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نشرة الممارس الصحي نشرة معلومات المريض بالعربية نشرة معلومات المريض بالانجليزية صور الدواء بيانات الدواء
  SFDA PIL (Patient Information Leaflet (PIL) are under review by Saudi Food and Drug Authority)

CO-RIBEX is a combination of two active substances,
irbesartan and hydrochlorothiazide.
Irbesartan belongs to a group of medicines known as
angiotensin-II receptor antagonists. Angiotensin-II is a
substance produced in the body that binds to
receptors in blood vessels causing them to tighten.
This results in an increase in blood pressure.
Irbesartan prevents the binding of angiotensin-II to
these receptors, causing the blood vessels to relax
and the blood pressure to lower.
Hydrochlorothiazide is one of a group of medicines
(called thiazide diuretics) that causes increased urine
output and so causes a lowering of blood pressure.
The two active ingredients in CO-RIBEX work together
to lower blood pressure further than if either was given
alone.
CO-RIBEX is used to treat high blood pressure,
when treatment with irbesartan or hydrochlorothiazide
alone did not provide adequate control of your blood
pressure.


• if you are allergic to irbesartan or any of the other
ingredients of this medicine (listed in section 6)
• if you are allergic to hydrochlorothiazide or any other
sulfonamide-derived medicines
• if you are more than 3 months pregnant. (It is also
better to avoid CO-RIBEX in early pregnancy – see
pregnancy section)
• if you have severe liver or kidney problems
• if you have difficulty in producing urine
• if your doctor determines that you have persistently
high calcium or low potassium levels in your blood
• if you have diabetes or impaired kidney function
and you are treated with aliskiren (another medicine to treat high blood pressure). 

 

Warnings and Precautions
Talk to your doctor before taking CO-RIBEX and if any
of the following apply to you:
• if you have had skin cancer or if you develop an
unexpected skin lesion during the treatment.
Treatment with hydrochlorothiazide, particularly long
term use with high doses, may increase the risk of
some types of skin and lip cancer (non-melanoma skin
cancer). Protect your skin from sun exposure and UV
rays while taking CO-RIBEX.
• if you get excessive vomiting or diarrhea
• if you suffer from kidney problems or have a kidney
transplant
• if you suffer from heart problems
• if you suffer from liver problems
• if you suffer from diabetes
• if you suffer from lupus erythematous (also known
as lupus or SLE)
• if you suffer from primary aldosteronism (a
condition related to high production of the hormone
aldosterone, which causes sodium retention and, in
turn, an increase in blood pressure).
if you are taking any of the following medicines used to
treat high blood pressure:
• an ACE-inhibitor (for example enalapril, lisinopril,
ramipril), in particular if you have diabetes-related
kidney problems.
• aliskiren.
Your doctor may check your kidney function, blood
pressure, and the amount of electrolytes (e.g.
potassium) in your blood at regular intervals.
See also information under the heading “Do not take
CO-RIBEX”.
You must tell your doctor if you think you are (or might
become) pregnant. CO-RIBEX is not recommended in
early pregnancy, and must not be taken if you are more
than 3 months pregnant, as it may cause serious harm
to your baby if used at that stage (see pregnancy
section).
You should also tell your doctor:

if you are on a low-salt diet
• if you have signs such as abnormal thirst, dry
mouth, general weakness, drowsiness, muscle
pain or cramps, nausea, vomiting, or an abnormally
fast heart beat which may indicate an excessive
effect of hydrochlorothiazide (contained in CO-RIBEX)
• if you experience an increased sensitivity of the
skin to the sun with symptoms of sunburn (such as
redness, itching, swelling, blistering) occurring more
quickly than normal
• if you are going to have an operation (surgery) or
be given anaesthetics
• if you have changes in your vision or pain in one
or both of your eyes while taking CO-RIBEX. This
could be a sign that you are developing glaucoma,
increased pressure in your eye(s). You should
discontinue CO-RIBEX treatment and seek medical
attention.
The hydrochlorothiazide contained in this medicine
could produce a positive result in an anti-doping test.
Children and adolescents
CO-RIBEX should not be given to children and
adolescents (under 18 years).
Other medicines and CO-RIBEX
Tell your doctor or pharmacist if you are taking, have
recently taken or might take any other medicines.
Diuretic agents such as the hydrochlorothiazide

contained in CO-RIBEX may have an effect on other
medicines. Preparations containing lithium should not
be taken with CO-RIBEX without close supervision by
your doctor.
Your doctor may need to change your dose and/or to
take other precautions if you are taking an ACE-inhibitor
or aliskiren (see also information under the
headings “Do not take CO-RIBEX” and “Warnings and
precautions”).

 

You may need to have blood checks if you take:
• potassium supplements
• salt substitutes containing potassium
• potassium sparing medicines or other diuretics
(water tablets)
• some laxatives
• medicines for the treatment of gout
• therapeutic vitamin D supplements
• medicines to control heart rhythm
• medicines for diabetes (oral agents or insulins)
• carbamazepine (a medicine for the treatment of
epilepsy).
It is also important to tell your doctor if you are taking
other medicines to reduce your blood pressure,
steroids, medicines to treat cancer, pain killers,
arthritis medicines, or colestyramine and colestipol
resins for lowering blood cholesterol.
CO-RIBEX with food and drink:
CO-RIBEX can be taken with or without food.
Due to the hydrochlorothiazide contained in
CO-RIBEX, if you drink alcohol while on treatment with
this medicine, you may have an increased feeling of
dizziness on standing up, especially when getting up
from a sitting position.
Use during pregnancy and breast-feeding and
fertility:
Pregnancy

 

You must tell your doctor if you think you are (or might
become) pregnant. Your doctor will normally advise
you to stop taking CO-RIBEX before you become
pregnant or as soon as you know you are pregnant
and will advise you to take another medicine instead of
CO-RIBEX. CO-RIBEX is not recommended during
pregnancy, and must not be taken when more than 3
months pregnant, as it may cause serious harm to
your baby if used after the third month of pregnancy.
Breast-feeding
Tell your doctor if you are breast-feeding or about to
start breast-feeding. CO-RIBEX is not recommended
for mothers who are breast-feeding, and your doctor
may choose another treatment for you if you wish to
breast-feed, especially if your baby is newborn, or was
born prematurely.
Athletic:
The hydrochlorothiazide contained in this medicine
could produce a positive result in an anti-doping test.
Driving and using machines:
No studies on the effects on the ability to drive and use
machines have been performed. CO-RIBEX is unlikely
to affect your ability to drive or use machines.
However, occasionally dizziness or weariness may
occur during treatment of high blood pressure. If you
experience these, talk to your doctor before attempting
to drive or use machines.
CO-RIBEX contains lactose. If you have been told by
your doctor that you have an intolerance to some
sugars (e.g. lactose), contact your doctor before taking
this medicine.

 

 


Always take this medicine exactly as your doctor has
told you. Check with your doctor or pharmacist if you
are not sure.
Dosage
The recommended dose of CO-RIBEX is one tablet a
day. CO-RIBEX will usually be prescribed by your
doctor when your previous treatment did not reduce
your blood pressure enough. Your doctor will instruct
you how to switch from the previous treatment to
CO-RIBEX.
Method of administration
CO-RIBEX is for oral use. Swallow the tablets with a
sufficient amount of fluid (e.g. one glass of water). You
can take CO-RIBEX with or without food. Try to take
your daily dose at about the same time each day. It is
important that you continue to take CO-RIBEX until
your doctor tells you otherwise.
The maximal blood pressure lowering effect should be
reached 6-8 weeks after beginning treatment.
If you take more CO-RIBEX than you should
If you accidentally take too many tablets, contact your
doctor immediately.
Children should not take CO-RIBEX
CO-RIBEX should not be given to children under 18
years of age. If a child swallows some tablets, contact
your doctor immediately.
If you forget to take CO-RIBEX
If you accidentally miss a daily dose, just take the next
dose as normal. Do not take a double dose to make up
for a forgotten dose.
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. Some of these
effects may be serious and may require medical
attention.
Rare cases of allergic skin reactions (rash, urticaria),
as well as localized swelling of the face, lips and/or
tongue have been reported in patients taking
irbesartan.
If you get any of the above symptoms or get short
of breath, stop taking CO-RIBEX and contact your
doctor immediately.
Side effects reported in clinical studies for patients
treated with CO-RIBEX were:
Common side effects (may affect up to 1 in 10
people):
• nausea/vomiting
• abnormal urination
• fatigue
• dizziness (including when getting up from a lying or
sitting position)
• blood tests may show raised levels of an enzyme that
measures the muscle and heart function (creatine
kinase) or raised levels of substances that measure
kidney function (blood urea nitrogen, creatinine).
If any of these side effects causes you problems,
talk to your doctor.
Uncommon side effects (may affect up to 1 in 100
people):
• Diarrhea
• low blood pressure
• fainting
• heart rate increased
• flushing

• swelling
• sexual dysfunction (problems with sexual
performance)
• blood tests may show lowered levels of potassium
and sodium in your blood.
If any of these side effects causes you problems,
talk to your doctor.
Side effects reported since the launch of
Irbesartan/Hydrochlorothiazide
Some undesirable effects have been reported since
marketing of Irbesartan/Hydrochlorothiazide.
Undesirable effects where the frequency is not known
are: headache, ringing in the ears, cough, taste
disturbance, indigestion, pain in joints and muscles,
liver function abnormal and impaired kidney function,
increased level of potassium in your blood and allergic
reactions such as rash, hives, swelling of the face, lips,
mouth, tongue or throat. Uncommon cases of jaundice
(yellowing of the skin and/or whites of the eyes) have
also been reported.
As for any combination of two active substances, side
effects associated with each individual component
cannot be excluded.
Side effects associated with irbesartan alone
In addition to the side effects listed above, chest pain,
severe allergic reactions (anaphylactic shock), and
decrease in the number of platelets (a blood cell
essential for the clotting of the blood) have also been
reported

Side effects associated with hydrochlorothiazide
alone
Loss of appetite; stomach irritation; stomach cramps;
constipation; jaundice (yellowing of the skin and/or
whites of the eyes); inflammation of the pancreas
characterized by severe upper stomach pain, often
with nausea and vomiting; sleep disorders;
depression; blurred vision; lack of white blood cells,
which can result in frequent infections, fever; decrease
in the number of platelets (a blood cell essential for the
clotting of the blood), decreased number of red blood
cells (anaemia) characterized by tiredness,
headaches, being short of breath when exercising,
dizziness and looking pale; kidney disease; lung
problems including pneumonia or build-up of fluid in
the lungs; increased sensitivity of the skin to the sun;
inflammation of blood vessels; a skin disease
characterized by the peeling of the skin all over the
body; cutaneous lupus erythematous, which is
identified by a rash that may appear on the face, neck,
and scalp; allergic reactions; weakness and muscle
spasm; altered heart rate; reduced blood pressure
after a change in body position; swelling of the salivary
glands; high sugar levels in the blood; sugar in the
urine; increases in some kinds of blood fat; high uric
acid levels in the blood, which may cause gout.
Frequency not know:
Skin and lip cancer (Non-melanoma skin cancer)
related to hydrochlorothiazide.
It is known that side effects associated with hydrochlorothiazide
may increase with higher doses of
hydrochlorothiazide.
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 via the national reporting system

 


Do not store above 30°C.
Store in the original package in order to protect from
light
Keep out of the reach and the sight of children.


Active product ingredient:
CO-RIBEX 150 mg/ 12.5 mg: each tablet contains 150
mg of irbesartan and 12.5mg of hydrochlorothiazide.
CO-RIBEX 300 mg/ 12.5 mg: each tablet contains 300
mg of irbesartan and 12.5 mg of hydrochlorothiazide.
CO-RIBEX 300 mg/ 25 mg: each tablet contains 300
mg of irbesartan and 25 mg of hydrochlorothiazide.
The other ingredients are:
Microcrystalline cellulose; Pregelatinized starch;
Lactose monohydrated; Poloxamer 188; Croscarmellose
sodium; Magnesium stearate. Coating: hypromellose
6cP, stearic acid, titanium dioxide, Microcrystalline
cellulose, yellow iron oxide (CO-RIBEX 150 mg/
12.5 mg, CO-RIBEX 300 mg/ 12.5 mg), black iron
oxide (CO-RIBEX 300 mg/25 mg), red iron oxide.
What CO-RIBEX, Film-coated and scored tablets
looks like and contents of the pack
These medicines are in the form of film-coated and
scored tablets. Box of 14 and 28.
Name and address of the holder of the marketing
authorization and manufacturer
Laboratories SOTHEMA
P.O. Box N°1, 27182 Bouskoura
Morocco
Prescribing and dispensing conditions
Drug subject to medical prescription – list I/Table A
The last date of revision of this leaflet is November
2018 version 02.


These medicines are in the form of film-coated and scored tablets. Box of 14 and 28.

Name and address of the holder of the marketing
authorization and manufacturer
Laboratories SOTHEMA
P.O. Box N°1, 27182 Bouskoura
Morocco
 


Prescribing and dispensing conditions Drug subject to medical prescription – list I/Table A The last date of revision of this leaflet is November 2018 version 02.
  نشرة الدواء تحت مراجعة الهيئة العامة للغذاء والدواء (اقرأ هذه النشرة بعناية قبل البدء في استخدام هذا المنتج لأنه يحتوي على معلومات مهمة لك)

كو-ريبكس أقراص ملبسة قابلة للكسر هو مركب من
مادتين فعالتين هما إيربيزارتان وهيدروكلوروثيازيد.
ينتمي إيربيزارتان إلى مجموعة من الأدوية تعرف بإسم
. II ضادات مستقبلات الأنجيوتونسين
هو عبارة عن مادة يتم إنتاجها في الجسم و II الأنجيوتونسين
ترتبط بالمستقبلات في الأوعية الدموية فتقلصها. هذا
يؤدي إلى ارتفاع في ضغط الدم.
بهذه المستقبلات، II يحول إيربيزارتان دون ربط الأنجيوتنسين
مما يؤدي إلى إرتخاء الأوعية الدموية وبالتالي انخفاض ضغط
الدم .
ينتمي هيدروكلوروثيازيد إلى مجموعة من الأدوية تُسمى
(مدرات البول التيآزيدية) التي تزيد من إفراز البول مما يؤدي
إلى خفض ضغط الدم.
تعمل المادتين الفعالتين في كو-ريبكس معاً على تخفيض
ضغط الدم بشكل أكبر عما إذا ما اس ُ تعملت كل مادة
بمفردها.
يستعمل كو-ريبكس لعلاج ضغط الدم المرتفع، عندما لا
يكون العلاج المنفرد بالإيربيزارتان أو بالهيدروكلوروثيازيد
كافيا للتحكم بشكل مناسب في ضغط الدم لديكم.

موانع استعمال كو-ريبكس
• إذا كنتم تعانون من الحساسية لمادة الإيربيزارتان أو لأيٍّ من
.( المكونات الأخرى لهذا الدواء (المدرجة في الفقرة 6
• إذا كنتم تعانون من الحساسية لمادة الهيدروكلوروثيازيد أو
لأي أدوية أخرى مشتقة من السلفوناميد.
• إذا كنت حاملاً لأكثر من 3 أشهر. ( يفضل كذلك تفادي
كو-ريبكس في الأشهر الأولى من الحمل أنظري فقرة الحمل).
• إذا كنتم تعانون من اضطرابات شديدة في الكبد أو الكلى.
• إذا كنتم تعانون من صعوبة في التبول.
• إذا رأى طبيبكم أن لديكم نسب عالية من الكالسيوم

أو نسب منخفضة من البوتاسيوم في الدم بشكل دائم.
• إذا كنتم تعانون من مرض السكري أو فشل كلوي وتتم
معالجتكم بدواء يحتوي على مادة الأليسكيرين (دواء آخر
لخفض ضغط الدم).

 

تحذيرات خاصة و احتياطات استعمال كو-ريبكس :
أخبروا طبيبكم قبل تناول كو-ريبكس إذا كانت أي من
الحالات التالية تنطبق عليكم:
• إذا كنتم تعانون من تقيؤ أو إسهال مفرط.
• إذا كنتم تعانون من اضطرابات في الكلى أو إذا كانت
لديكم كلية مزروعة.
• إذا كنتم تعانون من اضطرابات في القلب.
• إذا كنتم تعانون من اضطرابات في الكبد.
• إذا كنتم تعانون من مرض السكري.
• إذا كنتم تعانون من مرض الذئبة الحمامية (المعروف أيضا
.(SLE بإسم مرض الذئبة أو
• إذا كنتم تعانون من فرط الألدوستيرونية الأولية (وهي
حالة ناتجة عن إنتاج مرتفع من هرمون الألدوستيرون، الذي
يسبب احتباس الصوديوم، والذي بدوره يسبب إرتفاعا في
ضغط الدم).
• إذا كنتم تستعملون أي من الأدوية التالية لعلاج ارتفاع
ضغط الدم:
- مثبط الأنزيم المحول للأنجيوتنسين (على سبيل المثال إينالابريل،
ليسينوبريل، راميبريل)، ولا سيما إذا كان لديكم إضطرابات
في الكلى مرتبطة بمرض السكري.
- أليسكيرين.
قد يقوم طبيبكم بفحص منتظم لوظيفة الكلي، ضغط
الدم، ومستويات الإلكتروليت في الدم (مثل البوتاسيوم)
انظر أيضا المعلومات في الفقرة "موانع استعمال كو-ريبكس".
يجب أن تخبري طبيبك إذا كنت تعتقدين أنك (أو قد
تصبحين) حاملاً. لا يوصى باستعمال كو-ريبكس في
الأشهر الأولى من الحمل، ولا يجب أخذه إذا كنت حاملاً لأكثر
من 3 أشهر، حيث من الممكن أن يسبب ضررا بالغا للجنين
إذا ما استعمل في هذه المرحلة (انظر فقرة الحمل).
يجب عليكم أيضا أن تخبروا طبيبكم:
إذا كنتم قد أصبتم بسرطان الجلد أو إذا كنتم تعانون من
آفة جلدية غير متوقعة أثناء العلاج. قد يؤدي العلاج باستخدام
هيدروكلوروثيازيد، وخاص ً ة على المدى الطويل مع الجرعات
العالية، إلى زيادة خطر الإصابة ببعض أنواع سرطان الجلد
والشفة (سرطان الجلد غير الميلانيني). احموا بشرتكم من
التعرض لأشعة الشمس والأشعة فوق البنفسجية أثناء
تناول كو-ريبكس.
• إذا كنتم تتبعون نظام غذائي منخفض الملح.
• إذا كنتم تعانون من علامات مثل عطش غير طبيعي،
جفاف الفم، ضعف عام، خمول، آلام في العضلات أو
تشنجات، غثيان، تقيؤ، أو ضربات متسارعة غير طبيعية
للقلب مما قد يدل على التأثير المفرط للهيدروكلوروثيازيد
(الذي يحتوي عليه كو-ريبكس.
• إذا كنتم تعانون من حساسية متزايدة في الجلد حيال
أشعة الشمس مع ظهور أعراض حروق الشمس (مثل
احمرار، حكة، تورم، تنفط) والتي تحدث بسرعة أكثر من المعتاد.
• إذا كنتم ستخضعون لعملية جراحية (جراحة) أو
للتخدير.
إذا عانيتم من تغيرات في الرؤية أو ألم في إحدى أو كلتا
العينين أثناء تناول كو-ريبكس يمكن أن يكون علامة على
أنكم ستصابون بالزرق (الجلوكوما)، أي زيادة الضغط في
العين. يجب عليكم التوقف عن تناول كو-ريبكس واستشارة
الطبيب.
إن الهيدروكلوروثيازيد الذي يحتوي عليه هذا الدواء يمكن أن
يعطي نتيجة إيجابية في فحص كشف تناول المنشطات.
الأطفال والمراهقون
لا ينبغي إعطاء كو-ريبكس للأطفال والمراهقين (أقل من 18
سنة).

 

إستخدام الأدوية أخرى مع كو-ريبكس
يرجى إخبار طبيبكم أو الصيدلاني إذا كنتم تستعملون أو
إذا استعملتم مؤخراً أو قد تستعملون أي أدوية أخرى.
إن مدرات البول مثل الهيدروكلوروثيازيد الذي يحتويه
كو-ريبكس يمكن أن تتفاعل مع بعض الأدوية الأخرى. يجب
عدم تناول الأدوية التي تحتوي على الليثيوم مع كو-ريبكس
بدون إشراف طبي عن كثب.
قد يحتاج طبيبكم إلى تغيير جرعة الدواء و / أو اتخاذ
احتياطات أخرى إذا كنتم تستعملون مثبط الأنزيم المحول
للأنجيوتنسين أو الأليسكيرين (أنظر أيضا المعلومات تحت عناوين
"موانع استعمال كو-ريبكس "و" تحذيرات خاصة و احتياطات
الإستعمال").
قد تحتاجون إلى إجراء فحوصات الدم إذا كنتم تتناولون:
• مكملات البوتاسيوم
• بدائل عن الملح التي تحتوي على البوتاسيوم
• الأدوية التي تحافظ على البوتاسيوم أو مدرات البول
الأخرى (أقراص الماء)
• بعض الملينات
• أدوية لعلاج النقرس
• مكملات فيتامين د العلاجية
• أدوية ضبط النظم القلبي
• أدوية لعلاج السكري (الأدوية التي تؤخذ عن طريق الفم أو
الأنسولين)
• كاربامازيبين (دواء لعلاج الصرع).
من المهم أيضا إخبار طبيبكم إذا كنتم تتناولون أدوية أخرى
لتخفيض ضغط الدم، ستيرويد، أدوية لعلاج السرطان،
مسكنات الألم ، أدوية التهاب المفاصل، أو الكوليسترامين
والكوليستيبول لتخفيض الكولسترول في الدم.
كو-ريبكس مع الطعام والشراب:
يمكن تناول كو-ريبكس مع الطعام أو بدونه.
نظرا لوجود الهيدروكلوروثيازيد الذي يحتوي عليه كو-ريبكس،
إذا كنتم تشربون الكحول خلال فترة العلاج، قد يزداد لديكم
الشعور بالدوار عند الوقوف، وخصوصا عند الانتقال من
وضعية الجلوس إلى وضعية الوقوف.
إستعمال الدواء خلال فترة الحمل و الإرضاع والخصوبة:
الحمل
يجب عليك إخبار طبيبك إذا كنت تعتقدين أنك (أو قد
تصبحين) حاملا. سوف ينصحك طبيبك الخاص عادة
بالتوقف عن تناول كو-ريبكس قبل أن تصبحي حاملا أو
حالما تعرفين أنك حامل وسوف ينصحك بأخذ دواء آخر بدلا
من كو-ريبكس. لا يوصى بتناول كو-ريبكس في الأشهر
الأولى من الحمل ، ويجب ألا يؤخذ إذا كان عمر الحمل أكثر من
ثلاثة شهور، حيث من الممكن أن يسبب ضررا بالغا للجنين
إذا ما استعمل بعد الشهر الثالث من الحمل.
الرضاعة الطبيعية
أخبري طبيبك إذا كنت ترضعين أو على وشك الإرضاع. لا
ينصح بتناول كو-ريبكس من قبل الأمهات المرضعات، قد
يختار طبيبك علاجاً آخر إذا كنت ترغبين في الإرضاع،
ولاسيما إذا كان طفلك حديث الولادة، أو ولد قبل أوانه.
الرياضيون:
إن الهيدروكلوروثيازيد الذي يحتوي عليه هذا الدواء يمكن أن
يعطي نتيجة إيجابية في فحص كشف تناول المنشطات.
تأثير كو-ريبكس على قيادة السيارات واستعمال الآلات:
لم تتم إجراء دراسات حول تأثير الدواء على القدرة على
القيادة واستعمال الآلات. من غير المحتمل أن يؤثر كو-ريبكس
على قدرتكم على القيادة أو استعمال الآلات. ولكن قد
يصاب المريض في بعض الأحيان بالدوار أو بالإرهاق أثناء علاج
ارتفاع ضغط الدم. إذا واجهتم هذا الأمر، تحدثوا مع
طبيبكم قبل محاولة القيادة أو استعمال الآلات.

 

يحتوي كو-ريبكس على اللاكتوز. في حال أخبركم
طبيبكم بأنكم تعانون من عدم تق ّ بل بعض أنواع
السكريات (مثل اللاكتوز)، راجعوا طبيبكم المعالج قبل
تناول هذا الدواء.

 

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إستشروا طبيبكم أو الصيدلاني في حالة الشك.
الجرعة
الجرعة الموصى بها من كو-ريبكس هي قرص واحد في اليوم.
يصف طبيبكم عادة كو-ريبكس إذا لم يؤدي علاجكم
السابق إلى تخفيض ضغطكم بشكل كاف. سوف يعلمكم
طبيبكم بكيفية الإنتقال من العلاج السابق إلى كو-ريبكس.
طريقة الإستعمال
يؤخذ كو-ريبكس عن طريق الفم. تُبلع الأقراص مع كمية
كافية من السائل (كوب من الماء مثلا). يمكنكم أخذ
كو-ريبكس مع الطعام أو بدونه. حاولوا أخذ جرعتكم
اليومية في الوقت نفسه كل يوم. من الضروري مواصلة
تناول كو-ريبكس حتى يخبركم طبيبكم خلاف ذلك.
ينبغي تحقيق التخفيض الأقصى لضغط الدم خلال 6 إلى 8
أسابيع من بدء العلاج.
إذا قمتم بتناول أكثر مما ينبغي من كو-ريبكس
إذا كنتم قد تناولتم عن غير قصد عددا كبيرا من الأقراص،
إتصلوا بطبيبكم على الفور.
لا يجب على الأطفال تناول كو-ريبكس
لا يجب إعطاء كو-ريبكس للأطفال الذين تقل أعمارهم عن
18 سنة. إذا بلع طفل بعض الأقراص، إتصلوا بطبيبكم على
الفور.
إذا نسيتم تناول كو-ريبكس
في حال نسيان تناول جرعة يومية عن غير قصد، تناولوا
الجرعة التالية في الوقت المعتاد، لا تتناولوا جرعة مضاعفة
لتعويض الجرعة التي نسيتم تناولها.
إذا كان لديكم أي استفسارات تتع ّ لق باستخدام هذا الدواء،
عليكم استشارة طبيبكم أو الصيدلاني.

كما هو شأن كافة الأدوية ، قد يسبب هذا الدواء أعراض
جانبية إلا أنها لا تصيب كل من يستعمل هذا الدواء. قد
تكون بعض الأعراض خطيرة و تتطلب عناية طبية.
أبلغ عن حالات نادرة من الحساسية الجلدية (طفح جلدي،
شرى)، وعن انتفاخ موضعي للوجه والشفتين و / أو اللسان
لدى المرضى الذين يتناولون الإربيزارتان.
إذا أصبتم بإحدى هاته الأعراض المذكورة أعلاه أو بضيق
في التنفس، توقفوا عن تناول كو-ريبكس واتصلوا بطبيبكم
على الفور.
الأعراض الجانبية التي أعلن عنها خلال الدراسات السريرية
للمرضى المعالجين بكو-ريبكس :
أعراض جانبية شائعة (قد تصيب ما يصل إلى شخص
واحد من بين كل 10 أشخاص):
• غثيان / تقيؤ
• تبول غير طبيعي
• تعب
• دوار (بما في ذلك عند الوقوف بعد التمدد أو الجلوس)
• قد تظهر فحوصات الدم مستويات مرتفعة من الأنزيم الذي يقيس
وظيفة العضلات و القلب (كرياتين كيناز) أو مستويات مرتفعة
من المواد التي تقيس وظائف الكلى (نيتروجين اليوريا في الدم،
كرياتينين).
إذا سببت لكم إحدى هاته الأعراض الجانبية مشاكل،
يرجى التحدث إلى طبيبكم.

 

أعراض جانبية غير شائعة (قد تصيب ما يصل إلى
شخص واحد من بين كل 100 شخص):
• إسهال.
• انخفاض ضغط الدم.
• إغماء.
• تسارع ضربات القلب.
• نوبات السخونة.
• تورم.
• خلل جنسي (مشاكل في القدرة الجنسية).
• قد تظهر فحوصات الدم مستويات منخفضة من البوتاسيوم
والصوديوم في الدم.
إذا سببت لكم إحدى هاته الأعراض الجانبية مشاكل،
يرجى التحدث إلى طبيبكم.
الأعراض الجانبية التي تم الإبلاغ عنها منذ تسويق
إربيزارتان / هيدروكلوروثيازيد
أفيد عن بعض الأعراض غير المرغوب بها منذ تسويق
كو-ريبكس. الأعراض الجانبية غير المعروف معدل حدوثها
هي: صداع، طنين في الأذنين، سعال، إضطراب في التذوق،
عسر الهضم، آلام في المفاصل والعضلات، خلل في وظيفة
الكبد وقصور في وظيفة الكلى، إرتفاع مستوى البوتاسيوم
في الدم وحساسية جلدية مثل طفح جلدي، شرى، إنتفاخ
الوجه، الشفتين، الفم ، اللسان أو الحلق. أفيد كذلك عن
حالات غير شائعة من اليرقان (إصفرار الجلد و / أو الجزء
الأبيض من العينين).
كأي مركب من مادتين فعالتين، لا يمكن إستثناء الأعراض
الجانبية الناتجة عن كل مادة منهما على حدى.
الأعراض الجانبية المرتبطة بإربيزارتان بمفرده
أُفيد عن الآم في الصدر, تفاعلات حساسية شديدة (صدمة
الحساسية) ، وانخفاض في عدد الصفائح الدموية (وهي
خلية دم أساسية لتجلط الدم) أيضا بالإضافة إلى الأعراض
الجانبية المذكورة أعلاه.
الأعراض الجانبية المرتبطة بهيدروكلوروثيازيد بمفرده
فقدان الشهية؛ تهيج المعدة؛ تشنجات في المعدة؛ إمساك،
يرقان (إصفرار الجلد و / أو الجزء الأبيض من العينين)؛ إلتهاب
البنكرياس الذي يسبب آلماً حاداً في الجزء العلوي من المعدة ،
مصحوب غالبا بغثيان وتقيء، إضطرابات في النوم، اكتئاب،
عدم وضوح الرؤية، نقص في كريات الدم البيضاء يمكن أن
يسبب عدوى متكررة، حمى، انخفاض في عدد الصفيحات
الدموية (خلية دموية ضرورية لتخثر الدم)، نقص في عدد
كريات الدم الحمراء (فقر الدم) يسبب تعب، صداع، ضيق في
التنفس عند بذل الجهد، دوار وشحوب، مرض في الكلى،
اضطرابات في الرئتين تشمل التهاب رئوي أو تراكم السوائل
في الرئة، زيادة حساسية الجلد لأشعة الشمس، التهاب
الأوعية الدموية، مرض جلدي يتميز بتقشر الجلد في كامل
أنحاء الجسم، الذئبة الحمامية الجلدية تتمثل في طفح
جلدي قد يظهر على الوجه والعنق، و فروة الرأس، حساسية
جلدية، ضعف وتشنج عضلي، اضطراب في نضم القلب،
انخفاض ضغط الدم بعد تغيير وضعية الجسم، تورم الغدد
اللعابية، ارتفاع مستويات السكر في الدم، سكر في البول،
ارتفاع بعض أنواع الدهون في الدم، ارتفاع مستويات حمض
اليوريك في الدم، مما قد يسبب النقرس.
تردد غير معروف : سرطان الجلد والشفة (سرطان الجلد غير
الميلانيني) المتعلقة بهيدروكلوروثيازيد.
ومن المعروف أن الأعراض الجانبية الناتجة عن الهيدروكلوروثيازيد
قد تزيد مع ارتفاع الجرعات من الهيدروكلوروثيازيد.
الإبلاغ عن الآثار الجانبية
إذا حصلت على أي آثار جانبية، تحدث إلى طبيبك أو الصيدلي. يتضمن
ذلك أي آثار جانبية محتملة غير مدرجة في هذه النشرة. يمكنك
أيضا الإبلاغ عن الآثار الجانبية مباشرة عبر نظام الإبلاغ
الوطني.

 

يحفظ في درجة حرارة لا تزيد عن 30 درجة مئوية.
يحفظ الدواء في العبوة الخارجية الأصلية للوقاية من
الضوء.
يحفظ بعيدا عن مرأى ومتناول الأطفال.

على ماذا يحتوي كو-ريبكس أقراص ملبسة و قابلة
للكسر؟
المواد الفعالة هي:
كو-ريبكس 150 ملغ / 12.5 ملغ: كل قرص يحتوي على 150
ملغ من إربيزارتان و 12.5 ملغ من هيدروكلوروثيازيد.
كو-ريبكس 300 ملغ / 12.5 ملغ: كل قرص يحتوي على 300
ملغ إربيزارتان و 12.5 ملغ من هيدروكلوروثيازيد.
كو-ريبكس 300 ملغ / 25 ملغ: كل قرص يحتوي على 300
ملغ من إربيزارتان و 25 ملغ من هيدروكلوروثيازيد.
المكونات الأخرى هي:
سيلولوز دقيق التبلور، نشاء مسبق التجلتن، مونوهيدرات
اللاكتوز، بولوكسامير 188 ، كروس كارميلوز الصوديوم،
ستيارات المغنيسيوم.
6، َ ح ْ مض الستياريك، ثاني cP غلاف القرص: هيبروميلوز
أكسيد التيتانيوم، سيلولوز دقيق التبلور ، أكسيد الحديد
الأصفر (كو-ريبكس 150 ملغ / 12.5 ملغ، 300 ملغ / 12.5
ملغ)، أكسيد الحديد الأسود (كو-ريبكس 300 ملغ / 25 ملغ)،
أكسيد الحديد الأحمر.


يتوفر هذا الدواء على شكل أقراص ملبسة و قابلة للكسر.
العلبة تحتوي على 14 أو 28 قرصا.

مختبرات سوطيما
27182 بوسكورة - ص. ب رقم 1
المغرب
 

شروط صرف و وصف الدواء : الجدول (أ) (I) هذا الدواء يخضع لوصفة طبية القائمة تمت مراجعة هذه النشرة لآخر مرة بتاريخ: نوفمبر 2018 . النسخة 02
 Read this leaflet carefully before you start using this product as it contains important information for you

CO-RIBEX 150 mg/12.5 mg film-coated tablets.

Each film-coated tablet contains 150 mg of irbesartan and 12.5 mg of hydrochlorothiazide. Irbesartan ....................................................................................................... 150.000 mg Hydrochlorothiazide ........................................................................................ 12.500 mg Microcrystalline cellulose ................................................................................. 76.000 mg Starch pregelatinised .......................................................................................... 10.000 mg Lactose monohydrate ......................................................................................... 26.000 mg Poloxamer 188 ................................................................................................... 10.000 mg Croscarmellose sodium ..................................................................................... 11.000 mg Magnesium Stearate ............................................................................................ 4.500 mg Film-coating: Opadrypink03A34089 ........................................................................................ 12.000 mg Opadry composition Hypromellose 6cP ............................................................................................... 7.800 mg Titanium dioxide ................................................................................................. 1.774 mg Purified stearic acid ............................................................................................. 1.200 mg Microcrystalline cellulose ................................................................................... 1.200 mg Iron oxide yellow ................................................................................................. 0.014 mg Iron oxide red ....................................................................................................... 0.012 mg Per 1 film-coated tablet Total weight of coated-tablet 312.00mg For the full list of excipients, see section 6.1.

Film-coated tablet. Pink and oblong, with break line on 1 side.

4.1 Therapeutic indications
Treatment of essential hypertension.
This fixed dose combination is indicated in adult patients whose blood pressure is not adequately
controlled on irbesartan or hydrochlorothiazide alone (see section 5.1).


Posology
CO-RIBEX can be taken once daily, with or without food.
Dose titration with the individual components (i.e. irbesartan and hydrochlorothiazide) may be
recommended.
When clinically appropriate direct change from monotherapy to the fixed combinations may be
considered:
 CO-RIBEX 150 mg/12.5 mg may be administered in patients whose blood pressure is not
adequately controlled with hydrochlorothiazide or irbesartan 150 mg alone;
 CO-RIBEX 300 mg/12.5 mg may be administered in patients insufficiently controlled by
irbesartan 300 mg or by CO-RIBEX 150 mg/12.5 mg.
 CO-RIBEX 300 mg/25 mg may be administered in patients insufficiently controlled by CORIBEX
300 mg/12.5 mg.

 

Doses higher than 300 mg irbesartan/25 mg hydrochlorothiazide once daily are not recommended.
When necessary, CO-RIBEX may be administered with another antihypertensive medicinal
product(see sections 4.3, 4.4, 4.5 and 5.1).
Special Populations
Renal impairment: due to the hydrochlorothiazide component, CO-RIBEX is not recommended for
patients with severe renal dysfunction (creatinine clearance < 30 ml/min). Loop diuretics are
preferred to thiazides in this population. No dosage adjustment is necessary in patients with renal
impairmen twhose renal creatinine clearance is ≥30 ml/min (see sections 4.3 and 4.4).
Hepatic impairment: CO-RIBEX is not indicated in patients with severe hepatic impairment.
Thiazides should be used with caution in patients with impaired hepatic function. No dosage
adjustment of CO-RIBEX is necessary in patients with mild to moderate hepatic impairment (see
section 4.3).
Older people: no dosage adjustment of CO-RIBEX is necessary in older people.

 

Paediatric population: CO-RIBEX is not recommended for use in children and adolescents because
the safety and efficacy have not been established. No data are available.
Method of Administration
For oral use.

 


Hypersensitivity to the active substances or to any of the excipients listed in section 6.1, or to other sulfonamide-derived substances (hydrochlorothiazide is a sulfonamide-derived substance)  Second and third trimesters of pregnancy (see sections 4.4 and 4.6)  Severe renal impairment (creatinine clearance < 30 ml/min)  Refractory hypokalaemia, hypercalcaemia  Severe hepatic impairment, biliary cirrhosis and cholestasis The concomitant use of CO-RIBEX with aliskiren-containing products is contraindicated inpatients with diabetes mellitus or renal impairment (glomerular filtration rate (GFR)<60 ml/min/1.73 m²) (see sections 4.5 and 5.1).

Hypotension - Volume-depleted patients: CO-RIBEX has been rarely associated with symptomatic
hypotension in hypertensive patients without other risk factors for hypotension. Symptomatic
hypotension may be expected to occur in patients who are volume and/or sodium depleted by
vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be
corrected before initiating therapy with CO-RIBEX.
Renal artery stenosis - Renovascular hypertension: there is an increased risk of severe hypotension
and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a
single functioning kidney are treated with angiotensin converting enzyme inhibitors or angiotensin-
II receptor antagonists. While this is not documented with CO-RIBEX, a similar effect should be
anticipated.
Renal impairment and kidney transplantation: when CO-RIBEX is used in patients with impaired
renalfunction, a periodic monitoring of potassium, creatinine and uric acid serum levels is
recommended. There is no experience regarding the administration of CO-RIBEX in patients with a
recent kidney transplantation. CO-RIBEX should not be used in patients with severe renal
impairment (creatinine clearance < 30 ml/min) (see section 4.3). Thiazide diuretic-associated
azotemia may occur in patients with impaired renal function. No dosage adjustment is necessary in
patients with renal impairment whose creatinine clearance is ≥30 ml/min. However, in patients with
mild to moderate renal impairment (creatinine clearance ≥ 30 ml/min but < 60 ml/min) this fixed
dose combination should be administered with caution.

 

Dual blockade of the renin-angiotensin-aldosterone system (RAAS):
There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers oral
iskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including
acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors,
angiotensinII receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1).
If dualblockade therapy is considered absolutely necessary, this should only occur under specialist
supervision and subject to frequent close monitoring of renal function, electrolytes and blood
pressure.
ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients
with diabetic nephropathy.
Hepatic impairment: thiazides should be used with caution in patients with impaired hepatic
function or progressive liver disease, since minor alterations of fluid and electrolyte balance may
precipitate hepatic coma. There is no clinical experience with CO-RIBEX in patients with hepatic
impairment.

 

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy: as with other
vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or
obstructive hypertrophic cardiomyopathy.
Primary aldosteronism: patients with primary aldosteronism generally will not respond to
antihypertensive medicinal products acting through inhibition of the renin-angiotensin system.
Therefore, the use of CO-RIBEX is not recommended.

 

Metabolic and endocrine effects: thiazide therapy may impair glucose tolerance. In diabetic
patientsdosage adjustments of insulin or oral hypoglycemic agents may be required. Latent diabetes
mellitusmay become manifest during thiazide therapy.
Increases in cholesterol and triglyceride levels have been associated with thiazide diuretic
therapy;however at the 12.5 mg dose contained in CO-RIBEX, minimal or no effects were reported.
Hyperuricaemia may occur or frank gout may be precipitated in certain patients receiving
thiazidetherapy.

 

Non-melanoma skin cancer
An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and
squamous cell carcinoma (SCC)] with increasing cumulative dose of hydrochlorothiazide (HCTZ)
exposure has been observed in two epidemiological studies based on the Danish National Cancer
Registry. Photosensitizing actions of HCTZ could act as a possible mechanism for NMSC.
Patients taking HCTZ should be informed of the risk of NMSC and advised to regularly check their
skin for any new lesions and promptly report any suspicious skin lesions. Possible preventive
measures such as limited exposure to sunlight and UV rays and, in case of exposure, adequate
protection should be advised to the patients in order to minimize the risk of skin cancer. Suspicious
skin lesions should be promptly examined potentially including histological examinations of
biopsies. The use of HCTZ may also need to be reconsidered in patients who have experienced
previous NMSC (see also section 4.8).

 

Electrolyte imbalance: as for any patient receiving diuretic therapy, periodic determination of
serumelectrolytes should be performed at appropriate intervals.
Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance
(hypokalaemia,hyponatraemia, and hypochloremic alkalosis). Warning signs of fluid or electrolyte
imbalance aredryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or
cramps,muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such
as nauseaor vomiting.
Although hypokalaemia may develop with the use of thiazide diuretics, concurrent therapy
withirbesartan may reduce diuretic-induced hypokalaemia. The risk of hypokalaemia is greatest in
patientswith cirrhosis of the liver, in patients experiencing brisk diuresis, in patients who are
receivinginadequate oral intake of electrolytes and in patients receiving concomitant therapy
withcorticosteroids or ACTH. Conversely, due to the irbesartan component of CORIBEXhyperkalaemiamight
occur, especially in the presence of renal impairment and/or heart
failure, and diabetes mellitus.Adequate monitoring of serum potassium in patients at risk is
recommended. Potassium-sparingdiuretics, potassium supplements or potassium-containing salts
substitutes should be co-administeredcautiously with CO-RIBEX (see section 4.5).
There is no evidence that irbesartan would reduce or prevent diuretic-induced hyponatraemia.
Chloridedeficit is generally mild and usually does not require treatment.
Thiazides may decrease urinary calcium excretion and cause an intermittent and slight elevation
ofserum calcium in the absence of known disorders of calcium metabolism. Marked
hypercalcaemiamay be evidence of hidden hyperparathyroidism. Thiazides should be discontinued
before carrying outtests for parathyroid function.
Thiazides have been shown to increase the urinary excretion of magnesium, which may result
inhypomagnaesemia.

 

Lithium: the combination of lithium and CO-RIBEX is not recommended (see section 4.5).
Anti-doping test: hydrochlorothiazide contained in this medicinal product could produce a
positiveanalytic result in an anti-doping test.

 

General: in patients whose vascular tone and renal function depend predominantly on the activity
ofthe renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure
orunderlying renal disease, including renal artery stenosis), treatment with angiotensin
convertingenzyme inhibitors or angiotensin-II receptor antagonists that affect this system has been
associatedwith acute hypotension, azotemia, oliguria, or rarely acute renal failure (see section 4.5).
As with anyantihypertensive agent, excessive blood pressure decrease in patients with ischemic
cardiopathy orischemic cardiovascular disease could result in a myocardial infarction or stroke.
Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history
ofallergy or bronchial asthma, but are more likely in patients with such a history.
Exacerbation or activation of systemic lupus erythematosus has been reported with the use of
thiazidediuretics.
Cases of photosensitivity reactions have been reported with thiazides diuretics (see section 4.8).
Ifphotosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If a
readministrationof the diuretic is deemed necessary, it is recommended to protect exposed areas to
thesun or to artificial UVA.
Pregnancy: Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during
pregnancy.Unless continued AIIRA therapy is considered essential, patients planning pregnancy
should bechanged to alternative antihypertensive treatments which have an established safety
profile for use inpregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be
stopped immediately,and, if appropriate, alternative therapy should be started (see sections 4.3 and
4.6).

Lactose: this medicinal product contains lactose. Patients with rare hereditary problems of
galactoseintolerance, the Lapp lactase deficiency or glucose-galactosemalabsorption should not take
thismedicinal product.
Acute Myopia and Secondary Acute Angle-Closure Glaucoma: sulfonamide drugs or
sulfonamidederivative drugs can cause an idiosyncratic reaction, resulting in transient myopia and
acute angleclosureglaucoma. While hydrochlorothiazide is a sulfonamide, only isolated cases of
acute angleclosureglaucoma have been reported so far with hydrochlorothiazide. Symptoms include
acute onsetof decreased visual acuity or ocular pain and typically occur within hours to weeks of
drug initiation.Untreated acute angle-closure glaucoma can lead to permanent vision loss. The
primary treatment is todiscontinue drug intake as rapidly as possible. Prompt medical or surgical
treatments may need to beconsidered if the intraocular pressure remains uncontrolled. Risk factors
for developing acute angleclosureglaucoma may include a history of sulfonamide or penicillin
allergy (see section 4.8).


Other antihypertensive agents: the antihypertensive effect of CO-RIBEX may be increased with
theconcomitant use of other antihypertensive agents. Irbesartan and hydrochlorothiazide (at doses
up to300 mg irbesartan/25 mg hydrochlorothiazide) have been safely administered with
otherantihypertensive agents including calcium channel blockers and beta-adrenergic blockers.
Priortreatment with high dose diuretics may result in volume depletion and a risk of hypotension
wheninitiating therapy with irbesartan with or without thiazide diuretics unless the volume
depletion iscorrected first (see section 4.4).
Aliskiren-containing products or ACE-inhibitors:
Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone system
(RAAS)through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is
associatedwith a higher frequency of adverse events such as hypotension, hyperkalaemia and

 

decreased renalfunction (including acute renal failure) compared to the use of a single RAAS-acting
agent (seesections 4.3, 4.4 and 5.1).
Lithium: reversible increases in serum lithium concentrations and toxicity have been reported
duringconcomitant administration of lithium with angiotensin converting enzyme inhibitors. Similar
effectshave been very rarely reported with irbesartan so far. Furthermore, renal clearance of lithium
isreduced by thiazides so the risk of lithium toxicity could be increased with CO-RIBEX. Therefore,
thecombination of lithium and CO-RIBEX is not recommended (see section 4.4). If the
combinationproves necessary, careful monitoring of serum lithium levels is recommended.
Medicinal products affecting potassium: the potassium-depleting effect of hydrochlorothiazide
isattenuated by the potassium-sparing effect of irbesartan. However, this effect of
hydrochlorothiazideon serum potassium would be expected to be potentiated by other medicinal
products associated withpotassium loss and hypokalaemia (e.g. other kaliuretic diuretics, laxatives,
amphotericin,carbenoxolone, penicillin G sodium). Conversely, based on the experience with the
use of othermedicinal products that blunt the renin-angiotensin system, concomitant use of
potassium-sparingdiuretics, potassium supplements, salt substitutes containing potassium or other
medicinal productsthat may increase serum potassium levels (e.g. heparin sodium) may lead to
increases in serumpotassium. Adequate monitoring of serum potassium in patients at risk is
recommended (seesection 4.4).

 

Medicinal products affected by serum potassium disturbances: periodic monitoring of
serumpotassium is recommended when CO-RIBEX is administered with medicinal products
affected byserum potassium disturbances (e.g. digitalis glycosides, antiarrhythmics).

 

Non-steroidal anti-inflammatory drugs: when angiotensin II antagonists are
administeredsimultaneously with non-steroidal anti- inflammatory drugs (i.e. selective COX-2
inhibitors,acetylsalicylic acid (> 3 g/day) and non-selective NSAIDs), attenuation of the
antihypertensive effectmay occur.
As with ACE inhibitors, concomitant use of angiotensin II antagonists and NSAIDs may lead to
anincreased risk of worsening of renal function, including possible acute renal failure, and an
increase inserum potassium, especially in patients with poor pre-existing renal function. The
combination shouldbe administered with caution, especially in the elderly. Patients should be
adequately hydrated andconsideration should be given to monitoring renal function after initiation
of concomitant therapy, andperiodically thereafter.
Additional information on irbesartan interactions: in clinical studies, the pharmacokinetic of
irbesartanis not affected by hydrochlorothiazide. Irbesartan is mainly metabolised by CYP2C9 and
to a lesserextent by glucuronidation. No significant pharmacokinetic or pharmacodynamic
interactions wereobserved when irbesartan was coadministered with warfarin, a medicinal product
metabolised byCYP2C9. The effects of CYP2C9 inducers such as rifampicin on the
pharmacokinetic of irbesartanhave not been evaluated. The pharmacokinetic of digoxin was not
altered by co-administration ofirbesartan.
Additional information on hydrochlorothiazide interactions: when administered concurrently,
thefollowing medicinal products may interact with thiazide diuretics:

 

Alcohol: potentiation of orthostatic hypotension may occur;
Antidiabetic medicinal products (oral agents and insulins): dosage adjustment of the
antidiabeticmedicinal product may be required (see section 4.4);

 

Colestyramine and Colestipol resins: absorption of hydrochlorothiazide is impaired in the presence
ofanionic exchange resins. CO-RIBEX should be taken at least one hour before or four hours after
thesemedications;
Corticosteroids, ACTH: electrolyte depletion, particularly hypokalaemia, may be increased;
Digitalis glycosides: thiazide induced hypokalaemia or hypomagnaesemiafavour the onset
ofdigitalis-induced cardiac arrhythmias (see section 4.4);
Non-steroidal anti-inflammatory drugs: the administration of a non-steroidal anti-inflammatory
drugmay reduce the diuretic, natriuretic and antihypertensive effects of thiazide diuretics in some
patients;
Pressor amines (e.g. noradrenaline): the effect of pressor amines may be decreased, but not
sufficiently to preclude their use;
Nondepolarizing skeletal muscle relaxants (e.g. tubocurarine): the effect of nondepolarizing
skeletal muscle relaxants may be potentiated by hydrochlorothiazide;

 

Antigout medicinal products: dosage adjustments of antigout medicinal products may be necessary
as hydrochlorothiazide may raise the level of serum uric acid. Increase in dosage of probenecid or
sulfinpyrazone may be necessary. Co-administration of thiazide diuretics may increase the
incidence of hypersensitivity reactions to allopurinol;
Calcium salts: thiazide diuretics may increase serum calcium levels due to decreased excretion. If
calcium supplements or calcium sparing medicinal products (e.g. vitamin D therapy) must be
prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly;
Carbamazepine: concomitant use of carbamazepine and hydrochlorothiazide has been associated
with the risk of symptomatic hyponatraemia. Electrolytes should be monitored during concomitant
use. If possible, another class of diuretics should be used;
Other interactions: the hyperglycaemic effect of beta-blockers and diazoxide may be enhanced by
thiazides. Anticholinergic agents (e.g. atropine, beperiden) may increase the bioavailability of
thiazide-type diuretics by decreasing gastrointestinal motility and stomach emptying rate. Thiazides
may increase the risk of adverse effects caused by amantadine. Thiazides may reduce the renal
excretion of cytotoxic medicinal products (e.g. cyclophosphamide, methotrexate) and potentiate
their myelosuppressive effects.

 


Pregnancy:
Angiotensin II Receptor Antagonists (AIIRAs):
The use of AIIRAs is not recommended during the first trimester of pregnancy (see section 4.4).
The use of AIIRAs is contraindicated during the second and third trimesters of pregnancy (see
sections 4.3 and 4.4).
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE
inhibitorsduring the first trimester of pregnancy has not been conclusive; however a small increase
in riskcannot be excluded. Whilst there is no controlled epidemiological data on the risk with

 

Angiotensin IIReceptor Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless
continuedAIIRA therapy is considered essential, patients planning pregnancy should be changed to
alternativeantihypertensive treatments which have an established safety profile for use in
pregnancy. Whenpregnancy is diagnosed, treatment with AIIRAs should be stopped immediately,
and, if appropriate,alternative therapy should be started.
Exposure to AIIRA therapy during the second and third trimesters is known to induce
humanfetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and
neonataltoxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3).
Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound
checkof renal function and skull is recommended.
Infants whose mothers have taken AIIRAs should be closely observed for hypotension (seesections
4.3 and 4.4).

 

Hydrochlorothiazide:
There is limited experience with hydrochlorothiazide during pregnancy, especially during the
firsttrimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on
thepharmacological mechanism of action of hydrochlorothiazide its use during the second and
thirdtrimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects
likeicterus, disturbance of electrolyte balance and thrombocytopenia.
Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension
orpreeclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without
abeneficial effect on the course of the disease.
Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in
raresituations where no other treatment could be used.
Since CO-RIBEX contains hydrochlorothiazide, it is not recommended during the first trimester
ofpregnancy. A switch to a suitable alternative treatment should be carried out in advance of a
plannedpregnancy.
Breast-feeding:

 

Angiotensin II Receptor Antagonists (AIIRAs):
Because no information is available regarding the use of CO-RIBEX during breast-feeding, CO
RIBEXis not recommended and alternative treatments with better established safety profiles during
breastfeedingare preferable, especially while nursing a newborn or preterm infant.
It is unknown whether irbesartan or its metabolites are excreted in human milk.
Available pharmacodynamic/toxicological data in rats have shown excretion of irbesartan or
itsmetabolites in milk (for details see 5.3).
Hydrochlorothiazide:
Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses
causingintense diuresis can inhibit the milk production. The use of CO-RIBEX during breast
feeding is notrecommended. If CO-RIBEX is used during breast feeding, doses should be kept as
low as possible.

Fertility:

Irbesartan had no effect upon fertility of treated rats and their offspring up to the dose levels
inducingthe first signs of parental toxicity (see section 5.3).

 


No studies on the effects on the ability to drive and use machines have been performed. Based on
itspharmacodynamic properties, CO-RIBEX is unlikely to affect this ability. When driving vehicles
oroperating machines, it should be taken into account that occasionally dizziness or weariness may
occurduring treatment of hypertension.


Irbesartan/hydrochlorothiazide combination:
Among 898 hypertensive patients who received various doses ofirbesartan/hydrochlorothiazide
(range: 37.5 mg/6.25 mg to 300 mg/25 mg) in placebo-controlled trials, 29.5% of the patients
experienced adverse reactions. The most commonly reported ADRs were dizziness (5.6%), fatigue
(4.9%), nausea/vomiting (1.8%), and abnormal urination (1.4%). In addition, increases in blood
urea nitrogen (BUN) (2.3%), creatine kinase (1.7%) and creatinine (1.1%) were also commonly
observed in the trials.
Table 1 gives the adverse reactions observed from spontaneous reporting and in placebo-controlled
trials.

The frequency of adverse reactions listed below is defined using the following convention:
very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare
(≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, undesirable
effects are presented in order of decreasing seriousness

 

 

Table 1: Adverse Reactions in Placebo-Controlled Trials and Spontaneous Reports
Investigations: Common: increases in blood urea nitrogen (BUN),
creatinine and creatine kinase
Uncommon: decreases in serum potassium and sodium
Cardiacdisorders: Uncommon: syncope, hypotension, tachycardia, oedema
Nervous system disorders: Common: dizziness
Uncommon: orthostaticdizziness
Not known: headache
Ear and labyrinthdisorders: Not known: tinnitus
Respiratory, thoracic and
mediastinal disorders:
Not known: cough
Gastrointestinaldisorders: Common: nausea/vomiting
Uncommon: diarrhoea
Not known: dyspepsia, dysgeusia
Renal and urinarydisorders: Common: abnormal urination
Not known: impaired renal function including isolated
casesof renal failure in patients at risk (see
section 4.4)
Musculoskeletal and connective
tissue disorders:
Uncommon:
Not known:
swellingextremity
arthralgia, myalgia
Metabolism and nutrition
disorders:
Not known: hyperkalaemia
Vasculardisorders: Uncommon: flushing
General disorders and Common: fatigue

 

 

administration site conditions:
Immune system disorders: Not known: cases of hypersensitivity reactions such as
angioedema, rash, urticaria
Hepatobiliarydisorders: Uncommon: jaundice
Not known: hepatitis, abnormalliverfunction
Reproductive system and breast
disorders:
Uncommon: sexualdysfunction, libido changes

 

Additional information on individual components: in addition to the adverse reactions listed above
forthe combination product, other adverse reactions previously reported with one of the individual
components may be potential adverse reactions with CO-RIBEX. Tables 2 and 3 below detail the
adverse reactions reported with the individual components of CO-RIBEX.

 

Table 2: Adverse reactions reported with the use of irbesartanalone
General disorders and
administration site conditions:
Uncommon: chest pain
Blood and lymphatic system
disorders:
Not known thrombocytopenia
Immune system disorders: Not known: Anaphylactic reaction including anaphylactic
shock

 

Table 3: Adverse reactions reported with the use of hydrochlorothiazide alone
Investigations: Not known: electrolyte imbalance (including
hypokalaemiaand hyponatraemia, see section
4.4),hyperuricaemia, glycosuria,
hyperglycaemia,increases in cholesterol and
triglycerides
Cardiacdisorders: Not known: cardiacarrhythmias
Blood and lymphatic system
disorders:
Not known: aplastic anaemia, bone marrow depression,
neutropenia/agranulocytosis, haemolytic
anaemia, leucopenia, thrombocytopenia
Nervous system disorders: Not known: vertigo, paraesthesia, light-headedness,
restlessness
Eyedisorders: Not known: transient blurred vision, xanthopsia, acute
myopia and secondary acute angle-closure
glaucoma
Respiratory, thoracic and
mediastinal disorders:
Not known: respiratory distress (including pneumonitis
andpulmonary oedema)
Gastrointestinaldisorders: Not known: pancreatitis, anorexia, diarrhoea, constipation,
gastric irritation, sialadenitis, loss of appetite
Renal and urinarydisorders: Not known: interstitialnephritis, renaldysfunction
Skin and subcutaneous tissue
disorders:
Not known: anaphylactic reactions, toxic epidermal
necrolysis, necrotizing angitis (vasculitis,
cutaneous vasculitis), cutaneous lupus
erythematosus-like reactions, reactivation of
cutaneous lupus erythematosus,
photosensitivityreactions, rash, urticaria
Musculoskeletal and connective
tissue disorders:
Not known: weakness, muscle spasm
Vasculardisorders: Not known: postural hypotension

 

 

General disorders and
administration site conditions:
Not known: fever
Hepatobiliarydisorders: Not known: jaundice (intrahepaticcholestaticjaundice)
Psychiatricdisorders: Not known: depression, sleepdisturbances
Neoplasms benign, malignant
and unspecified (incl cysts and
polyps)
Not known melanoma skin cancer (Basal cell carcinoma
and Squamous cell carcinoma)
The dose dependent adverse events of hydrochlorothiazide (particularly electrolyte disturbances)
may increase when titrating the hydrochlorothiazide.

 

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare
professionals are asked to report any suspected adverse reactions via the national reporting system
listed.

Saudi Arabia:

The National Pharmacovigilance and Drug Safety Centre (NPC)
o Fax: +966-11-205-7662
o Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.
o Toll free phone: 8002490000
o E-mail: npc.drug@sfda.gov.sa
o Website: www.sfda.gov.sa/npc

 

 


No specific information is available on the treatment of overdose with CO-RIBEX. The patient
should be closely monitored, and the treatment should be symptomatic and supportive. Management
depends on the time since ingestion and the severity of the symptoms. Suggested measures include
induction of emesis and/or gastric lavage. Activated charcoal may be useful in the treatment of
overdose. Serum electrolytes and creatinine should be monitored frequently. If hypotension occurs,
the patient should be placed in a supine position, with salt and volume replacements given quickly.
The most likely manifestations of irbesartan overdose are expected to be hypotension and
tachycardia; bradycardia might also occur.
Overdose with hydrochlorothiazide is associated with electrolyte depletion
(hypokalaemia,hypochloremia, hyponatraemia) and dehydration resulting from excessive diuresis.
The most common signs and symptoms of overdose are nausea and somnolence. Hypokalaemia
may result in muscle spasms and/or accentuate cardiac arrhythmias associated with the concomitant
use of digitalis glycosides or certain anti-arrhythmic medicinal products.
Irbesartan is not removed by haemodialysis. The degree to which hydrochlorothiazide is removed
by haemodialysis has not been established.


Pharmacotherapeutic group: angiotensin-II antagonists, combinations
ATC code: C09DA04.

CO-RIBEX is a combination of an angiotensin-II receptor antagonist, irbesartan, and a thiazide
diuretic, hydrochlorothiazide. The combination of these ingredients has an additive antihypertensive
effect, reducing blood pressure to a greater degree than either component alone.
Irbesartan is a potent, orally active, selective angiotensin-II receptor (AT1 subtype) antagonist. It is
expected to block all actions of angiotensin-II mediated by the AT1 receptor, regardless of the
source or route of synthesis of angiotensin-II. The selective antagonism of the angiotensin-II (AT1)
receptors results in increases in plasma renin levels and angiotensin-II levels, and a decrease in
plasma aldosterone concentration. Serum potassium levels are not significantly affected by
irbesartan alone at the recommended doses in patients without risk of electrolyte imbalance (see
sections 4.4 and 4.5).
Irbesartan does not inhibit ACE (kininase-II), an enzyme which generates angiotensin-II and also
degrades bradykinin into inactive metabolites. Irbesartan does not require metabolic activation for
its activity.
Hydrochlorothiazide is a thiazide diuretic. The mechanism of antihypertensive effect of thiazide
diuretics is not fully known. Thiazides affect the renal tubular mechanisms of electrolyte
reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent
amounts. The diuretic action of hydrochlorothiazide reduces plasma volume, increases plasma renin
activity, increases aldosterone secretion, with consequent increases in urinary potassium and
bicarbonate loss, and decreases in serum potassium. Presumably through blockade of the reninangiotensin-
aldosterone system, co-administration of irbesartan tends to reverse the potassium loss
associated with these diuretics. With hydrochlorothiazide, onset of diuresis occurs in 2 hours, and
peak effect occurs at about 4 hours, while the action persists for approximately 6-12 hours.
The combination of hydrochlorothiazide and irbesartan produces dose-related additive reductions in
blood pressure across their therapeutic dose ranges. The addition of 12.5 mg hydrochlorothiazide to
300 mg irbesartan once daily in patients not adequately controlled on 300 mg irbesartan alone
resulted in further placebo-corrected diastolic blood pressure reductions at trough (24 hours postdosing)
of 6.1 mm Hg. The combination of 300 mg irbesartan and 12.5 mg hydrochlorothiazide
resulted in an overall placebo-subtracted systolic/diastolic reductions of up to 13.6/11.5 mm Hg.
Limited clinical data (7 out of 22 patients) suggest that patients not controlled with the 300 mg/12.5
mg combination may respond when uptitrated to 300 mg/25 mg. In these patients, an incremental
blood pressure lowering effect was observed for both systolic blood pressure (SBP) and diastolic
blood pressure (DBP) (13.3 and 8.3 mm Hg, respectively).
Once daily dosing with 150 mg irbesartan and 12.5 mg hydrochlorothiazide gave systolic/diastolic
mean placebo-adjusted blood pressure reductions at trough (24 hours post-dosing) of 12.9/6.9 mm
Hg in patients with mild-to-moderate hypertension. Peak effects occurred at 3-6 hours. When
assessed by ambulatory blood pressure monitoring, the combination 150 mg irbesartan and 12.5 mg
hydrochlorothiazide once daily produced consistent reduction in blood pressure over the 24 hours
period with mean 24-hour placebo-subtracted systolic/diastolic reductions of 15.8/10.0 mm Hg.
When measured by ambulatory blood pressure monitoring, the trough to peak effects of CO-RIBEX
150 mg/12.5 mg were 100%. The trough to peak effects measured by cuff during office visits were
68% and 76% for CO-RIBEX 150 mg/12.5 mg and CO-RIBEX 300 mg/12.5 mg, respectively.
These 24-hour effects were observed without excessive blood pressure lowering at peak and are
consistent with safe and effective blood-pressure lowering over the once-daily dosing interval.
In patients not adequately controlled on 25 mg hydrochlorothiazide alone, the addition of
irbesartangave an added placebo-subtracted systolic/diastolic mean reduction of 11.1/7.2 mm Hg.

 

 

The blood pressure lowering effect of irbesartan in combination with hydrochlorothiazide is
apparent after the first dose and substantially present within 1-2 weeks, with the maximal effect
occurring by 6-8 weeks. In long-term follow-up studies, the effect of irbesartan/hydrochlorothiazide
was maintained for over one year. Although not specifically studied with the CO-RIBEX, rebound
hypertension has not been seen with either irbesartan or hydrochlorothiazide.
The effect of the combination of irbesartan and hydrochlorothiazide on morbidity and mortality has
not been studied. Epidemiological studies have shown that long term treatment with
hydrochlorothiazide reduces the risk of cardiovascular mortality and morbidity.
There is no difference in response to CO-RIBEX, regardless of age or gender. As is the case with
other medicinal products that affect the renin-angiotensin system, black hypertensive patients have
notably less response to irbesartanmonotherapy. When irbesartan is administered concomitantly
with a low dose of hydrochlorothiazide (e.g. 12.5 mg daily), the antihypertensive response in black
patients approaches that of non-black patients.
Efficacy and safety of CO-RIBEX as initial therapy for severe hypertension (defined as SeDBP
≥110 mmHg) was evaluated in a multicenter, randomized, double-blind, active-controlled, 8-week,
parallel-arm study. A total of 697 patients were randomized in a 2:1 ratio to either
irbesartan/hydrochlorothiazide 150 mg/12.5 mg or to irbesartan 150 mg and systematically
forcetitrated(before assessing the response to the lower dose) after one week to
irbesartan/hydrochlorothiazide 300 mg/25 mg or irbesartan 300 mg, respectively.
The study recruited 58% males. The mean age of patients was 52.5 years, 13% were ≥ 65 years of
age, and just 2% were ≥ 75 years of age. Twelve percent (12%) of patients were diabetic, 34% were
hyperlipidemic and the most frequent cardiovascular condition was stable angina pectoris in 3.5%
of the participants.

 

The primary objective of this study was to compare the proportion of patients whose SeDBP was
controlled (SeDBP< 90 mmHg) at Week 5 of treatment. Forty-seven percent (47.2%) of patients on
the combination achieved troughSeDBP< 90 mmHg compared to 33.2% of patients on irbesartan(p
= 0.0005). The mean baseline blood pressure was approximately 172/113 mmHg in each treatment
group and decreases of SeSBP/SeDBP at five weeks were 30.8/24.0 mmHg and 21.1/19.3 mmHg
for irbesartan/hydrochlorothiazide and irbesartan, respectively (p < 0.0001).
The types and incidences of adverse events reported for patients treated with the combination were
similar to the adverse event profile for patients on monotherapy. During the 8-week treatment
period, there were no reported cases of syncope in either treatment group. There were 0.6% and 0%
of patients with hypotension and 2.8% and 3.1% of patients with dizziness as adverse reactions
reported in the combination and monotherapy groups, respectively.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
Two large randomised, controlled trials (ONTARGET (ONgoingTelmisartan Alone and in
combination with Ramipril Global Endpoint Trial) andVA NEPHRON-D (The Veterans Affairs
Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an
angiotensin II receptor blocker. ONTARGET was a study conducted in patients with a history of
cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of
end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and
diabetic nephropathy.
These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes
and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as

 

compared to monotherapy was observed. Given their similar pharmacodynamic properties, these
results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.
ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in
patients with diabetic nephropathy.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease
Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an
ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and
chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of
an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more
frequent in the aliskiren group than in the placebo group and adverse events and serious adverse
events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently
reported in the aliskirengroup than in the placebo group.
Non-melanoma skin cancer: Based on available data from epidemiological studies, cumulative
dose-dependent association between HCTZ and NMSC has been observed. One study included a
population comprised of 71,533 cases of BCC and of 8,629 cases of SCC matched to 1,430,833 and
172,462 population controls, respectively. High HCTZ use (≥50,000 mg cumulative) was associated
with an adjusted OR of 1.29 (95% CI: 1.23-1.35) for BCC and 3.98 (95% CI: 3.68-4.31) for SCC. A
clear cumulative dose response relationship was observed for both BCC and SCC. Another study
showed a possible association between lip cancer (SCC) and exposure to HCTZ: 633 cases of lipcancer
were matched with 63,067 population controls, using a risk-set sampling strategy. A
cumulative dose-response relationship was demonstrated with an adjusted OR 2.1 (95% CI: 1.7-2.6)
increasing to OR 3.9 (3.0-4.9) for high use (~25,000 mg) and OR 7.7 (5.7-10.5) for the highest
cumulative dose (~100,000 mg) (see also section 4.4).

 


Concomitant administration of hydrochlorothiazide and irbesartan has no effect on
thepharmacokinetics of either medicinal product.
Irbesartan and hydrochlorothiazide are orally active agents and do not require biotransformation for
their activity. Following oral administration of CO-RIBEX, the absolute oral bioavailability is 60-
80% and 50-80% for irbesartan and hydrochlorothiazide, respectively. Food does not affect the
bioavailability of CO-RIBEX. Peak plasma concentration occurs at 1.5-2 hours after oral
administration for irbesartan and 1-2.5 hours for hydrochlorothiazide.
Plasma protein binding of irbesartan is approximately 96%, with negligible binding to cellular
blood components. The volume of distribution for irbesartan is 53-93 litres. Hydrochlorothiazide is
68% protein-bound in the plasma, and its apparent volume of distribution is 0.83-1.14 l/kg.
Irbesartan exhibits linear and dose proportional pharmacokinetics over the dose range of 10 to 600
mg. A less than proportional increase in oral absorption at doses beyond 600 mg was observed; the
mechanism for this is unknown. The total body and renal clearance are 157-176 and 3.0-3.5 ml/min,
respectively. The terminal elimination half-life of irbesartan is 11-15 hours. Steady-state plasma
concentrations are attained within 3 days after initiation of a once-daily dosing regimen. Limited
accumulation of irbesartan (< 20%) is observed in plasma upon repeated once-daily dosing. In a
study, somewhat higher plasma concentrations of irbesartan were observed in female hypertensive
patients.
However, there was no difference in the half-life and accumulation of irbesartan. No dosage
adjustment is necessary in female patients. Irbesartan AUC and Cmax values were also somewhat
greater in older subjects (≥65 years) than those of young subjects (18-40 years). However the

terminal half-life was not significantly altered. No dosage adjustment is necessary in older people.
The mean plasma half-life of hydrochlorothiazide reportedly ranges from 5-15 hours.
Following oral or intravenous administration of 14C irbesartan, 80-85% of the circulating plasma
radioactivity is attributable to unchanged irbesartan. Irbesartanis metabolised by the liver via
glucuronide conjugation and oxidation. The major circulating metabolite is
irbesartanglucuronide(approximately 6%). In vitro studies indicate that irbesartan is primarily
oxidised by the cytochrome P450 enzyme CYP2C9; isoenzyme CYP3A4 has negligible effect.
Irbesartan and its metabolites are eliminated by both biliary and renal pathways. After either oral or
intravenous administration of 14C irbesartan, about 20% of the radioactivity is recovered in the
urine, and the remainder in the faeces. Less than 2% of the dose is excreted in the urine as
unchanged irbesartan. Hydrochlorothiazide is not metabolized but is eliminated rapidly by the
kidneys. At least 61% of the oral dose is eliminated unchanged within 24 hours.
Hydrochlorothiazide crosses the placental but not the blood-brain barrier, and is excreted in breast
milk.

 

Renal impairment: in patients with renal impairment or those undergoing haemodialysis, the
pharmacokinetic parameters of irbesartan are not significantly altered. Irbesartan is not removed by
haemodialysis. In patients with creatinine clearance < 20 ml/min, the elimination half-life of
hydrochlorothiazide was reported to increase to 21 hours.
Hepatic impairment: in patients with mild to moderate cirrhosis, the pharmacokinetic parameters of
irbesartan are not significantly altered. Studies have not been performed in patients with severe
hepatic impairment.


 


 

Irbesartan/hydrochlorothiazide: the potential toxicity of theirbesartan/hydrochlorothiazide
combination after oral administration was evaluated in rats and macaques in studies lasting up to6
months. There were no toxicological findings observed of relevance to human therapeutic use.
The following changes, observed in rats and macaques receiving the
irbesartan/hydrochlorothiazidecombination at 10/10 and 90/90 mg/kg/day, were also seen with one
of the two medicinal products alone and/or were secondary to decreases in blood pressure (no
significant toxicologic interactions were observed):
 kidney changes, characterized by slight increases in serum urea and creatinine,
andhyperplasia/hypertrophy of the juxtaglomerular apparatus, which are a direct consequence of
theinteraction of irbesartan with the renin-angiotensin system;
 slight decreases in erythrocyte parameters (erythrocytes, haemoglobin, haematocrit);
 stomach discoloration, ulcers and focal necrosis of gastric mucosa were observed in few rats ina
6 months toxicity study at irbesartan 90 mg/kg/day, hydrochlorothiazide 90 mg/kg/day,
andirbesartan/hydrochlorothiazide 10/10 mg/kg/day. These lesions were not observed in
macaques;
 decreases in serum potassium due to hydrochlorothiazide and partly prevented
whenhydrochlorothiazide was given in combination with irbesartan.
Most of the above mentioned effects appear to be due to the pharmacological activity of
irbesartan(blockade of angiotensin-II-induced inhibition of renin release, with stimulation of the
renin-producing cells) and occur also with angiotensin converting enzyme inhibitors. These findings
appear to have no relevance to the use of therapeutic doses of irbesartan/hydrochlorothiazide in
humans.

No teratogenic effects were seen in rats given irbesartan and hydrochlorothiazide in combination at
doses that produced maternal toxicity. The effects of the irbesartan/hydrochlorothiazide
combination on fertility have not been evaluated in animal studies, as there is no evidence of
adverse effect on fertility in animals or humans with either irbesartan or hydrochlorothiazide when
administered alone. However, another angiotensin-II antagonist affected fertility parameters in
animal studies when given alone. These findings were also observed with lower doses of this other
angiotensin-II antagonist when given in combination with hydrochlorothiazide.
There was no evidence of mutagenicity or clastogenicity with theirbesartan/hydrochlorothiazide
combination. The carcinogenic potential of irbesartan and hydrochlorothiazide in combination has
not been evaluated in animal studies.

 

Irbesartan: there was no evidence of abnormal systemic or target organ toxicity at clinically relevant
doses. In non-clinical safety studies, high doses of irbesartan (≥ 250 mg/kg/day in rats and ≥ 100
mg/kg/day in macaques) caused a reduction of red blood cell parameters (erythrocytes,
haemoglobin, haematocrit). At very high doses (≥ 500 mg/kg/day) degenerative changes in the
kidneys (such as interstitial nephritis, tubular distention, basophilic tubules, increased plasma
concentrations of urea and creatinine) were induced by irbesartan in the rat and the macaque and are
considered secondary to the hypotensive effects of the medicinal product which led to decreased
renal perfusion.
Furthermore, irbesartan induced hyperplasia/hypertrophy of the juxtaglomerular cells (in rats at ≥
90 mg/kg/day, in macaques at ≥ 10 mg/kg/day). All of these changes were considered to be caused
by the pharmacological action of irbesartan. For therapeutic doses of irbesartan in humans, the
hyperplasia/hypertrophy of the renal juxtaglomerular cells does not appear to have any relevance.
There was no evidence of mutagenicity, clastogenicity or carcinogenicity.
Fertility and reproductive performance were not affected in studies of male and female rats even at
oral doses of irbesartan causing some parental toxicity (from 50 to 650 mg/kg/day), including
mortality at the highest dose. No significant effects on the number of corpora lutea, implants, or live
fetuses were observed. Irbesartan did not affect survival, development, or reproduction of offspring.
Studies in animals indicate that the radiolabeled irbesartan is detected in rat and rabbit fetuses.
Irbesartan is excreted in the milk of lactating rats.
Animal studies with irbesartan showed transient toxic effects (increased renal pelvic cavitation,
hydroureter or subcutaneous oedema) in rat foetuses, which were resolved after birth. In rabbits,
abortion or early resorption was noted at doses causing significant maternal toxicity, including
mortality. No teratogenic effects were observed in the rat or rabbit.

 

Hydrochlorothiazide: although equivocal evidence for a genotoxic or carcinogenic effect was found
in some experimental models, the extensive human experience with hydrochlorothiazide has failed
to show an association between its use and an increase in neoplasms.


Tablet core:
Microcrystalline cellulose
Starch pregelatinised
Lactose monohydrate
Poloxamer 188
Croscarmellose sodium
Magnesium Stearate

 

Film-coating:
Opadry pink 03A34089
consisting of:
Hypromellose 6cP
Titanium dioxide
Purified stearic acid
Microcrystalline cellulose
Iron oxide yellow
Iron oxide red


Not applicable.


3 years.

Do not store above 30°C.
Store in the original package in order to protect from moisture


Cartons of 14 film-coated tablets in PVC/PE/PVDC/Aluminium blisters.
Cartons of 28 film-coated tablets in PVC/PE/PVDC/Aluminium blisters.


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


Box of 14: 486/15 DMP/21/NCN Box of 28: 487/15 DMP/21/NCN 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Box of 14: Date of latest renewal: 07/09/2015 (name change) Date of first authorization: 10/10/2013 (number 350/13 DMP/21/NNP) Box of 28: Date of latest renewal: 07/09/2015 (name change) Date of first authorization: 10/10/2013 (number 351/13 DMP/21/NNP)

November 2018
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