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نشرة الممارس الصحي نشرة معلومات المريض بالعربية نشرة معلومات المريض بالانجليزية
صور الدواء بيانات الدواء
رقم التسجيل
92-68-09
سنة التسجيل
2009
الاسم التجاري
PRADAXA 110MG CAPSULES
الاسم العلمي
DABIGATRAN ETEXILATE
التركيز
110
وحدة التركيز
mg
طريقة الإستعمال
Oral use
الشكل الصيدلاني
Capsule, hard
الحجم
وحدة الحجم
حجم العبوة
60
انواع العبوات
Blister
طريقة الصرف
Prescription
حالة المراقبة
Uncontrolled
نوع الدواء
NCE
مدة الصلاحية بالأشهر
24
شروط التخزين
store below 30°c
سعر الجمهور بالريال ( السعر )
308
المصنع
BOEHRINGER INGELHEIM
الوكيل
Cigalah Group
الشركة المسوقة
BOEHRINGER INGELHEIM
كود الكيمياء العلاجية التشريحية 1
B01AE07
كود الكيمياء العلاجية التشريحية 2
SFDA PIL (Patient Information Leaflet (PIL) are under review by Saudi Food and
Drug Authority)
1. What this product is and what it is used for
Pradaxa contains the active substance dabigatran etexilate and belongs to a
group of medicines called anticoagulants. It works by blocking a substance in
the body which is involved in blood clot formation.
Pradaxa is used in adults to:
‑ prevent the formation of blood clots in the veins after knee or hip
replacement surgery.
‑ prevent blood clots in the brain (stroke) and other blood vessels in
the body if you have a form of irregular heart rhythm called nonvalvular atrial
fibrillation and at least one additional risk factor.
‑ treat blood clots in the veins of your legs and lungs and to prevent
blood clots from re-occurring in the vein of your legs and lungs.
2. What you need to know before you use this product
Do not take Pradaxa
‑ if you are allergic to dabigatran etexilate or any of the other
ingredients of this medicine (listed in section 6).
‑ if you have severely reduced kidney function.
‑ if you are currently bleeding.
‑ if you have a disease in an organ of the body that increases the risk
of serious bleeding (e.g., stomach ulcer, injury or bleeding in the brain,
recent surgery of the brain or eyes).
‑ if you have an increased tendency to bleed. This may be inborn, of
unknown cause or due to other medicines.
‑ if you are taking medicines to prevent blood clotting (e.g.warfarin,
rivaroxaban, apixaban 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 while your heart beat is being restored to normal by a procedure
called catheter ablation for atrial fibrillation.
‑ if you have a severely reduced liver function or liver disease which
could possibly cause death.
‑ if you are taking oral ketoconazole or itraconazole, medicines to treat
fungal infections.
‑ if you are taking oral cyclosporine, a medicine to prevent organ
rejection after transplantation.
‑ if you are taking dronedarone, a medicine used to treat abnormal heart
beat.
‑ if you are taking a combination product of glecaprevir and
pibrentasvir, an antiviral medicine used to treat hepatitis C
‑ if you have received an artificial heart valve which requires permanent
blood thinning.
Warnings and precautions
Talk to your doctor before taking Pradaxa. You may also need to talk to your
doctor during treatment with Pradaxa if you experience symptoms or if you have
to undergo surgery.
Tell your doctor if you have or have had any medical conditions or illnesses, in
particular any of those included in the following list:
‑ if you have an increased bleeding risk, such as:
§ if you have been recently bleeding.
§ if you have had a surgical tissue removal (biopsy) in the past month.
§ if you have had a serious injury (e.g. a bone fracture, head injury or any
injury requiring surgical treatment).
§ if you are suffering from an inflammation of the gullet or stomach.
§ if you have problems with reflux of gastric juice into the gullet.
§ if you are receiving medicines which could increase the risk of bleeding. See
'Other medicines and Pradaxa' below.
§ if you are taking anti‑inflammatory medicines such as diclofenac,
ibuprofen,piroxicam.
§ if you are suffering from an infection of the heart (bacterial endocarditis).
§ if you know you have impaired kidney function, or you are suffering from
dehydration (symptoms include feeling thirsty and passing reduced amounts of
dark-coloured (concentrated) urine).
§ if you are older than 75 years.
§ if you weigh 50 kg or less.
‑ if you have had a heart attack or if you have been diagnosed with
conditions that increase the risk to develop a heart attack.
‑ if you have a liver disease that is associated with changes in the
blood tests. The use of Pradaxa is not recommended in this case.
Take special care with Pradaxa
‑ if you need to have an operation:
In this case Pradaxa will need to be stopped temporarily due to an increased
bleeding risk during and shortly after an operation. It is very important to
take Pradaxa before and after the operation exactly at the times you have been
told by your doctor.
‑ if an operation involves a catheter or injection into your spinal
column (e.g. for epidural or spinal anaesthesia or pain reduction):
§ it is very important to take Pradaxa before and after the operation exactly
at the times you have been told by your doctor.
§ tell your doctor immediately if you get numbness or weakness of your legs or
problems with your bowel or bladder after the end of anaesthesia, because urgent
care is necessary.
‑ if you fall or injure yourself during treatment, especially if you hit
your head. Please seek urgent medical attention. You may need to be checked by a
doctor, as you may be at increased risk of bleeding.
‑ 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.
Children and adolescents
Pradaxa is not recommended in children and adolescents below 18 years old.
Other medicines and Pradaxa
Tell your doctor or pharmacist if you are taking, have recently taken or might
take any other medicines. In particular you should tell your doctor before
taking Pradaxa, if you are taking one of the medicines listed below:
‑ Medicines to reduce blood clotting (e.g. warfarin, phenprocoumon,
acenocoumarol, heparin, clopidogrel, prasugrel, ticagrelor, rivaroxaban,
acetylsalicylic acid)
‑ Medicines to treat fungal infections (e.g. ketoconazole, itraconazole),
unless they are only applied to the skin
‑ Medicines to treat abnormal heart beats (e.g. amiodarone, dronedarone,
quinidine, verapamil).
If you are taking amiodarone, quinidine or verapamil containing medicines, your
doctor may tell you to use a reduced dose of Pradaxa depending on the condition
for which Pradaxa is prescribed to you. See section 3.
‑ Medicines to prevent organ rejection after transplantation (e.g.
tacrolimus, cyclosporine)
‑ A combination product of glecaprevir and pibrentasvir (an antiviral
medicine used to treat hepatitis C)
‑ Anti‑inflammatory and pain reliever medicines (e.g. acetylsalicylic
acid, ibuprofen, diclofenac)
‑ St. John´s wort, a herbal medicine for depression
‑ Antidepressant medicines called selective serotonin re-uptake
inhibitors or serotonin-norepinephrine re-uptake inhibitors
‑ Rifampicin or clarithromycin (two antibiotics)
‑ Anti‑viral medicines for AIDS (e.g. ritonavir)
‑ Certain medicines for treatment of epilepsy (e.g. carbamazepine,
phenytoin)
Pregnancy and breast‑feeding
The effects of Pradaxa on pregnancy and the unborn child are not known. You
should not take Pradaxa if you are pregnant unless your doctor advises you that
it is safe to do so. If you are a woman of child‑bearing age, you should avoid
becoming pregnant while you are taking Pradaxa.
You should not breast‑feed while you are taking Pradaxa.
Driving and using machines
Pradaxa has no known effects on the ability to drive or use machines.
3. How to use this product.
Always take this medicine exactly as your doctor has told you. Check with your
doctor if you are not sure.
Take Pradaxa as recommended for the following conditions:
Prevention of blood clot formation after knee or hip replacement surgery
The recommended dose is 220 mg once a day (taken as 2 capsules of 110 mg).
If your kidney function is decreased by more than half or if you are 75 years of
age or older, the recommended dose is 150 mg once a day (taken as 2 capsules of
75 mg).
If you are taking amiodarone, quinidine or verapamil containing medicines the
recommended dose is 150 mg once a day (taken as 2 capsules of 75 mg).
If you are taking verapamil containing medicines and your kidney function is
decreased by more than half, you should be treated with a reduced dose of 75 mg
Pradaxa because your bleeding risk may be increased.
For both surgery types, treatment should not be started if there is bleeding
from the site of operation. If the treatment cannot be started until the day
after surgery, dosing should be started with 2 capsules once a day.
After knee replacement surgery
You should start treatment with Pradaxa within 1‑4 hours after surgery finishes,
taking a single capsule. Thereafter two capsules once a day should be taken for
a total of 10 days.
After hip replacement surgery
You should start treatment with Pradaxa within 1‑4 hours after surgery finishes,
taking a single capsule. Thereafter two capsules once a day should be taken for
a total of 28‑35 days.
Prevention of brain or body vessel obstruction by blood clot formation
developing after abnormal heart beats and Treatment of blood clots in the veins
of your legs and lungs including prevention of blood clots from re-occurring in
the vein of your legs and lungs
The recommended dose is 300 mg taken as one 150 mg capsule twice a day.
If you are 80 years or older, the recommended dose of Pradaxa is 220 mg taken as
one 110 mg capsule twice a day.
If you are taking verapamil containing medicines, you should be treated with a
reduced Pradaxa dose of 220 mg taken as one 110 mg capsule twice a day, because
your bleeding risk may be increased.
If you have a potentially higher risk for bleeding, your doctor may decide to
prescribe a dose of Pradaxa 220 mg taken as one 110 mg capsule twice a day.
You can continue to take Pradaxa if your heart beat needs to be restored to
normal by a procedure called cardioversion. Take Pradaxa as your physician has
told you.
If a medical device (stent) has been deployed in a blood vessel to keep it open
in a procedure called percutaneous coronary intervention with stenting, you can
be treated with Pradaxa after your physician has decided that normal control of
blood coagulation is achieved. Take Pradaxa as your physician has told you.
How to take Pradaxa
Pradaxa can be taken with or without food. The capsule should be swallowed whole
with a glass of water, to ensure delivery to the stomach. Do not break, chew, or
empty the pellets from the capsule since this may increase the risk of bleeding.
Instructions for opening the blisters
The following pictogram illustrates how to take Pradaxa capsules out of the
blister
Tear off one individual blister from the blister card along the perforated line
Peel off the backing foil and remove the capsule.
· Do not push the capsules through the blister foil.
· Do not peel off the blister foil until a capsule is required.
Change of anticoagulant treatment
Without specific guidance from your doctor do not change your anticoagulant
treatment.
If you take more Pradaxa than you should
Taking too much Pradaxa increases the risk of bleeding. Contact your doctor
immediately if you have taken too many Pradaxa capsules. Specific treatment
options are available.
If you forget to take Pradaxa
Prevention of blood clot formation after knee or hip replacement surgery
Continue with your remaining daily doses of Pradaxa at the same time of the next
day.
Do not take a double dose to make up for a forgotten dose.
Prevention of brain or body vessel obstruction by blood clot formation
developing after abnormal heart beats and treatment of blood clots in the veins
of your legs and lungs including prevention of blood clots from re-occurring in
the vein of your legs and lungs
A forgotten dose can still be taken up to 6 hours prior to the next due dose.
A missed dose should be omitted if the remaining time is below 6 hours prior to
the next due dose.
Do not take a double dose to make up for a forgotten dose.
If you stop taking Pradaxa
Take Pradaxa exactly as prescribed. Do not stop taking Pradaxa without talking
to your doctor first, because the risk of developing a blood clot could be
higher if you stop treatment too early. Contact your doctor if you experience
indigestion after taking Pradaxa.
If you have any further questions on the use of this medicine, ask your doctor
or pharmacist.
4. Possible side effects
Like all medicines, this medicine can cause side effects, although not everybody
gets them.
Pradaxa affects blood clotting, so most side effects are related to signs such
as bruising or bleeding. Major or severe bleeding may occur, these constitute
the most serious side effects and, regardless of location, may become disabling,
life‑threatening or even lead to death. In some cases these bleedings may not be
obvious.
If you experience any bleeding event that does not stop by itself or if you
experience signs of excessive bleeding (exceptional weakness, tiredness,
paleness, dizziness, headache or unexplained swelling) consult your doctor
immediately. Your doctor may decide to keep you under closer observation or
change your medicine.
Tell your doctor immediately, if you experience a serious allergic reaction
which causes difficulty in breathing or dizziness.
Possible side effects are listed below, grouped by how likely they are to
happen.
Prevention of blood clot formation after knee or hip replacement surgery
Common (may affect up to 1 in 10 people):
A fall in the amount of haemoglobin in the blood (the substance in the
red blood cells)
Unusual laboratory test results on liver function
Uncommon (may affect up to 1 in 100 people):
Bleeding may happen from the nose, into the stomach or bowel, from
penis/vagina or urinary tract (incl. blood in the urine that stains the urine
pink or red), from piles, from the rectum, under the skin, into a joint, from or
after an injury or after an operation
Haematoma formation or bruising occurring after an operation
Blood detected in the stools by a laboratory test
A fall in the number of red cells in the blood
A decrease in the proportion of red cells in the blood
Allergic reaction
Vomiting
Frequent loose or liquid bowel movements
Feeling sick
Wound secretion (liquid exuding from the surgical wound)
Liver enzymes increased
Yellowing of the skin or whites of the eyes, caused by liver or blood
problems
Rare (may affect up to 1 in 1,000 people):
Bleeding
Bleeding may happen in the brain, from a surgical incision, from the site
of entry of an injection or from the site of entry of a catheter into a vein
Blood-stained discharge from the site of entry of a catheter into a vein
Coughing of blood or blood stained sputum
A fall in the number of platelets in the blood
A fall in the number of red cells in the blood after an operation
Serious allergic reaction which causes difficulty in breathing or
dizziness
Serious allergic reaction which causes swelling of the face or throat
Skin rash notable for dark red, raised, itchy bumps caused by an allergic
reaction
Sudden change of the skin which affects its colour and appearance
Itching
Ulcer in the stomach or bowel (incl. ulcer in the gullet)
Inflammation of the gullet and stomach
Reflux of gastric juice into the gullet
Belly ache or stomach ache
Indigestion
Difficulty in swallowing
Fluid exiting a wound
Fluid exiting a wound after an operation
Not known (frequency cannot be estimated from the available data):
Difficulty in breathing or wheezing
Decreases in the number or even lack of white blood cells (which help to
fight infections)
Hair loss
Prevention of brain or body vessel obstruction by blood clot formation
developing after abnormal heart beats
Common (may affect up to 1 in 10 people):
Bleeding may happen from the nose, into the stomach or bowel, from
penis/vagina or urinary tract (incl. blood in the urine that stains the urine
pink or red), or under the skin
A fall in the number of red cells in the blood
Belly ache or stomach ache
Indigestion
Frequent loose or liquid bowel movements
Feeling sick
Uncommon (may affect up to 1 in 100 people):
Bleeding
Bleeding may happen from piles, from the rectum, or in the brain.
Haematoma formation
Coughing of blood or blood stained sputum
A fall in the number of platelets in the blood
A fall in the amount of haemoglobin in the blood (the substance in the
red blood cells)
Allergic reaction
Sudden change of the skin which affects its colour and appearance
Itching
Ulcer in the stomach or bowel (incl. ulcer in the gullet)
Inflammation of the gullet and stomach
Reflux of gastric juice into the gullet
Vomiting
Difficulty in swallowing
Unusual laboratory test results on liver function
Rare (may affect up to 1 in 1,000 people):
Bleeding may happen into a joint, from a surgical incision, from an
injury, from the site of entry of an injection or from the site of entry of a
catheter into a vein
Serious allergic reaction which causes difficulty in breathing or
dizziness
Serious allergic reaction which causes swelling of the face or throat
Skin rash notable for dark red, raised, itchy bumps caused by an allergic
reaction
A decrease in the proportion of red cells in the blood
Liver enzymes increased
Yellowing of the skin or whites of the eyes, caused by liver or blood
problems
Not known (frequency cannot be estimated from the available data):
Difficulty in breathing or wheezing
Decreases in the number or even lack of white blood cells (which help to
fight infections)
Hair loss
In a clinical trial the rate of heart attacks with Pradaxa was numerically
higher than with warfarin. The overall occurence was low.
Treatment of blood clots in the veins of your legs and lungs including
prevention of blood clots from re-occurring in the veins of your legs and/or
lungs
Common (may affect up to 1 in 10 people):
Bleeding may happen from the nose, into the stomach or bowel, from the
rectum, from penis/vagina or urinary tract (incl. blood in the urine that stains
the urine pink or red), or under the skin
Indigestion
Uncommon (may affect up to 1 in 100 people):
Bleeding
Bleeding may happen into a joint or from an injury
Bleeding may happen from piles
A fall in the number of red cells in the blood
Haematoma formation
Coughing of blood or blood stained sputum
Allergic reaction
Sudden change of the skin which affects its colour and appearance
Itching
Ulcer in the stomach or bowel
Inflammation of the gullet and stomach
Reflux of gastric juice into the gullet
Feeling sick
Vomiting
Belly ache or stomach ache
Frequent loose or liquid bowel movements
Unusual laboratory test results on liver function
Liver enzymes increased
Rare (may affect up to 1 in 1,000 people):
Bleeding may happen, from a surgical incision, or from the site of entry
of an injection or from the site of entry of a catheter into a vein or from the
brain
A fall in the number of platelets in the blood
Serious allergic reaction which causes difficulty in breathing or
dizziness
Serious allergic reaction which causes swelling of the face or throat
Skin rash notable for dark red, raised, itchy bumps caused by an allergic
reaction
Difficulty in swallowing
A decrease in the proportion of red cells in the blood
Not known (frequency cannot be estimated from the available data):
Difficulty in breathing or wheezing
A fall in the amount of haemoglobin in the blood (the substance in the
red blood cells)
A fall in the number of red cells in the blood
Decreases in the number or even lack of white blood cells (which help to
fight infections)
Yellowing of the skin or whites of the eyes, caused by liver or blood
problems
Hair loss
In the trial program the rate of heart attacks with Pradaxa was higher than with
warfarin. The overall occurence was low. No imbalance in the rate of heart
attacks was observed in patients treated with dabigatran versus patients treated
with placebo.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes
any possible side effects not listed in this leaflet. You can also report side
effects directly. By reporting side effects you can help provide more
information on the safety of this medicine.
5. How to store this product
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton,
blister or bottle after “EXP”. The expiry date refers to the last day of that
month.
Blister: Store below 30⁰ C in the original package in order to protect from
moisture.
Do not throw away any medicines via wastewater. Ask your pharmacist how to throw
away medicines you no longer use. These measures will help protect the
environment.
6. Further information
a. What this product contains
‑ The active substance is dabigatran. Each hard capsule contains 110 mg
dabigatran etexilate (as mesilate).
‑ The other ingredients are tartaric acid, acacia, hypromellose,
dimeticone 350, talc, and hydroxypropylcellulose.
‑ The capsule shell contains carrageenan, potassium chloride, titanium
dioxide, indigo carmine, and hypromellose.
‑ The black printing ink contains shellac, iron oxide black and potassium
hydroxide.
b. What this product looks like and contents of the pack
Pradaxa 110 mg are hard capsules with an opaque, light blue coloured cap and an
opaque, light blue coloured body. The Boehringer Ingelheim logo is printed on
the cap and “R110” on the body of the capsule. Pradaxa is available in packs
containing 10 x 1, 30 x 1 or 60 x 1 capsules, a multipack containing 3 packs of
60 x 1 hard capsules (180 hard capsules) or a multipack containing 2 packs of 50
x 1 hard capsules (100 hard capsules) in aluminium perforated unit dose
blisters. Furthermore, Pradaxa is available in packs containing 60 x 1 capsules
in aluminium perforated unit dose white blisters. Not all pack sizes may be
marketed.
c. Marketing Authorization Holder and Manufacturer
Marketing Authorisation Holder
Boehringer Ingelheim International GmbH
Binger Strasse 173
D‑55216 Ingelheim am Rhein
Germany
Manufacturer
Boehringer Ingelheim Pharma GmbH & Co. KG
Binger Strasse 173
D‑55216 Ingelheim am Rhein
Germany
For any information about this medicinal product, please contact the local
representative of the Marketing Authorisation Holder:
Kingdom of Saudi Arabia (Scientific Office)
Riyadh.
Tel: +966-11-5116504
Fax: +966-11-5116545
d. This leaflet was last revised in {MM/YYYY}
05/2020
نشرة الدواء تحت مراجعة الهيئة العامة للغذاء والدواء (اقرأ هذه النشرة بعناية
قبل البدء في استخدام هذا المنتج لأنه يحتوي على معلومات مهمة لك)
1. ما ھو هذا المستحضر وماھي دواعي استعماله
براداكسا هو دواء يحتوي على المادة الفعالة دابيجاتران إيتيكسيلات. وهو يعمل عن
طريق منع مادة في الجسم مسؤولة عن تكون الجلطات الدموية.
يُستخدم براداكسا في الوقاية من تكون الجلطات الدموية في الأوردة بعد إجراء جراحة
استبدال مفصل الورك أو الركبة في المرضى البالغين .
براداكسا هو دواء يُستخدم لخفض خطورة انسداد أوعية المخ أو الجسم بفعل تكون الجلطات
الدموية لدى المرضى البالغين المصابين بضربات القلب غير العادية (الرجفان
الأذيني) وعوامل الخطورة الإضافية. براداكسا هو دواء من أدوية سيولة الدم التي
تخفِّض خطورة تكون الجلطات الدموية.
2. ما الذي يجب عليك معرفته قبل استعمال هذا المستحضر
لا تتناول براداكسا
- إذا كانت لديك حساسية للدابيجاتران إيتيكسيلات أو دابيجاتران أو لأي من مكونات
هذا الدواء الأخرى (الواردة في القسم 6).
- إذا كنت تعاني من قصور شديد في وظائف الكلى.
- إذا كنت تعاني من نزيف في الوقت الحالي.
- إذا كان لديك مرض في أحد أعضاء الجسم يزيد من خطر حدوث نزيف خطير (على سبيل
المثال ، قرحة في المعدة ، إصابة أو نزيف في الدماغ ، جراحة حديثة للمخ أو العين).
- إذا كان لديك قابلية زائدة للنزيف. قد يكون هذا وراثيًا بسبب غير معروف أو
بسبب أدوية أخرى.
- إذا كنت تتناول أدوية لمنع تخثر الدم ( مثل الوارفرين، أو ريفاروكسابان ، أو
الهيبارين ، أبيكسابان)، ما عدا عند تغيير العلاج المضاد للتخثر أو أثناء وجود خط
وريدي أو شرياني وتحصل على الهيبارين من خلال هذا الخط لابقائه مفتوحا أو أثناء
تنظيم ضربات قلبك إلى طبيعتها من خلال إجراء يسمى الاستئصال بالقسطرة للرجفان
الأذيني.
- إذا كنت تعاني من قصور شديد في وظائف الكبد أو من أمراض الكبد التي قد تتسبب
في الوفاة.
- إذا كنت تتناول عقار كيتوكينازول أو إيتراكونازول الذي يؤخذ عن طريق الفم وهي
أدوية لعلاج حالات العدوى الفطرية.
- إذا كنت تتناول عقار سيكلوسبورين وهو دواء لمنع رفض العضو بعد إجراء عملية
الزرع.
- إذا كنت تتناول عقار دروندارن، و هو عقار يستخدم لمنع تكرار مشكلة عدم انتظام
دقات القلب.
- إذا كنت تتناول تركيبة من جليكابريفير وبيبرنتاسفير ، وهو دواء مضاد للفيروسات
يستخدم لعلاج التهاب الكبد سي.
- إذا كنت قد تلقيت صمام القلب صناعي
تحذيرات واحتياطات
تحدث إلى طبيبك قبل تناول براداكسا. قد تحتاج أيضا إلى التحدث مع طبيبك أثناء
العلاج بعقار براداكسا في حالة ظهور أعراض أو إذا كان يجب أن تجري عملية جراحية.
أخبر طبيبك إذا كنت تعاني أو سبق أن عانيت من أي من الحالات الطبية أو الأمراض،
وبالأخص أي مما هو وارد في القائمة التالية:
- لا يُوصى باستخدام براداكسا عند الإصابة بمرض الكبد المرتبط بتغيرات في فحوصات
الدم.
- عند زيادة خطورة النزيف كما قد يكون هو الوضع في الحالات التالية:
إذا كنت قد تعرضت لنزيف في الأونة الأخيرة
عند خضوعك لإزالة النسيج بطريقة جراحية (أخذ عينة) في الشهر السابق.
عند إصابتك إصابة بالغة (كسر بالعظم أو إصابة بالرأس أو أي إصابة تتطلب علاجًا
جراحيًا).
عند معاناتك من التهاب المريء أو المعدة.
إذا كانت لديك مشكلات في ارتجاع عصارة المعدة إلى المريء.
إذا كنت تتناول أدوية تزيد من خطورة النزيف مثل الاسبرين (حَمْضُ الأسيتيل
ساليسيليك) كلوبيدوجريل، تيكاجريلور.
إذا كنت تتناول أدوية مضادة للالتهابات مثل ديكلوفيناك، إيبوبروفين،
بايروكسيكام.
إذا كنت تعاني من عدوى في القلب (الإلتهاب الجرثومي للغشاء المبطن للقلب).
إذا كنت مصابًا باختلال في وظائف الكلى أو اذا كنت تعاني من الجفاف (تتضمن
الأعراض الشعور بالعطش وتمرير كميات مخفضة من البول (مركزة) داكنة اللون).
إذا كان عمرك فوق 75 عامًا.
إذا كان وزنك 50 كجم أو أقل.
- إذا كنت قد عانيت مسبقًا من نوبة قلبية أو تم تشخيصك بحالات تؤدي إلى ارتفاع
خطر حدوث نوبة قلبية.
احتياطات خاصة عند استخدام برادكسا
- سيلزم إيقاف براداكسا مؤقتًا بسبب زيادة خطورة النزيف خلال العملية وبعدها
مباشرة. من المهم تناول برادكسا قبل و بعد العملية بالضبط حسب وصف الطبيب
- إذا كانت العملية تتطلب إدخال أنبوب (قسطرة) أو حقن في الحبل الشوكي (إدخال
أنبوب في الظهر للتخدير أو تسكين الألم) :
o من المهم تناول برادكسا قبل و بعد العملية بالضبط حسب وصف الطبيب.
o أخبر طبيبك فوراً إذا شعرت بخدور أو ضعف في ساقيك أو مشاكل مع أمعائك أو
مثانتك بعد نهاية التخدير ، لأن الرعاية العاجلة ضرورية.
- إذا سقط أو أصبت نفسك أثناء العلاج، خاصةً إذا أديت إلى إصابة رأسك، فيُرجى
طلب العناية الطبية العاجلة. قد تحتاج للفحص بواسطة الطبيب، لأنك قد تكون معرضًا
لارتفاع خطر حدوث نزيف
- إذا كنت تتناول عقار كيتوكينازول أو إيتراكونازول الذي يؤخذ عن طريق الفم وهي
أدوية لعلاج حالات العدوى الفطرية.
الأطفال والمراهقون
يجب عدم استعمال براداكسا في الأطفال والمراهقين الذين يبلغ عمرهم أقل من 18عامًا
.
تناول براداكسا مع الأدوية الأخرى
يُرجى إخطار الطبيب أو الصيدلي إذا كنت تتناول أي أدوية أخرى أو تكون قد تناولتها
مؤخرًا أو قد تتناولها مستقبلاً،. مثل:
أدوية خفض تجلط الدم (على سبيل المثال الوارفارين ، فينبروكومون ،
اسينوكومارول ، الهيبارين ، كلوبيدوقرل ، براسوجريل ، تيكاجريلار ، ريفاروكابان ،
حمض أسيتيل الساليسيليك)
أدوية لعلاج الالتهابات الفطرية (مثل الكيتوكونازول ، إيتراكونازول) ، إلا إذا
تم استخدامها على الجلد فقط
أدوية لعلاج ضربات القلب غير الطبيعية (مثل أميودارون ، درونيدارون ،
الكينيدين ، فيراباميل). إذا كنت تتناول دواء الأميودارون أو الكينيدين أو
فيراباميل ، سيطلب منك الطبيب استخدام جرعة مخفضة من براداكسا. انظر أيضا القسم 3.
الأدوية المستخدمة في منع رفض العضو بعد إجراء عملية الزرع (مثل تاكروليمس،
سيكلوسبورين)
إذا كنت تتناول عقار كيتوكينازول أو إيتراكونازول الذي يؤخذ عن طريق الفم وهي
أدوية لعلاج حالات العدوى الفطرية.
الأدوية المضادة للالتهاب والألم المخفف (مثل حمض أسيتيل الساليسيليك ،
ايبوبروفين ، ديكلوفيناك)
نبتة سانت جونز ، وهو دواء عشبي لعلاج الاكتئاب
أدوية مضادة للاكتئاب تُسمى مثبطات إعادة امتصاص السيروتونين الإنتقائية أو
مثبطات إعادة امتصاص السيروتونين والنورابِينِفْرين.
ريفامبيسين أو كلاريثروميسين وهما مضادان حيويان
الأدوية المضادة لفيروس الإيدز (مثل ريتونافير)
أدوية علاج الصرع (مثل كاربامازيبين، فينوتوين)
الحمل والرضاعة الطبيعية
تأثيرات براداكسا على الحمل والجنين غير معروفة. يجب ألا تأخذي براداكسا إذا كنت
حاملاً ما لم يرشدك طبيبك بأن أخذ هذا العقار آمن بالنسبة لك. إذا كنت من السيدات
اللاتي في سن الإنجاب، فيجب تجنب الحمل أثناء العلاج باستخدام براداكسا.
يجب ألا تقومين بالرضاعة الطبيعية أثناء فترة العلاج باستخدام براداكسا.
قيادة السيارات واستخدام الآلات
عقار برادكسا ليس له أي آثار معروفة على القدرة على القيادة أو استخدام الآلات
https://localhost:44358/Dashboard 3. ماھي طريقة استعمال هذا المستحضر
يجب دومًا تناول هذا الدواء حسب إرشادات الطبيب. وإذا لم تكن متأكدًا، فيجب عليك
مراجعة الطبيب المعالج.
تناول براداكسا وفق الجرعة الموصى بها في الحالات التالية:
منع تكون الجلطات الدموية بعد إجراء جراحة استبدال مفصل الورك أو الركبة
الجرعة الموصى بها من براداكسا بشكل عام هي 220 ملجم مرة واحدة يوميًا تؤخذ بواقع
كبسولتين 110 ملجم.
إذا كنت تعاني من قصور وظائف الكلى بأكثر من النصف أو إذا كان عمرك 75 عامًا فأكثر،
فإن الجرعة الموصى بها هي 150 ملجم مرة واحدة يوميًا (تؤخذ بواقع كبسولتين 75
ملجم).
إذا كنت تتناول أدوية محتوية على أميودارون أو كوينيدين أو فيراباميل، فإن الجرعة
الموصى بها هي 150 ملجم مرة واحدة يوميًا (تؤخذ بواقع كبسولتين 75 ملجم).
إذا كنت تتناول أدوية محتوية على فيراباميل وعانيت من قصور وظائف الكلى بأكثر من
النصف، فيجب علاجك بجرعة منخفضة من براداكسا 75 ملجم نظرًا لزيادة خطورة النزيف
لديك.
بالنسبة لكلا النوعين من العمليات الجراحية ، يجب ألا يتم بدء العلاج إذا كان هناك
نزيف من موقع العملية. إذا لم يمكن بدء العلاج حتى اليوم التالي للجراحة ، يجب أن
تبدأ الجرعات مع كبسولتين مرة واحدة يومياً.
بعد جراحة استبدال مفصل الركبة
يجب أن تبدأ العلاج مع برادكسا في غضون 1-4 ساعات بعد انتهاء الجراحة ، مع أخذ
كبسولة واحدة. بعد ذلك يجب أخذ كبسولتين110 ملجم مرة واحدة في اليوم لمدة 10 أيام.
بعد استبدال الحوض
يجب أن تبدأ العلاج مع برادكسا في غضون 1-4 ساعات بعد انتهاء الجراحة ، مع أخذ
كبسولة واحدة. بعد ذلك يجب أخذ كبسولتين 110 ملجم مرة واحدة في اليوم لمدة ما
مجموعه 28-35 يوما.
الوقاية من انسداد الأوعية الدموية في المخ أو الجسم بتكوين الجلطة الدموية بعد
حدوث دقات قلب غير طبيعية وعلاج جلطات الدم في عروق الساقين والرئتين ، بما في ذلك
الوقاية من الجلطات الدموية من الظهور من جديد في الوريد في الساقين والرئتين
تبلغ الجرعة الموصى بها 300 ملجم تؤخذ بواقع كبسولة واحدة 150 ملجم مرتين يوميًا.
إذا كان عمرك 80 عامًا فأكثر، فإن الجرعة الموصى بها من براداكسا هي 220 ملجم تؤخذ
بواقع كبسولة واحدة 110 ملجم مرتين يوميًا.
إذا كنت تتناول أدوية محتوية على فيراباميل، فيجب علاجك بجرعة منخفضة من براداكسا
220 ملجم تؤخذ بواقع كبسولة 110 ملجم مرتين يوميًا نظرًا لزيادة خطورة النزيف لديك.
إذا كانت هناك احتمالية لزيادة خطورة النزيف لديك، فقد يقرر طبيبك وصف جرعة
براداكسا 220 ملجم تؤخذ بواقع كبسولة واحدة 110 ملجم مرتين يوميًا.
يمكنك الاستمرار في تناول براداكسا إذا كانت ضربات قلبك بحاجة إلى تنظيم وضعها
الطبيعي عن طريق إجراء يسمى تقويم نظم القلب. خذ براداكسا كما أخبرك طبيبك.
إذا تم وضع جهاز طبي (دعامة) في وعاء دموي لإبقائه مفتوحًا في إجراء يسمى التدخل
التاجي عن طريق الجلد باستخدام الدعامة ، يمكنك العلاج باستخدام براداكسا بعد أن
يقرر طبيبك تحقيق السيطرة الطبيعية على تخثر الدم خذ براداكسا كما أخبرك طبيبك.
ويمكن تناوله مع الطعام أو بدونه. يجب بلع الكبسولة كاملةً بكوب من الماء للتأكد من
الوصول الى لمعدة. لا تقم بتكسير الحبيبات أو مضغها أو تفريغها من الكبسولة فقد
يزيد هذا من خطورة النزيف.
عند إخراج كبسولات عقار براداكسا من أشرطة العبوة، يُرجى ملاحظة التَّعليمات
التَّالية:
يوضح الرسم التَّوضيحي التَّالي كيفية إخراج كبسولات عقار براداكسا من الأشرطة
اقطع شريطًا واحدًا من بطاقة الشَّرائط على طول الخط المثقوب.
قشر رقاقة غلاف الألومينيوم وأخرج الكبسولة.
· لا تدفع الكبسولات عبر رقاقة الألومينيوم بالشريط.
· لا تقم بتقشير رقاقة الألومنيوم بالشَّريط حتى تكون بحاجة إلى كبسولة.
تغيير العلاج المضاد للتجلط
بدون توجيه من طبيبك لا تقم بتغير مضاد التجلط الخاص بك
ما يجب فعله عند تناول جرعة زائدة من براداكسا
عند تناول جرعة زائدة عن الموصى بها من براداكسا، فقد تزداد لديك خطورة النزيف.
أخبر الطبيب في فوراً إذا كنت تتناول أكثر من الجرعة التي وصفها لك من عقار
براداكسا. خيارات علاجية خاصة متاحة.
ما يجب فعله عند نسيان تناول دواء براداكسا
منع تكون الجلطات الدموية بعد إجراء جراحة استبدال مفصل الورك أو الركبة
استمر على الجرعات اليومية المتبقية من براداكسا في نفس الموعد من اليوم التالي.
يجب عدم تناول جرعة مزدوجة لتعويض الجرعات المنسية.
الوقاية من انسداد أوعية المخ أو الجسم بفعل تكون الجلطات الدموية بعد ضربات القلب
غير العادية
عند نسيان تناول أي جرعة، فإنه يمكن تناولها خلال فترة تصل إلى 6 ساعات قبل موعد
الجرعة التالية.
يجب تخطي الجرعة المنسية إذا كان الوقت المتبقي قبل موعد الجرعة التالية أقل من 6
ساعات.
ولا يجب تناول جرعة مضاعفة لتعويض قرص تم نسيانه.
إذا توقفت عن تناول براداكسا
تناول براداكسا كما هو موصوف بالضبط. لا تتوقف عن تناول براداكسا بدون استشارة
الطبيب أولاً. إن إيقاف براداكسا قد يزيد من خطورة تكون الجلطة الدموية لدى المرضى
الخاضعين للعلاج بعد جراحة استبدال مفصل الورك أو الركبة.
كما ينبغي إخبار الطبيب أو الصيدلي في حالة وجود أية أسئلة إضافية متعلقة باستعمال
هذا الدواء.
4. الأعراض الجانبية المحتملة
يمكن أن يتسبب هذا الدواء في حدوث آثار جانبية، شأنه في ذلك شأن جميع العقاقير
الأخرى، وإن كانت لا تصيب كل من يتناوله.
وبما أن عقار براداكسا يؤثر على تجلط الدم، فإن معظم الآثار الجانبية مرتبطة
بعلامات مثل الكدمات أو النزيف. قد تحدث حالات نزيف كبرى أو حادة و تمثل أخطر
الأثار الجانبية ، وبغض النظر عن موقعها، فقد تصبح معيقة أو مهددة للحياة أو تؤدي
إلى الوفاة. في بعض الحالات، قد تكون حالات النزيف هذه غير واضحة.
استشير طبيبك فورًا إذا تعرضت لأي حالة نزيف لا يتوقف من تلقاء نفسه أو أعراض
نزيف ممتد أو شديد أو شعور استثنائي بالضعف أو تعب أو شحوب أو دوخة أو صداع أو تورم
غير معروفة أسبابه. قد يقرر طبيبك إبقاءك تحت الملاحظة عن قرب أو تغيير دوائك.
أخبر طبيبك فورا إذا كنت تعاني من الحساسيه رد فعل خطير والذي يسبب صعوبة في التنفس
أو دوار.
وفيما يلي الآثار الجانبية مصنفة بحسب احتمالية الحدوث:
منع تكون الجلطات الدموية بعد إجراء جراحة استبدال مفصل الورك أو الركبة
الآثار الجانبية الشائعة (قد تظهر في مريض من كل 10 مرضي ):
-انخفاض كمية الهيموجلوبين في الدم (المادة الموجودة في خلايا الدم الحمراء)
-نتائج الفحوصات المعملية التي أجريت على وظائف الكبد غير عادية
الآثار الجانبية غير الشائعة (قد تظهر في مريض من كل 100 مريض):
- قد يحدث النزيف من الأنف الى المعدة أوالأمعاء من القضيب / المهبل أو المسالك
البولية (بما في ذلك الدم في البول بما يجعل لون البول وردي أو أحمر)، من البواسير
الى المستقيم أو تحت الجلد أو في المخ أو في مفصل ناتج عن إصابة أو بعدها أو بعد
إجراء العملية.
- تكون ورم دموي أو كدمات تحدث بعد إجراء العملية
-وجود دم في البراز تكشف عنه نتائج الفحوصات المعملية
-انخفاض عدد خلايا الدم الحمراء
-انخفاض نسبة الخلايا الحمراء في الدم
-تفاعلات الحساسية
-القيء
-تكرار التغوط الرخو أو السائل
-الشعور بالإعياء
-نضح كمية قليلة من السائل من الشق الذي تم فتحه لإجراء جراحي
-إفرازات الجرح (السائل الذي ينضح من الجرح الجراحي)
-زيادة إنزيمات الكبد
-اصفرار الجلد او زيادة بياض العين بسبب مشاكل الكبد أو الدم
الآثار الجانبية النادرة (تظهر في مريض من كل 1000 مريض):
-نزيف
-نزيف قد يحدث في المخ من شق جراحي من موضع دخول الحقنة أو من موضع دخول القسطرة
في الوريد
-إفرازات مبقعة بدم من موضع دخول القسطرة في الوريد
- - سعال دموي أو بلغم بلون الدم
-انخفاض عدد الصفيحات في الدم
-انخفاض عدد كرات الدم الحمراء في الدم بعد العملية
- تفاعلات حساسية خطيرة تسبب صعوبة في التنفس أو دوخة
- تفاعلات حساسية خطيرة تسبب تورم الوجه أو الحلق.
-طفح جلدي مميز بنتوءات حمراء داكنة اللون مثيرة للحكة ناتجة عن تفاعلات الحساسية
-تغير مفاجئ في الجلد مما يؤثر على لونه وشكله
-حكة
-قرحة في المعدة أو الأمعاء (و ذلك يتضمن قرحة في المريء)
-التهاب المريء أو المعدة
- ارتجاع عصارة المعدة إلى المريء
-ألم بالبطن أو ألم بالمعدة
-عسر الهضم
-صعوبة في البلع
-خروج سائل من الجرح
-خروج سائل من الجرح بعد العملية
آثار غير معروفة (لا يمكن تقديرتكرارها من البيانات المتاحة):
-صعوبة التنفس أو أزيز
- انخفاض في عدد أو حتى نقص خلايا الدم البيضاء (التي تساعد في مكافحة العدوى)
- تساقط الشعر
الوقاية من انسداد أوعية المخ أو الجسم بفعل تكون الجلطات الدموية بعد ضربات القلب
غير العادية
الآثار الجانبية الشائعة (قد تظهر في مريض من كل 10 مرضي ):
- قد يحدث النزيف من الأنف الى المعدة أوالأمعاء من القضيب / المهبل أو المسالك
البولية (بما في ذلك الدم في البول بما يجعل لون البول وردي أو أحمر)، أو تحت .
-انخفاض عدد خلايا الدم الحمراء
-ألم بالبطن أو ألم بالمعدة
-عسر الهضم
-تكرار التغوط الرخو أو السائل
-الشعور بالإعياء
الآثار الجانبية غير الشائعة (قد تظهر في مريض من كل 100 مريض):
- نزيف
- نزيف: قد يحدث نزيف من البواسير أو داخل المستقيم أو داخل المخ.
-تكون ورم دموي
- سعال دموي أو بلغم بلون الدم
-انخفاض عدد الصفيحات في الدم
-انخفاض كمية الهيموجلوبين في الدم (المادة الموجودة في خلايا الدم الحمراء)
-تفاعلات الحساسية
-تغير مفاجئ في الجلد مما يؤثر على لونه وشكله
-حكة
-قرحة في المعدة أو الأمعاء (و ذلك يتضمن قرحة في المريء)
- التهاب المريء والمعدة
- ارتجاع عصارة المعدة إلى المريء
-القيء
-صعوبة في البلع
-نتائج الفحوصات المعملية التي أجريت على وظائف الكبد غير عادية
الآثار الجانبية النادرة (تظهر في مريض من كل 1000 مريض):
- قد يحدث النزيف في مفصل ناتج عن إصابة أو بعد إجراء العملية أومن موضع دخول
الحقنة أو موضع دخول القسطرة في الوريد
- تفاعلات حساسية خطيرة تسبب صعوبة في التنفس أو دوخة
- تفاعلات حساسية خطيرة تسبب تورم الوجه أو الحلق.
-طفح جلدي مميز بنتوءات حمراء داكنة اللون مثيرة للحكة ناتجة عن تفاعلات الحساسية
-انخفاض نسبة الخلايا الحمراء في الدم
-زيادة إنزيمات الكبد
-اصفرار الجلد أو بياض العين الناتج عن مشكلات بالكبد أو الدم
آثار غير معروفة (لا يمكن تقديرتكرارها من البيانات المتاحة):
-صعوبة التنفس أو أزيز
- انخفاض في عدد أو حتى نقص خلايا الدم البيضاء (التي تساعد في مكافحة العدوى)
- تساقط الشعر
في تجربة سريرية كان معدل النوبات القلبية مع برادكسا أعلى رقمياً من الوارفارين.
كان التواجد الكلي منخفضًا.
علاج جلطات الدم في عروق الساقين والرئتين بما في ذلك الوقاية من الجلطات الدموية
من الظهور في أوردة الساقين و / أو الرئتين
شائع (قد يؤثر على شخص واحد من كل 10 أشخاص):
- النزيف قد يحدث من الأنف أو المعدة أو الأمعاء ، من المستقيم ، من القضيب /
المهبل أو المسالك البولية (بما في ذلك الدم في البول الذي يلوث البول الوردي أو
الأحمر) ، أو تحت الجلد
- عسر الهضم
غير شائع (قد يؤثر على شخص واحد من كل 100 شخص):
- نزيف
- قد يحدث النزيف في المفصل أو بسبب الإصابة
- قد يحدث النزف من الأكوام
- انخفاض عدد الخلايا الحمراء في الدم
- تكوين ورم دموي
- سعال الدم أو البلغم الملطخ بالدم
- رد فعل تحسسي
- تغير مفاجئ في الجلد الذي يؤثر على لونه ومظهره
- متلهف، متشوق
- قرحة في المعدة أو الأمعاء
- التهاب المريمية والمعدة
- ارتجاع عصارة المعدة في المريء
- الشعور بالإعياء
- القيء
- ألم البطن أو آلام المعدة
- تكرار التغوط الرخو أو السائل
- نتائج الاختبارات المعملية غير العادية على وظائف الكبد
- زيادة انزيمات الكبد
نادر (قد يصل إلى 1 من كل 1000 شخص):
- قد يحدث النزيف ، من شق جراحي ، أو من موضع إدخال حقنة أو من موقع دخول قسطرة إلى
الوريد أو من الدماغ.
- انخفاض في عدد الصفائح الدموية في الدم
- تفاعل حساسي خطير يسبب صعوبة في التنفس أو الدوخة
- تفاعل حساسي خطير يسبب تورم الوجه أو الحلق
- طفح جلدي ملحوظ للون الأحمر الداكن ، والمطرقة ، والحكة الناجمة عن رد فعل تحسسي
- صعوبة في البلع
- انخفاض في نسبة الخلايا الحمراء في الدم
غير معروف (لا يمكن تقدير التردد من البيانات المتاحة):
- صعوبة في التنفس أو التنفس
- انخفاض في كمية الهيموجلوبين في الدم (المادة الموجودة في خلايا الدم الحمراء)
- انخفاض عدد الخلايا الحمراء في الدم
- انخفاض في عدد أو حتى نقص خلايا الدم البيضاء (التي تساعد في مكافحة العدوى)
- اصفرار الجلد أو بياض العين ، بسبب مشاكل في الكبد أو الدم
- تساقط الشعر
في البرنامج التجريبي، كان معدل حدوث النوبات القلبية مع عقار براداكسا أعلى من
عقار وارفارين. كان معدل الحدوث العام منخفضًا. لم يلاحظ أي اختلال في معدل حدوث
النوبات القلبية في المرضى الذين تم علاجهم بدابيجاتران مقابل المرضى ممن تم علاجهم
بالعقار المُمَوَّه.
الإبلاغ عن الآثار الجانبية
إذا أُصبت بأيٍّ من الآثار الجانبية، فتحدَّث إلى طبيبك أو الصيدلي أو الممرض(ة).
ويشمل ذلك أية آثار جانبية مُحتمَلة، غير المُدرجة في هذه النَّشرة. من خلال
إبلاغك عن الآثار الجانبية، يمكنك المساعدة في توفير معلومات إضافية حول أمان
استخدام هذا الدَّواء.
5. طريقة تخزين المستحضر
يحفظ الدواء بعيدًا عن متناول الأطفال ومرآهم.
تجنب استعمال الدواء بعد انتهاء تاريخ الصلاحية، والذي يكون موضحًا على علبة
الكرتون أو الشريط الحبيبي بعد “EXP” .
ويشير تاريخ انتهاء الصلاحية إلى آخر يوم في ذلك الشهر.
الشريط الحبيبي: يخزن داخل العبوة الأصلية في درجة حرارة أقل من 30 درجة مئوية
للحماية من الرطوبة.
لا تتخلص من أي أدوية عبر مرحاض المياه. اسأل الصيدلي عن كيفية التخلص من الأدوية
التي لم تعد تستخدمها. هذه التدابير سوف تساعد في حماية البيئة.
6. معلومات أخرى
أ. على ماذا يحتوي هذا المستحضر
- المادة الفعالة هي: دابيجاتران، ويتم إعطاؤها على هيئة ١١٠ مجم
دابيجاتران إتيكسيلات في شكل ميسيلات.
- المكونات الأخرى هي حمض الطرطريك، أكاشيا ، هيبروميلوز،
ديميتيكون٣٥٠، تلك وهيدروكسي بروبيل السليلوز.
- يحتوي غلاف الكبسولة على كاراجينان، كلُوريد البُوتاسْيُوم، ثاني
أكسيد التيتانيوم، أنديجو كارمين، وهيبروميلوز.
- يحتوي حبر الطباعة الأسود على صَمْغ اللَّكّ (الشيلاك)، أكسيد الحديد
الأسود وهيدروكسيد البوتاسيوم.
ب. كيف يبدو شكل هذا المستحضر وماهي محتويات العلبة
براداكسا عبارة عن كبسولات صلبة.
كبسولات عقار براداكسا ١١٠ مجم الصلبة لها غطاء معتم لونه أزرق فاتح وجسم غير شفاف
لونه أزرق فاتح.
تمت طباعة شعار بوهرينجر إنجيلهايم على الغطاء والعبارة "R110" على جسم الكبسولة.
كبسولات براداكسا 110 ملجم الصلبة متوفرة في عبوات تحتوي على 10 X 1أو 30 X 1أو 60
X 1 كبسولات أو عبوة متعددة المحتويات تحتوي على 3 أشرطة من الكبسولات الصلبة 60
(180 كبسولة صلبة) أو عبوات متعددة تحتوي علي عبوتان 50 كبسولة صلبة (100 كبسولة
صلبة) في شرائط ألمونيوم مثقوبة تبعًا للجرعة .
بالاضافة الى ذلك، تتوفر كبسولات براداكسا 110 ملجم الصلبة في عبوات تحتوي على 60
كبسولة في شكل أشرطة بيضاء مغطاة بطبقة رقيقة من الألومنيوم المثقوب
قد لا تتوفر جميع أحجام العبوات في الأسواق.
ت. الشركة المصنعة ومالك حق التسويق
مالك حق التسويق
شركة بوهرينجر إنجيلهايم إنترناشونال المحدودة
173 شارع بينجر
إنجيلهايم أم راين د-55216
ألمانيا
الشركة المصنعة
بوهرينجر إنجيلهايم فارما المحدودة وشركاه "شراكة محدودة"
173 شارع بينجر
إنجيلهايم أم راين د-55216
ألمانيا
للحصول على أي معلومات بخصوص ھذا الدواء یرجى التواصل مع الممثل المحلي
المملكة العربية السعودية (المكتب العلمي)
هاتف: +966115116504
فاكس: +966115116545
ث. تمت مراجعة هذه النشرة في التاريخ الذي تمت فيه مراجعة النشرة بالشهر والسنة
مايو 2020
Read this leaflet carefully before you start using this product as it contains
important information for you
1. NAME OF THE MEDICINAL PRODUCT
Pradaxa 110 mg hard capsules
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each hard capsule contains 110 mg of dabigatran etexilate (as mesilate). For the
full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Hard capsule. Capsules with light blue, opaque cap and light blue, opaque body
of size 1 filled with yellowish pellets. The cap is imprinted with the
Boehringer Ingelheim company symbol, the body with “R110”.
4. CLINICAL PARTICULARS
4.1 Therapeutic Indications
Primary prevention of venous thromboembolic events in adult patients who have
undergone elective total hip replacement surgery or total 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 ischemic attack (TIA); age ≥ 75 years; heart failure (NYHA Class
≥ II); diabetes mellitus; hypertension.
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and
prevention of recurrent DVT and PE in adults
4.2 Posology And Method Administration
Posology
Primary prevention of Venous Thromboembolism in Orthopaedic Surgery
The recommended doses of Pradaxa and the duration of therapy for primary
prevention of venous thromboembolism in orthopaedic surgery are shown in table
1.
Table 1: Dose recommendations and duration of therapy for primary prevention
of venous thromboembolism in orthopaedic surgery
Treatment initiation on the day of surgery 1 4 hours after completed
surgery Maintenance dose starting on the first day after surgery Duration
of maintenance dose
Patients following elective knee replacement surgery single capsule of 110 mg
Pradaxa 220 mg Pradaxa once daily taken as 2 capsules of 110 mg 10 days
Patients following elective hip replacement surgery 28-35 days
Dose reduction recommended
Patients with moderate renal impairment (creatinine clearance (CrCL) 30 50
mL/min) single capsule of 75 mg Pradaxa 150 mg Pradaxa once daily taken
as 2 capsules of 75 mg 10 days (knee replacement surgery) or 28-35 days (hip
replacement surgery)
Patients who receive concomitant verapamil*, amiodarone, quinidine
Patients aged 75 or above
*For patients with moderate renal impairment concomitantly treated with
verapamil see Special populations
For both surgeries, if haemostasis is not secured, initiation of treatment
should be delayed. If treatment is not started on the day of surgery then
treatment should be initiated with 2 capsules once daily.
Assessment of renal function prior to and during Pradaxa treatment
In all patients and especially in the elderly (>75 years), as renal impairment
may be frequent in this age group:
• Renal function should be assessed by calculating the creatinine clearance
(CrCL) prior to initiation of treatment with Pradaxa to exclude patients with
severe renal impairment (i.e. CrCL < 30 mL/min) (see sections 4.3, 4.4 and
5.2).
• Renal function should also be assessed when a decline in renal function is
suspected during treatment (e.g. hypovolaemia, dehydration, and in case of
concomitant use of certain medicinal products).
The method to be used to estimate renal function (CrCL in mL/min) is the
Cockcroft-Gault method.
Missed dose
It is recommended to continue with the remaining daily doses of Pradaxa at the
same time of the next day.
No double dose should be taken to make up for missed individual doses.
Discontinuation of Pradaxa
Pradaxa treatment should not be discontinued without medical advice. Patients
should be instructed to contact the treating physician if they develop
gastrointestinal symptoms such as dyspepsia (see section 4.8).
Switching
Pradaxa treatment to parenteral anticoagulant:
It is recommended to wait 24 hours after the last dose before switching from
Pradaxa to a parenteral anticoagulant (see section 4.5).
Parenteral anticoagulants to Pradaxa:
The parenteral anticoagulant should be discontinued and Pradaxa should be
started 0 2 hours prior to the time that the next dose of the alternate therapy
would be due, or at the time of discontinuation in case of continuous treatment
(e.g. intravenous Unfractionated Heparin (UFH)) (see section 4.5).
Special populations
Renal impairment
Treatment with Pradaxa in patients with severe renal impairment (CrCL < 30
mL/min) is contraindicated (see section 4.3).
In patients with moderate renal impairment (CrCL 30 50 mL/min), a dose reduction
is recommended (see table 1 above and sections 4.4 and 5.1).
Concomitant use of Pradaxa with mild to moderate P glycoprotein (P gp)
inhibitors, i.e. amiodarone, quinidine or verapamil
Dosing should be reduced as indicated in table 1 (see also sections 4.4 and
4.5). In this situation Pradaxa and these medicinal products should be taken at
the same time.
In patients with moderate renal impairment and concomitantly treated with
verapamil, a dose reduction of Pradaxa to 75 mg daily should be considered (see
sections 4.4 and 4.5).
Elderly
For elderly patients > 75 years, a dose reduction is recommended (see table 1
above and sections 4.4 and 5.1).
Weight
There is very limited clinical experience in patients with a body weight < 50 kg
or > 110 kg at the recommended posology. Given the available clinical and
kinetic data no adjustment is necessary (see section 5.2), but close clinical
surveillance is recommended (see section 4.4).
Gender
No dose adjustment is necessary (see section 5.2).
Paediatric population
There is no relevant use of Pradaxa in the paediatric population for the
indication of primary prevention of venous thromboembolic events in patients who
have undergone elective total hip replacement surgery or total knee replacement
surgery.
Prevention of stroke and systemic embolism in adult patients with NVAF with one
or more risk factors (SPAF)
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and
prevention of recurrent DVT, and PE in adults (DVT/PE)
The recommended doses of Pradaxa in the indications SPAF, DVT and PE are shown
in table 2.
Table 2: Dose recommendations for SPAF, DVT and PE
Dose recommendation
Prevention of stroke and systemic embolism in adult patients with NVAF with one
or more risk factors (SPAF) 300 mg Pradaxa taken as one 150 mg capsule twice
daily
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and
prevention of recurrent DVT, and PE in adults (DVT/PE) 300 mg Pradaxa taken
as one 150 mg capsule twice daily following treatment with a parenteral
anticoagulant for at least 5 days
Dose reduction recommended
Patients aged ≥80 years daily dose of 220 mg Pradaxa taken as one 110 mg
capsule twice daily
Patients who receive concomitant verapamil
Dose reduction for consideration
Patients between 75-80 years daily dose of Pradaxa of 300 mg or 220 mg should
be selected based on an individual assessment of the thromboembolic risk and the
risk of bleeding
Patients with moderate renal impairment (CrCL 30 50 mL/min)
Patients with gastritis, esophagitis or gastroesophageal reflux
Other patients at increased risk of bleeding
For DVT/PE the recommendation for the use of Pradaxa 220 mg taken as one 110 mg
capsule twice daily is based on pharmacokinetic and pharmacodynamic analyses and
has not been studied in this clinical setting. See further down and sections
4.4, 4.5, 5.1 and 5.2.
In case of intolerability to Pradaxa, patients should be instructed to
immediately consult their treating physician in order to be switched to
alternate acceptable treatment options for prevention of stroke and systemic
embolism associated with atrial fibrillation or for DVT/PE.
Assessment of renal function prior to and during Pradaxa treatment
In all patients and especially in the elderly (>75 years), as renal impairment
may be frequent in this age group:
• Renal function should be assessed by calculating the creatinine clearance
(CrCL) prior to initiation of treatment with Pradaxa to exclude patients with
severe renal impairment (i.e. CrCL < 30 mL/min) (see sections 4.3, 4.4 and
5.2).
• Renal function should also be assessed when a decline in renal function is
suspected during treatment (e.g. hypovolaemia, dehydration, and in case of
concomitant use of certain medicinal products).
Additional requirements in patients with mild to moderate renal impairment and
in patients aged over 75 years:
• Renal function should be assessed during treatment with Pradaxa at least
once a year or more frequently as needed in certain clinical situations when it
is suspected that the renal function could decline or deteriorate (e.g.
hypovolaemia, dehydration, and in case of concomitant use of certain medicinal
products).
The method to be used to estimate renal function (CrCL in mL/min) is the
Cockcroft-Gault method.
Duration of use
The duration of use of Pradaxa in the indications SPAF, DVT and PE are shown in
table 3.
Table 3: Duration of use for SPAF and DVT/PE
Indication Duration of use
SPAF Therapy should be continued long term.
DVT/PE The duration of therapy should be individualised after careful
assessment of the treatment benefit against the risk for bleeding (see section
4.4).
Short duration of therapy (at least 3 months) should be based on transient risk
factors (e.g. recent surgery, trauma, immobilisation) and longer durations
should be based on permanent risk factors or idiopathic DVT or PE.
Missed dose
A forgotten Pradaxa dose may still be taken up to 6 hours prior to the next
scheduled dose. From 6 hours prior to the next scheduled dose on, the missed
dose should be omitted.
No double dose should be taken to make up for missed individual doses.
Discontinuation of Pradaxa
Pradaxa treatment should not be discontinued without medical advice. Patients
should be instructed to contact the treating physician if they develop
gastrointestinal symptoms such as dyspepsia (see section 4.8).
Switching
Pradaxa treatment to parenteral anticoagulant:
It is recommended to wait 12 hours after the last dose before switching from
Pradaxa to a parenteral anticoagulant (see section 4.5).
Parenteral anticoagulants to Pradaxa:
The parenteral anticoagulant should be discontinued and Pradaxa should be
started 0 2 hours prior to the time that the next dose of the alternate therapy
would be due, or at the time of discontinuation in case of continuous treatment
(e.g. intravenous Unfractionated Heparin (UFH)) (see section 4.5).
Pradaxa treatment to Vitamin K antagonists (VKA):
The starting time of the VKA should be adjusted based on CrCL as follows:
• CrCL ≥ 50 mL/min, VKA should be started 3 days before discontinuing Pradaxa
• CrCL ≥ 30 < 50 mL/min, VKA should be started 2 days before discontinuing
Pradaxa
Because Pradaxa can impact the International Normalized Ratio (INR), the INR
will better reflect VKA’s effect only after Pradaxa has been stopped for at
least 2 days. Until then, INR values should be interpreted with caution.
VKA to Pradaxa:
The VKA should be stopped. Pradaxa can be given as soon as the INR is < 2.0.
Cardioversion (SPAF)
Patients can stay on Pradaxa while being cardioverted.
Catheter ablation for atrial fibrillation (SPAF)
There are no data available for 110 mg twice daily Pradaxa treatment.
Percutaneous coronary intervention (PCI) with stenting (SPAF)
Patients with non valvular atrial fibrillation who undergo a PCI with stenting
can be treated with Pradaxa in combination with antiplatelets after haemostasis
is achieved (see section 5.1).
Special populations
Elderly
For dose modifications in this population see table 2 above.
Patients at risk of bleeding
Patients with an increased bleeding risk (see sections 4.4, 4.5, 5.1 and 5.2)
should be closely monitored clinically (looking for signs of bleeding or
anaemia). Dose adjustment should be decided at the discretion of the physician,
following assessment of the potential benefit and risk to an individual patient
(see table 2 above). A coagulation test (see section 4.4) may help to identify
patients with an increased bleeding risk caused by excessive dabigatran
exposure. When excessive dabigatran exposure is identified in patients at high
risk of bleeding, a reduced dose of 220 mg taken as one 110 mg capsule twice
daily is recommended. When clinically relevant bleeding occurs, treatment should
be interrupted.
For subjects with gastritis, esophagitis, or gastroesophageal reflux, a dose
reduction may be considered due to the elevated risk of major gastro intestinal
bleeding (see table 2 above and section 4.4).
Renal impairment
Treatment with Pradaxa in patients with severe renal impairment (CrCL < 30
mL/min) is contraindicated (see section 4.3).
No dose adjustment is necessary in patients with mild renal impairment (CrCL 50
≤ 80 mL/min). For patients with moderate renal impairment (CrCL 30 50 mL/min)
the recommended dose of Pradaxa is also 300 mg taken as one 150 mg capsule twice
daily. However, for patients with high risk of bleeding, a dose reduction of
Pradaxa to 220 mg taken as one 110 mg capsule twice daily should be considered
(see sections 4.4 and 5.2). Close clinical surveillance is recommended in
patients with renal impairment.
Concomitant use of Pradaxa with mild to moderate P glycoprotein (P gp)
inhibitors, i.e. amiodarone, quinidine or verapamil
No dose adjustment is necessary for concomitant use of amiodarone or quinidine
(see sections 4.4, 4.5 and 5.2).
Dose reductions are recommended for patients who receive concomitantly verapamil
(see table 2 above and sections 4.4 and 4.5). In this situation Pradaxa and
verapamil should be taken at the same time.
Weight
No dose adjustment is necessary (see section 5.2), but close clinical
surveillance is recommended in patients with a body weight < 50 kg (see section
4.4).
Gender
No dose adjustment is necessary (see section 5.2).
Paediatric population
There is no relevant use of Pradaxa in the paediatric population for the
indication of prevention of stroke and systemic embolism in patients with NVAF.
For the indication DVT/PE, the safety and efficacy of Pradaxa in children from
birth to less than 18 years of age have not yet been established. Currently
available data are described in section 4.8 and 5.1, but no recommendation on a
posology can be made.
Method of administration
Pradaxa is for oral use.
The capsules can be taken with or without food. Pradaxa should be swallowed as a
whole with a glass of water, to facilitate delivery to the stomach.
Patients should be instructed not to open the capsule as this may increase the
risk of bleeding (see sections 5.2 and 6.6).
4.3 Contraindications
• Hypersensitivity to the active substance or to any of the excipients listed in
section 6.1 • Patients with severe renal impairment (CrCL < 30 mL/min) • Active
clinically significant bleeding • 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
anticoagulants e.g. unfractionated heparin (UFH), low molecular weight heparins
(enoxaparin, dalteparin etc), heparin derivatives (fondaparinux etc), oral
anticoagulants (warfarin, rivaroxaban, apixaban etc) except under specific
circumstances. These are 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 section 4.5) • Hepatic impairment or liver disease expected to have any
impact on survival • Concomitant treatment with the following strong P-gp
inhibitors: systemic ketoconazole, cyclosporine, itraconazole, dronedarone and
the fixed-dose combination glecaprevir/pibrentasvir (see section 4.5) •
Prosthetic heart valves requiring anticoagulant treatment (see section 5.1).
4.4. Special warnings and precautions for use
Haemorrhagic risk
Pradaxa should be used with caution in conditions with an increased risk of
bleeding or with concomitant use of medicinal products affecting haemostasis by
inhibition of platelet aggregation. Bleeding can occur at any site during
therapy with Pradaxa. An unexplained fall in haemoglobin and/or haematocrit or
blood pressure should lead to a search for a bleeding site.
For situations of life-threatening or uncontrolled bleeding, when rapid reversal
of the anticoagulation effect of dabigatran is required, the specific reversal
agent (Praxbind, idarucizumab) is available (see section 4.9).
In clinical trials, Pradaxa was associated with higher rates of major
gastrointestinal (GI) bleeding. An increased risk was seen in the elderly
(≥ 75 years) for the 150 mg twice daily dose regimen. Further risk factors (see
also table 4) comprise co-medication with platelet aggregation inhibitors such
as clopidogrel and acetylsalicylic acid (ASA) or non steroidal antiinflammatory
drugs (NSAID), as well as the presence of esophagitis, gastritis or
gastroesophageal reflux.
Risk factors
Table 4 summarises factors which may increase the haemorrhagic risk.
Table 4: Factors which may increase the haemorrhagic risk.
Pharmacodynamic and kinetic factors
Age ≥ 75 years
Factors increasing dabigatran plasma levels
Major:
· Moderate renal impairment (30‑50 mL/min CrCL)
· Strong P‑gp inhibitors (see section 4.3 and 4.5)
· Mild to moderate P‑gp inhibitor co‑medication (e.g. amiodarone,
verapamil, quinidine and ticagrelor; see section 4.5)
Minor:
· Low body weight (< 50 kg)
Pharmacodynamic interactions (see section 4.5)
· ASA and other platelet aggregation inhibitors such as clopidogrel
· NSAID
· SSRIs or SNRIs
· Other medicinal products which may impair haemostasis
Diseases / procedures with special haemorrhagic risks
· Congenital or acquired coagulation disorders
· Thrombocytopenia or functional platelet defects
· Recent biopsy, major trauma
· Bacterial endocarditis
· Esophagitis, gastritis or gastroesophageal reflux
Limited data is available in patients < 50 kg (see section 5.2).
Precautions and management of the haemorrhagic risk
For the management of bleeding complications, see also section 4.9.
Benefit‑risk assessment
The presence of lesions, conditions, procedures and/or pharmacological treatment
(such as NSAIDs, antiplatelets, SSRIs and SNRIs, see section 4.5), which
significantly increase the risk of major bleeding requires a careful
benefit‑risk assessment. Pradaxa should only be given if the benefit outweighs
bleeding risks.
Close clinical surveillance
Close observation for signs of bleeding or anaemia is recommended throughout the
treatment period, especially if risk factors are combined (see table 4 above).
Particular caution should be exercised when Pradaxa is co‑administered with
verapamil, amiodarone, quinidine or clarithromycin (P-gp inhibitors) and
particularly in the occurrence of bleeding, notably in patients having a mild to
moderate renal impairment (see section 4.5).
Close observation for signs of bleeding is recommended in patients concomitantly
treated with NSAIDs (see section 4.5).
Discontinuation of Pradaxa
Patients who develop acute renal failure must discontinue Pradaxa (see also
section 4.3).
When severe bleedings occur, treatment must be discontinued, the source of
bleeding investigated and use of the specific reversal agent Praxbind
(idarucizumab) may be considered (see section 4.9 Management of bleeding
complications).
Dose reduction
A dose reduction should be either considered or is recommended as indicated in
section 4.2.
Use of proton-pump inhibitors
The administration of a proton-pump inhibitor (PPI) can be considered to prevent
GI bleeding.
Laboratory coagulation parameters
Although Pradaxa does not in general require routine anticoagulant monitoring,
the measurement of dabigatran related anticoagulation may be helpful to detect
excessive high exposure to dabigatran in the presence of additional risk
factors.
Diluted thrombin time (dTT), ecarin clotting time (ECT) and activated partial
thromboplastin time (aPTT) may provide useful information, but results should be
interpreted with caution due to inter-test variability (see section 5.1). The
International Normalised Ratio (INR) test is unreliable in patients on Pradaxa
and false positive INR elevations have been reported. Therefore, INR tests
should not be performed.
Table 5 shows coagulation test thresholds at trough that may be associated with
an increased risk of bleeding (see section 5.1)
Table 5: Coagulation test thresholds at trough that may be associated with an
increased risk of bleeding.
Test (trough value)
Indication
Primary prevention of venous thromboembolism in orthopaedic surgery
SPAF and DVT/PE
dTT [ng/mL]
> 67
> 200
ECT [x-fold upper limit of normal]
No data
> 3
aPTT [x-fold upper limit of normal]
> 1.3
> 2
INR
Should not be performed
Should not be performed
Use of fibrinolytic medicinal products for the treatment of acute ischemic
stroke
The use of fibrinolytic medicinal products for the treatment of acute ischemic
stroke may be considered if the patient presents with a dTT, ECT or aPTT not
exceeding the upper limit of normal (ULN) according to the local reference
range.
Surgery and interventions
Patients on Pradaxa who undergo surgery or invasive procedures are at increased
risk for bleeding. Therefore, surgical interventions may require the temporary
discontinuation of Pradaxa.
Patients can stay on Pradaxa while being cardioverted. There are no data
available for 110 mg twice daily Pradaxa treatment in patients undergoing
catheter ablation for atrial fibrillation (see section 4.2).
Caution should be exercised when treatment is temporarily discontinued for
interventions and anticoagulant monitoring is warranted. Clearance of dabigatran
in patients with renal insufficiency may take longer (see section 5.2). This
should be considered in advance of any procedures. In such cases a coagulation
test (see sections 4.4 and 5.1) may help to determine whether haemostasis is
still impaired.
Emergency surgery or urgent procedures
Pradaxa should be temporarily discontinued. When rapid reversal of the
anticoagulation effect is required the specific reversal agent (Praxbind,
idarucizumab) to Pradaxa is available.
Reversing dabigatran therapy exposes patients to the thrombotic risk of their
underlying disease. Pradaxa treatment can be re-initiated 24 hours after
administration of Praxbind (idarucizumab), if the patient is clinically stable
and adequate haemostasis has been achieved.
Subacute surgery/interventions
Pradaxa should be temporarily discontinued. A surgery / intervention should be
delayed if possible until at least 12 hours after the last dose. If surgery
cannot be delayed the risk of bleeding may be increased. This risk of bleeding
should be weighed against the urgency of intervention.
Elective surgery
If possible, Pradaxa should be discontinued at least 24 hours before invasive or
surgical procedures. In patients at higher risk of bleeding or in major surgery
where complete haemostasis may be required consider stopping Pradaxa 2-4 days
before surgery.
Table 6 summarises discontinuation rules before invasive or surgical procedures.
Table 6: Discontinuation rules before invasive or surgical procedures
Renal function
(CrCL in mL/min)
Estimated half‑life
(hours)
Pradaxa should be stopped before elective surgery
High risk of bleeding or major surgery
Standard risk
≥ 80
~ 13
2 days before
24 hours before
≥ 50‑< 80
~ 15
2‑3 days before
1‑2 days before
≥ 30‑< 50
~ 18
4 days before
2‑3 days before (> 48 hours)
Spinal anaesthesia/epidural anaesthesia/lumbar puncture
Procedures such as spinal anaesthesia may require complete haemostatic function.
The risk of spinal or epidural haematoma may be increased in cases of traumatic
or repeated puncture and by the prolonged use of epidural catheters. After
removal of a catheter, an interval of at least 2 hours should elapse before the
administration of the first dose of Pradaxa. These patients require frequent
observation for neurological signs and symptoms of spinal or epidural haematoma.
Postoperative phase
Pradaxa treatment should be resumed / started after the invasive procedure or
surgical intervention as soon as possible provided the clinical situation allows
and adequate haemostasis has been established.
Patients at risk for bleeding or patients at risk of overexposure, notably
patients with moderate renal impairment (CrCL 30-50 mL/min), should be treated
with caution (see sections 4.4 and 5.1).
Patients at high surgical mortality risk and with intrinsic risk factors for
thromboembolic events
There are limited efficacy and safety data for Pradaxa available in these
patients and therefore they should be treated with caution.
Hip fracture surgery
There is no data on the use of Pradaxa in patients undergoing hip fracture
surgery. Therefore treatment is not recommended.
Hepatic impairment
Patients with elevated liver enzymes > 2 ULN were excluded in the main trials.
No treatment experience is available for this subpopulation of patients, and
therefore the use of Pradaxa is not recommended in this population. Hepatic
impairment or liver disease expected to have any impact on survival is
contraindicated (see section 4.3).
Interaction with P‑gp inducers
Concomitant administration of P‑gp inducers is expected to result in decreased
dabigatran plasma concentrations, and should be avoided (see sections 4.5 and
5.2).
Patients with antiphospholipid syndrome
Direct acting Oral Anticoagulants (DOACs) including dabigatran etexilate 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.
Myocardial Infarction (MI)
In the phase III study RE‑LY (SPAF, see section 5.1) the overall rate of MI was
0.82, 0.81, and 0.64 % / year for dabigatran etexilate 110 mg twice daily,
dabigatran etexilate 150 mg twice daily and warfarin, respectively, an increase
in relative risk for dabigatran of 29 % and 27 % compared to warfarin.
Irrespective of therapy, the highest absolute risk of MI was seen in the
following subgroups, with similar relative risk: patients with previous MI,
patients ≥ 65 years with either diabetes or coronary artery disease, patients
with left ventricular ejection fraction < 40 %, and patients with moderate renal
dysfunction. Furthermore a higher risk of MI was seen in patients concomitantly
taking ASA plus clopidogrel or clopidogrel alone.
In the three active controlled DVT/PE phase III studies, a higher rate of MI was
reported in patients who received dabigatran etexilate than in those who
received warfarin: 0.4% vs. 0.2% in the short-term RE-COVER and RE-COVER II
studies; and 0.8% vs. 0.1% in the long-term RE-MEDY trial. The increase was
statistically significant in this study (p=0.022).
In the RE-SONATE study, which compared dabigatran etexilate to placebo, the rate
of MI was 0.1% for patients who received dabigatran etexilate and 0.2% for
patients who received placebo
Active Cancer Patients (DVT/PE)
The efficacy and safety have not been established for DVT/PE patients with
active cancer.
4.5. Interactions with other medicinal products
Transporter interactions
Dabigatran etexilate is a substrate for the efflux transporter P gp. Concomitant
administration of P gp inhibitors (see table 7) is expected to result in
increased dabigatran plasma concentrations.
If not otherwise specifically described, close clinical surveillance (looking
for signs of bleeding or anaemia) is required when dabigatran is co administered
with strong P gp inhibitors. Dose reductions may be required in combination with
some P gp inhibitors (see sections 4.2, 4.3, 4.4 and 5.1).
Table 7: Transporter interactions
P gp inhibitors
Concomitant use contraindicated (see section 4.3)
Ketoconazole Ketoconazole increased total dabigatran AUC0 ∞ and Cmax values
by 2.38-fold and 2.35-fold, respectively, after a single oral dose of 400 mg,
and by 2.53-fold and 2.49-fold, respectively, after multiple oral dosing of 400
mg ketoconazole once daily.
Dronedarone When dabigatran etexilate and dronedarone were given at the same
time total dabigatran AUC0 ∞ and Cmax values increased by about 2.4 fold and 2.3
fold, respectively, after multiple dosing of 400 mg dronedarone bid, and about
2.1 fold and 1.9 fold, respectively, after a single dose of 400 mg.
Itraconazole, cyclosporine Based on in vitro results a similar effect as with
ketoconazole may be expected.
Glecaprevir / pibrentasvir The concomitant use of dabigatran etexilate with
the fixed-dose combination of the P-gp inhibitors glecaprevir/pibrentasvir has
been shown to increase exposure of dabigatran and may increase the risk of
bleeding.
Concomitant use not recommended
Tacrolimus Tacrolimus has been found in vitro to have a similar level of
inhibitory effect on P-gp as that seen with itraconazole and cyclosporine.
Dabigatran etexilate has not been clinically studied together with tacrolimus.
However, limited clinical data with another P-gp substrate (everolimus) suggest
that the inhibition of P-gp with tacrolimus is weaker than that observed with
strong P-gp inhibitors.
Cautions to be exercised in case concomitant use (see sections 4.2 and 4.4)
Verapamil When dabigatran etexilate (150 mg) was co administered with oral
verapamil, the Cmax and AUC of dabigatran were increased but the magnitude of
this change differs depending on timing of administration and formulation of
verapamil (see sections 4.2 and 4.4).
The greatest elevation of dabigatran exposure was observed with the first dose
of an immediate release formulation of verapamil administered one hour prior to
the dabigatran etexilate intake (increase of Cmax by about 2.8 fold and AUC by
about 2.5 fold). The effect was progressively decreased with administration of
an extended release formulation (increase of Cmax by about 1.9 fold and AUC by
about 1.7 fold) or administration of multiple doses of verapamil (increase of
Cmax by about 1.6 fold and AUC by about 1.5 fold).
There was no meaningful interaction observed when verapamil was given 2 hours
after dabigatran etexilate (increase of Cmax by about 1.1 fold and AUC by about
1.2 fold). This is explained by completed dabigatran absorption after 2 hours.
Amiodarone When Pradaxa was co administered with a single oral dose of 600 mg
amiodarone, the extent and rate of absorption of amiodarone and its active
metabolite DEA were essentially unchanged. The dabigatran AUC and Cmax were
increased by about 1.6 fold and 1.5 fold, respectively. In view of the long half
life of amiodarone the potential for an interaction may exist for weeks after
discontinuation of amiodarone (see sections 4.2 and 4.4).
Quinidine Quinidine was given as 200 mg dose every 2nd hour up to a total
dose of 1,000 mg. Dabigatran etexilate was given twice daily over 3 consecutive
days, on the 3rd day either with or without quinidine. Dabigatran AUCτ,ss and
Cmax,ss were increased on average by 1.53 fold and 1.56 fold, respectively with
concomitant quinidine (see sections 4.2 and 4.4).
Clarithromycin When clarithromycin (500 mg twice daily) was administered
together with dabigatran etexilate in healthy volunteers, increase of AUC by
about 1.19 fold and Cmax by about 1.15 fold was observed.
Ticagrelor When a single dose of 75 mg dabigatran etexilate was
coadministered simultaneously with a loading dose of 180 mg ticagrelor, the
dabigatran AUC and Cmax were increased by 1.73-fold and 1.95-fold, respectively.
After multiple doses of ticagrelor 90 mg b.i.d. the increase of dabigatran
exposure is 1.56-fold and 1.46-fold for Cmax and AUC, respectively.
Concomitant administration of a loading dose of 180 mg ticagrelor and 110 mg
dabigatran etexilate (in steady state) increased the dabigatran AUCτ,ss and
Cmax,ss by 1.49-fold and 1.65-fold, respectively, compared with dabigatran
etexilate given alone. When a loading dose of 180 mg ticagrelor was given 2
hours after 110 mg dabigatran etexilate (in steady state), the increase of
dabigatran AUCτ,ss and Cmax,ss was reduced to 1.27-fold and 1.23-fold,
respectively, compared with dabigatran etexilate given alone. This staggered
intake is the recommended administration for start of ticagrelor with a loading
dose.
Concomitant administration of 90 mg ticagrelor b.i.d. (maintenance dose) with
110 mg dabigatran etexilate increased the adjusted dabigatran AUCτ,ss and
Cmax,ss 1.26-fold and 1.29-fold, respectively, compared with dabigatran
etexilate given alone.
Posaconazole Posaconazole also inhibits P-gp to some extent but has not been
clinically studied. Caution should be exercised when Pradaxa is co-administered
with posaconazole.
P gp inducers
Concomitant use should be avoided.
e.g. rifampicin, St. John´s wort (Hypericum perforatum), carbamazepine, or
phenytoin Concomitant administration is expected to result in decreased
dabigatran concentrations.
Pre dosing of the probe inducer rifampicin at a dose of 600 mg once daily for 7
days decreased total dabigatran peak and total exposure by 65.5 % and 67 %,
respectively. The inducing effect was diminished resulting in dabigatran
exposure close to the reference by day 7 after cessation of rifampicin
treatment. No further increase in bioavailability was observed after another 7
days.
Protease inhibitors such as ritonavir
Concomitant use not recommended
e.g. ritonavir and its combinations with other protease inhibitors These
affect P gp (either as inhibitor or as inducer). They have not been studied and
are therefore not recommended for concomitant treatment with Pradaxa.
P gp substrate
Digoxin In a study performed with 24 healthy subjects, when Pradaxa was co
administered with digoxin, no changes on digoxin and no clinically relevant
changes on dabigatran exposure have been observed.
Anticoagulants and antiplatelet aggregation medicinal products
There is no or only limited experience with the following treatments which may
increase the risk of bleeding when used concomitantly with Pradaxa:
anticoagulants such as unfractionated heparin (UFH), low molecular weight
heparins (LMWH), and heparin derivatives (fondaparinux, desirudin), thrombolytic
medicinal products, and vitamin K antagonists, rivaroxaban or other oral
anticoagulants (see section 4.3), and antiplatelet aggregation medicinal
products such as GPIIb/IIIa receptor antagonists, ticlopidine, prasugrel,
ticagrelor, dextran, and sulfinpyrazone (see section 4.4).
From the data collected in the phase III study RE-LY (see section 5.1) it was
observed that the concomitant use of other oral or parenteral anticoagulants
increases major bleeding rates with both dabigatran etexilate and warfarin by
approximately 2.5-fold, mainly related to situations when switching from one
anticoagulant to another (see section 4.3). Furthermore, concomitant use of
antiplatelets, ASA or clopidogrel approximately doubled major bleeding rates
with both dabigatran etexilate and warfarin (see section 4.4).
UFH can be administered at doses necessary to maintain a patent central venous
or arterial catheter or during catheter ablation for atrial fibrillation (see
section 4.3).
Table 8: Interactions with anticoagulants and antiplatelet aggregation
medicinal products
NSAIDs NSAIDs given for short term analgesia have been shown not to be
associated with increased bleeding risk when given in conjunction with
dabigatran etexilate. With chronic use in the RE LY study, NSAIDs increased the
risk of bleeding by approximately 50 % on both dabigatran etexilate and
warfarin.
Clopidogrel In young healthy male volunteers, the concomitant administration
of dabigatran etexilate and clopidogrel resulted in no further prolongation of
capillary bleeding times compared to clopidogrel monotherapy. In addition,
dabigatran AUCτ,ss and Cmax,ss and the coagulation measures for dabigatran
effect or the inhibition of platelet aggregation as measure of clopidogrel
effect remained essentially unchanged comparing combined treatment and the
respective mono treatments. With a loading dose of 300 mg or 600 mg clopidogrel,
dabigatran AUCτ,ss and Cmax,ss were increased by about 30 40 % (see section 4.4)
.
ASA Co administration of ASA and 150 mg dabigatran etexilate twice daily may
increase the risk for any bleeding from 12 % to 18 % and 24 % with 81 mg and 325
mg ASA, respectively (see section 4.4).
LMWH The concomitant use of LMWHs, such as enoxaparin and dabigatran
etexilate has not been specifically investigated. After switching from 3 day
treatment of once daily 40 mg enoxaparin s.c., 24 hours after the last dose of
enoxaparin the exposure to dabigatran was slightly lower than that after
administration of dabigatran etexilate (single dose of 220 mg) alone. A higher
anti FXa/FIIa activity was observed after dabigatran etexilate administration
with enoxaparin pre treatment compared to that after treatment with dabigatran
etexilate alone. This is considered to be due to the carry over effect of
enoxaparin treatment, and regarded as not clinically relevant. Other dabigatran
related anti coagulation tests were not changed significantly by the pre
treatment of enoxaparin.
Other interactions
Table 9: Other interactions
Selective serotonin re-uptake inhibitors (SSRIs) or selective serotonin
norepinephrine re-uptake inhibitors (SNRIs)
SSRIs, SNRIs SSRIs and SNRIs increased the risk of bleeding in RE-LY in all
treatment groups,
Substances influencing gastric pH
Pantoprazole When Pradaxa was co administered with pantoprazole, a decrease
in the dabigatran AUC of approximately 30 % was observed. Pantoprazole and other
proton pump inhibitors (PPI) were co administered with Pradaxa in clinical
trials, and concomitant PPI treatment did not appear to reduce the efficacy of
Pradaxa.
Ranitidine Ranitidine administration together with Pradaxa had no clinically
relevant effect on the extent of absorption of dabigatran.
Interactions linked to dabigatran etexilate and dabigatran metabolic profile
Dabigatran etexilate and dabigatran are not metabolised by the cytochrome P450
system and have no in vitro effects on human cytochrome P450 enzymes. Therefore,
related medicinal product interactions are not expected with dabigatran.
4.6. Fertility, pregnancy and lactation
Women of childbearing potential
Women of childbearing potential should avoid pregnancy during treatment with
Pradaxa.
Pregnancy
There is limited amount of data from the use of Pradaxa in pregnant women.
Studies in animals have shown reproductive toxicity (see section 5.3). The
potential risk for humans is unknown.
Pradaxa should not be used during pregnancy unless clearly necessary.
Breast‑feeding
There are no clinical data of the effect of dabigatran on infants during
breast-feeding.
Breast‑feeding should be discontinued during treatment with Pradaxa.
Fertility
No human data available.
In animal studies an effect on female fertility was observed in the form of a
decrease in implantations and an increase in pre‑implantation loss at 70 mg/kg
(representing a 5‑fold higher plasma exposure level compared to patients). No
other effects on female fertility were observed. There was no influence on male
fertility. At doses that were toxic to the mothers (representing a 5‑ to 10‑fold
higher plasma exposure level to patients), a decrease in foetal body weight and
embryofoetal viability along with an increase in foetal variations were observed
in rats and rabbits. In the pre‑ and post‑natal study, an increase in foetal
mortality was observed at doses that were toxic to the dams (a dose
corresponding to a plasma exposure level 4‑fold higher than observed in
patients).
4.7. Effects on ability to drive and use machines
Pradaxa has no or negligible influence on the ability to drive and use machines.
4.8. Undesirable effects
Summary of the safety profile
The safety of Pradaxa has been evaluated in ten phase III studies including
23,393 patients exposed to Pradaxa (see Table 10).
Table 10: Number of patients studied, maximum daily dose in phase III studies
Indication
Number of patients treated with Pradaxa
Maximum daily dose
Primary Prevention of Venous Thromboembolism in Orthopaedic Surgery
6,684
220 mg
Stroke and systemic embolism prevention in patients with atrial fibrillation
6,059
5,983
300 mg
220 mg
DVT/PE treatment (RE-COVER, RE-COVER II)
2,553
300 mg
DVT/PE prevention (RE-MEDY, RE-SONATE)
2,114
300 mg
In total, about 9 % of patients treated for elective hip or knee surgery
(short‑term treatment for up to 42 days), 22 % of patients with atrial
fibrillation treated for the prevention of stroke and systemic embolism
(long‑term treatment for up to 3 years), 14 % of patients treated for DVT/PE and
15 % of patients treated for DVT/PE prevention experienced adverse reactions.
The most commonly reported events are bleedings occurring in approximately 14 %
of patients treated short‑term for elective hip or knee replacement surgery,
16.6 % in patients with atrial fibrillation treated long-term for the prevention
of stroke and systemic embolism, and in 14.4 % of patients treated for DVT/PE.
Furthermore, bleeding occurred in 19.4 % of patients in the DVT/PE prevention
trial RE-MEDY and in 10.5 % of patients in the DVT/PE prevention trial
RE-SONATE.
Since the patient populations treated in the three indications are not
comparable and bleeding events are distributed over several System Organ Classes
(SOC), a summary description of major and any bleeding are broken down by
indication and provided in tables 12-16 below.
Although low in frequency in clinical trials, major or severe bleeding may occur
and, regardless of location, may lead to disabling, life‑threatening or even
fatal outcomes.
Tabulated list of adverse reactions
Table 11 shows the adverse reactions identified from studies and post-marketing
data in the indications primary VTE prevention after hip or knee replacement
surgery, prevention of thromboembolic stroke and systemic embolism in patients
with atrial fibrillation, DVT/PE treatment and DVT/PE prevention. They are
ranked under headings of System Organ Class (SOC) and frequency using the
following convention: very common (³ 1/10), common (³ 1/100 to < 1/10), uncommon
(³ 1/1,000 to < 1/100), rare (³ 1/10,000 to < 1/1,000), very rare (< 1/10,000),
not known (cannot be estimated from the available data).
Table 11: Adverse reactions
Frequency
SOC / Preferred term.
Primary VTE prevention after hip or knee replacement surgery
Stroke and systemic embolism prevention in patients with atrial fibrillation
DVT/PE treatment and DVT/PE prevention
Blood and lymphatic system disorders
Anaemia
Uncommon
Common
Uncommon
Haemoglobin decreased
Common
Uncommon
Not known
Thrombocytopenia
Rare
Uncommon
Rare
Haematocrit decreased
Uncommon
Rare
Not known
Neutropenia
Not known
Not known
Not known
Agranulocytosis
Not known
Not known
Not known
Immune system disorder
Drug hypersensitivity
Uncommon
Uncommon
Uncommon
Rash
Rare
Uncommon
Uncommon
Pruritus
Rare
Uncommon
Uncommon
Anaphylactic reaction
Rare
Rare
Rare
Angioedema
Rare
Rare
Rare
Urticaria
Rare
Rare
Rare
Bronchospasm
Not known
Not known
Not known
Nervous system disorders
Intracranial haemorrhage
Rare
Uncommon
Rare
Vascular disorders
Haematoma
Uncommon
Uncommon
Uncommon
Haemorrhage
Rare
Uncommon
Uncommon
Wound haemorrhage
Uncommon
-
Respiratory, thoracic and mediastinal disorders
Epistaxis
Uncommon
Common
Common
Haemoptysis
Rare
Uncommon
Uncommon
Gastrointestinal disorders
Gastrointestinal haemorrhage
Uncommon
Common
Common
Abdominal pain
Rare
Common
Uncommon
Diarrhoea
Uncommon
Common
Uncommon
Dyspepsia
Rare
Common
Common
Nausea
Uncommon
Common
Uncommon
Rectal haemorrhage
Uncommon
Uncommon
Common
Haemorrhoidal haemorrhage
Uncommon
Uncommon
Uncommon
Gastrointestinal ulcer, including oesophageal ulcer
Rare
Uncommon
Uncommon
Gastroesophagitis
Rare
Uncommon
Uncommon
Gastroesophageal reflux disease
Rare
Uncommon
Uncommon
Vomiting
Uncommon
Uncommon
Uncommon
Dysphagia
Rare
Uncommon
Rare
Hepatobiliary disorders
Hepatic function abnormal/ Liver function Test abnormal
Common
Uncommon
Uncommon
Alanine aminotransferase increased
Uncommon
Uncommon
Uncrommon
Aspartate aminotransferase increased
Uncommon
Uncommon
Uncommon
Hepatic enzyme increased
Uncommon
Rare
Uncommon
Hyperbilirubinaemia
Uncommon
Rare
Not known
Skin and subcutaneous tissue disorder
Skin haemorrhage
Uncommon
Common
Common
Alopecia
Not known
Not known
Not known
Musculoskeletal and connective tissue disorders
Haemarthrosis
Uncommon
Rare
Uncommon
Renal and urinary disorders
Genitourological haemorrhage, including haematuria
Uncommon
Common
Common
General disorders and administration site conditions
Injection site haemorrhage
Rare
Rare
Rare
Catheter site haemorrhage
Rare
Rare
Rare
Bloody discharge
Rare
-
Injury, poisoning and procedural complications
Traumatic haemorrhage
Uncommon
Rare
Uncommon
Incision site haemorrhage
Rare
Rare
Rare
Post procedural haematoma
Uncommon
-
-
Post procedural haemorrhage
Uncommon
-
Anaemia postoperative
Rare
-
-
Post procedural discharge
Uncommon
-
-
Wound secretion
Uncommon
-
-
Surgical and medical procedures
Wound drainage
Rare
-
-
Post procedural drainage
Rare
-
.
Description of selected adverse reactions
Bleeding reactions
Due to the pharmacological mode of action, the use of Pradaxa may be associated
with an increased risk of occult or overt bleeding from any tissue or organ. The
signs, symptoms, and severity (including fatal outcome) will vary according to
the location and degree or extent of the bleeding and/or anaemia. In the
clinical studies mucosal bleedings (e.g. gastrointestinal, genitourinary) were
seen more frequently during long term Pradaxa treatment compared with VKA
treatment. Thus, in addition to adequate clinical surveillance, laboratory
testing of haemoglobin/haematocrit is of value to detect occult bleeding. The
risk of bleedings may be increased in certain patient groups e.g. those patients
with moderate renal impairment and/or on concomitant treatment affecting
haemostasis or strong P-gp inhibitors (see section 4.4 Haemorrhagic risk).
Haemorrhagic complications may present as weakness, paleness, dizziness,
headache or unexplained swelling, dyspnoea, and unexplained shock.
Known bleeding complications such as compartment syndrome and acute renal
failure due to hypoperfusion have been reported for Pradaxa. Therefore, the
possibility of haemorrhage is to be considered in evaluating the condition in
any anticoagulated patient. A specific reversal agent for dabigatran,
idarucizumab, is available in case of uncontrollable bleeding (see Section 4.9).
Primary Prevention of Venous Thromboembolism in Orthopaedic Surgery
The table 12 shows the number (%) of patients experiencing the adverse reaction
bleeding during the treatment period in the VTE prevention in the two pivotal
clinical trials, according to dose.
Table 12: Number (%) of patients experiencing the adverse reaction bleeding
Pradaxa
150 mg once daily
N (%)
Pradaxa
220 mg once daily
N (%)
Enoxaparin
N (%)
Treated
1,866 (100.0)
1,825 (100.0)
1,848 (100.0)
Major bleeding
24 (1.3)
33 (1.8)
27 (1.5)
Any bleeding
258 (13.8)
251 (13.8)
247 (13.4)
Prevention of stroke and systemic embolism in adult patients with NVAF with one
or more risk factors
The table 13 shows bleeding events broken down to major and any bleeding in the
pivotal study testing the prevention of thromboembolic stroke and systemic
embolism in patients with atrial fibrillation.
Table 13: Bleeding events in a study testing the prevention of thromboembolic
stroke and systemic embolism in patients with atrial fibrillation
Pradaxa 110 mg twice daily
Pradaxa 150 mg twice daily
Warfarin
Subjects randomized
6,015
6,076
6,022
Major bleeding
347 (2.92 %)
409 (3.40 %)
426 (3.61 %)
Intracranial bleeding
27 (0.23 %)
39 (0.32 %)
91 (0.77 %)
GI bleeding
134 (1.13 %)
192 (1.60 %)
128 (1.09 %)
Fatal bleeding
26 (0.22 %)
30 (0.25 %)
42 (0.36 %)
Minor bleeding
1,566 (13.16 %)
1,787 (14.85 %)
1,931 (16.37 %)
Any bleeding
1,759 (14.78 %)
1,997 (16.60 %)
2,169 (18.39 %)
Subjects randomized to Pradaxa 110 mg twice daily or 150 mg twice daily had a
significantly lower risk for life‑threatening bleeds and intracranial bleeding
compared to warfarin [p < 0.05]. Both dose strengths of Pradaxa had also a
statistically significant lower total bleed rate. Subjects randomized to 110 mg
Pradaxa twice daily had a significantly lower risk for major bleeds compared
with warfarin (hazard ratio 0.81 [p=0.0027]). Subjects randomized to 150 mg
Pradaxa twice daily had a significantly higher risk for major GI bleeds compared
with warfarin (hazard ratio 1.48 [p=0.0005]. This effect was seen primarily in
patients ≥ 75 years.
The clinical benefit of dabigatran with regard to stroke and systemic embolism
prevention and decreased risk of ICH compared to warfarin is preserved across
individual subgroups, e.g. renal impairment, age, concomitant medicinal product
use such as anti‑platelets or P‑gp inhibitors. While certain patient subgroups
are at an increased risk of major bleeding when treated with an anticoagulant,
the excess bleeding risk for dabigatran is due to GI bleeding, typically seen
within the first 3‑6 months following initiation of Pradaxa therapy.
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and
prevention of recurrent DVT and PE in adults (DVT/PE treatment)
Table 14 shows bleeding events in the pooled pivotal studies RE-COVER and
RE-COVER II testing the treatment of deep vein thrombosis (DVT) and pulmonary
embolism (PE). In the pooled studies the primary safety endpoints of major
bleeding, major or clinically relevant bleeding and any bleeding were
significantly lower than warfarin at a nominal alpha level of 5 %.
Table 14: Bleeding events in the studies RE-COVER and RE-COVER II testing the
treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE)
Pradaxa 150 mg twice daily
Warfarin
Hazard ratio vs. warfarin
(95% confidence interval)
Patients included in safety analysis
2,456
2,462
Major bleeding events
24 (1.0 %)
40 (1.6 %)
0.60 (0.36, 0.99)
Intracranial
Bleeding
2 (0.1 %)
4 (0.2 %)
0.50 (0.09, 2.74)
Major GI bleeding
10 (0.4 %)
12 (0.5 %)
0.83 (0.36, 1.93)
Life-threatening
bleed
4 (0.2 %)
6 (0.2 %)
0.66 (0.19, 2.36)
Major bleeding events/clinically relevant bleeds
109 (4.4 %)
189 (7.7 %)
0.56 (0.45, 0.71)
Any bleeding
354 (14.4 %)
503 (20.4 %)
0.67 (0.59, 0.77)
Any GI bleeding
70 (2.9 %)
55 (2.2 %)
1.27 (0.90, 1.82)
Bleeding events for both treatments are counted from the first intake of Pradaxa
or warfarin after the parenteral therapy has been discontinued (oral only
treatment period). This includes all bleeding events, which occurred during
Pradaxa therapy. All bleeding events which occurred during warfarin therapy are
included except for those during the overlap period between warfarin and
parenteral therapy.
Table 15 shows bleeding events in pivotal study RE-MEDY testing prevention of
deep vein thrombosis (DVT) and pulmonary embolism (PE). Some bleeding events
(MBEs/CRBEs; any bleeding) were significantly lower at a nominal alpha level of
5% in patients receiving Pradaxa as compared with those receiving warfarin.
Table 15: Bleeding events in study RE-MEDY testing prevention of deep vein
thrombosis (DVT) and pulmonary embolism (PE)
Pradaxa
150 mg twice daily
Warfarin
Hazard ratio vs warfarin
(95% Confidence Interval)
Treated patients
1,430
1,426
Majory bleeding events
13 (0.9 %)
25 (1.8 %)
0.54 (0.25, 1.16)
Intracranial bleeding
2 (0.1 %)
4 (0.3 %)
Not calculable*
Major GI bleeding
4 (0.3%)
8 (0.5%)
Not calculable*
Life-threatening bleed
1 (0.1 %)
3 (0.2 %))
Not calculable*
Major bleeding event /clinically relevant bleeds
80 (5.6 %)
145 (10.2 %)
0.55 ( 0.41, 0.72)
Any bleeding
278 (19.4 %)
373 (26.2 %)
0.71 (0.61, 0.83)
Any GI bleeds
45 (3.1%)
32 (2.2%)
1.39 (0.87, 2.20)
*HR not estimable as there is no event in either one cohort/treatment
Table 16 shows bleeding events in pivotal study RE-SONATE testing prevention of
deep vein thrombosis (DVT) and pulmonary embolism (PE). The rate of the
combination of MBEs/CRBEs and the rate of any bleeding was significantly lower
at a nominal alpha level of 5 % in patients receiving placebo as compared with
those receiving Pradaxa.
Table 16: Bleeding events in study RE-SONATE testing prevention of deep vein
thrombosis (DVT) and pulmonary embolism (PE)
Pradaxa
150 mg twice daily
Placebo
Hazard ratio vs placebo
(95% confidence interval)
Treated patients
684
659
Major bleeding events
2 (0.3 %)
0
Not calculable*
Intracranial bleeding
0
0
Not calculable*
Major GI bleeding
2 (0.3%)
0
Not calculable*
Life-threatening bleeds
0
0
Not calculable*
Major bleeding event/clinical relevant bleeds
36 (5.3 %)
13 (2.0 %)
2.69 (1.43, 5.07)
Any bleeding
72 (10.5 %)
40 (6.1 %)
1.77 (1.20, 2.61)
Any GI bleeds
5 (0.7%)
2 (0.3%)
2.38 (0.46, 12.27)
*HR not estimable as there is no event in either one treatment
Agranulocytosis and neutropenia
Agranulocytosis and neutropenia have been reported very rarely during post
approval use of Pradaxa. Because adverse reactions are reported in the
postmarketing surveillance setting from a population of uncertain size, it is
not possible to reliably determine their frequency. The reporting rate was
estimated as 7 events per 1 million patient years for agranulocytosis and as 5
events per 1 million patient years for neutropenia.
Paediatric population (DVT/PE)
In the clinical study 1160.88 in total, 9 adolescent patients (age 12 to
< 18 years) with diagnosis of primary VTE received an initial oral dose of
dabigatran etexilate of 1.71 (± 10 %) mg/kg bodyweight. Based on dabigatran
concentrations as determined by the diluted thrombin time test and clinical
assessment, the dose was adjusted to the target dose of 2.14 (± 10%) mg/kg
bodyweight of dabigatran etexilate. On treatment 2 (22.1 %) patients experienced
mild related adverse events (gastrooesophageal reflux / abdominal pain;
abdominal discomfort) and 1 (11.1 %) patient experienced a not related serious
adverse event (recurrent VTE of the leg) in the post treatment period > 3 days
after stop of dabigatran etexilate.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal
product is important. It allows continued monitoring of the benefit/risk balance
of the medicinal product. Healthcare professionals are asked to report any
suspected adverse reactions via:
To report any side effect(s):
• Saudi Arabia:
- The National Pharmacovigilance Centre (NPC):
· Fax: +966-11-205-7662
· SFDA Call Center: 19999
· E-mail: npc.drug@sfda.gov.sa
· Website: https://ade.sfda.gov.sa
• Other countries:
- Please contact the relevant competent authority.
4.9. Overdoes
Pradaxa doses beyond those recommended expose the patient to increased risk of
bleeding.
In case of an overdose suspicion, coagulation tests can help to determine a
bleeding risk (see sections 4.4 and 5.1). A calibrated quantitative dTT test or
repetitive dTT measurements allow prediction of the time by when certain
dabigatran levels will be reached (see section 5.1), also in case additional
measures e.g. dialysis have been initiated.
Excessive anticoagulation may require interruption of Pradaxa treatment. Since
dabigatran is excreted predominantly by the renal route adequate diuresis must
be maintained. As protein binding is low, dabigatran can be dialysed; there is
limited clinical experience to demonstrate the utility of this approach in
clinical studies (see section 5.2).
Management of bleeding complications
In the event of haemorrhagic complications, Pradaxa treatment must be
discontinued and the source of bleeding investigated. Depending on the clinical
situation appropriate supportive treatment, such as surgical haemostasis and
blood volume replacement, should be undertaken at the prescriber’s discretion.
For situations when rapid reversal of the anticoagulant effect of Pradaxa is
required the specific reversal agent (Praxbind, idarucizumab) antagonizing the
pharmacodynamic effect of Pradaxa is available (see section 4.4).
Coagulation factor concentrates (activated or non-activated) or recombinant
Factor VIIa may be taken into account. There is some experimental evidence to
support the role of these medicinal products in reversing the anticoagulant
effect of dabigatran, but data on their usefulness in clinical settings and also
on the possible risk of rebound thromboembolism is very limited. Coagulation
tests may become unreliable following administration of suggested coagulation
factor concentrates. Caution should be exercised when interpreting these tests.
Consideration should also be given to administration of platelet concentrates in
cases where thrombocytopenia is present or long acting antiplatelet medicinal
products have been used. All symptomatic treatment should be given according to
the physician's judgement.
Depending on local availability, a consultation of a coagulation expert should
be considered in case of major bleedings.
5. PHARMACOLOGICAL PROPERTIES
5.1. Pharmacodynamic Properties
Pharmacotherapeutic group: antithrombotic agents, direct thrombin inhibitors,
ATC code: B01AE07.
Mechanism of action
Dabigatran etexilate is a small molecule prodrug which does not exhibit any
pharmacological activity. After oral administration, dabigatran etexilate is
rapidly absorbed and converted to dabigatran by esterase‑catalysed hydrolysis in
plasma and in the liver. Dabigatran is a potent, competitive, reversible direct
thrombin inhibitor and is the main active principle in plasma.
Since thrombin (serine protease) enables the conversion of fibrinogen into
fibrin during the coagulation cascade, its inhibition prevents the development
of thrombus. Dabigatran inhibits free thrombin, fibrin‑bound thrombin and
thrombin‑induced platelet aggregation.
Pharmacodynamic effects
In vivo and ex vivo animal studies have demonstrated antithrombotic efficacy and
anticoagulant activity of dabigatran after intravenous administration and of
dabigatran etexilate after oral administration in various animal models of
thrombosis.
There is a clear correlation between plasma dabigatran concentration and degree
of anticoagulant effect based on phase II studies. Dabigatran prolongs the
thrombin time (TT), ECT, and aPTT.
The calibrated quantitative diluted TT (dTT) test provides an estimation of
dabigatran plasma concentration that can be compared to the expected dabigatran
plasma concentrations. When the calibrated dTT assay delivers a dabigatran
plasma concentration result at or below the limit of quantification, an
additional coagulation assay such as TT, ECT or aPTT should be considered.
The ECT can provide a direct measure of the activity of direct thrombin
inhibitors.
The aPTT test is widely available and provides an approximate indication of the
anticoagulation intensity achieved with dabigatran. However, the aPTT test has
limited sensitivity and is not suitable for precise quantification of
anticoagulant effect, especially at high plasma concentrations of dabigatran.
Although high aPTT values should be interpreted with caution, a high aPTT value
indicates that the patient is anticoagulated.
In general, it can be assumed that these measures of anti-coagulant activity may
reflect dabigatran levels and can provide guidance for the assessment of
bleeding risk, i.e. exceeding the 90th percentile of dabigatran trough levels or
a coagulation assay such as aPTT measured at trough (for aPTT thresholds see
section 4.4, table 5) is considered to be associated with an increased risk of
bleeding.
Primary Prevention of Venous Thromboembolism in Orthopaedic Surgery
Steady state (after day 3) geometric mean dabigatran peak plasma concentration,
measured around 2 hours after 220 mg dabigatran etexilate administration, was
70.8 ng/mL, with a range of 35.2‑162 ng/mL (25th–75th percentile range).The
dabigatran geometric mean trough concentration, measured at the end of the
dosing interval (i.e. 24 hours after a 220 mg dabigatran dose), was on average
22.0 ng/mL, with a range of 13.0‑35.7 ng/mL (25th‑75th percentile range).
In a dedicated study exclusively in patients with moderate renal impairment
(creatinine clearance, CrCL 30-50 mL/min) treated with dabigatran etexilate
150 mg QD, the dabigatran geometric mean trough concentration, measured at the
end of the dosing interval, was on average 47.5 ng/mL, with a range of
29.6 - 72.2 ng/mL (25th-75th percentile range).
In patients treated for prevention of VTEs after hip or knee replacement surgery
with 220 mg dabigatran etexilate once daily,
· the 90th percentile of dabigatran plasma concentrations was
67 ng/mL, measured at trough (20‑28 hours after the previous dose) (see section
4.4 and 4.9),
· the 90th percentile of aPTT at trough (20‑28 hours after the
previous dose) was 51 seconds, which would be 1.3‑fold upper limit of normal.
The ECT was not measured in patients treated for prevention of VTEs after hip or
knee replacement surgery with 220 mg dabigatran etexilate once daily.
Prevention of stroke and systemic embolism in adult patients with NVAF with one
or more risk factors (SPAF)
Steady state geometric mean dabigatran peak plasma concentration, measured
around 2 hours after 150 mg dabigatran etexilate administration twice daily, was
175 ng/mL, with a range of 117‑275 ng/mL (25th‑75th percentile range). The
dabigatran geometric mean trough concentration, measured at trough in the
morning, at the end of the dosing interval (i.e. 12 hours after the 150 mg
dabigatran evening dose), was on average 91.0 ng/mL, with a range of
61.0‑143 ng/mL (25th‑75th percentile range).
For patients with NVAF treated for prevention of stroke and systemic embolism
with 150 mg dabigatran etexilate twice daily,
· the 90th percentile of dabigatran plasma concentrations measured at
trough (10‑16 hours after the previous dose) was about 200 ng/mL,
· an ECT at trough (10‑16 hours after the previous dose), elevated
approximately 3‑fold upper limit of normal refers to the observed
90th percentile of ECT prolongation of 103 seconds,
· an aPTT ratio greater than 2‑fold upper limit of normal (aPTT
prolongation of about 80 seconds), at trough (10‑16 hours after the previous
dose) reflects the 90th percentile of observations.
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and
prevention of recurrent DVT and PE in adults (DVT/PE)
In patients treated for DVT and PE with 150 mg dabigatran etexilate twice daily,
the dabigatran geometric mean trough concentration, measured within 10−16 hours
after dose, at the end of the dosing interval (i.e. 12 hours after the 150 mg
dabigatran evening dose), was 59.7 ng/ml, with a range of 38.6 - 94.5 ng/ml
(25th-75th percentile range). For treatment of DVT and PE, with dabigatran
etexilate 150 mg twice daily,
· the 90th percentile of dabigatran plasma concentrations measured at
trough (10-16 hours after the previous dose) was about 146 ng/ml,
· an ECT at trough (10-16 hours after the previous dose), elevated
approximately 2.3-fold compared to baseline refers to the observed 90th
percentile of ECT prolongation of 74 seconds,
· the 90th percentile of aPTT at trough (10-16 hours after the
previous dose) was 62 seconds, which would be 1.8-fold compared to baseline.
In patients treated for prevention of recurrent of DVT and PE with 150 mg
dabigatran etexilate twice daily no pharmacokinetic data are available.
Clinical efficacy and safety
Ethnic origin
No clinically relevant ethnic differences among Caucasians, African‑American,
Hispanic, Japanese or Chinese patients were observed.
Clinical trials in Venous Thromboembolism (VTE) prophylaxis following major
joint replacement surgery
In 2 large randomized, parallel group, double‑blind, dose‑confirmatory trials,
patients undergoing elective major orthopaedic surgery (one for knee replacement
surgery and one for hip replacement surgery) received Pradaxa 75 mg or 110 mg
within 1‑4 hours of surgery followed by 150 mg or 220 mg once daily thereafter,
haemostasis having been secured, or enoxaparin 40 mg on the day prior to surgery
and daily thereafter.
In the RE‑MODEL trial (knee replacement) treatment was for 6‑10 days and in the
RE‑NOVATE trial (hip replacement) for 28‑35 days. Totals of 2,076 patients
(knee) and 3,494 (hip) were treated respectively.
Composite of total VTE (including PE, proximal and distal DVT, whatever
symptomatic or asymptomatic detected by routine venography) and all‑cause
mortality constituted the primary end‑point for both studies. Composite of major
VTE (including PE and proximal DVT, whatever symptomatic or asymptomatic
detected by routine venography) and VTE‑related mortality constituted a
secondary end‑point and is considered of better clinical relevance.
Results of both studies showed that the antithrombotic effect of Pradaxa 220 mg
and 150 mg were statistically non‑inferior to that of enoxaparin on total VTE
and all‑cause mortality. The point estimate for incidence of Major VTE and VTE
related mortality for the 150 mg dose was slightly worse than enoxaparin (table
17). Better results were seen with the 220 mg dose where the point estimate of
Major VTE was slightly better than enoxaparin (table 17).
The clinical studies have been conducted in a patient population with a mean age
> 65 years.
There were no differences in the phase 3 clinical studies for efficacy and
safety data between men and women.
In the studied patient population of RE‑MODEL and RE‑NOVATE (5,539 patients
treated), 51 % suffered from concomitant hypertension, 9 % from concomitant
diabetes, 9 % from concomitant coronary artery disease and 20 % had a history of
venous insufficiency. None of these diseases showed an impact on the effects of
dabigatran on VTE‑prevention or bleeding rates.
Data for the major VTE and VTE‑related mortality endpoint were homogeneous with
regards to the primary efficacy endpoint and are shown in table 17.
Data for the total VTE and all cause mortality endpoint are shown in table 18.
Data for adjudicated major bleeding endpoints are shown in table 19 below.
Table 17: Analysis of major VTE and VTE‑related mortality during the treatment
period in the RE‑MODEL and the RE‑NOVATE orthopaedic surgery studies.
Trial
Pradaxa
220 mg once daily
Pradaxa
150 mg once daily
Enoxaparin
40 mg
RE‑NOVATE (hip)
N
909
888
917
Incidences (%)
28 (3.1)
38 (4.3)
36 (3.9)
Risk ratio over enoxaparin
0.78
1.09
95 % CI
0.48, 1.27
0.70, 1.70
RE‑MODEL (knee)
N
506
527
511
Incidences (%)
13 (2.6)
20 (3.8)
18 (3.5)
Risk ratio over enoxaparin
0.73
1.08
95 % CI
0.36, 1.47
0.58, 2.01
Table 18: Analysis of total VTE and all cause mortality during the treatment
period in the RE‑NOVATE and the RE‑MODEL orthopaedic surgery studies.
Trial
Pradaxa
220 mg once daily
Pradaxa
150 mg once daily
Enoxaparin
40 mg
RE‑NOVATE (hip)
N
880
874
897
Incidences (%)
53 (6.0)
75 (8.6)
60 (6.7)
Risk ratio over enoxaparin
0.9
1.28
95 % CI
(0.63, 1.29)
(0.93, 1.78)
RE‑MODEL (knee)
N
503
526
512
Incidences (%)
183 (36.4)
213 (40.5)
193 (37.7)
Risk ratio over enoxaparin
0.97
1.07
95 % CI
(0.82, 1.13)
(0.92, 1.25)
Table 19: Major bleeding events by treatment in the individual RE‑MODEL and the
RE‑NOVATE studies.
Trial
Pradaxa
220 mg once daily
Pradaxa
150 mg once daily
Enoxaparin
40 mg
RE‑NOVATE (hip)
Treated patients N
1,146
1,163
1,154
Number of MBE N(%)
23 (2.0)
15 (1.3)
18 (1.6)
RE‑MODEL (knee)
Treated patients N
679
703
694
Number of MBE N(%)
10 (1.5)
9 (1.3)
9 (1.3)
Prevention of stroke and systemic embolism in adult patients with NVAF with one
or more risk factors
The clinical evidence for the efficacy of dabigatran etexilate is derived from
the RE‑LY study (Randomized Evaluation of Long–term anticoagulant therapy) a
multi‑centre, multi‑national, randomized parallel group study of two blinded
doses of dabigatran etexilate (110 mg and 150 mg twice daily) compared to
open‑label warfarin in patients with atrial fibrillation at moderate to high
risk of stroke and systemic embolism. The primary objective in this study was to
determine if dabigatran etexilate was non‑inferior to warfarin in reducing the
occurrence of the composite endpoint stroke and systemic embolism. Statistical
superiority was also analysed.
In the RE‑LY study, a total of 18,113 patients were randomized, with a mean age
of 71.5 years and a mean CHADS2 score of 2.1. The patient population was 64 %
male, 70 % Caucasian and 16 % Asian. For patients randomized to warfarin, the
mean percentage of time in therapeutic range (TTR) (INR 2‑3) was 64.4 % (median
TTR 67 %).
The RE‑LY study demonstrated that dabigatran etexilate, at a dose of 110 mg
twice daily, is non‑inferior to warfarin in the prevention of stroke and
systemic embolism in subjects with atrial fibrillation, with a reduced risk of
ICH, total bleeding and major bleeding. The dose of 150 mg twice daily reduces
significantly the risk of ischemic and haemorrhagic stroke, vascular death, ICH
and total bleeding compared to warfarin. Major bleeding rates with this dose
were comparable to warfarin. Myocardial infarction rates were slightly increased
with dabigatran etexilate 110 mg twice daily and 150 mg twice daily compared to
warfarin (hazard ratio 1.29; p=0.0929 and hazard ratio 1.27; p=0.1240,
respectively). With improving monitoring of INR the observed benefits of
dabigatran etexilate compared to warfarin diminish.
Tables 20‑22 display details of key results in the overall population:
Table 20: Analysis of first occurrence of stroke or systemic embolism (primary
endpoint) during the study period in RE‑LY.
Pradaxa
110 mg twice daily
Pradaxa
150 mg twice daily
Warfarin
Subjects randomized
6,015
6,076
6,022
Stroke and/or systemic embolism
Incidences (%)
183 (1.54)
135 (1.12)
203 (1.72)
Hazard ratio over warfarin (95 % CI)
0.89 (0.73, 1.09)
0.65 (0.52, 0.81)
p value superiority
p=0.2721
p=0.0001
% refers to yearly event rate
Table 21: Analysis of first occurrence of ischemic or haemorrhagic strokes
during the study period in RE‑LY.
Pradaxa
110 mg twice daily
Pradaxa
150 mg twice daily
Warfarin
Subjects randomized
6,015
6,076
6,022
Stroke
Incidences (%)
171 (1.44)
123 (1.02)
187 (1.59)
Hazard ratio vs. warfarin (95 % CI)
0.91 (0.74, 1.12)
0.64 (0.51, 0.81)
p‑value
0.3553
0.0001
Systemic embolism
Incidences (%)
15 (0.13)
13 (0.11)
21 (0.18)
Hazard ratio vs. warfarin (95 % CI)
0.71 (0.37, 1.38)
0.61 (0.30, 1.21)
p‑value
0.3099
0.1582
Ischemic stroke
Incidences (%)
152 (1.28)
104 (0.86)
134 (1.14)
Hazard ratio vs. warfarin (95 % CI)
1.13 (0.89, 1.42)
0.76 (0.59, 0.98)
p‑value
0.3138
0.0351
Haemorrhagic stroke
Incidences (%)
14 (0.12)
12 (0.10)
45 (0.38)
Hazard ratio vs. warfarin (95 % CI)
0.31 (0.17, 0.56)
0.26 (0.14, 0.49)
p‑value
0.0001
< 0.0001
% refers to yearly event rate
Table 22: Analysis of all cause and cardiovascular survival during the study
period in RE‑LY.
Pradaxa
110 mg twice daily
Pradaxa
150 mg twice daily
Warfarin
Subjects randomized
6,015
6,076
6,022
All‑cause mortality
Incidences (%)
446 (3.75)
438 (3.64)
487 (4.13)
Hazard ratio vs. warfarin (95 % CI)
0.91 (0.80, 1.03)
0.88 (0.77, 1.00)
p‑value
0.1308
0.0517
Vascular mortality
Incidences (%)
289 (2.43)
274 (2.28)
317 (2.69)
Hazard ratio vs. warfarin (95 % CI)
0.90 (0.77, 1.06)
0.85 (0.72, 0.99)
p‑value
0.2081
0.0430
% refers to yearly event rate
Tables 23‑25 display results of the primary efficacy and safety endpoint in
relevant sub‑populations:
For the primary endpoint, stroke and systemic embolism, no subgroups (i.e., age,
weight, gender, renal function, ethnicity, etc.) were identified with a
different risk ratio compared to warfarin.
Table 23: Hazard Ratio and 95 % CI for stroke/systemic embolism by subgroups
Endpoint
Pradaxa
110 mg twice daily vs. Warfarin
Pradaxa
150 mg twice daily vs. warfarin
Age (years)
< 65
1.10 (0.64, 1.87)
0.51 (0.26, 0.98)
65 ≤ and < 75
0.86 (0.62, 1.19)
0.67 (0.47, 0.95)
≥ 75
0.88 (0.66, 1.17)
0.68 (0.50, 0.92)
≥ 80
0.68 (0.44, 1.05)
0.67 (0.44, 1.02)
CrCL(mL/min)
30 ≤ and < 50
0.89 (0.61, 1.31)
0.48 (0.31, 0.76)
50 ≤ and < 80
0.91 (0.68, 1.20)
0.65 (0.47, 0.88)
≥ 80
0.81 (0.51, 1.28)
0.69 (0.43, 1.12)
For the primary safety endpoint of major bleeding there was an interaction of
treatment effect and age. The relative risk of bleeding with dabigatran compared
to warfarin increased with age. Relative risk was highest in patients
≥ 75 years. The concomitant use of antiplatelets ASA or clopidogrel
approximately doubles MBE rates with both dabigatran etexilate and warfarin.
There was no significant interaction of treatment effects with the subgroups of
renal function and CHADS2 score.
Table 24: Hazard Ratio and 95 % CI for major bleeds by subgroups
Endpoint
Pradaxa
110 mg twice daily vs. Warfarin
Pradaxa
150 mg twice daily vs. Warfarin
Age (years)
< 65
0.32 (0.18, 0.57)
0.35 (0.20, 0.61)
65 ≤ and < 75
0.71 (0.56, 0.89)
0.82 (0.66, 1.03)
≥ 75
1.01 (0.84, 1.23)
1.19 (0.99, 1.43)
≥ 80
1.14 (0.86, 1.51)
1.35 (1.03, 1.76)
CrCL(mL/min)
30 ≤ and < 50
1.02 (0.79, 1.32)
0.94 (0.73, 1.22)
50 ≤ and < 80
0.75 (0.61, 0.92)
0.90 (0.74, 1.09)
≥ 80
0.59 (0.43, 0.82)
0.87 (0.65, 1.17)
ASA use
0.84 (0.69, 1.03)
0.97 (0.79, 1.18)
Clopidogrel use
0.89 (0.55, 1.45)
0.92 (0.57, 1.48)
RELY-ABLE (Long term multi-center extension of dabigatran treatment in patients
with atrial fibrillation who completed the RE-LY trial)
The RE-LY extension study (RELY-ABLE) provided additional safety information for
a cohort of patients which continued the same dose of dabigatran etexilate as
assigned in the RE-LY trial. Patients were eligible for the RELY-ABLE trial if
they had not permanently discontinued study medication at the time of their
final RE-LY study visit. Enrolled patients continued to receive the same
double-blind dabigatran etexilate dose randomly allocated in RE-LY, for up to
43 months of follow up after RE-LY (total mean follow-up RE-LY + RELY-ABLE,
4.5 years). There were 5897 patients enrolled, representing 49 % of patients
originally randomly assigned to receive dabigatran etexilate in RE-LY and 86 %
of RELY-ABLE–eligible patients.
During the additional 2.5 years of treatment in RELY-ABLE, with a maximum
exposure of over 6 years (total exposure in RELY + RELY-ABLE), the long-term
safety profile of dabigatran etexilate was confirmed for both test doses
110 mg b.i.d. and 150 mg b.i.d.. No new safety findings were observed.
The rates of outcome events including, major bleed and other bleeding events
were consistent with those seen in RE-LY.
Data from non-interventional studies
A non-interventional study (GLORIA-AF) prospectively collected (in its second
phase) safety and effectiveness data in newly diagnosed NVAF patients on
dabigatran etexilate in a real-world setting. The study included 4,859 patients
on dabigatran etexilate (55% treated with 150 mg bid, 43% treated with 110 mg
bid, 2% treated with 75 mg bid). Patients were followed-up for 2 years. The mean
CHADS2 and HAS-BLED scores were 1.9 and 1.2, respectively. Mean on-therapy
follow-up time was 18.3 months. Major bleeding occurred in 0.97 per 100
patient-years. Life-threatening bleeding was reported in 0.46 per 100
patient-years, intracranial haemorrhage in 0.17 per 100 patient-years and
gastrointestinal bleeding in 0.60 per 100 patient-years. Stroke occurred in 0.65
per 100 patient-years.
In addition, in a non-interventional study [Graham DJ et al., Circulation.
2015;131:157-164] in more than 134,000 elderly patients with NVAF in the United
States (contributing more than 37,500 patient-years of on-therapy follow-up
time) dabigatran etexilate (84 % patients treated with 150 mg bid, 16 % patients
treated with 75 mg bid) was associated with a reduced risk of ischemic stroke
(hazard ratio 0.80, 95 % confidence interval [CI] 0.67 – 0.96), intracranial
haemorrhage (hazard ratio 0.34, CI 0.26 – 0.46), and mortality (hazard ratio
0.86, CI 0.77 – 0.96) and increased risk of gastrointestinal bleeding (hazard
ratio 1.28, CI 1.14 – 1.44) compared to warfarin. No difference was found for
major bleeding (hazard ratio 0.97, CI 0.88 – 1.07).
These observations in real-world settings are consistent with the established
safety and efficacy profile for dabigatran etexilate in the RE-LY study in this
indication.
Patients who underwent Percutaneous coronary intervention (PCI) with stenting
A prospective, randomized, open-label, blinded endpoint (PROBE) study (Phase
IIIb) to evaluate dual-therapy with dabigatran etexilate (110 mg or 150 mg bid)
plus clopidogrel or ticagrelor (P2Y12 antagonist) vs. triple-therapy with
warfarin (adjusted to a INR 2.0 – 3.0) plus clopidogrel or ticagrelor and
aspirin was conducted in 2725 patients with non valvular atrial fibrillation who
underwent a PCI with stenting (RE-DUAL PCI). Patients were randomized to
dabigatran etexilate 110 mg bid dual-therapy, dabigatran etexilate 150 mg bid
dual-therapy or warfarin triple-therapy. Elderly patients outside of the United
States (≥80 years of age for all countries, ≥70 years of age for Japan) were
randomly assigned to the dabigatran etexilate 110 mg dual-therapy group or the
warfarin triple-therapy group. The primary endpoint was a combined endpoint of
major bleeds based on ISTH definition or clinically relevant non-major bleeding
event.
The incidence of the primary endpoint was 15.4 % (151 patients) in the
dabigatran etexilate 110 mg dual-therapy group as compared with 26.9 % (264
patients) in the warfarin triple-therapy group (HR 0.52; 95% CI 0.42, 0.63;
P<0.0001 for non-inferiority and P<0.0001 for superiority) and 20.2 % (154
patients) in the dabigatran etexilate 150 mg dual-therapy group as compared with
25.7 % (196 patients) in the corresponding warfarin triple-therapy group (HR
0.72; 95% CI 0.58, 0.88; P<0.0001 for non-inferiority and P=0.002 for
superiority). As part of the descriptive analysis, TIMI (Thrombolysis In
Myocardial Infarction) major bleeding events was lower in both dabigatran
etexilate dual-therapy groups than in the warfarin triple-therapy group: 14
events (1.4%) in the dabigatran etexilate 110 mg dual-therapy group as compared
with 37 events (3.8%) in the warfarin triple-therapy group (HR 0.37; 95% CI
0.20, 0.68; P=0.002) and 16 events (2.1%) in the dabigatran etexilate 150 mg
dual-therapy group as compared with 30 events (3.9%) in the corresponding
warfarin triple-therapy group (HR 0.51; 95% CI 0.28, 0.93; P=0.03). Both
dabigatran etexilate dual-therapy groups had lower rates of intracranial
hemorrhage than the corresponding warfarin triple-therapy group: 3 events (0.3%)
in the 110 mg dabigatran etexilate dual-therapy group as compared with 10 events
(1.0%) in the warfarin triple-therapy group (HR 0.30; 95% CI 0.08, 1.07; P=0.06)
and 1 event (0.1%) in the 150 mg dabigatran etexilate dual-therapy group as
compared with 8 events (1.0%) in the corresponding warfarin triple-therapy group
(HR 0.12; 95% CI 0.02, 0.98; P=0.047). The incidence of the composite efficacy
endpoint of death, thromboembolic events (myocardial infarction, stroke, or
systemic embolism) or unplanned revascularization in the two dabigatran
etexilate dual-therapy groups combined was non-inferior to the warfarin
triple-therapy group (13.7% vs. 13.4% respectively; HR 1.04; 95% CI: 0.84, 1.29;
P=0.0047 for non-inferiority).There were no statistical differences in the
individual components of the efficacy endpoints between either dabigatran
etexilate dual-therapy groups and warfarin triple-therapy.
This study demonstrated that dual-therapy with dabigatran etexilate and a P2Y12
antagonist significantly reduced the risk of bleeding vs. warfarin
triple-therapy with non-inferiority for composite of thromboembolic events in
patients with atrial fibrillation who underwent a PCI with stenting.
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) in adults
(DVT/PE treatment)
The efficacy and safety was investigated in two multi-center, randomised, double
blind, parallel-group, replicate studies RE-COVER and RE-COVER II. These studies
compared dabigatran etexilate (150 mg bid) with warfarin (target INR 2.0-3.0) in
patients with acute DVT and/or PE. The primary objective of these studies was to
determine if dabigatran etexilate was non-inferior to warfarin in reducing the
occurrence of the primary endpoint which was the composite of recurrent
symptomatic DVT and/or PE and related deaths within the 6 month treatment
period.
In the pooled RE-COVER and RE-COVER II studies, a total of 5,153 patients were
randomised and 5,107 were treated.
The duration of treatment with fixed dose of dabigatran was 174.0 days without
coagulation monitoring. For patients randomized to warfarin, the median time in
therapeutic range (INR 2.0 to 3.0) was 60.6 %.
The trials, demonstrated that treatment with dabigatran etexilate 150 mg twice
daily was non-inferior to the treatment with warfarin (non-inferiority margin
for RE-COVER, and RE-COVER II: 3.6 for risk difference and 2.75 for hazard
ratio).
Table 25: Analysis of the primary and secondary efficacy endpoints (VTE is a
composite of DVT and/or PE) until the end of post-treatment period for the
pooled studies RE-COVER and RE-COVER II
Pradaxa
150 mg twice daily
Warfarin
Treated patients
2,553
2,554
Recurrent symptomatic VTE and VTE-related death
68 ( 2.7 %)
62 ( 2.4 %)
Hazard ratio vs warfarin
(95% confidence interval)
1.09
(0.77, 1.54)
Secondary efficacy endpoints
Recurrent symptomatic VTE and all-cause deaths
109 (4.3 %)
104 (4.1 %)
95 % confidence interval
3.52, 5.13
3.34, 4.91
Symptomatic DVT
45 (1.8 %)
39 (1.5 %)
95 % confidence interval
1.29, 2.35
1.09, 2.08
Symptomatic PE
27 (1.1 %)
26 (1.0 %)
95 % confidence interval
0.70, 1.54
0.67, 1.49
VTE-related deaths
4 (0.2 %)
3 (0.1 %)
95 % confidence interval
0.04, 0.40
0.02, 0.34
All-cause deaths
51 (2.0 %)
52 (2.0 %)
95 % confidence interval
1.49, 2.62
1.52, 2.66
Prevention of recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE)
in adults (DVT/PE prevention)
Two randomized, parallel group, double-blind studies were performed in patients
previously treated with anticoagulation therapy. RE-MEDY, warfarin controlled
study, enrolled patients already treated for 3 to 12 months with the need for
further anticoagulant treatment and RE-SONATE, the placebo controlled study,
enrolled patients already treated for 6 to 18 months with Vitamin K inhibitors.
The objective of the RE-MEDY study was to compare the safety and efficacy of
oral dabigatran etexilate (150 mg bid) to warfarin (target INR 2.0-3.0) for the
long-term treatment and prevention of recurrent, symptomatic DVT and/or PE. A
total of 2,866 patients were randomized and 2,856 patients were treated.
Duration of dabigatran etexilate treatment ranged from 6 to 36 months (median
534.0 days). For patients randomized to warfarin, the median time in therapeutic
range (INR 2.0-3.0) was 64.9 %.
RE-MEDY demonstrated that treatment with dabigatran etexilate 150 mg twice daily
was non-inferior to warfarin (non-inferiority margin: 2.85 for hazard ratio and
2.8 for risk difference).
Table 26: Analysis of the primary and secondary efficacy endpoints (VTE is a
composite of DVT and/or PE) until the end of post-treatment period for the
RE-MEDY study
Pradaxa
150 mg twice daily
Warfarin
Treated patients
1430
1426
Recurrent symptomatic VTE and VTE-related death
26 (1.8 %)
18 (1.3 %)
Hazard ratio vs warfarin
(95% confidence interval)
1.44
(0.78, 2.64)
non-inferiority margin
2.85
Patients with event at 18 months
22
17
Cumulative risk at
18 months (%)
1.7
1.4
Risk difference vs. warfarin (%)
0.4
95% confidence interval
non-inferiority margin
2.8
Secondary efficacy endpoints
Recurrent symptomatic VTE and all-cause deaths
42 (2.9 %)
36 (2.5 %)
95 % confidence interval
2.12, 3.95
1.77, 3.48
Symptomatic DVT
17 (1.2 %)
13 (0.9 %)
95 % confidence interval
0.69, 1.90
0.49, 1.55
Symptomatic PE
10 (0.7 %)
5 (0.4 %)
95 % confidence interval
0.34, 1.28
0.11, 0.82
VTE-related deaths
1 (0.1 %)
1 (0.1 %)
95 % confidence interval
0.00, 0.39
0.00, 0.39
All-cause deaths
17 (1.2 %)
19 (1.3 %)
95 % confidence interval
0.69, 1.90
0.80, 2.07
The objective of the RE-SONATE study was to evaluate superiority of dabigatran
etexilate versus placebo for the prevention of recurrent symptomatic DVT and/or
PE in patients who had already completed 6 to 18 months of treatment with VKA.
The intended therapy was 6 months dabigatran etexilate 150 mg twice daily
without need for monitoring.
RE-SONATE demonstrated dabigatran etexilate was superior to placebo for the
prevention of recurrent symptomatic DVT/PE events including unexplained deaths,
with a risk reduction from 5.6 % to 0.4 % (relative risk reduction 92 % based on
hazard ratio ) during the treatment period (p<0.0001). All secondary and
sensitivity analyses of the primary endpoint and all secondary endpoints showed
superiority of dabigatran etexilate over placebo.
The study included observational follow-up for 12 months after the conclusion of
treatment. After discontinuation of study medication the effect was maintained
until the end of the follow-up, indicating that the initial treatment effect of
dabigatran etexilate was sustained. No rebound effect was observed. At the end
of the follow-up VTE events in patients treated with dabigatran etexilate was
6.9 % vs. 10.7 % among the placebo group (hazard ratio 0.61 (95% CI 0.42, 0.88),
p=0.0082).
Table 27: Analysis of the primary and secondary efficacy endpoints (VTE is a
composite of DVT and/or PE) until the end of post-treatment period for the
RE-SONATE study.
Pradaxa
150 mg twice daily
Placebo
Treated patients
681
662
Recurrent symptomatic VTE and related deaths
3 (0.4 %)
37 (5.6 %)
Hazard Ratio vs
placebo
(95% confidence interval)
0.08
(0.02, 0.25)
p-value for superiority
< 0.0001
Secondary efficacy endpoints
Recurrent symptomatic VTE and all-cause deaths
3 (0.4 %)
37 (5.6 %)
95% confidence interval
0.09, 1.28
3.97, 7.62
Symptomatic DVT
2 (0.3 %)
23 (3.5 %)
95% confidence interval
0.04, 1.06
2.21, 5.17
Symptomatic PE
1 (0.1 %)
14 (2.1 %)
95% confidence interval
0.00, 0.82
1.16, 3.52
VTE-related deaths
0 (0)
0 (0)
95% confidence interval
0.00, 0.54
0.00, 0.56
Unexplained deaths
0 (0)
2 (0.3 %)
95% confidence interval
0.00, 0.54
0.04, 1.09
All-cause deaths
0 (0)
2 (0.3 %)
95% confidence interval
0.00, 0.54
0.04, 1.09
Clinical trials for the prevention of thromboembolism in patients with
prosthetic heart valves
A phase II study examined dabigatran etexilate and warfarin in a total of 252
patients with recent mechanical valve replacement surgery (i.e. within the
current hospital stay) and in patients who received a mechanical heart valve
replacement more than three months ago. More thromboembolic events (mainly
strokes and symptomatic/asymptomatic prosthetic valve thrombosis) and more
bleeding events were observed with dabigatran etexilate than with warfarin. In
the early post-operative patients, major bleeding manifested predominantly as
haemorrhagic pericardial effusions, specifically in patients who started
dabigatran etexilate early (i.e. on Day 3) after heart valve replacement surgery
(see section 4.3).
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of
studies with Pradaxa in all subsets of the paediatric population for the granted
indications (see section 4.2 for information on paediatric use).
The pharmacokinetics and pharmacodynamics of dabigatran etexilate administered
twice daily for three consecutive days (total 6 doses) at the end of standard
anticoagulant therapy were assessed in an open-label safety and tolerability
study in 9 stable adolescents (12 to < 18 years). All patients received an
initial oral dose of 1.71 (± 10%) mg/kg of dabigatran etexilate (80 % of the
adult dose of 150 mg/70 kg adjusted for the patient’s weight). Based on
dabigatran concentrations and clinical assessment, the dose was subsequently
modified to a target dose of 2.14 (± 10 %) mg/kg of dabigatran etexilate (100 %
of the adult dose adjusted for the patient’s weight). In this small number of
adolescents, dabigatran etexilate capsules were apparently tolerated with only
three mild and transient gastrointestinal adverse events reported by two
patients. According to the relatively low exposure, coagulation at 72 hrs
(presumed dabigatran trough level at steady state or close to steady state
conditions) was only slightly prolonged with aPTT at maximum 1.60 fold, ECT
1.86 fold, and Hemoclot® TT (Anti-FIIa) 1.36 fold, respectively. Dabigatran
plasma concentrations observed at 72 hrs were relatively low, between 32.9 ng/mL
and 97.2 ng/mL at final doses between 100 mg and 150 mg (gMean dose normalized
total dabigatran plasma concentration of 0.493 ng/mL/mg).
5.2. Pharmacokinetic Properties
Pharmacotherapeutic group: antithrombotic agents, direct thrombin inhibitors,
ATC code: B01AE07.
Mechanism of action
Dabigatran etexilate is a small molecule prodrug which does not exhibit any
pharmacological activity. After oral administration, dabigatran etexilate is
rapidly absorbed and converted to dabigatran by esterase‑catalysed hydrolysis in
plasma and in the liver. Dabigatran is a potent, competitive, reversible direct
thrombin inhibitor and is the main active principle in plasma.
Since thrombin (serine protease) enables the conversion of fibrinogen into
fibrin during the coagulation cascade, its inhibition prevents the development
of thrombus. Dabigatran inhibits free thrombin, fibrin‑bound thrombin and
thrombin‑induced platelet aggregation.
Pharmacodynamic effects
In vivo and ex vivo animal studies have demonstrated antithrombotic efficacy and
anticoagulant activity of dabigatran after intravenous administration and of
dabigatran etexilate after oral administration in various animal models of
thrombosis.
There is a clear correlation between plasma dabigatran concentration and degree
of anticoagulant effect based on phase II studies. Dabigatran prolongs the
thrombin time (TT), ECT, and aPTT.
The calibrated quantitative diluted TT (dTT) test provides an estimation of
dabigatran plasma concentration that can be compared to the expected dabigatran
plasma concentrations. When the calibrated dTT assay delivers a dabigatran
plasma concentration result at or below the limit of quantification, an
additional coagulation assay such as TT, ECT or aPTT should be considered.
The ECT can provide a direct measure of the activity of direct thrombin
inhibitors.
The aPTT test is widely available and provides an approximate indication of the
anticoagulation intensity achieved with dabigatran. However, the aPTT test has
limited sensitivity and is not suitable for precise quantification of
anticoagulant effect, especially at high plasma concentrations of dabigatran.
Although high aPTT values should be interpreted with caution, a high aPTT value
indicates that the patient is anticoagulated.
In general, it can be assumed that these measures of anti-coagulant activity may
reflect dabigatran levels and can provide guidance for the assessment of
bleeding risk, i.e. exceeding the 90th percentile of dabigatran trough levels or
a coagulation assay such as aPTT measured at trough (for aPTT thresholds see
section 4.4, table 5) is considered to be associated with an increased risk of
bleeding.
Primary Prevention of Venous Thromboembolism in Orthopaedic Surgery
Steady state (after day 3) geometric mean dabigatran peak plasma concentration,
measured around 2 hours after 220 mg dabigatran etexilate administration, was
70.8 ng/mL, with a range of 35.2‑162 ng/mL (25th–75th percentile range).The
dabigatran geometric mean trough concentration, measured at the end of the
dosing interval (i.e. 24 hours after a 220 mg dabigatran dose), was on average
22.0 ng/mL, with a range of 13.0‑35.7 ng/mL (25th‑75th percentile range).
In a dedicated study exclusively in patients with moderate renal impairment
(creatinine clearance, CrCL 30-50 mL/min) treated with dabigatran etexilate
150 mg QD, the dabigatran geometric mean trough concentration, measured at the
end of the dosing interval, was on average 47.5 ng/mL, with a range of
29.6 - 72.2 ng/mL (25th-75th percentile range).
In patients treated for prevention of VTEs after hip or knee replacement surgery
with 220 mg dabigatran etexilate once daily,
· the 90th percentile of dabigatran plasma concentrations was
67 ng/mL, measured at trough (20‑28 hours after the previous dose) (see section
4.4 and 4.9),
· the 90th percentile of aPTT at trough (20‑28 hours after the
previous dose) was 51 seconds, which would be 1.3‑fold upper limit of normal.
The ECT was not measured in patients treated for prevention of VTEs after hip or
knee replacement surgery with 220 mg dabigatran etexilate once daily.
Prevention of stroke and systemic embolism in adult patients with NVAF with one
or more risk factors (SPAF)
Steady state geometric mean dabigatran peak plasma concentration, measured
around 2 hours after 150 mg dabigatran etexilate administration twice daily, was
175 ng/mL, with a range of 117‑275 ng/mL (25th‑75th percentile range). The
dabigatran geometric mean trough concentration, measured at trough in the
morning, at the end of the dosing interval (i.e. 12 hours after the 150 mg
dabigatran evening dose), was on average 91.0 ng/mL, with a range of
61.0‑143 ng/mL (25th‑75th percentile range).
For patients with NVAF treated for prevention of stroke and systemic embolism
with 150 mg dabigatran etexilate twice daily,
· the 90th percentile of dabigatran plasma concentrations measured at
trough (10‑16 hours after the previous dose) was about 200 ng/mL,
· an ECT at trough (10‑16 hours after the previous dose), elevated
approximately 3‑fold upper limit of normal refers to the observed
90th percentile of ECT prolongation of 103 seconds,
· an aPTT ratio greater than 2‑fold upper limit of normal (aPTT
prolongation of about 80 seconds), at trough (10‑16 hours after the previous
dose) reflects the 90th percentile of observations.
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and
prevention of recurrent DVT and PE in adults (DVT/PE)
In patients treated for DVT and PE with 150 mg dabigatran etexilate twice daily,
the dabigatran geometric mean trough concentration, measured within 10−16 hours
after dose, at the end of the dosing interval (i.e. 12 hours after the 150 mg
dabigatran evening dose), was 59.7 ng/ml, with a range of 38.6 - 94.5 ng/ml
(25th-75th percentile range). For treatment of DVT and PE, with dabigatran
etexilate 150 mg twice daily,
· the 90th percentile of dabigatran plasma concentrations measured at
trough (10-16 hours after the previous dose) was about 146 ng/ml,
· an ECT at trough (10-16 hours after the previous dose), elevated
approximately 2.3-fold compared to baseline refers to the observed 90th
percentile of ECT prolongation of 74 seconds,
· the 90th percentile of aPTT at trough (10-16 hours after the
previous dose) was 62 seconds, which would be 1.8-fold compared to baseline.
In patients treated for prevention of recurrent of DVT and PE with 150 mg
dabigatran etexilate twice daily no pharmacokinetic data are available.
Clinical efficacy and safety
Ethnic origin
No clinically relevant ethnic differences among Caucasians, African‑American,
Hispanic, Japanese or Chinese patients were observed.
Clinical trials in Venous Thromboembolism (VTE) prophylaxis following major
joint replacement surgery
In 2 large randomized, parallel group, double‑blind, dose‑confirmatory trials,
patients undergoing elective major orthopaedic surgery (one for knee replacement
surgery and one for hip replacement surgery) received Pradaxa 75 mg or 110 mg
within 1‑4 hours of surgery followed by 150 mg or 220 mg once daily thereafter,
haemostasis having been secured, or enoxaparin 40 mg on the day prior to surgery
and daily thereafter.
In the RE‑MODEL trial (knee replacement) treatment was for 6‑10 days and in the
RE‑NOVATE trial (hip replacement) for 28‑35 days. Totals of 2,076 patients
(knee) and 3,494 (hip) were treated respectively.
Composite of total VTE (including PE, proximal and distal DVT, whatever
symptomatic or asymptomatic detected by routine venography) and all‑cause
mortality constituted the primary end‑point for both studies. Composite of major
VTE (including PE and proximal DVT, whatever symptomatic or asymptomatic
detected by routine venography) and VTE‑related mortality constituted a
secondary end‑point and is considered of better clinical relevance.
Results of both studies showed that the antithrombotic effect of Pradaxa 220 mg
and 150 mg were statistically non‑inferior to that of enoxaparin on total VTE
and all‑cause mortality. The point estimate for incidence of Major VTE and VTE
related mortality for the 150 mg dose was slightly worse than enoxaparin (table
17). Better results were seen with the 220 mg dose where the point estimate of
Major VTE was slightly better than enoxaparin (table 17).
The clinical studies have been conducted in a patient population with a mean age
> 65 years.
There were no differences in the phase 3 clinical studies for efficacy and
safety data between men and women.
In the studied patient population of RE‑MODEL and RE‑NOVATE (5,539 patients
treated), 51 % suffered from concomitant hypertension, 9 % from concomitant
diabetes, 9 % from concomitant coronary artery disease and 20 % had a history of
venous insufficiency. None of these diseases showed an impact on the effects of
dabigatran on VTE‑prevention or bleeding rates.
Data for the major VTE and VTE‑related mortality endpoint were homogeneous with
regards to the primary efficacy endpoint and are shown in table 17.
Data for the total VTE and all cause mortality endpoint are shown in table 18.
Data for adjudicated major bleeding endpoints are shown in table 19 below.
Table 17: Analysis of major VTE and VTE‑related mortality during the treatment
period in the RE‑MODEL and the RE‑NOVATE orthopaedic surgery studies.
Trial
Pradaxa
220 mg once daily
Pradaxa
150 mg once daily
Enoxaparin
40 mg
RE‑NOVATE (hip)
N
909
888
917
Incidences (%)
28 (3.1)
38 (4.3)
36 (3.9)
Risk ratio over enoxaparin
0.78
1.09
95 % CI
0.48, 1.27
0.70, 1.70
RE‑MODEL (knee)
N
506
527
511
Incidences (%)
13 (2.6)
20 (3.8)
18 (3.5)
Risk ratio over enoxaparin
0.73
1.08
95 % CI
0.36, 1.47
0.58, 2.01
Table 18: Analysis of total VTE and all cause mortality during the treatment
period in the RE‑NOVATE and the RE‑MODEL orthopaedic surgery studies.
Trial
Pradaxa
220 mg once daily
Pradaxa
150 mg once daily
Enoxaparin
40 mg
RE‑NOVATE (hip)
N
880
874
897
Incidences (%)
53 (6.0)
75 (8.6)
60 (6.7)
Risk ratio over enoxaparin
0.9
1.28
95 % CI
(0.63, 1.29)
(0.93, 1.78)
RE‑MODEL (knee)
N
503
526
512
Incidences (%)
183 (36.4)
213 (40.5)
193 (37.7)
Risk ratio over enoxaparin
0.97
1.07
95 % CI
(0.82, 1.13)
(0.92, 1.25)
Table 19: Major bleeding events by treatment in the individual RE‑MODEL and the
RE‑NOVATE studies.
Trial
Pradaxa
220 mg once daily
Pradaxa
150 mg once daily
Enoxaparin
40 mg
RE‑NOVATE (hip)
Treated patients N
1,146
1,163
1,154
Number of MBE N(%)
23 (2.0)
15 (1.3)
18 (1.6)
RE‑MODEL (knee)
Treated patients N
679
703
694
Number of MBE N(%)
10 (1.5)
9 (1.3)
9 (1.3)
Prevention of stroke and systemic embolism in adult patients with NVAF with one
or more risk factors
The clinical evidence for the efficacy of dabigatran etexilate is derived from
the RE‑LY study (Randomized Evaluation of Long–term anticoagulant therapy) a
multi‑centre, multi‑national, randomized parallel group study of two blinded
doses of dabigatran etexilate (110 mg and 150 mg twice daily) compared to
open‑label warfarin in patients with atrial fibrillation at moderate to high
risk of stroke and systemic embolism. The primary objective in this study was to
determine if dabigatran etexilate was non‑inferior to warfarin in reducing the
occurrence of the composite endpoint stroke and systemic embolism. Statistical
superiority was also analysed.
In the RE‑LY study, a total of 18,113 patients were randomized, with a mean age
of 71.5 years and a mean CHADS2 score of 2.1. The patient population was 64 %
male, 70 % Caucasian and 16 % Asian. For patients randomized to warfarin, the
mean percentage of time in therapeutic range (TTR) (INR 2‑3) was 64.4 % (median
TTR 67 %).
The RE‑LY study demonstrated that dabigatran etexilate, at a dose of 110 mg
twice daily, is non‑inferior to warfarin in the prevention of stroke and
systemic embolism in subjects with atrial fibrillation, with a reduced risk of
ICH, total bleeding and major bleeding. The dose of 150 mg twice daily reduces
significantly the risk of ischemic and haemorrhagic stroke, vascular death, ICH
and total bleeding compared to warfarin. Major bleeding rates with this dose
were comparable to warfarin. Myocardial infarction rates were slightly increased
with dabigatran etexilate 110 mg twice daily and 150 mg twice daily compared to
warfarin (hazard ratio 1.29; p=0.0929 and hazard ratio 1.27; p=0.1240,
respectively). With improving monitoring of INR the observed benefits of
dabigatran etexilate compared to warfarin diminish.
Tables 20‑22 display details of key results in the overall population:
Table 20: Analysis of first occurrence of stroke or systemic embolism (primary
endpoint) during the study period in RE‑LY.
Pradaxa
110 mg twice daily
Pradaxa
150 mg twice daily
Warfarin
Subjects randomized
6,015
6,076
6,022
Stroke and/or systemic embolism
Incidences (%)
183 (1.54)
135 (1.12)
203 (1.72)
Hazard ratio over warfarin (95 % CI)
0.89 (0.73, 1.09)
0.65 (0.52, 0.81)
p value superiority
p=0.2721
p=0.0001
% refers to yearly event rate
Table 21: Analysis of first occurrence of ischemic or haemorrhagic strokes
during the study period in RE‑LY.
Pradaxa
110 mg twice daily
Pradaxa
150 mg twice daily
Warfarin
Subjects randomized
6,015
6,076
6,022
Stroke
Incidences (%)
171 (1.44)
123 (1.02)
187 (1.59)
Hazard ratio vs. warfarin (95 % CI)
0.91 (0.74, 1.12)
0.64 (0.51, 0.81)
p‑value
0.3553
0.0001
Systemic embolism
Incidences (%)
15 (0.13)
13 (0.11)
21 (0.18)
Hazard ratio vs. warfarin (95 % CI)
0.71 (0.37, 1.38)
0.61 (0.30, 1.21)
p‑value
0.3099
0.1582
Ischemic stroke
Incidences (%)
152 (1.28)
104 (0.86)
134 (1.14)
Hazard ratio vs. warfarin (95 % CI)
1.13 (0.89, 1.42)
0.76 (0.59, 0.98)
p‑value
0.3138
0.0351
Haemorrhagic stroke
Incidences (%)
14 (0.12)
12 (0.10)
45 (0.38)
Hazard ratio vs. warfarin (95 % CI)
0.31 (0.17, 0.56)
0.26 (0.14, 0.49)
p‑value
0.0001
< 0.0001
% refers to yearly event rate
Table 22: Analysis of all cause and cardiovascular survival during the study
period in RE‑LY.
Pradaxa
110 mg twice daily
Pradaxa
150 mg twice daily
Warfarin
Subjects randomized
6,015
6,076
6,022
All‑cause mortality
Incidences (%)
446 (3.75)
438 (3.64)
487 (4.13)
Hazard ratio vs. warfarin (95 % CI)
0.91 (0.80, 1.03)
0.88 (0.77, 1.00)
p‑value
0.1308
0.0517
Vascular mortality
Incidences (%)
289 (2.43)
274 (2.28)
317 (2.69)
Hazard ratio vs. warfarin (95 % CI)
0.90 (0.77, 1.06)
0.85 (0.72, 0.99)
p‑value
0.2081
0.0430
% refers to yearly event rate
Tables 23‑25 display results of the primary efficacy and safety endpoint in
relevant sub‑populations:
For the primary endpoint, stroke and systemic embolism, no subgroups (i.e., age,
weight, gender, renal function, ethnicity, etc.) were identified with a
different risk ratio compared to warfarin.
Table 23: Hazard Ratio and 95 % CI for stroke/systemic embolism by subgroups
Endpoint
Pradaxa
110 mg twice daily vs. Warfarin
Pradaxa
150 mg twice daily vs. warfarin
Age (years)
< 65
1.10 (0.64, 1.87)
0.51 (0.26, 0.98)
65 ≤ and < 75
0.86 (0.62, 1.19)
0.67 (0.47, 0.95)
≥ 75
0.88 (0.66, 1.17)
0.68 (0.50, 0.92)
≥ 80
0.68 (0.44, 1.05)
0.67 (0.44, 1.02)
CrCL(mL/min)
30 ≤ and < 50
0.89 (0.61, 1.31)
0.48 (0.31, 0.76)
50 ≤ and < 80
0.91 (0.68, 1.20)
0.65 (0.47, 0.88)
≥ 80
0.81 (0.51, 1.28)
0.69 (0.43, 1.12)
For the primary safety endpoint of major bleeding there was an interaction of
treatment effect and age. The relative risk of bleeding with dabigatran compared
to warfarin increased with age. Relative risk was highest in patients
≥ 75 years. The concomitant use of antiplatelets ASA or clopidogrel
approximately doubles MBE rates with both dabigatran etexilate and warfarin.
There was no significant interaction of treatment effects with the subgroups of
renal function and CHADS2 score.
Table 24: Hazard Ratio and 95 % CI for major bleeds by subgroups
Endpoint
Pradaxa
110 mg twice daily vs. Warfarin
Pradaxa
150 mg twice daily vs. Warfarin
Age (years)
< 65
0.32 (0.18, 0.57)
0.35 (0.20, 0.61)
65 ≤ and < 75
0.71 (0.56, 0.89)
0.82 (0.66, 1.03)
≥ 75
1.01 (0.84, 1.23)
1.19 (0.99, 1.43)
≥ 80
1.14 (0.86, 1.51)
1.35 (1.03, 1.76)
CrCL(mL/min)
30 ≤ and < 50
1.02 (0.79, 1.32)
0.94 (0.73, 1.22)
50 ≤ and < 80
0.75 (0.61, 0.92)
0.90 (0.74, 1.09)
≥ 80
0.59 (0.43, 0.82)
0.87 (0.65, 1.17)
ASA use
0.84 (0.69, 1.03)
0.97 (0.79, 1.18)
Clopidogrel use
0.89 (0.55, 1.45)
0.92 (0.57, 1.48)
RELY-ABLE (Long term multi-center extension of dabigatran treatment in patients
with atrial fibrillation who completed the RE-LY trial)
The RE-LY extension study (RELY-ABLE) provided additional safety information for
a cohort of patients which continued the same dose of dabigatran etexilate as
assigned in the RE-LY trial. Patients were eligible for the RELY-ABLE trial if
they had not permanently discontinued study medication at the time of their
final RE-LY study visit. Enrolled patients continued to receive the same
double-blind dabigatran etexilate dose randomly allocated in RE-LY, for up to
43 months of follow up after RE-LY (total mean follow-up RE-LY + RELY-ABLE,
4.5 years). There were 5897 patients enrolled, representing 49 % of patients
originally randomly assigned to receive dabigatran etexilate in RE-LY and 86 %
of RELY-ABLE–eligible patients.
During the additional 2.5 years of treatment in RELY-ABLE, with a maximum
exposure of over 6 years (total exposure in RELY + RELY-ABLE), the long-term
safety profile of dabigatran etexilate was confirmed for both test doses
110 mg b.i.d. and 150 mg b.i.d.. No new safety findings were observed.
The rates of outcome events including, major bleed and other bleeding events
were consistent with those seen in RE-LY.
Data from non-interventional studies
A non-interventional study (GLORIA-AF) prospectively collected (in its second
phase) safety and effectiveness data in newly diagnosed NVAF patients on
dabigatran etexilate in a real-world setting. The study included 4,859 patients
on dabigatran etexilate (55% treated with 150 mg bid, 43% treated with 110 mg
bid, 2% treated with 75 mg bid). Patients were followed-up for 2 years. The mean
CHADS2 and HAS-BLED scores were 1.9 and 1.2, respectively. Mean on-therapy
follow-up time was 18.3 months. Major bleeding occurred in 0.97 per 100
patient-years. Life-threatening bleeding was reported in 0.46 per 100
patient-years, intracranial haemorrhage in 0.17 per 100 patient-years and
gastrointestinal bleeding in 0.60 per 100 patient-years. Stroke occurred in 0.65
per 100 patient-years.
In addition, in a non-interventional study [Graham DJ et al., Circulation.
2015;131:157-164] in more than 134,000 elderly patients with NVAF in the United
States (contributing more than 37,500 patient-years of on-therapy follow-up
time) dabigatran etexilate (84 % patients treated with 150 mg bid, 16 % patients
treated with 75 mg bid) was associated with a reduced risk of ischemic stroke
(hazard ratio 0.80, 95 % confidence interval [CI] 0.67 – 0.96), intracranial
haemorrhage (hazard ratio 0.34, CI 0.26 – 0.46), and mortality (hazard ratio
0.86, CI 0.77 – 0.96) and increased risk of gastrointestinal bleeding (hazard
ratio 1.28, CI 1.14 – 1.44) compared to warfarin. No difference was found for
major bleeding (hazard ratio 0.97, CI 0.88 – 1.07).
These observations in real-world settings are consistent with the established
safety and efficacy profile for dabigatran etexilate in the RE-LY study in this
indication.
Patients who underwent Percutaneous coronary intervention (PCI) with stenting
A prospective, randomized, open-label, blinded endpoint (PROBE) study (Phase
IIIb) to evaluate dual-therapy with dabigatran etexilate (110 mg or 150 mg bid)
plus clopidogrel or ticagrelor (P2Y12 antagonist) vs. triple-therapy with
warfarin (adjusted to a INR 2.0 – 3.0) plus clopidogrel or ticagrelor and
aspirin was conducted in 2725 patients with non valvular atrial fibrillation who
underwent a PCI with stenting (RE-DUAL PCI). Patients were randomized to
dabigatran etexilate 110 mg bid dual-therapy, dabigatran etexilate 150 mg bid
dual-therapy or warfarin triple-therapy. Elderly patients outside of the United
States (≥80 years of age for all countries, ≥70 years of age for Japan) were
randomly assigned to the dabigatran etexilate 110 mg dual-therapy group or the
warfarin triple-therapy group. The primary endpoint was a combined endpoint of
major bleeds based on ISTH definition or clinically relevant non-major bleeding
event.
The incidence of the primary endpoint was 15.4 % (151 patients) in the
dabigatran etexilate 110 mg dual-therapy group as compared with 26.9 % (264
patients) in the warfarin triple-therapy group (HR 0.52; 95% CI 0.42, 0.63;
P<0.0001 for non-inferiority and P<0.0001 for superiority) and 20.2 % (154
patients) in the dabigatran etexilate 150 mg dual-therapy group as compared with
25.7 % (196 patients) in the corresponding warfarin triple-therapy group (HR
0.72; 95% CI 0.58, 0.88; P<0.0001 for non-inferiority and P=0.002 for
superiority). As part of the descriptive analysis, TIMI (Thrombolysis In
Myocardial Infarction) major bleeding events was lower in both dabigatran
etexilate dual-therapy groups than in the warfarin triple-therapy group: 14
events (1.4%) in the dabigatran etexilate 110 mg dual-therapy group as compared
with 37 events (3.8%) in the warfarin triple-therapy group (HR 0.37; 95% CI
0.20, 0.68; P=0.002) and 16 events (2.1%) in the dabigatran etexilate 150 mg
dual-therapy group as compared with 30 events (3.9%) in the corresponding
warfarin triple-therapy group (HR 0.51; 95% CI 0.28, 0.93; P=0.03). Both
dabigatran etexilate dual-therapy groups had lower rates of intracranial
hemorrhage than the corresponding warfarin triple-therapy group: 3 events (0.3%)
in the 110 mg dabigatran etexilate dual-therapy group as compared with 10 events
(1.0%) in the warfarin triple-therapy group (HR 0.30; 95% CI 0.08, 1.07; P=0.06)
and 1 event (0.1%) in the 150 mg dabigatran etexilate dual-therapy group as
compared with 8 events (1.0%) in the corresponding warfarin triple-therapy group
(HR 0.12; 95% CI 0.02, 0.98; P=0.047). The incidence of the composite efficacy
endpoint of death, thromboembolic events (myocardial infarction, stroke, or
systemic embolism) or unplanned revascularization in the two dabigatran
etexilate dual-therapy groups combined was non-inferior to the warfarin
triple-therapy group (13.7% vs. 13.4% respectively; HR 1.04; 95% CI: 0.84, 1.29;
P=0.0047 for non-inferiority).There were no statistical differences in the
individual components of the efficacy endpoints between either dabigatran
etexilate dual-therapy groups and warfarin triple-therapy.
This study demonstrated that dual-therapy with dabigatran etexilate and a P2Y12
antagonist significantly reduced the risk of bleeding vs. warfarin
triple-therapy with non-inferiority for composite of thromboembolic events in
patients with atrial fibrillation who underwent a PCI with stenting.
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) in adults
(DVT/PE treatment)
The efficacy and safety was investigated in two multi-center, randomised, double
blind, parallel-group, replicate studies RE-COVER and RE-COVER II. These studies
compared dabigatran etexilate (150 mg bid) with warfarin (target INR 2.0-3.0) in
patients with acute DVT and/or PE. The primary objective of these studies was to
determine if dabigatran etexilate was non-inferior to warfarin in reducing the
occurrence of the primary endpoint which was the composite of recurrent
symptomatic DVT and/or PE and related deaths within the 6 month treatment
period.
In the pooled RE-COVER and RE-COVER II studies, a total of 5,153 patients were
randomised and 5,107 were treated.
The duration of treatment with fixed dose of dabigatran was 174.0 days without
coagulation monitoring. For patients randomized to warfarin, the median time in
therapeutic range (INR 2.0 to 3.0) was 60.6 %.
The trials, demonstrated that treatment with dabigatran etexilate 150 mg twice
daily was non-inferior to the treatment with warfarin (non-inferiority margin
for RE-COVER, and RE-COVER II: 3.6 for risk difference and 2.75 for hazard
ratio).
Table 25: Analysis of the primary and secondary efficacy endpoints (VTE is a
composite of DVT and/or PE) until the end of post-treatment period for the
pooled studies RE-COVER and RE-COVER II
Pradaxa
150 mg twice daily
Warfarin
Treated patients
2,553
2,554
Recurrent symptomatic VTE and VTE-related death
68 ( 2.7 %)
62 ( 2.4 %)
Hazard ratio vs warfarin
(95% confidence interval)
1.09
(0.77, 1.54)
Secondary efficacy endpoints
Recurrent symptomatic VTE and all-cause deaths
109 (4.3 %)
104 (4.1 %)
95 % confidence interval
3.52, 5.13
3.34, 4.91
Symptomatic DVT
45 (1.8 %)
39 (1.5 %)
95 % confidence interval
1.29, 2.35
1.09, 2.08
Symptomatic PE
27 (1.1 %)
26 (1.0 %)
95 % confidence interval
0.70, 1.54
0.67, 1.49
VTE-related deaths
4 (0.2 %)
3 (0.1 %)
95 % confidence interval
0.04, 0.40
0.02, 0.34
All-cause deaths
51 (2.0 %)
52 (2.0 %)
95 % confidence interval
1.49, 2.62
1.52, 2.66
Prevention of recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE)
in adults (DVT/PE prevention)
Two randomized, parallel group, double-blind studies were performed in patients
previously treated with anticoagulation therapy. RE-MEDY, warfarin controlled
study, enrolled patients already treated for 3 to 12 months with the need for
further anticoagulant treatment and RE-SONATE, the placebo controlled study,
enrolled patients already treated for 6 to 18 months with Vitamin K inhibitors.
The objective of the RE-MEDY study was to compare the safety and efficacy of
oral dabigatran etexilate (150 mg bid) to warfarin (target INR 2.0-3.0) for the
long-term treatment and prevention of recurrent, symptomatic DVT and/or PE. A
total of 2,866 patients were randomized and 2,856 patients were treated.
Duration of dabigatran etexilate treatment ranged from 6 to 36 months (median
534.0 days). For patients randomized to warfarin, the median time in therapeutic
range (INR 2.0-3.0) was 64.9 %.
RE-MEDY demonstrated that treatment with dabigatran etexilate 150 mg twice daily
was non-inferior to warfarin (non-inferiority margin: 2.85 for hazard ratio and
2.8 for risk difference).
Table 26: Analysis of the primary and secondary efficacy endpoints (VTE is a
composite of DVT and/or PE) until the end of post-treatment period for the
RE-MEDY study
Pradaxa
150 mg twice daily
Warfarin
Treated patients
1430
1426
Recurrent symptomatic VTE and VTE-related death
26 (1.8 %)
18 (1.3 %)
Hazard ratio vs warfarin
(95% confidence interval)
1.44
(0.78, 2.64)
non-inferiority margin
2.85
Patients with event at 18 months
22
17
Cumulative risk at
18 months (%)
1.7
1.4
Risk difference vs. warfarin (%)
0.4
95% confidence interval
non-inferiority margin
2.8
Secondary efficacy endpoints
Recurrent symptomatic VTE and all-cause deaths
42 (2.9 %)
36 (2.5 %)
95 % confidence interval
2.12, 3.95
1.77, 3.48
Symptomatic DVT
17 (1.2 %)
13 (0.9 %)
95 % confidence interval
0.69, 1.90
0.49, 1.55
Symptomatic PE
10 (0.7 %)
5 (0.4 %)
95 % confidence interval
0.34, 1.28
0.11, 0.82
VTE-related deaths
1 (0.1 %)
1 (0.1 %)
95 % confidence interval
0.00, 0.39
0.00, 0.39
All-cause deaths
17 (1.2 %)
19 (1.3 %)
95 % confidence interval
0.69, 1.90
0.80, 2.07
The objective of the RE-SONATE study was to evaluate superiority of dabigatran
etexilate versus placebo for the prevention of recurrent symptomatic DVT and/or
PE in patients who had already completed 6 to 18 months of treatment with VKA.
The intended therapy was 6 months dabigatran etexilate 150 mg twice daily
without need for monitoring.
RE-SONATE demonstrated dabigatran etexilate was superior to placebo for the
prevention of recurrent symptomatic DVT/PE events including unexplained deaths,
with a risk reduction from 5.6 % to 0.4 % (relative risk reduction 92 % based on
hazard ratio ) during the treatment period (p<0.0001). All secondary and
sensitivity analyses of the primary endpoint and all secondary endpoints showed
superiority of dabigatran etexilate over placebo.
The study included observational follow-up for 12 months after the conclusion of
treatment. After discontinuation of study medication the effect was maintained
until the end of the follow-up, indicating that the initial treatment effect of
dabigatran etexilate was sustained. No rebound effect was observed. At the end
of the follow-up VTE events in patients treated with dabigatran etexilate was
6.9 % vs. 10.7 % among the placebo group (hazard ratio 0.61 (95% CI 0.42, 0.88),
p=0.0082).
Table 27: Analysis of the primary and secondary efficacy endpoints (VTE is a
composite of DVT and/or PE) until the end of post-treatment period for the
RE-SONATE study.
Pradaxa
150 mg twice daily
Placebo
Treated patients
681
662
Recurrent symptomatic VTE and related deaths
3 (0.4 %)
37 (5.6 %)
Hazard Ratio vs
placebo
(95% confidence interval)
0.08
(0.02, 0.25)
p-value for superiority
< 0.0001
Secondary efficacy endpoints
Recurrent symptomatic VTE and all-cause deaths
3 (0.4 %)
37 (5.6 %)
95% confidence interval
0.09, 1.28
3.97, 7.62
Symptomatic DVT
2 (0.3 %)
23 (3.5 %)
95% confidence interval
0.04, 1.06
2.21, 5.17
Symptomatic PE
1 (0.1 %)
14 (2.1 %)
95% confidence interval
0.00, 0.82
1.16, 3.52
VTE-related deaths
0 (0)
0 (0)
95% confidence interval
0.00, 0.54
0.00, 0.56
Unexplained deaths
0 (0)
2 (0.3 %)
95% confidence interval
0.00, 0.54
0.04, 1.09
All-cause deaths
0 (0)
2 (0.3 %)
95% confidence interval
0.00, 0.54
0.04, 1.09
Clinical trials for the prevention of thromboembolism in patients with
prosthetic heart valves
A phase II study examined dabigatran etexilate and warfarin in a total of 252
patients with recent mechanical valve replacement surgery (i.e. within the
current hospital stay) and in patients who received a mechanical heart valve
replacement more than three months ago. More thromboembolic events (mainly
strokes and symptomatic/asymptomatic prosthetic valve thrombosis) and more
bleeding events were observed with dabigatran etexilate than with warfarin. In
the early post-operative patients, major bleeding manifested predominantly as
haemorrhagic pericardial effusions, specifically in patients who started
dabigatran etexilate early (i.e. on Day 3) after heart valve replacement surgery
(see section 4.3).
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of
studies with Pradaxa in all subsets of the paediatric population for the granted
indications (see section 4.2 for information on paediatric use).
The pharmacokinetics and pharmacodynamics of dabigatran etexilate administered
twice daily for three consecutive days (total 6 doses) at the end of standard
anticoagulant therapy were assessed in an open-label safety and tolerability
study in 9 stable adolescents (12 to < 18 years). All patients received an
initial oral dose of 1.71 (± 10%) mg/kg of dabigatran etexilate (80 % of the
adult dose of 150 mg/70 kg adjusted for the patient’s weight). Based on
dabigatran concentrations and clinical assessment, the dose was subsequently
modified to a target dose of 2.14 (± 10 %) mg/kg of dabigatran etexilate (100 %
of the adult dose adjusted for the patient’s weight). In this small number of
adolescents, dabigatran etexilate capsules were apparently tolerated with only
three mild and transient gastrointestinal adverse events reported by two
patients. According to the relatively low exposure, coagulation at 72 hrs
(presumed dabigatran trough level at steady state or close to steady state
conditions) was only slightly prolonged with aPTT at maximum 1.60 fold, ECT
1.86 fold, and Hemoclot® TT (Anti-FIIa) 1.36 fold, respectively. Dabigatran
plasma concentrations observed at 72 hrs were relatively low, between 32.9 ng/mL
and 97.2 ng/mL at final doses between 100 mg and 150 mg (gMean dose normalized
total dabigatran plasma concentration of 0.493 ng/mL/mg).
5.3 Preclinical Safety Data
Non‑clinical data reveal no special hazard for humans based on conventional
studies of safety pharmacology, repeated dose toxicity and genotoxicity.
Effects observed in the repeated dose toxicity studies were due to the
exaggerated pharmacodynamic effect of dabigatran.
An effect on female fertility was observed in the form of a decrease in
implantations and an increase in pre‑implantation loss at 70 mg/kg (5‑fold the
plasma exposure level in patients). At doses that were toxic to the mothers (5‑
to 10‑fold the plasma exposure level in patients), a decrease in foetal body
weight and viability along with an increase in foetal variations were observed
in rats and rabbits. In the pre‑ and post‑natal study, an increase in foetal
mortality was observed at doses that were toxic to the dams (a dose
corresponding to a plasma exposure level 4‑fold higher than observed in
patients).
In lifetime toxicology studies in rats and mice, there was no evidence for a
tumorigenic potential of dabigatran up to maximum doses of 200 mg/kg.
Dabigatran, the active moiety of dabigatran etexilate mesilate, is persistent in
the environment.
6. PHARMACEUTICAL PARTICULARS
6.1 Excipients List
Capsule content
Tartaric acid
Acacia
Hypromellose
Dimeticone 350
Talc
Hydroxypropylcellulose
Capsule shell
Carrageenan
Potassium chloride
Titanium dioxide
Indigo carmine (E132)
Hypromellose
Black printing ink
Shellac
Iron oxide black (E172)
Potassium hydroxide
6.2. Incompatibilities
Not applicable.
6.3. Shelf Life
Blister and bottle 3 years Once the bottle is opened, the medicinal product must
be used within 4 months.
6.4. Special precautions for storage
Blister
Store in the original package in order to protect from moisture.
Bottle
Store in the original package in order to protect from moisture.
Keep the bottle tightly closed.
6.5. Nature and contents of container
Cartons containing 10 x 1, 30 x 1 or 60 x 1 hard capsules in perforated
aluminium unit dose blisters.
Multipack containing 3 packs of 60 x 1 hard capsules (180 hard capsules) in
perforated aluminium unit dose blisters.
Multipack containing 2 packs of 50 x 1 hard capsules (100 hard capsules) in
perforated aluminium unit dose blisters.
Carton containing 6 blister strips (60 x 1) in perforated aluminium unit dose
white blisters.
Polypropylene bottle with a screw cap containing 60 hard capsules.
Not all pack sizes may be marketed.
6.6. Special precautions for disposal and other handling
When taking Pradaxa capsules out of the blister pack, the following instructions
should be followed:
· One individual blister should be teared off from the blister card
along the perforated line.
· The backing foil should be peeled off and the capsule can be
removed.
· The hard capsules should not be pushed through the blister foil.
· The blister foil should only be peeled off, when a hard capsule is
required.
When taking a hard capsule out of the bottle, the following instructions should
be observed:
· The cap opens by pushing and turning.
· After taking the capsule out, the cap should be returned on the
bottle right away and the bottle should be tightly closed.
Any unused medicinal product or waste material should be disposed of in
accordance with local
requirements.
7. MARKETING AUTHORISATION HOLDER
Boehringer Ingelheim International GmbH Binger Str. 173 D 55216 Ingelheim am
Rhein Germany
8. DATE OF REVISION OF THE TEXT
May 2020
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