة خلف تجويفك البطني؛

- نزيف في إحدى العضلات.

 

الأعراض الجانبية النادرة للغاية (قد تؤثر على ما يصل إلى شخص واحد بين كل ۱۰۰۰۰ شخص)

-        طفح جلدي قد يشكل بثورًا ويظهر في صورة حبوب صغيرة الحجم (بقع داكنة في المنتصف محاطة بمساحة أفتح لونًا مع وجود حلقة داكنة محيطة بالحافة) (الاحمرار الجلدي عديد الأشكال).

 

أعراض جانبية معدل تكرارها غير معروف (لا يمكن تقدير معدل التكرار من البيانات المتاحة)

-        التهاب الأوعية الدموية (التهاب وعائي) الذي قد يؤدي إلى ظهور طفح جلدي، أو تكدم، أو بقع بارزة، مسطحة، حمراء، دائرية تحت سطح الجلد.

 

الأعراض الجانبية التالية معروفة في حالة تناول إليكويس لعلاج جلطات الدم في أوردة ساقيك وجلطات الدم في أوعية رئتيك أو لمنع تكرار الإصابة بها.

 

الأعراض الجانبية الشائعة (قد تؤثر على ما يصل إلى شخص واحد بين كل ۱۰ أشخاص)

-           حالات نزيف بما في ذلك:

- نزيف من أنفك؛

- نزيف من لثتك؛

- وجود دم في البول؛

- التكدم والتورم؛

- نزيف في معدتك، أو أمعائك، أو من مستقيمك؛

- نزيف في فمك؛

- نزيف من المهبل؛

- فقر الدم الذي قد يسبب التعب أو الشحوب؛

- انخفاض عدد الصفائح الدموية في دمك (مما يمكن أن يؤثر على التجلط)؛

- الغثيان (الشعور برغبة في التقيؤ)؛

- الطفح الجلدي؛

- قد تُظهر فحوصات الدم:

                   - زيادة في إنزيم جاما جلوتاميل ترانسفيراز (GGT) أو في ناقلة أمين الألانين (ALT).

 

 

الأعراض الجانبية غير الشائعة (قد تؤثر على ما يصل إلى شخص واحد من بين كل ۱۰۰ شخص)

-           ضغط الدم المنخفض الذي يجعلك تشعر بالإغماء أو أن ضربات قلبك سريعة

-           حالات نزيف:

- نزيف في عينيك؛

- نزيف في فمك أو وجود دم في البصاق أثناء السعال؛

- وجود دم زاهي اللون/أحمر في البراز؛

- اختبارات تظهر وجود دم في البراز أو البول؛

- النزيف الذي يحدث بعد عملية تقوم بها بما في ذلك التكدم والتورم، أو تسرب دم أو سائل من الجرح/الشق الجراحي (إفراز من الجرح) أو من موضع الحقن؛

- نزيف من البواسير؛

- نزيف في إحدى العضلات؛

-                  الحكة؛

-                  تساقط الشعر؛

-                  تفاعلات الحساسية (فرط الحساسية) التي قد تتسبب في: تورم الوجه و/أو الشفتين و/أو الفم و/أو اللسان و/أو الحلق وصعوبة في التنفس. اتصل بطبيبك على الفور إذا واجهت أيًا من هذه الأعراض.

- قد تُظهر فحوصات الدم:

-         قصور في وظائف الكبد؛

-         ارتفاع في بعض إنزيمات الكبد؛

-         زيادة في البيليروبين، وهو مادة ناتجة عن تحلل خلايا الدم الحمراء، مما يمكن أن يسبب اصفرار الجلد والعينين.

 

الأعراض الجانبية النادرة (قد تؤثر على ما يصل إلى شخص واحد بين كل ۱۰۰۰ شخص)

حالات نزيف:

- نزيف في دماغك أو في عمودك الفقري؛

- نزيف في رئتيك.

 

أعراض جانبية معدل تكرارها غير معروف (لا يمكن تقدير معدل التكرار من البيانات المتاحة):

-        حالات نزيف:

- نزيف في بطنك أو المساحة الموجودة خلف تجويفك البطني.

-        طفح جلدي قد يشكل بثورًا ويظهر في صورة حبوب صغيرة الحجم (بقع داكنة في المنتصف محاطة بمساحة أفتح لونًا مع وجود حلقة داكنة محيطة بالحافة) (الاحمرار الجلدي عديد الأشكال).

-        التهاب الأوعية الدموية (التهاب وعائي) الذي قد يؤدي إلى ظهور طفح جلدي، أو تكدم، أو بقع بارزة، مسطحة، حمراء، دائرية تحت سطح الجلد.

 

الإبلاغ عن الأعراض الجانبية

إذا أُصِبت بأي أعراض جانبية، فتحدث إلى طبيبك أو الصيدلي أو الممرضة. يتضمن ذلك أي أعراض جانبية محتملة لم يرد ذكرها في هذه النشرة. يمكنك أيضًا الإبلاغ عن الأعراض الجانبية مباشرة إلى المركز الوطني للتيقظ الدوائي (NPC). بالإبلاغ عن الأعراض الجانبية يمكنك المساعدة في توفير المزيد من المعلومات حول سلامة هذا الدواء.

 

الإبلاغ عن الأعراض الجانبية:

·       المملكة العربية السعودية:

 

 المركز الوطني للتيقظ الدوائي

  • مركز الاتصال الموحد: ١٩٩٩٩
  • البريد الإلكتروني: npc.drug@sfda.gov.sa

·   الموقع الإلكتروني: https://ade.sfda.gov.sa

 

·       دول الخليج الأخرى

 

الرجاء الاتصال بالمؤسسات والهيئات الوطنية في كل دولة.

 

 

احتفظ بهذا الدواء بعيدًا عن مرأى ومتناول الأطفال.

يحفظ في درجة حرارة لاتزيد عن 30 درجة مئوية.

لا تستخدم هذا الدواء بعد تاريخ انتهاء الصلاحية المدون على العبوة الكرتونية وعلى شريط البليستر بعد رمز "EXP". يشير تاريخ انتهاء الصلاحية إلى آخر يوم من الشهر المذكور.

 

لا يتطلب هذا الدواء أي ظروف خاصة للتخزين.

 

لا تتخلص من أي أدوية عبر مياه الصرف أو في المخلفات المنزلية. اسأل الصيدلي عن كيفية التخلص من الأدوية التي لم تعد تستخدمها. ستساعد هذه الإجراءات على حماية البيئة.

 

 

المادة الفعالة هي أبيكسابان. يحتوي كل قرص على ٢,٥ ملجم من أبيكسابان.

•     المكونات الأخرى هي:

- المكونات الأساسية للقرص: لاكتوز لامائي (انظر القسم ۲ "يحتوي إليكويس على اللاكتوز (وهو نوع من السكر) والصوديوم")، سليلوز بلوري مكروي، كروسكارميلوز الصوديوم (انظر القسم ۲ "يحتوي إليكويس على اللاكتوز (وهو نوع من السكر) والصوديوم")، لوريل سلفات الصوديوم، ستيارات المغنيسيوم (E470b)؛

-  الطبقة الرقيقة المغلفة للقرص: لاكتوز أحادي الهيدرات (انظر القسم ۲ "يحتوي إليكويس على اللاكتوز (وهو نوع من السكر) والصوديوم")، هيبروميلوز (E464)، ثاني أكسيد التيتانيوم (E171)، ثلاثي الأستين، أكسيد الحديد الأصفر (E172).

 

الأقراص المغلفة بطبقة رقيقة صفراء مستديرة (بقطر ٥,۹٥ مم) وتحمل الرقم "893" على جانب و"2½" على الجانب الآخر.

 

-        تأتي هذه الأقراص في شرائط دواء في عبوات كرتونية تحتوي على ۱۰ و۲۰ و٦۰ و۱٦٨ و۲۰۰ قرص مغلف بطبقة رقيقة.

-        تتوفر أيضًا شرائط دواء للجرعات الموحدة في العبوات الكرتونية التي تحتوي على ٦۰×۱ و۱۰۰×۱ قرص مغلف بطبقة رقيقة لإعطائها في المستشفيات.

 

قد لا تُطرح جميع أحجام العبوات في الأسواق.

 

بطاقة المريض التنبيهية: معلومات التعامل مع الدواء

 

سوف تجد داخل عبوة إليكويس بطاقة المريض التنبيهية مع نشرة العبوة أو قد يعطيك طبيبك بطاقة مماثلة.

 

تتضمن بطاقة المريض التنبيهية هذه معلومات ستكون مفيدة لك وستنبه الأطباء الآخرين إلى أنك تتناول إليكويس. يجب عليك أن تحتفظ بهذه البطاقة معك دائمًا.

 

۱. خذ البطاقة.

۲. افصل الجزء الخاص بلغتك حسب الحاجة (يسهل ذلك بفضل الأطراف المثقوبة).

۳. أكمل الأقسام التالية أو اطلب من طبيبك القيام بذلك:

-    الاسم:

-    تاريخ الميلاد:

-    دواعي الاستعمال:

-    الجرعة: ........ملجم مرتين يوميًا

-    اسم الطبيب:

-    رقم هاتف الطبيب:

 

٤. اطوِ البطاقة واحتفظ بها معك دائمًا

 

Bristol-Myers Squibb/Pfizer EEIG,Ireland

 

الشركات الصانعة

 

Pfizer Ireland Pharmaceuticals, Newbridge, Ireland

 شركة التغليف والفسح النهائي

Pfizer Manufacturing Deutschland GmbH, Freiburg, Germany

فبراير 2022
 Read this leaflet carefully before you start using this product as it contains important information for you

Eliquis 2.5 mg film-coated tablets

Each film-coated tablet contains 2.5 mg apixaban. Excipient(s) with known effect Each 2.5 mg film-coated tablet contains 51.43 mg lactose (see section 4.4). For the full list of excipients, see section 6.1.

Film-coated tablet (tablet) Yellow, round tablets (diameter of 5.95 mm) debossed with 893 on one side and 2½ on the other side.

Prevention of venous thromboembolic events (VTE) in adult patients who have undergone elective hip or knee replacement surgery.

 

Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF), with one or more risk factors, such as prior stroke or transient ischaemic attack (TIA); age ≥ 75 years; hypertension; diabetes mellitus; symptomatic heart failure (NYHA Class ≥ II).

 

Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults (see section 4.4 for haemodynamically unstable PE patients).


 

Posology

 

Prevention of VTE (VTEp): elective hip or knee replacement surgery

The recommended dose of apixaban is 2.5 mg taken orally twice daily. The initial dose should be taken 12 to 24 hours after surgery.

 

Physicians may consider the potential benefits of earlier anticoagulation for VTE prophylaxis as well as the risks of post-surgical bleeding in deciding on the time of administration within this time window.

 

In patients undergoing hip replacement surgery

The recommended duration of treatment is 32 to 38 days.

 

In patients undergoing knee replacement surgery

The recommended duration of treatment is 10 to 14 days.

 

Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF)

The recommended dose of apixaban is 5 mg taken orally twice daily.

 

Dose reduction

The recommended dose of apixaban is 2.5 mg taken orally twice daily in patients with NVAF and at least two of the following characteristics: age ≥ 80 years, body weight ≤ 60 kg, or serum creatinine ≥ 1.5 mg/dL (133 micromole/L).

 

Therapy should be continued long-term.

 

Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt)

The recommended dose of apixaban for the treatment of acute DVT and treatment of PE is 10 mg taken orally twice daily for the first 7 days followed by 5 mg taken orally twice daily. As per available medical guidelines, short duration of treatment (at least 3 months) should be based on transient risk factors (e.g., recent surgery, trauma, immobilisation).

 

The recommended dose of apixaban for the prevention of recurrent DVT and PE is 2.5 mg taken orally twice daily. When prevention of recurrent DVT and PE is indicated, the 2.5 mg twice daily dose should be initiated following completion of 6 months of treatment with apixaban 5 mg twice daily or with another anticoagulant, as indicated in Table 1 below (see also section 5.1).

 

Table 1: Dose recommendation (VTEt)

 

Dosing schedule

Maximum daily dose

Treatment of DVT or PE

10 mg twice daily for the first 7 days

20 mg

followed by 5 mg twice daily

10 mg

Prevention of recurrent DVT and/or PE following completion of 6 months of treatment for DVT or PE

2.5 mg twice daily

 

5 mg

 

The duration of overall therapy should be individualised after careful assessment of the treatment benefit against the risk for bleeding (see section 4.4).

 

Missed dose

If a dose is missed, the patient should take Eliquis immediately and then continue with twice daily intake as before.

 

Switching

Switching treatment from parenteral anticoagulants to Eliquis (and vice versa) can be done at the next scheduled dose (see section 4.5). These medicinal products should not be administered simultaneously.

 

Switching from vitamin K antagonist (VKA) therapy to Eliquis

When converting patients from vitamin K antagonist (VKA) therapy to Eliquis, warfarin or other VKA therapy should be discontinued and Eliquis started when the international normalised ratio (INR) is < 2.

 

Switching from Eliquis to VKA therapy

When converting patients from Eliquis to VKA therapy, administration of Eliquis should be continued for at least 2 days after beginning VKA therapy. After 2 days of coadministration of Eliquis with VKA therapy, an INR should be obtained prior to the next scheduled dose of Eliquis. Coadministration of Eliquis and VKA therapy should be continued until the INR is ≥ 2.

 

Elderly

VTEp and VTEt – No dose adjustment required (see sections 4.4 and 5.2).

 

NVAF – No dose adjustment required, unless criteria for dose reduction are met (see Dose reduction at the beginning of section 4.2).

 

Renal impairment

In patients with mild or moderate renal impairment, the following recommendations apply:

 

-        for the prevention of VTE in elective hip or knee replacement surgery (VTEp), for the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt), no dose adjustment is necessary (see section 5.2).

 

-        for the prevention of stroke and systemic embolism in patients with NVAF and serum creatinine ≥ 1.5 mg/dL (133 micromole/L) associated with age ≥ 80 years or body weight ≤ 60 kg, a dose reduction is necessary and described above. In the absence of other criteria for dose reduction (age, body weight), no dose adjustment is necessary (see section 5.2).

 

In patients with severe renal impairment (creatinine clearance 15-29 mL/min) the following recommendations apply (see sections 4.4 and 5.2):

 

-        for the prevention of VTE in elective hip or knee replacement surgery (VTEp), for the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt) apixaban is to be used with caution;

 

-             for the prevention of stroke and systemic embolism in patients with NVAF, patients should receive the lower dose of apixaban 2.5 mg twice daily.

 

In patients with creatinine clearance < 15 mL/min, or in patients undergoing dialysis, there is no clinical experience therefore apixaban is not recommended (see sections 4.4 and 5.2).

 

Hepatic impairment

Eliquis is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk (see section 4.3).

 

It is not recommended in patients with severe hepatic impairment (see sections 4.4. and 5.2).

 

It should be used with caution in patients with mild or moderate hepatic impairment (Child Pugh A or B). No dose adjustment is required in patients with mild or moderate hepatic impairment (see sections 4.4 and 5.2).

 

Patients with elevated liver enzymes alanine aminotransferase (ALT)/aspartate aminotransferase (AST) >2 x ULN or total bilirubin ≥ 1.5 x ULN were excluded in clinical studies. Therefore Eliquis should be used with caution in this population (see sections 4.4 and 5.2). Prior to initiating Eliquis, liver function testing should be performed.

 

Body weight

VTEp and VTEt - No dose adjustment required (see sections 4.4 and 5.2).

 

NVAF - No dose adjustment required, unless criteria for dose reduction are met (see Dose reduction at the beginning of section 4.2).

 

Gender

No dose adjustment required (see section 5.2).

 

Patients undergoing catheter ablation (NVAF)

Patients can continue apixaban use while undergoing catheter ablation (see sections 4.3, 4.4 and 4.5).

 

Patients undergoing cardioversion

Apixaban can be initiated or continued in NVAF patients who may require cardioversion.

 

For patients not previously treated with anticoagulants, exclusion of left atrial thrombus using an image guided approach (e.g. transesophageal echocardiography (TEE) or computed tomographic scan (CT)) prior to cardioversion should be considered, in accordance with established medical guidelines.

For patients initiating treatment with apixaban, 5 mg should be given twice daily for at least 2.5 days (5 single doses) before cardioversion to ensure adequate anticoagulation (see section 5.1). The dosing regimen should be reduced to 2.5 mg apixaban given twice daily for at least 2.5 days (5 single doses) if the patient meets the criteria for dose reduction (see above sections Dose reduction and Renal impairment).

 

If cardioversion is required before 5 doses of apixaban can be administered, a 10 mg loading dose should be given, followed by 5 mg twice daily. The dosing regimen should be reduced to a 5 mg loading dose followed by 2.5 mg twice daily if the patient meets the criteria for dose reduction (see above sections Dose reduction and Renal impairment). The administration of the loading dose should be given at least 2 hours before cardioversion (see section 5.1).

 

For all patients undergoing cardioversion, confirmation should be sought prior to cardioversion that the patient has taken apixaban as prescribed. Decisions on initiation and duration of treatment should take established guideline recommendations for anticoagulant treatment in patients undergoing cardioversion into account.

 

Patients with NVAF and acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI)

There is limited experience of treatment with apixaban at the recommended dose for NVAF patients when used in combination with antiplatelet agents in patients with ACS and/or undergoing PCI after haemostasis is achieved (see sections 4.4, 5.1).

 

Paediatric population

The safety and efficacy of Eliquis in children and adolescents below age 18 have not been established. No data are available.

 

Method of administration

 

Oral use

Eliquis should be swallowed with water, with or without food.

 

For patients who are unable to swallow whole tablets, Eliquis tablets may be crushed and suspended in water, or 5% glucose in water (G5W), or apple juice or mixed with apple puree and immediately administered orally (see section 5.2). Alternatively, Eliquis tablets may be crushed and suspended in 60 mL of water or G5W and immediately delivered through a nasogastric tube (see section 5.2).

Crushed Eliquis tablets are stable in water, G5W, apple juice, and apple puree for up to 4 hours.


• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. • Active clinically significant bleeding. • Hepatic disease associated with coagulopathy and clinically relevant bleeding risk (see section 5.2). • Lesion or condition if considered a significant risk factor for major bleeding. This may include current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities. • Concomitant treatment with any other anticoagulant agent e.g., unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, rivaroxaban, dabigatran, etc.) except under specific circumstances of switching anticoagulant therapy (see section 4.2), when UFH is given at doses necessary to maintain an open central venous or arterial catheter or when UFH is given during catheter ablation for atrial fibrillation (see sections 4.4 and 4.5).

Haemorrhage risk

 

As with other anticoagulants, patients taking apixaban are to be carefully observed for signs of bleeding. It is recommended to be used with caution in conditions with increased risk of haemorrhage. Apixaban administration should be discontinued if severe haemorrhage occurs (see sections 4.8 and 4.9).

 

Although treatment with apixaban does not require routine monitoring of exposure, a calibrated quantitative anti-Factor Xa assay may be useful in exceptional situations where knowledge of apixaban exposure may help to inform clinical decisions, e.g., overdose and emergency surgery (see section 5.1).

 

An agent to reverse the anti-factor Xa activity of apixaban is available.

 

Interaction with other medicinal products affecting haemostasis

 

Due to an increased bleeding risk, concomitant treatment with any other anticoagulants is contraindicated (see section 4.3).

 

The concomitant use of apixaban with antiplatelet agents increases the risk of bleeding (see section 4.5).

 

Care is to be taken if patients are treated concomitantly with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs), or non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid.

 

Following surgery, other platelet aggregation inhibitors are not recommended concomitantly with apixaban (see section 4.5).

 

In patients with atrial fibrillation and conditions that warrant mono or dual antiplatelet therapy, a careful assessment of the potential benefits against the potential risks should be made before combining this therapy with apixaban.

 

In a clinical study of patients with atrial fibrillation, concomitant use of ASA increased the major bleeding risk on apixaban from 1.8% per year to 3.4% per year and increased the bleeding risk on warfarin from 2.7% per year to 4.6% per year. In this clinical study, there was limited (2.1%) use of concomitant dual antiplatelet therapy (see section 5.1).

 

A clinical study enrolled patients with atrial fibrillation with ACS and/or undergoing PCI and a planned treatment period with a P2Y12 inhibitor, with or without ASA, and oral anticoagulant (either apixaban or VKA) for 6 months. Concomitant use of ASA increased the risk of ISTH (International Society on Thrombosis and Hemostasis) major or CRNM (Clinically Relevant Non-Major) bleeding in apixaban-treated subjects from 16.4% per year to 33.1% per year (see section 5.1).

 

In a clinical study of high-risk post acute coronary syndrome patients without atrial fibrillation, characterised by multiple cardiac and non-cardiac comorbidities, who received ASA or the combination of ASA and clopidogrel, a significant increase in risk of ISTH major bleeding was reported for apixaban (5.13% per year) compared to placebo (2.04% per year).

 

Use of thrombolytic agents for the treatment of acute ischemic stroke

 

There is very limited experience with the use of thrombolytic agents for the treatment of acute ischemic stroke in patients administered apixaban (see section 4.5).

 

Patients with prosthetic heart valves

 

Safety and efficacy of apixaban have not been studied in patients with prosthetic heart valves, with or without atrial fibrillation. Therefore, the use of apixaban is not recommended in this setting.

 

Patients with antiphospholipid syndrome

 

Direct acting Oral Anticoagulants (DOACs) including apixaban are not recommended for patients with a history of thrombosis who are diagnosed with antiphospholipid syndrome. In particular for patients that are triple positive (for lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2-glycoprotein I antibodies), treatment with DOACs could be associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.

 

Surgery and invasive procedures

 

Apixaban should be discontinued at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of bleeding. This includes interventions for which the probability of clinically significant bleeding cannot be excluded or for which the risk of bleeding would be unacceptable.

 

Apixaban should be discontinued at least 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding. This includes interventions for which any bleeding that occurs is expected to be minimal, non-critical in its location or easily controlled.

 

If surgery or invasive procedures cannot be delayed, appropriate caution should be exercised, taking into consideration an increased risk of bleeding. This risk of bleeding should be weighed against the urgency of intervention.

 

Apixaban should be restarted after the invasive procedure or surgical intervention as soon as possible provided the clinical situation allows and adequate haemostasis has been established (for cardioversion see section 4.2).

 

For patients undergoing catheter ablation for atrial fibrillation, apixaban treatment does not need to be interrupted (see sections 4.2, 4.3 and 4.5).

 

Temporary discontinuation

 

Discontinuing anticoagulants, including apixaban, for active bleeding, elective surgery, or invasive procedures places patients at an increased risk of thrombosis. Lapses in therapy should be avoided and if anticoagulation with apixaban must be temporarily discontinued for any reason, therapy should be restarted as soon as possible.

 

Spinal/epidural anaesthesia or puncture

 

When neuraxial anaesthesia (spinal/epidural anaesthesia) or spinal/epidural puncture is employed, patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal haematoma which can result in long-term or permanent paralysis. The risk of these events may be increased by the post-operative use of indwelling epidural catheters or the concomitant use of medicinal products affecting haemostasis. Indwelling epidural or intrathecal catheters must be removed at least 5 hours prior to the first dose of apixaban. The risk may also be increased by traumatic or repeated epidural or spinal puncture. Patients are to be frequently monitored for signs and symptoms of neurological impairment (e.g., numbness or weakness of the legs, bowel or bladder dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial intervention the physician should consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis.

 

There is no clinical experience with the use of apixaban with indwelling intrathecal or epidural catheters. In case there is such need and based on the general PK characteristics of apixaban, a time interval of 20‑30 hours (i.e., 2 x half-life) between the last dose of apixaban and catheter withdrawal should elapse, and at least one dose should be omitted before catheter withdrawal. The next dose of apixaban may be given at least 5 hours after catheter removal. As with all new anticoagulant medicinal products, experience with neuraxial blockade is limited and extreme caution is therefore recommended when using apixaban in the presence of neuraxial blockade.

 

Haemodynamically unstable PE patients or patients who require thrombolysis or pulmonary embolectomy

 

Apixaban is not recommended as an alternative to unfractionated heparin in patients with pulmonary embolism who are haemodynamically unstable or may receive thrombolysis or pulmonary embolectomy since the safety and efficacy of apixaban have not been established in these clinical situations.

 

Patients with active cancer

 

Patients with active cancer can be at high risk of both venous thromboembolism and bleeding events. When apixaban is considered for DVT or PE treatment in cancer patients, a careful assessment of the benefits against the risks should be made (see also section 4.3).

 

Patients with renal impairment

 

Limited clinical data indicate that apixaban plasma concentrations are increased in patients with severe renal impairment (creatinine clearance 15-29 mL/min) which may lead to an increased bleeding risk. For the prevention of VTE in elective hip or knee replacement surgery (VTEp), the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt), apixaban is to be used with caution in patients with severe renal impairment (creatinine clearance 15-29 mL/min) (see sections 4.2 and 5.2).

 

For the prevention of stroke and systemic embolism in patients with NVAF, patients with severe renal impairment (creatinine clearance 15-29 mL/min), and patients with serum creatinine ≥ 1.5 mg/dL (133 micromole/L) associated with age ≥ 80 years or body weight ≤ 60 kg should receive the lower dose of apixaban 2.5 mg twice daily (see section 4.2).

 

In patients with creatinine clearance < 15 mL/min, or in patients undergoing dialysis, there is no clinical experience therefore apixaban is not recommended (see sections 4.2 and 5.2).

 

Elderly patients

 

Increasing age may increase haemorrhagic risk (see section 5.2).

 

Also, the coadministration of apixaban with ASA in elderly patients should be used cautiously because of a potentially higher bleeding risk.

 

Body weight

 

Low body weight (< 60 kg) may increase haemorrhagic risk (see section 5.2).

 

Patients with hepatic impairment

 

Apixaban is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk (see section 4.3).

 

It is not recommended in patients with severe hepatic impairment (see section 5.2).

 

It should be used with caution in patients with mild or moderate hepatic impairment (Child Pugh A or B) (see sections 4.2 and 5.2).

 

Patients with elevated liver enzymes ALT/AST > 2 x ULN or total bilirubin ≥ 1.5 x ULN were excluded in clinical studies. Therefore apixaban should be used cautiously in this population (see section 5.2). Prior to initiating apixaban, liver function testing should be performed.

 

Interaction with inhibitors of both cytochrome P450 3A4 (CYP3A4) and P‑glycoprotein (P‑gp)

 

The use of apixaban is not recommended in patients receiving concomitant systemic treatment with strong inhibitors of both CYP3A4 and P‑gp, such as azole-antimycotics (e.g., ketoconazole, itraconazole, voriconazole and posaconazole) and HIV protease inhibitors (e.g., ritonavir). These medicinal products may increase apixaban exposure by 2‑fold (see section 4.5), or greater in the presence of additional factors that increase apixaban exposure (e.g., severe renal impairment).

 

Interaction with inducers of both CYP3A4 and P‑gp

 

The concomitant use of apixaban with strong CYP3A4 and P‑gp inducers (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital or St. John’s Wort) may lead to a ~50% reduction in apixaban exposure. In a clinical study in atrial fibrillation patients, diminished efficacy and a higher risk of bleeding were observed with coadministration of apixaban with strong inducers of both CYP3A4 and P‑gp compared with using apixaban alone.

 

In patients receiving concomitant systemic treatment with strong inducers of both CYP3A4 and P-gp the following recommendations apply (see section 4.5):

 

-        for the prevention of VTE in elective hip or knee replacement surgery, for the prevention of stroke and systemic embolism in patients with NVAF and for the prevention of recurrent DVT and PE, apixaban should be used with caution;

 

-        for the treatment of DVT and treatment of PE, apixaban should not be used since efficacy may be compromised.

 

Hip fracture surgery

 

Apixaban has not been studied in clinical studies in patients undergoing hip fracture surgery to evaluate efficacy and safety in these patients. Therefore, it is not recommended in these patients.

 

Laboratory parameters

 

Clotting tests [e.g., prothrombin time (PT), INR, and activated partial thromboplastin time (aPTT)] are affected as expected by the mechanism of action of apixaban. Changes observed in these clotting tests at the expected therapeutic dose are small and subject to a high degree of variability (see section 5.1).

 

Information about excipients

 

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

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially "sodium-free".

 


 

Inhibitors of CYP3A4 and P‑gp

Coadministration of apixaban with ketoconazole (400 mg once a day), a strong inhibitor of both CYP3A4 and P‑gp, led to a 2‑fold increase in mean apixaban AUC and a 1.6‑fold increase in mean apixaban Cmax.

 

The use of apixaban is not recommended in patients receiving concomitant systemic treatment with strong inhibitors of both CYP3A4 and P‑gp, such as azole-antimycotics (e.g., ketoconazole, itraconazole, voriconazole and posaconazole) and HIV protease inhibitors (e.g., ritonavir) (see section 4.4).

 

Active substances which are not considered strong inhibitors of both CYP3A4 and P-gp, (e.g., amiodarone, clarithromycin, diltiazem, fluconazole, naproxen, quinidine, verapamil) are expected to increase apixaban plasma concentration to a lesser extent. No dose adjustment for apixaban is required when coadministered with agents that are not strong inhibitors of both CYP3A4 and P‑gp. For example, diltiazem (360 mg once a day), considered a moderate CYP3A4 and a weak P‑gp inhibitor, led to a 1.4‑fold increase in mean apixaban AUC and a 1.3‑fold increase in Cmax. Naproxen (500 mg, single dose) an inhibitor of P‑gp but not an inhibitor of CYP3A4, led to a 1.5‑fold and 1.6‑fold increase in mean apixaban AUC and Cmax, respectively. Clarithromycin (500 mg, twice a day), an inhibitor of P-gp and a strong inhibitor of CYP3A4, led to a 1.6-fold and 1.3-fold increase in mean apixaban AUC and Cmax respectively.

 

Inducers of CYP3A4 and P‑gp

 

Coadministration of apixaban with rifampicin, a strong inducer of both CYP3A4 and P‑gp, led to an approximate 54% and 42% decrease in mean apixaban AUC and Cmax, respectively. The concomitant use of apixaban with other strong CYP3A4 and P‑gp inducers (e.g., phenytoin, carbamazepine, phenobarbital or St. John’s Wort) may also lead to reduced apixaban plasma concentrations. No dose adjustment for apixaban is required during concomitant therapy with such medicinal products, however in patients receiving concomitant systemic treatment with strong inducers of both CYP3A4 and P-gp apixaban should be used with caution for the prevention of VTE in elective hip or knee replacement surgery, for the prevention of stroke and systemic embolism in patients with NVAF and for the prevention of recurrent DVT and PE.

 

Apixaban is not recommended for the treatment of DVT and PE in patients receiving concomitant systemic treatment with strong inducers of both CYP3A4 and P-gp since efficacy may be compromised (see section 4.4).

 

Anticoagulants, platelet aggregation inhibitors, SSRIs/SNRIs and NSAIDs

 

Due to an increased bleeding risk, concomitant treatment with any other anticoagulants is contraindicated except under specific circumstances of switching anticoagulant therapy, when UFH is given at doses necessary to maintain an open central venous or arterial catheter or when UFH is given during catheter ablation for atrial fibrillation (see section 4.3).

 

After combined administration of enoxaparin (40 mg single dose) with apixaban (5 mg single dose), an additive effect on anti-Factor Xa activity was observed.

 

Pharmacokinetic or pharmacodynamic interactions were not evident when apixaban was coadministered with ASA 325 mg once a day.

 

Apixaban coadministered with clopidogrel (75 mg once a day) or with the combination of clopidogrel 75 mg and ASA 162 mg once daily, or with prasugrel (60 mg followed by 10 mg once daily) in Phase I studies did not show a relevant increase in template bleeding time, or further inhibition of platelet aggregation, compared to administration of the antiplatelet agents without apixaban. Increases in clotting tests (PT, INR, and aPTT) were consistent with the effects of apixaban alone.

 

Naproxen (500 mg), an inhibitor of P‑gp, led to a 1.5‑fold and 1.6‑fold increase in mean apixaban AUC and Cmax, respectively. Corresponding increases in clotting tests were observed for apixaban. No changes were observed in the effect of naproxen on arachidonic acid-induced platelet aggregation and no clinically relevant prolongation of bleeding time was observed after concomitant administration of apixaban and naproxen.

 

Despite these findings, there may be individuals with a more pronounced pharmacodynamic response when antiplatelet agents are coadministered with apixaban. Apixaban should be used with caution when coadministered with SSRIs/SNRIs, NSAIDs, ASA and/or P2Y12 inhibitors because these medicinal products typically increase the bleeding risk (see section 4.4).

 

There is limited experience of co-administration with other platelet aggregation inhibitors (such as GPIIb/IIIa receptor antagonists, dipyridamole, dextran or sulfinpyrazone) or thrombolytic agents. As such agents increase the bleeding risk, co-administration of these medicinal products with apixaban is not recommended (see section 4.4).

 

Other concomitant therapies

 

No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when apixaban was coadministered with atenolol or famotidine. Coadministration of apixaban 10 mg with atenolol 100 mg did not have a clinically relevant effect on the pharmacokinetics of apixaban. Following administration of the two medicinal products together, mean apixaban AUC and Cmax were 15% and 18% lower than when administered alone. The administration of apixaban 10 mg with famotidine 40 mg had no effect on apixaban AUC or Cmax.

 

Effect of apixaban on other medicinal products

 

In vitro apixaban studies showed no inhibitory effect on the activity of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6 or CYP3A4 (IC50 > 45 µM) and weak inhibitory effect on the activity of CYP2C19 (IC50 > 20 µM) at concentrations that are significantly greater than peak plasma concentrations observed in patients. Apixaban did not induce CYP1A2, CYP2B6, CYP3A4/5 at a concentration up to 20 µM. Therefore, apixaban is not expected to alter the metabolic clearance of coadministered medicinal products that are metabolised by these enzymes. Apixaban is not a significant inhibitor of P‑gp.

 

In studies conducted in healthy subjects, as described below, apixaban did not meaningfully alter the pharmacokinetics of digoxin, naproxen, or atenolol.

 

Digoxin

Coadministration of apixaban (20 mg once a day) and digoxin (0.25 mg once a day), a P‑gp substrate, did not affect digoxin AUC or Cmax. Therefore, apixaban does not inhibit P‑gp mediated substrate transport.

 

Naproxen

Coadministration of single doses of apixaban (10 mg) and naproxen (500 mg), a commonly used NSAID, did not have any effect on the naproxen AUC or Cmax.

 

Atenolol

Coadministration of a single dose of apixaban (10 mg) and atenolol (100 mg), a common beta-blocker, did not alter the pharmacokinetics of atenolol.

 

Activated charcoal

 

Administration of activated charcoal reduces apixaban exposure (see section 4.9).


Pregnancy

 

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

 

Breast-feeding

 

It is unknown whether apixaban or its metabolites are excreted in human milk. Available data in animals have shown excretion of apixaban in milk (see section 5.3). A risk to the suckling child cannot be excluded.

 

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from apixaban therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

 

Fertility

 

Studies in animals dosed with apixaban have shown no effect on fertility (see section 5.3).

 


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


 

Summary of the safety profile

 

The safety of apixaban has been investigated in 7 Phase III clinical studies including more than 21,000 patients: more than 5,000 patients in VTEp studies, more than 11,000 patients in NVAF studies and more than 4,000 patients in the VTE treatment (VTEt) studies, for an average total exposure of 20 days, 1.7 years and 221 days respectively (see section 5.1).

 

Common adverse reactions were haemorrhage, contusion, epistaxis, and haematoma (see Table 2 for adverse reaction profile and frequencies by indication).

 

In the VTEp studies, in total, 11% of the patients treated with apixaban 2.5 mg twice daily experienced adverse reactions. The overall incidence of adverse reactions related to bleeding with apixaban was 10% in the apixaban vs enoxaparin studies.

 

In the NVAF studies, the overall incidence of adverse reactions related to bleeding with apixaban was 24.3% in the apixaban vs warfarin study and 9.6% in the apixaban vs acetylsalicylic acid study. In the apixaban vs warfarin study the incidence of ISTH major gastrointestinal bleeds (including upper GI, lower GI, and rectal bleeding) with apixaban was 0.76%/year. The incidence of ISTH major intraocular bleeding with apixaban was 0.18%/year.

 

In the VTEt studies, the overall incidence of adverse reactions related to bleeding with apixaban was 15.6% in the apixaban vs enoxaparin/warfarin study and 13.3% in the apixaban vs placebo study (see section 5.1).

 

Tabulated list of adverse reactions

 

Table 2 shows the adverse reactions ranked under headings of system organ class and frequency using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data) for VTEp, NVAF, and VTEt respectively.

 

Table 2: Tabulated adverse reactions

System organ class

Prevention of VTE in adult patients who have undergone elective hip or knee replacement surgery (VTEp)

Prevention of stroke and systemic embolism in adult patients with NVAF, with one or more risk factors (NVAF)

Treatment of DVT and PE, and prevention of recurrent DVT and PE (VTEt)

Blood and lymphatic system disorders

Anaemia

Common

Common

Common

Thrombocytopenia

Uncommon

Uncommon

Common

Immune system disorders

Hypersensitivity, allergic oedema and Anaphylaxis

Rare

Uncommon

Uncommon

Pruritus

Uncommon

Uncommon

Uncommon*

Angioedema

Not known

Not known

Not known

Nervous system disorders

Brain haemorrhage

Not known

Uncommon

Rare

Eye disorders

Eye haemorrhage (including conjunctival haemorrhage)

Rare

Common

Uncommon

Vascular disorders

Haemorrhage, haematoma

Common

Common

Common

Hypotension (including procedural hypotension)

Uncommon

Common

Uncommon

Intra-abdominal haemorrhage

Not known

Uncommon

Not known

Respiratory, thoracic and mediastinal disorders

Epistaxis

Uncommon

Common

Common

Haemoptysis

Rare

Uncommon

Uncommon

Respiratory tract haemorrhage

Not known

Rare

Rare

Gastrointestinal disorders

Nausea

Common

Common

Common

Gastrointestinal haemorrhage

Uncommon

Common

Common

Haemorrhoidal haemorrhage

Not known

Uncommon

Uncommon

Mouth haemorrhage

Not known

Uncommon

Common

Haematochezia

Uncommon

Uncommon

Uncommon

Rectal haemorrhage, gingival bleeding

Rare

Common

Common

Retroperitoneal haemorrhage

Not known

Rare

Not known

Hepatobiliary disorders

Liver function test abnormal, asparate aminotransferase increased, blood alkaline phosphatase increased, blood bilirubin increased

Uncommon

Uncommon

Uncommon

Gamma-glutamyltransferase increased

Uncommon

Common

Common

Alanine aminotransferase increased

Uncommon

Uncommon

Common

Skin and subcutaneous tissue disorders

Skin rash

Not known

Uncommon

Common

Alopecia

Rare

Uncommon

Uncommon

Erythema multiforme

Not known

Very rare

Not known

Cutaneous vasculitis

Not known

Not known

Not known

Musculoskeletal and connective tissue disorders

Muscle haemorrhage

Rare

Rare

Uncommon

Renal and urinary disorders

Haematuria

Uncommon

Common

Common

Reproductive system and breast disorders

Abnormal vaginal haemorrhage, urogenital haemorrhage

Uncommon

Uncommon

Common

General disorders and administration site conditions

Application site bleeding

Not known

Uncommon

Uncommon

Investigations

Occult blood positive

Not known

Uncommon

Uncommon

Injury, poisoning and procedural complications

Contusion

Common

Common

Common

Post procedural haemorrhage (including post procedural haematoma, wound haemorrhage, vessel puncture site haematoma and catheter site haemorrhage), wound secretion, incision site haemorrhage (including incision site haematoma), operative haemorrhage

Uncommon

Uncommon

Uncommon

Traumatic haemorrhage

Not known

Uncommon

Uncommon

* There were no occurrences of generalised pruritus in CV185057 (long term prevention of VTE)

The term “Brain haemorrhage” encompasses all intracranial or intraspinal haemorrhages (i.e., haemorrhagic stroke or putamen, cerebellar, intraventricular, or subdural haemorrhages).

 

The use of apixaban may be associated with an increased risk of occult or overt bleeding from any tissue or organ, which may result in posthaemorrhagic anaemia. The signs, symptoms, and severity will vary according to the location and degree or extent of the bleeding (see sections 4.4 and 5.1).

 

Reporting of suspected adverse reactions

 

Reporting suspected adverse reactions after marketing authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions to National Pharmacovigilance Centre (NPC).

To Report side effects

 

·       Saudi Arabia:

National Pharmacovigilance Center ( NPC )

 

·       Call center : 19999

·       E-mail: npc.drug@sfda.gov.sa

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

 

·       Other GCC States

 

-   Please contact the relevant competent authority.

 


 

Overdose of apixaban may result in a higher risk of bleeding. In the event of haemorrhagic complications, treatment must be discontinued and the source of bleeding investigated. The initiation of appropriate treatment, e.g., surgical haemostasis, the transfusion of fresh frozen plasma or the administration of a reversal agent for factor Xa inhibitors should be considered.

 

In controlled clinical studies, orally-administered apixaban in healthy subjects at doses up to 50 mg daily for 3 to 7 days (25 mg twice daily (bid) for 7 days or 50 mg once daily (od) for 3 days) had no clinically relevant adverse reactions.

 

In healthy subjects, administration of activated charcoal 2 and 6 hours after ingestion of a 20 mg dose of apixaban reduced mean apixaban AUC by 50% and 27%, respectively, and had no impact on Cmax. Mean half-life of apixaban decreased from 13.4 hours when apixaban was administered alone to 5.3 hours and 4.9 hours, respectively, when activated charcoal was administered 2 and 6 hours after apixaban. Thus, administration of activated charcoal may be useful in the management of apixaban overdose or accidental ingestion.

 

For situations when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding, a reversal agent for factor Xa inhibitors is available (see section 4.4). Administration of prothrombin complex concentrates (PCCs) or recombinant factor VIIa may also be considered. Reversal of apixaban pharmacodynamic effects, as demonstrated by changes in the thrombin generation assay, was evident at the end of infusion and reached baseline values within 4 hours after the start of a 4-factor PCC 30 minute infusion in healthy subjects. However, there is no clinical experience with the use of 4‑factor PCC products to reverse bleeding in individuals who have received apixaban. Currently there is no experience with the use of recombinant factor VIIa in individuals receiving apixaban. Re-dosing of recombinant factor VIIa could be considered and titrated depending on improvement of bleeding.

 

Depending on local availability, a consultation of a coagulation expert should be considered in case of major bleedings.

 

Haemodialysis decreased apixaban AUC by 14% in subjects with end-stage renal disease (ESRD), when a single dose of apixaban 5 mg was administered orally. Therefore, haemodialysis is unlikely to be an effective means of managing apixaban overdose.

 


Pharmacotherapeutic group: Antithrombotic agents, direct factor Xa inhibitors, ATC code: B01AF02

 

Mechanism of action

 

Apixaban is a potent, oral, reversible, direct and highly selective active site inhibitor of factor Xa. It does not require antithrombin III for antithrombotic activity. Apixaban inhibits free and clot-bound factor Xa, and prothrombinase activity. Apixaban has no direct effects on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting factor Xa, apixaban prevents thrombin generation and thrombus development. Preclinical studies of apixaban in animal models have demonstrated antithrombotic efficacy in the prevention of arterial and venous thrombosis at doses that preserved haemostasis.

 

Pharmacodynamic effects

 

The pharmacodynamic effects of apixaban are reflective of the mechanism of action (FXa inhibition). As a result of FXa inhibition, apixaban prolongs clotting tests such as prothrombin time (PT), INR and activated partial thromboplastin time (aPTT). Changes observed in these clotting tests at the expected therapeutic dose are small and subject to a high degree of variability. They are not recommended to assess the pharmacodynamic effects of apixaban. In the thrombin generation assay, apixaban reduced endogenous thrombin potential, a measure of thrombin generation in human plasma.

 

Apixaban also demonstrates anti-Factor Xa activity as evident by reduction in Factor Xa enzyme activity in multiple commercial anti-Factor Xa kits, however results differ across kits. Data from clinical studies are only available for the Rotachrom® Heparin chromogenic assay. Anti-Factor Xa activity exhibits a close direct linear relationship with apixaban plasma concentration, reaching maximum values at the time of apixaban peak plasma concentrations. The relationship between apixaban plasma concentration and anti-Factor Xa activity is approximately linear over a wide dose range of apixaban.

 

Table 3 below shows the predicted steady state exposure and anti-Factor Xa activity for each indication. In patients taking apixaban for the prevention of VTE following hip or knee replacement surgery, the results demonstrate a less than 1.6-fold fluctuation in peak-to-trough levels. In non‑valvular atrial fibrillation patients taking apixaban for the prevention of stroke and systemic embolism, the results demonstrate a less than 1.7-fold fluctuation in peak-to-trough levels. In patients taking apixaban for the treatment of DVT and PE or prevention of recurrent DVT and PE, the results demonstrate a less than 2.2-fold fluctuation in peak-to-trough levels.

Table 3: Predicted apixaban steady-state exposure and anti-Factor Xa activity

 

Apix.

Cmax (ng/mL)

Apix.

Cmin (ng/mL)

Apix. anti-Factor Xa activity max (IU/mL)

Apix. anti-Factor Xa activity min (IU/mL)

 

Median [5th, 95th percentile]

Prevention of VTE: elective hip or knee replacement surgery

2.5 mg twice daily

77 [41, 146]

51 [23, 109]

1.3 [0.67, 2.4]

0.84 [0.37, 1.8]

Prevention of stroke and systemic embolism: NVAF

2.5 mg twice daily*

123 [69, 221]

79 [34, 162]

1.8 [1.0, 3.3]

1.2 [0.51, 2.4]

5 mg twice daily

171 [91, 321]

103 [41, 230]

2.6 [1.4, 4.8]

1.5 [0.61, 3.4]

Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt)

2.5 mg twice daily

67 [30, 153]

32 [11, 90]

1.0 [0.46, 2.5]

0.49 [0.17, 1.4]

5 mg twice daily

132 [59, 302]

63 [22, 177]

2.1 [0.91, 5.2]

1.0 [0.33, 2.9]

10 mg twice daily

251 [111, 572]

120 [41, 335]

4.2 [1.8, 10.8]

1.9 [0.64, 5.8]

* Dose adjusted population based on 2 of 3 dose reduction criteria in the ARISTOTLE study.

 

Although treatment with apixaban does not require routine monitoring of exposure, a calibrated quantitative anti-Factor Xa assay may be useful in exceptional situations where knowledge of apixaban exposure may help to inform clinical decisions, e.g., overdose and emergency surgery.

 

Clinical efficacy and safety

 

Prevention of VTE (VTEp): elective hip or knee replacement surgery

The apixaban clinical program was designed to demonstrate the efficacy and safety of apixaban for the prevention of VTE in a broad range of adult patients undergoing elective hip or knee replacement. A total of 8,464 patients were randomised in two pivotal, double-blind, multi-national studies, comparing apixaban 2.5 mg given orally twice daily (4,236 patients) or enoxaparin 40 mg once daily (4,228 patients). Included in this total were 1,262 patients (618 in the apixaban group) of age 75 or older, 1,004 patients (499 in the apixaban group) with low body weight (≤ 60 kg), 1,495 patients (743 in the apixaban group) with BMI ≥ 33 kg/m2, and 415 patients (203 in the apixaban group) with moderate renal impairment.

 

The ADVANCE-3 study included 5,407 patients undergoing elective hip replacement, and the ADVANCE-2 study included 3,057 patients undergoing elective knee replacement. Subjects received either apixaban 2.5 mg given orally twice daily (po bid) or enoxaparin 40 mg administered subcutaneously once daily (sc od). The first dose of apixaban was given 12 to 24 hours post-surgery, whereas enoxaparin was started 9 to 15 hours prior to surgery. Both apixaban and enoxaparin were given for 32‑38 days in the ADVANCE-3 study and for 10-14 days in the ADVANCE‑2 study.

 

Based on patient medical history in the studied population of ADVANCE-3 and ADVANCE-2 (8,464 patients), 46% had hypertension, 10% had hyperlipidemia, 9% had diabetes, and 8% had coronary artery disease.

 

Apixaban demonstrated a statistically superior reduction in the primary endpoint, a composite of all VTE/all cause death, and in the Major VTE endpoint, a composite of proximal DVT, non-fatal PE, and VTE-related death, compared to enoxaparin in both elective hip or knee replacement surgery (see Table 4).

 

Table 4: Efficacy results from pivotal phase III studies

Study

ADVANCE-3 (hip)

ADVANCE-2 (knee)

Study treatment

Dose

Duration of treatment

Apixaban

2.5 mg po twice daily

35 ± 3 d

Enoxaparin

40 mg sc once daily

35 ± 3 d

p-value

Apixaban

2.5 mg po twice daily

12 ± 2 d

Enoxaparin

40 mg sc once daily

12 ± 2 d

p-value

Total VTE/all-cause death

Number of events/subjects

Event rate

27/1,949

1.39%

74/1,917

3.86%

< 0.0001

147/976

15.06%

243/997

24.37%

<0.0001

Relative risk

95% CI

0.36

(0.22, 0.54)

 

0.62

(0.51, 0.74)

 

Major VTE

Number of events/subjects

Event rate

10/2,199

0.45%

25/2,195

1.14%

0.0107

13/1,195

1.09%

26/1,199

2.17%

0.0373

Relative risk

95% CI

0.40

(0.15, 0.80)

 

0.50

(0.26, 0.97)

 

        

 

The safety endpoints of major bleeding, the composite of major and CRNM bleeding, and all bleeding showed similar rates for patients treated with apixaban 2.5 mg compared with enoxaparin 40 mg (see Table 5). All the bleeding criteria included surgical site bleeding.

 

Table 5: Bleeding results from pivotal phase III studies*

 

ADVANCE-3

ADVANCE-2

 

Apixaban

2.5 mg po twice daily

35 ± 3 d

Enoxaparin

40 mg sc once daily

35 ± 3 d

Apixaban

2.5 mg po twice daily

12 ± 2 d

Enoxaparin

40 mg sc once daily

12 ± 2 d

All treated

n = 2,673

n = 2,659

n = 1,501

n = 1,508

Treatment period 1

Major

22 (0.8%)

18 (0.7%)

9 (0.6%)

14 (0.9%)

  Fatal

0

0

0

0

Major + CRNM

129 (4.8%)

134 (5.0%)

53 (3.5%)

72 (4.8%)

All

313 (11.7%)

334 (12.6%)

104 (6.9%)

126 (8.4%)

Post-surgery treatment period 2

Major

9 (0.3%)

11 (0.4%)

4 (0.3%)

9 (0.6%)

  Fatal

0

0

0

0

Major + CRNM

96 (3.6%)

115 (4.3%)

41 (2.7%)

56 (3.7%)

All

261 (9.8%)

293 (11.0%)

89 (5.9%)

103 (6.8%)

* All the bleeding criteria included surgical site bleeding

1 Includes events occurring after first dose of enoxaparin (pre-surgery)

2 Includes events occurring after first dose of apixaban (post-surgery)

 

The overall incidences of adverse reactions of bleeding, anaemia and abnormalities of transaminases (e.g., ALT levels) were numerically lower in patients on apixaban compared to enoxaparin in the phase II and phase III studies in elective hip and knee replacement surgery.

 

In the knee replacement surgery study during the intended treatment period, in the apixaban arm 4 cases of PE were diagnosed against no cases in the enoxaparin arm. No explanation can be given to this higher number of PE.

 

Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF)

A total of 23,799 patients were randomised in the clinical program (ARISTOTLE: apixaban versus warfarin, AVERROES: apixaban versus ASA) including 11,927 randomised to apixaban. The program was designed to demonstrate the efficacy and safety of apixaban for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) and one or more additional risk factors, such as:

·            prior stroke or transient ischaemic attack (TIA)

·            age ≥ 75 years

·            hypertension

·            diabetes mellitus

·            symptomatic heart failure (NYHA Class ≥ II)

 

ARISTOTLE study

In the ARISTOTLE study a total of 18,201 patients were randomised to double-blind treatment with apixaban 5 mg twice daily (or 2.5 mg twice daily in selected patients [4.7%], see section 4.2) or warfarin (target INR range 2.0‑3.0), patients were exposed to study active substance for a mean of 20 months. The mean age was 69.1 years, the mean CHADS2 score was 2.1 and 18.9% of patients had prior stroke or TIA.

 

In the study, apixaban achieved statistically significant superiority in the primary endpoint of prevention of stroke (haemorrhagic or ischaemic) and systemic embolism (see Table 6) compared with warfarin.

 

Table 6: Efficacy outcomes in patients with atrial fibrillation in the ARISTOTLE study

 

Apixaban
N=9,120

n (%/yr)

Warfarin
N=9,081

n (%/yr)

Hazard ratio

(95% CI)

 

p-value

Stroke or systemic embolism

212 (1.27)

265 (1.60)

0.79 (0.66, 0.95)

0.0114

Stroke

 

 

 

 

Ischaemic or unspecified

162 (0.97)

175 (1.05)

0.92 (0.74, 1.13)

 

Haemorrhagic

40 (0.24)

78 (0.47)

0.51 (0.35, 0.75)

 

Systemic embolism

15 (0.09)

17 (0.10)

0.87 (0.44, 1.75)

 

 

For patients randomised to warfarin, the median percentage of time in therapeutic range (TTR) (INR 2-3) was 66%.

 

Apixaban showed a reduction of stroke and systemic embolism compared to warfarin across the different levels of center TTR; within the highest quartile of TTR according to center, the hazard ratio for apixaban vs warfarin was 0.73 (95% CI, 0.38, 1.40).

 

Key secondary endpoints of major bleeding and all cause death were tested in a pre-specified hierarchical testing strategy to control the overall type 1 error in the trial. Statistically significant superiority was also achieved in the key secondary endpoints of both major bleeding and all-cause death (see Table 7). With improving monitoring of INR the observed benefits of apixaban compared to warfarin regarding all cause death diminish.

 

Table 7: Secondary endpoints in patients with atrial fibrillation in the ARISTOTLE study

 

Apixaban

N = 9,088

n (%/year)

Warfarin

N = 9,052

n (%/year)

Hazard ratio

(95% CI)

p-value

Bleeding outcomes

Major*

327 (2.13)

462 (3.09)

0.69 (0.60, 0.80)

< 0.0001

Fatal

10 (0.06)

37 (0.24)

 

 

Intracranial

52 (0.33)

122 (0.80)

 

 

Major + CRNM

613 (4.07)

877 (6.01)

0.68 (0.61, 0.75)

< 0.0001

All

2356 (18.1)

3060 (25.8)

0.71 (0.68, 0.75)

< 0.0001

Other endpoints

All-cause death

603 (3.52)

669 (3.94)

0.89 (0.80, 1.00)

0.0465

Myocardial infarction

90 (0.53)

102 (0.61)

0.88 (0.66, 1.17)

 

* Major bleeding defined per International Society on Thrombosis and Haemostasis (ISTH) criteria.

 

The overall discontinuation rate due to adverse reactions was 1.8% for apixaban and 2.6% for warfarin in the ARISTOTLE study.

 

The efficacy results for prespecified subgroups, including CHADS2 score, age, body weight, gender, status of renal function, prior stroke or TIA and diabetes were consistent with the primary efficacy results for the overall population studied in the trial.

 

The incidence of ISTH major gastrointestinal bleeds (including upper GI, lower GI, and rectal bleeding) was 0.76%/year with apixaban and 0.86%/year with warfarin.

 

The major bleeding results for prespecified subgroups including CHADS2 score, age, body weight, gender, status of renal function, prior stroke or TIA and diabetes were consistent with the results for the overall population studied in the trial.

 

AVERROES study

In the AVERROES study a total of 5,598 patients considered to be unsuitable for VKA by the investigators were randomised to treatment with apixaban 5 mg twice daily (or 2.5 mg twice daily in selected patients [6.4%], see section 4.2) or ASA. ASA was given at a once daily dose of 81 mg (64%), 162 (26.9%), 243 (2.1%), or 324 mg (6.6%) at the discretion of the investigator. Patients were exposed to study active substance for a mean of 14 months. The mean age was 69.9 years, the mean CHADS2 score was 2.0 and 13.6% of patients had prior stroke or TIA.

 

Common reasons for unsuitability for VKA therapy in the AVERROES study included unable/unlikely to obtain INRs at requested intervals (42.6%), patient refused treatment with VKA (37.4%), CHADS2 score = 1 and physician did not recommend VKA (21.3%), patient could not be relied on to adhere to VKA medicinal product instruction (15.0%), and difficulty/expected difficulty in contacting patient in case of urgent dose change (11.7%).

 

AVERROES was stopped early based on a recommendation by the independent Data Monitoring Committee due to clear evidence of reduction of stroke and systemic embolism with an acceptable safety profile.

 

The overall discontinuation rate due to adverse reactions was 1.5% for apixaban and 1.3% for ASA in the AVERROES study.

 

In the study, apixaban achieved statistically significant superiority in the primary endpoint of prevention of stroke (haemorrhagic, ischaemic or unspecified) or systemic embolism (see Table 8) compared to ASA.

 

Table 8: Key efficacy outcomes in patients with atrial fibrillation in the AVERROES study

 

Apixaban

N = 2,807

n (%/year)

ASA

N = 2,791

n (%/year)

Hazard ratio

(95% CI)

 

p-value

Stroke or systemic embolism*

51 (1.62)

113 (3.63)

0.45 (0.32, 0.62)

< 0.0001

Stroke

 

 

 

 

Ischaemic or unspecified

43 (1.37)

97 (3.11)

0.44 (0.31, 0.63)

 

Haemorrhagic

6 (0.19)

9 (0.28)

0.67 (0.24, 1.88)

   

Systemic embolism

2 (0.06)

13 (0.41)

0.15 (0.03, 0.68)

 

Stroke, systemic embolism, MI, or vascular death*

132 (4.21)

197 (6.35)

0.66 (0.53, 0.83)

0.003

Myocardial infarction

24 (0.76)

28 (0.89)

0.86 (0.50, 1.48)

 

Vascular death

84 (2.65)

96 (3.03)

0.87 (0.65, 1.17)

 

All-cause death

111 (3.51)

140 (4.42)

0.79 (0.62, 1.02)

0.068

* Assessed by sequential testing strategy designed to control the overall type I error in the trial.

† Secondary endpoint.

 

There was no statistically significant difference in the incidence of major bleeding between apixaban and ASA (see Table 9).

 

Table 9: Bleeding events in patients with atrial fibrillation in the AVERROES study

 

Apixaban

N = 2,798

n(%/year)

ASA

N = 2,780

n (%/year)

Hazard ratio (95%CI)

p-value

Major*

45 (1.41)

29 (0.92)

1.54 (0.96, 2.45)

0.0716

Fatal, n

5 (0.16)

5 (0.16)

 

 

Intracranial, n

11 (0.34)

11 (0.35)

 

 

Major + CRNM†

140 (4.46)

101 (3.24)

1.38 (1.07, 1.78)

0.0144

All

325 (10.85)

250 (8.32)

1.30 (1.10, 1.53)

0.0017

*Major bleeding defined per International Society on Thrombosis and Haemostasis (ISTH) criteria.

† Clinically relevant non-major

 

NVAF patients with ACS and/or undergoing PCI

AUGUSTUS, an open-label, randomised, controlled, 2 by 2 factorial design trial, enrolled 4614 patients with NVAF who had ACS (43%) and/or underwent PCI (56%). All patients received background therapy with a P2Y12 inhibitor (clopidogrel: 90.3%) prescribed per local standard of care.

 

Patients were randomised up to 14 days after the ACS and/or PCI to either apixaban 5 mg twice daily (2.5 mg twice daily if two or more of the dose-reduction criteria were met; 4.2% received lower dose) or VKA and to either ASA (81 mg once daily) or placebo. The mean age was 69.9 years, 94% of patients randomised had a CHA2DS2-VASc score > 2, and 47% had a HAS-BLED score > 3. For patients randomised to VKA, the proportion of time in therapeutic range (TTR) (INR 2-3) was 56%, with 32% of time below TTR and 12% above TTR.

 

The primary objective of AUGUSTUS was to assess safety, with a primary endpoint of ISTH major or CRNM bleeding. In the apixaban versus VKA comparison, the primary safety endpoint of ISTH major or CRNM bleeding at month 6 occurred in 241 (10.5%), and 332 (14.7%) patients in the apixaban arm and in the VKA arm respectively (HR=0.69, 95% CI: 0.58, 0.82; 2-sided p<0.0001 for non inferiority and p<0.0001 for superiority). For VKA, additional analyses using subgroups by TTR showed that the highest rate of bleeding was associated with the lowest quartile of TTR. The rate of bleeding was similar between apixaban and the highest quartile of TTR.

In the ASA versus placebo comparison, the primary safety endpoint of ISTH major or CRNM bleeding at month 6 occurred in 367 (16.1%), and 204 (9.0%) patients in the ASA arm and in the placebo arm respectively (HR=1.88, 95% CI: 1.58, 2.23; two-sided p<0.0001).

 

Specifically, in apixaban-treated patients, major or CRNM bleeding occurred in 157 (13.7%), and 84 (7.4%) patients in the ASA arm and in the placebo arm respectively. In VKA-treated patients, major or CRNM bleeding occurred in 208 (18.5%), and 122 (10.8%) patients in the ASA arm and in the placebo arm respectively.

 

Other treatment effects were evaluated as a secondary objective of the study, with composite endpoints.

In the apixaban versus VKA comparison, the composite endpoint of death or re-hospitalisation occurred in 541 (23.5%) and 632 (27.4%) patients in the apixaban and in the VKA arm, respectively. The composite endpoint of death or ischemic event (stroke, myocardial infarction, stent thrombosis or urgent revascularisation) occurred in 170 (7.4%), and 182 (7.9%) patients in the apixaban and in the VKA arm, respectively.

In the ASA versus placebo comparison, the composite endpoint of death or re-hospitalisation occurred in 604 (26.2%) and 569 (24.7%) patients in the ASA and in the placebo arm, respectively. The composite endpoint of death or ischemic event (stroke, myocardial infarction, stent thrombosis or urgent revascularisation) occurred in 163 (7.1%), and 189 (8.2%) patients in the ASA and in the placebo arm, respectively.

 

Patients undergoing cardioversion

EMANATE, an open-label, multi-center study, enrolled 1500 patients who were either oral anticoagulant naïve or pre-treated less than 48 hours, and scheduled for cardioversion for NVAF. Patients were randomised 1:1 to apixaban or to heparin and/or VKA for the prevention of cardiovascular events. Electrical and/or pharmacologic cardioversion was conducted after at least 5 doses of 5 mg twice daily apixaban (or 2.5 mg twice daily in selected patients (see section 4.2)) or at least 2 hours after a 10 mg loading dose (or a 5 mg loading dose in selected patients (see section 4.2)) if earlier cardioversion was required. In the apixaban group, 342 patients received a loading dose (331 patients received the 10 mg dose and 11 patients received the 5 mg dose).

 

There were no strokes (0%) in the apixaban group (n= 753) and 6 (0.80%) strokes in the heparin and/or VKA group (n = 747; RR 0.00, 95% CI 0.00, 0.64). All‑cause death occurred in 2 patients (0.27%) in the apixaban group and 1 patient (0.13%) in the heparin and/or VKA group. No systemic embolism events were reported.

 

Major bleeding and CRNM bleeding events occurred in 3 (0.41%) and 11 (1.50%) patients, respectively, in the apixaban group, compared to 6 (0.83%) and 13 (1.80%) patients in the heparin and/or VKA group.

 

This exploratory study showed comparable efficacy and safety between apixaban and heparin and/or VKA treatment groups in the setting of cardioversion.

 

Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt)

The clinical program (AMPLIFY: apixaban versus enoxaparin/warfarin, AMPLIFY-EXT: apixaban versus placebo) was designed to demonstrate the efficacy and safety of apixaban for the treatment of DVT and/or PE (AMPLIFY), and extended therapy for the prevention of recurrent DVT and/or PE following 6 to 12 months of anticoagulant treatment for DVT and/or PE (AMPLIFY-EXT). Both studies were randomised, parallel-group, double-blind, multinational trials in patients with symptomatic proximal DVT or symptomatic PE. All the key safety and efficacy endpoints were adjudicated by an independent blinded committee.

 

AMPLIFY study

In the AMPLIFY study a total of 5,395 patients were randomised to treatment with apixaban 10 mg twice daily orally for 7 days followed by apixaban 5 mg twice daily orally for 6 months, or enoxaparin 1 mg/kg twice daily subcutaneously for at least 5 days (until INR≥ 2) and warfarin (target INR range 2.0-3.0) orally for 6 months.

 

The mean age was 56.9 years and 89.8% of randomised patients had unprovoked VTE events.

 

For patients randomised to warfarin, the mean percentage of time in therapeutic range (INR 2.0-3.0) was 60.9. Apixaban showed a reduction in recurrent symptomatic VTE or VTE- related death across the different levels of center TTR; within the highest quartile of TTR according to center, the relative risk for apixaban vs enoxaparin/warfarin was 0.79 (95% CI, 0.39, 1.61).

 

In the study, apixaban was shown to be non-inferior to enoxaparin/warfarin in the combined primary endpoint of adjudicated recurrent symptomatic VTE (nonfatal DVT or nonfatal PE) or VTE-related death (see Table 10).

 

Table 10: Efficacy results in the AMPLIFY study

 

Apixaban

N=2,609

n (%)

Enoxaparin/Warfarin

N=2,635

n (%)

Relative risk

(95% CI)

VTE or VTE-related death

59 (2.3)

71 (2.7)

0.84 (0.60, 1.18)*

      DVT

20 (0.7)

33 (1.2)

 

      PE

27 (1.0)

23 (0.9)

 

      VTE-related       death

12 (0.4)

15 (0.6)

 

VTE or all-cause death

84 (3.2)

104 (4.0)

0.82 (0.61, 1.08)

VTE or CV-related death

61 (2.3)

77 (2.9)

0.80 (0.57, 1.11)

VTE, VTE-related death, or major bleeding

73 (2.8)

118 (4.5)

0.62 (0.47, 0.83)

* Noninferior compared to enoxaparin/warfarin (p-value <0.0001)

 

Apixaban efficacy in initial treatment of VTE was consistent between patients who were treated for a PE [Relative Risk 0.9; 95% CI (0.5, 1.6)] or DVT [Relative Risk 0.8; 95% CI (0.5, 1.3)]. Efficacy across subgroups, including age, gender, body mass index (BMI), renal function, extent of index PE, location of DVT thrombus, and prior parenteral heparin use was generally consistent.

 

The primary safety endpoint was major bleeding. In the study, apixaban was statistically superior to enoxaparin/warfarin in the primary safety endpoint [Relative Risk 0.31, 95% confidence interval (0.17, 0.55), P-value <0.0001] (see Table 11).

 

Table 11: Bleeding results in the AMPLIFY study

 

Apixaban

N=2,676

n (%)

Enoxaparin/

Warfarin

N=2,689

n (%)

Relative risk

(95% CI)

Major

15 (0.6)

49 (1.8)

0.31 (0.17, 0.55)

Major + CRNM

115 (4.3)

261 (9.7)

0.44 (0.36, 0.55)

Minor

313 (11.7)

505 (18.8)

0.62 (0.54, 0.70)

All

402 (15.0)

676 (25.1)

0.59 (0.53, 0.66)

 

The adjudicated major bleeding and CRNM bleeding at any anatomical site were generally lower in the apixaban group as compared to the enoxaparin/warfarin group. Adjudicated ISTH major gastrointestinal bleeding occurred in 6 (0.2%) apixaban-treated patients and 17 (0.6%) enoxaparin/warfarin-treated patients.

 

AMPLIFY-EXT study

In the AMPLIFY-EXT study a total of 2,482 patients were randomised to treatment with apixaban 2.5 mg twice daily orally, apixaban 5 mg twice daily orally, or placebo for 12 months after completing 6 to 12 months of initial anticoagulant treatment. Of these, 836 patients (33.7%) participated in the AMPLIFY study prior to enrollment in the AMPLIFY-EXT study.

 

The mean age was 56.7 years and 91.7% of randomised patients had unprovoked VTE events.

 

In the study, both doses of apixaban were statistically superior to placebo in the primary endpoint of symptomatic, recurrent VTE (nonfatal DVT or nonfatal PE) or all-cause death (see Table 12).

 

Table 12: Efficacy results in the AMPLIFY-EXT study

 

Apixaban

Apixaban

Placebo

Relative risk (95% CI)

 

2.5 mg

(N=840)

5.0 mg

(N=813)

 

(N=829)

Apix 2.5 mg

vs. placebo

Apix 5.0 mg

vs. placebo

 

n (%)

 

 

Recurrent VTE or all-cause death

19 (2.3)

14 (1.7)

77 (9.3)

0.24

(0.15, 0.40)¥

0.19

(0.11, 0.33)¥

DVT*

6 (0.7)

7 (0.9)

53 (6.4)

 

 

PE*

7 (0.8)

4 (0.5)

13 (1.6)

 

 

All-cause death

6 (0.7)

3 (0.4)

11 (1.3)

 

 

Recurrent VTE or VTE-related death

14 (1.7)

14 (1.7)

73 (8.8)

0.19

(0.11, 0.33)

0.20

(0.11, 0.34)

Recurrent VTE or CV-related death

14 (1.7)

14 (1.7)

76 (9.2)

0.18

(0.10, 0.32)

0.19

(0.11, 0.33)

Nonfatal DVT

6 (0.7)

8 (1.0)

53 (6.4)

0.11

(0.05, 0.26)

0.15

(0.07, 0.32)

Nonfatal PE

8 (1.0)

4 (0.5)

15 (1.8)

0.51

(0.22, 1.21)

0.27

(0.09, 0.80)

VTE-related death

2 (0.2)

3 (0.4)

7 (0.8)

0.28

(0.06, 1.37)

0.45

(0.12, 1.71)

¥ p-value < 0.0001

* For patients with more than one event contributing to the composite endpoint, only the first event was reported (eg, if a subject experienced both a DVT and then a PE, only the DVT was reported)

† Individual subjects could experience more than one event and be represented in both classifications

 

Apixaban efficacy for prevention of a recurrence of a VTE was maintained across subgroups, including age, gender, BMI, and renal function.

 

The primary safety endpoint was major bleeding during the treatment period. In the study, the incidence in major bleeding for both apixaban doses was not statistically different from placebo. There was no statistically significant difference in the incidence of major + CRNM, minor, and all bleeding between the apixaban 2.5 mg twice daily and placebo treatment groups (see Table 13).

 

Table 13: Bleeding results in the AMPLIFY-EXT study

 

Apixaban

Apixaban

Placebo

Relative risk (95% CI)

 

2.5 mg

(N=840)

5.0 mg

(N=811)

 

(N=826)

Apix 2.5 mg

vs. placebo

Apix 5.0 mg

vs. placebo

 

 

n (%)

 

 

 

Major

2 (0.2)

1 (0.1)

4 (0.5)

0.49

(0.09, 2.64)

0.25

(0.03, 2.24)

Major + CRNM

27 (3.2)

35 (4.3)

22 (2.7)

1.20

(0.69, 2.10)

1.62

(0.96, 2.73)

Minor

75 (8.9)

98 (12.1)

58 (7.0)

1.26

(0.91, 1.75)

1.70

(1.25, 2.31)

All

94 (11.2)

121 (14.9)

74 (9.0)

1.24

(0.93, 1.65)

1.65

(1.26, 2.16)

 

Adjudicated ISTH major gastrointestinal bleeding occurred in 1 (0.1%) apixaban-treated patient at the 5 mg twice daily dose, no patients at the 2.5 mg twice daily dose, and 1 (0.1%) placebo-treated patient.

 

Paediatric population

 

The European Medicines Agency has deferred the obligation to submit the results of studies with Eliquis in one or more subsets of the paediatric population in venous and arterial embolism and thrombosis (see section 4.2 for information on paediatric use).

 


Absorption

 

The absolute bioavailability of apixaban is approximately 50% for doses up to 10 mg. Apixaban is rapidly absorbed with maximum concentrations (Cmax) appearing 3 to 4 hours after tablet intake. Intake with food does not affect apixaban AUC or Cmax at the 10 mg dose. Apixaban can be taken with or without food.

 

Apixaban demonstrates linear pharmacokinetics with dose proportional increases in exposure for oral doses up to 10 mg. At doses ≥ 25 mg apixaban displays dissolution limited absorption with decreased bioavailability. Apixaban exposure parameters exhibit low to moderate variability reflected by a within-subject and inter-subject variability of ~20% CV and ~30% CV, respectively.

 

Following oral administration of 10 mg of apixaban as 2 crushed 5 mg tablets suspended in 30 mL of water, exposure was comparable to exposure after oral administration of 2 whole 5 mg tablets. Following oral administration of 10 mg of apixaban as 2 crushed 5 mg tablets with 30 g of apple puree, the Cmax and AUC were 21% and 16% lower, respectively, when compared to administration of 2 whole 5 mg tablets. The reduction in exposure is not considered clinically relevant.

 

Following administration of a crushed 5 mg apixaban tablet suspended in 60 mL of G5W and delivered via a nasogastric tube, exposure was similar to exposure seen in other clinical studies involving healthy subjects receiving a single oral 5 mg apixaban tablet dose.

 

Given the predictable, dose-proportional pharmacokinetic profile of apixaban, the bioavailability results from the conducted studies are applicable to lower apixaban doses.

 

Distribution

 

Plasma protein binding in humans is approximately 87%. The volume of distribution (Vss) is approximately 21 litres.

 

Biotransformation and elimination

 

Apixaban has multiple routes of elimination. Of the administered apixaban dose in humans, approximately 25% was recovered as metabolites, with the majority recovered in faeces. Renal excretion of apixaban accounts for approximately 27% of total clearance. Additional contributions from biliary and direct intestinal excretion were observed in clinical and nonclinical studies, respectively.

 

Apixaban has a total clearance of about 3.3 L/h and a half-life of approximately 12 hours.

 

O-demethylation and hydroxylation at the 3-oxopiperidinyl moiety are the major sites of biotransformation. Apixaban is metabolised mainly via CYP3A4/5 with minor contributions from CYP1A2, 2C8, 2C9, 2C19, and 2J2. Unchanged apixaban is the major active substance-related component in human plasma with no active circulating metabolites present. Apixaban is a substrate of transport proteins, P-gp and breast cancer resistance protein (BCRP).

 

Elderly

 

Elderly patients (above 65 years) exhibited higher plasma concentrations than younger patients, with mean AUC values being approximately 32% higher and no difference in Cmax.

 

Renal impairment

 

There was no impact of impaired renal function on peak concentration of apixaban. There was an increase in apixaban exposure correlated to decrease in renal function, as assessed via measured creatinine clearance. In individuals with mild (creatinine clearance 51‑80 mL/min), moderate (creatinine clearance 30‑50 mL/min) and severe (creatinine clearance 15‑29 mL/min) renal impairment, apixaban plasma concentrations (AUC) were increased 16, 29, and 44% respectively, compared to individuals with normal creatinine clearance. Renal impairment had no evident effect on the relationship between apixaban plasma concentration and anti-Factor Xa activity.

 

In subjects with end-stage renal disease (ESRD), the AUC of apixaban was increased by 36% when a single dose of apixaban 5 mg was administered immediately after haemodialysis, compared to that seen in subjects with normal renal function. Haemodialysis, started two hours after administration of a single dose of apixaban 5 mg, decreased apixaban AUC by 14% in these ESRD subjects, corresponding to an apixaban dialysis clearance of 18 mL/min. Therefore, haemodialysis is unlikely to be an effective means of managing apixaban overdose.

 

Hepatic impairment

 

In a study comparing 8 subjects with mild hepatic impairment, Child-Pugh A score 5 (n = 6) and score 6 (n = 2), and 8 subjects with moderate hepatic impairment, Child-Pugh B score 7 (n = 6) and score 8 (n = 2), to 16 healthy control subjects, the single-dose pharmacokinetics and pharmacodynamics of apixaban 5 mg were not altered in subjects with hepatic impairment. Changes in anti-Factor Xa activity and INR were comparable between subjects with mild to moderate hepatic impairment and healthy subjects.

 

Gender

 

Exposure to apixaban was approximately 18% higher in females than in males.

 

Ethnic origin and race

 

The results across phase I studies showed no discernible difference in apixaban pharmacokinetics between White/Caucasian, Asian and Black/African American subjects. Findings from a population pharmacokinetic analysis in patients who received apixaban were generally consistent with the phase I results.

 

Body weight

 

Compared to apixaban exposure in subjects with body weight of 65 to 85 kg, body weight > 120 kg was associated with approximately 30% lower exposure and body weight < 50 kg was associated with approximately 30% higher exposure.

 

Pharmacokinetic/pharmacodynamic relationship

 

The pharmacokinetic /pharmacodynamic (PK/PD) relationship between apixaban plasma concentration and several PD endpoints (anti-Factor Xa activity, INR, PT, aPTT) has been evaluated after administration of a wide range of doses (0.5 – 50 mg). The relationship between apixaban plasma concentration and anti-Factor Xa activity was best described by a linear model. The PK/PD relationship observed in patients was consistent with that established in healthy subjects.

 


Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, fertility and embryo-foetal development and juvenile toxicity.

 

The major observed effects in the repeated dose toxicity studies were those related to the pharmacodynamic action of apixaban on blood coagulation parameters. In the toxicity studies little to no increase of bleeding tendency was found. However, since this may be due to a lower sensitivity of the non-clinical species compared to humans, this result should be interpreted with caution when extrapolating to humans.

 


Tablet core:

Anhydrous lactose

Microcrystalline cellulose (E460)

Croscarmellose sodium

Sodium laurilsulfate

Magnesium stearate (E470b)

 

Film coat:

Lactose monohydrate

Hypromellose (E464)

Titanium dioxide (E171)

Triacetin (E1518)

Yellow iron oxide (E172)


Not applicable


3 years Do not use Eliquis after the expiry date which is stated on the carton after EXP:. The expiry date refers to the last day of that month.

Do not store above 30 ° C.


Alu‑PVC/PVdC blisters. Cartons of  20 and 60 film-coated tablets


No special requirements.

 

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


Bristol-Myers Squibb / Pfizer EEIG, Ireland MANUFACTURED BY: Pfizer Ireland Pharmaceuticals, Newbridge, Ireland Packaging & Release By Pfizer Manufacturing Deutschland GmbH, Freiburg, Germany

February 2022
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