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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)

Gizlan® HCT 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 Gizlan® HCT work together to lower blood pressure further than if either was given alone.

Gizlan® HCT is used to treat high blood pressure, when treatment with irbesartan or hydrochlorothiazide alone did not provide adequate control of your blood pressure.


Do not take Gizlan® HCT

·         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 Gizlan® HCT 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 a blood pressure lowering medicine containing aliskiren.

 

Warnings and precautions

Talk to your doctor before taking Gizlan® HCT and if any of the following apply to you:

·         if you get excessive vomiting or diarrhoea

·         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 erythematosus (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.

·         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 Gizlan® HCT.

 

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 Gizlan® HCT”.

 

You must tell your doctor if you think you are (or might become) pregnant. Gizlan® HCT 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 Gizlan® HCT)

·         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 decrease in your vision or pain in one or both of your eyes while taking Gizlan® HCT. These could be symptoms of fluid accumulation in the vascular layer of the eye (choroidal effusion) or an increase of pressure in your eye (glaucoma) and can happen within hours to a week of taking Gizlan® HCT. This can lead to permanent vision loss, if not treated. If you earlier have had a penicillin or sulfonamide allergy, you can be at higher risk of developing this. You should discontinue Gizlan® HCT treatment and seek prompt medical attention.

The hydrochlorothiazide contained in this medicine could produce a positive result in an anti-doping test.

 

Children and adolescents

Gizlan® HCT should not be given to children and adolescents (under 18 years).

 

Taking other medicines, herbal or dietary supplements

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 Gizlan® HCT may have an effect on other medicines. Preparations containing lithium should not be taken with Gizlan® HCT 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 Gizlan® HCTandWarnings 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.

 

Gizlan® HCT with food and drink

Gizlan® HCT can be taken with or without food.

Due to the hydrochlorothiazide contained in Gizlan® HCT, if you drink alcohol while on treatment with this medicine, you may have an increased feeling of dizziness on standing up, specially when getting up from a sitting position.

 

Pregnancy, 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 Gizlan® HCT before you become pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of Gizlan® HCT. Gizlan® HCT is not recommended in early 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. Gizlan® HCT 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.

 

Driving and using machines

Gizlan® HCT 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.

 

Important information about some of the ingredients of Gizlan® HCT

Gizlan® HCT tablets contain lactose, if you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

 


Always take Gizlan® HCT exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.

 

Dosage

The recommended dose of Gizlan® HCT 150/12.5 mg is one or two tablets a day.

The recommended dose of Gizlan® HCT 300/12.5 mg and Gizlan® HCT 300/25 mg is one tablet a day.

Gizlan® HCT 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 Gizlan® HCT.

 

Method of administration

Gizlan® HCT is for oral use. Swallow the tablets with a sufficient amount of fluid (e.g. one glass of water). You can take Gizlan® HCT 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 Gizlan® HCT 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 Gizlan® HCT than you should

If you accidently take too many tablets, contact your doctor immediately.

·      Children should not take Gizlan® HCT

Gizlan® HCT 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 Gizlan® HCT

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.

 

 


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 these symptoms or get short of breath, stop taking Gizlan® HCT and contact your doctor immediately.

The frequency of the side effects listed below is defined using the following convention:

Common: may affect up to 1 in 10 people

Uncommon: may affect up to 1 in 100 people

Side effects reported in clinical studies for patients treated with irbesartan/ hydrochlorothiazide combination 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)

-          diarrhoea

-          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 combination

Some undesirable effects have been reported since marketing of irbesartan/ hydrochlorothiazide combination. 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 erythematosus, 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.

Not known (frequency cannot be estimated from the available data): skin and lip cancer (non-melanoma skin cancer), decrease in vision or pain in your eyes due to high pressure (possible signs of fluid accumulation in the vascular layer of the eye (choroidal effusion) or acute angle-closure glaucoma).

It is known that side effects associated with hydrochlorothiazide may increase with higher doses of hydrochlorothiazide.

 

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

 


·         Keep out of the reach and sight of children.

·         Do not store above 30 °C.

·         Do not take Gizlan® HCT tablets after the expiry date which is printed on the outer pack. The expiry date refers to the last day of that month.

·         Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

 


The active substances of Gizlan® HCT are irbesartan and hydrochlorothiazide.

Each tablet of Gizlan® HCT 150/12.5 contains 150 mg irbesartan and 12.5 mg hydrochlorothiazide.

Each tablet of Gizlan® HCT 300/12.5 contains 300 mg irbesartan and 12.5 mg hydrochlorothiazide.

Each tablet of Gizlan® HCT 300/25 contains 300 mg irbesartan and 25 mg hydrochlorothiazide.

The other ingredients are: Lactose monohydrate, croscarmellose sodium, pregelatinized starch, magnesium stearate, colloidal anhydrous silica, microcrystalline cellulose, hypromellose, macrogol, titanium dioxide, talc, red iron oxide (E172), yellow iron oxide (E172), Gizlan® HCT 300 /25 contains black iron oxide (E172) as well.

 


Gizlan® HCT 150/12.5 are pink oval – shaped film coated tablet coded C109 on one side, plain on the other side. Gizlan® HCT 300/12.5 are pink oval – shaped film coated tablet coded C117 on one side, plain on the other side. Gizlan® HCT 300/25 are pinkish brown oval – shaped film coated tablet coded C108 on one side, plain on the other side Gizlan® HCT Tablets are available in packs of 30 (3 blisters of 10) and 500 (50 blisters of 10). Not all pack sizes may be marketed.

Dar Al Dawa Development & Investment Co. Ltd.

Prince Hashem Bin Al-Hussein Street.

Na'ur - Amman - Jordan

Tel. (+962 6) 57 27 132

Fax. (+962 6) 57 27 776


04/2021
  نشرة الدواء تحت مراجعة الهيئة العامة للغذاء والدواء (اقرأ هذه النشرة بعناية قبل البدء في استخدام هذا المنتج لأنه يحتوي على معلومات مهمة لك)

جزلان اتش سي تي هو مزيج من مادتين فعالتين، إربيزارتان وهيدروكلوروثيازايد.

 ينتمي إربيزارتان الى مجموعة من الادوية تعرف بمناهضات مستقبلات الأنجيوتنسين 2. إن أنجيوتنسين 2 مادة يتم انتاجها في الجسم ترتبط بمستقبلات في الأوعية الدموية مما يسبب تضيقها. وينتج عن ذلك ارتفاع في ضغط الدم. يحول إربيزارتان دون ارتباط الأنجيوتنسين 2 بهذه المستقبلات، وبالتالي تسترخي الأوعية الدموية وينخفض ضغط الدم.

ينتمي هيدروكلوروثيازايد الى مجموعة من الادوية (تعرف بمدرات البول الثيازايدية) والتي تعمل على زيادة إخراج البول وبالتالي تخفض من ضغط الدم.

تعمل المادتين الفعالتين في جزلان اتش سي تي معاً على تخفيض ضغط الدم بشكل أكبر من إعطاء أي من المادتين بشكل منفرد.   

 

يستخدم جزلان اتش سي تي لعلاج ارتفاع ضغط الدم الذي لم تتم السيطرة عليه بشكل كافٍ عن طريق العلاج المنفرد بإربيزارتان أوهيدروكلوروثيازايد.

موانع استعمال جزلان اتش سي تي

·        إذا كان لديك حساسية تجاه إربيزارتان او اي من المكونات الاخرى في هذا الدواء (المذكورة في القسم 6)

·        إذا كان لديك حساسية تجاه هيدروكلوروثيازايد او اي من الأدوية المشتقة من مركب السلفوناميد الاخرى

·        اذا كنتِ حامل وتجاوزتِ الاشهر الثلاثة الاولى من الحمل. (من المستحسن أيضا تجنب جزلان اتش سي تي في المراحل المبكرة من الحمل – انظر قسم الحمل)

·        اذا كنت تعاني من مشاكل شديدة في الكبد او الكلى

·        اذا كنت تعاني من صعوبة في انتاج البول

·        اذا أخبرك الطبيب بأنك لديك وبشكل مستمر ارتفاع في مستويات الكالسيوم او انخفاض في مستويات البوتاسيوم في الدم

·        إذا كنت تعاني من السكري أو لديك إختلال في وظائف الكلى وكنت تتلقى دواء خافض لضغط الدم يحتوي على اليسكيرين.

 

المحاذير والاحتياطات

تحدث الى طبيبك  قبل تناول جزلان اتش سي تي اذا انطبقت عليك أي من الحالات التالية:

·        اذا كان لديك تقيؤ او إسهال شديدين

·        اذا كنت تعاني من مشاكل في الكلى او خضعت لزراعة كلية

·        اذا كنت تعاني من مشاكل في القلب

·        اذا كنت تعاني من مشاكل في الكبد

·        اذا كنت تعاني من السكري

·        اذا كنت تعاني من الحمى الذئبية (تعرف ايضا بالذئبة الحمامية)

·        اذا كنت تعاني من مرض فرط الالدوستيرونية الأساسي (حالة ترتبط بإنتاج كميات كبيرة من هرمون الالدوستيرون، والذي يسبب احتباس الصوديوم و بالتالي زيادة ضغط الدم)

·        إذا كنت تتناول أي من الأدوية التالية التي تستخدم لعلاج ضغط الدم:

-         مثبطات الانزيم المحول للأنجيوتنسين (على سبيل المثال ايناليبريل، ليزينوبريل، راميبريل)، وتحديداً إذا كنت تعاني من مشاكل في الكلى مرتبطة بمرض السكري.

-         اليسكيرين.  

·        اذا سبق اصابتك بسرطان الجلد او ظهر لديك آفات جلدية غير متوقعة اثناء العلاج. قد يؤدي العلاج بهيدروكلوروثيازايد لا سيما اذا كان لفترات طويلة وبجرعات عالية الى زيادة خطر حدوث بعض أنواع من سرطان الجلد والشفاه (سرطان الجلد غير الميلانيني). يجب عليك وقاية الجلد من التعرض لأشعة الشمس والاشعة فوق البنفسجية اثناء تناول جزلان اتش سي تي.

قد يقوم طبيبك بالتحقق من وظائف الكلى، ضغط الدم ومستوى الكهارل (مثل البوتاسيوم) في الدم على فترات منتظمة.

انظر ايضا الى المعلومات تحت بند " موانع استعمال جزلان اتش سي تي"

في حال كنت تعتقدين بأنك حامل (او تخططين للحمل)، يجب عليك ابلاغ الطبيب بذلك. لا يوصى بتناول جزلان اتش سي تي في المراحل المبكرة من الحمل، ويمنع تناوله في حال تجاوزتِ الاشهر الثلاثة الاولى من الحمل، لأنه قد يسبب أذى شديد للطفل اذا تم استخدامه في هذه المرحلة. (انظري بند الحمل).

 

عليك أن تسأل طبيبك في حال:

·        كنت تتبع حمية غذائية منخفضة الصوديوم

·        حدوث علامات مثل عطش غير طبيعي، جفاف الفم، ضعف عام، دوار، ألم أو تشنجات في العضلات، غثيان، تقيؤ، أو زيادة في سرعة ضربات القلب بشكل غير طبيعي والذي يشيرالى تاثير زائد للهيدروكلوروثيازايد (الموجود في جزلان اتش سي تي).

·        أصبحت تعاني من زيادة حساسية الجلد لأشعة الشمس مع ظهور أعراض حرق الشمس (مثل احمرار، حكة، انتفاخ، تقرح) بحيث تحدث بشكل أسرع من الطبيعي

·        كنت ستخضع لاجراء عملية (جراحة) او سيتم إعطاؤك أدوية مخدرة

·        ظهرت اعراض انخفاض الرؤية او ألم في عين واحدة او كلتا العينين أثناء تناول جزلان اتش سي تي. قد تدل هذه العلامات على انحباس السوائل في الطبقة الوعائية للعين (الانصباب المشيمي) أو ارتفاع في ضغط العين (زرقة العين) والذي قد يحدث خلال ساعات إلى أسابيع من استخدام جزلان اتش سي تي. إذا لم يتم علاج هذه الحالة فإنها قد تتطور إلى فقدان دائم للبصر. في حال تعرضت في السابق لحساسية تجاه البنسلينات أو السلفوناميدات فقد تكون أكثر عرضة للتعرض لذلك مرة أخرى. توقف عن العلاج بجزلان اتش سي تي واطلب العناية الطبية على الفور.

إن وجود هيدروكلوروثيازايد في هذا الدواء قد يعطي نتيجة ايجابية في الاختبارالمضاد للمنشطات.

 

الاطفال واليافعين

يمنع استخدام جزلان اتش سي تي في الاطفال و اليافعين (دون سن 18 سنة).

 

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

أخبر طبيبك أو الصيدلي في حال كنت تتناول، تناولت مؤخرا او قد تتناول أي أدوية أخرى.

قد يكون للادوية المدرة للبول مثل هيدروكلوروثيازايد الموجود في جزلان اتش سي تي تأثيرعلى ادوية اخرى. يمنع إعطاء الادوية المحتوية على الليثيوم بالتزامن مع جزلان اتش سي تي بدون مراقبة حثيثة من قبل الطبيب.

قد يقوم طبيبك بتغيير الجرعة و/أو أخذ احتياطات أخرى:

اذا كنت تتناول مثبطات الانزيم المحول للأنجيوتنسين او اليسكيرين (انظر ايضا الى المعلومات تحت بندي " موانع استعمال جزلان اتش سي تي" و"المحاذير والاحتياطات")

قد تحتاج للقيام بفحوصات للدم في حال كنت تتناول:

·        المكملات الغذائية المحتوية على البوتاسيوم

·        بدائل الملح المحتوية على البوتاسيوم

·        الادوية الموفرة للبوتاسيوم او مدرات البول الاخرى

·        بعض الملينات

·        أدوية علاج النقرس

·        المكملات الغذائية العلاجية المحتوية على فيتامين (د)

·        الادوية التي تتحكم بمعدل ضربات القلب

·        ادوية السكري (التي تؤخذ عن طريق الفم او الانسولين)

·        كارباميزابين (دواء يستخدم في علاج الصرع)

من المهم ايضا أن تخبر طبيبك اذا كنت تتناول أي ادوية اخرى تخفض ضغط الدم، ستيرويدات، وادوية علاج السرطان، مسكنات الالم، ادوية التهاب المفاصل، او كوليستيرامين وراتنجات الكوليستيبول التي تستخدم لخفض الكوليسترول في الدم.

 

تناول جزلان اتش سي تي مع الطعام والشراب

من الممكن تناول جزلان اتش سي تي مع او بدون الطعام.

نتيجة لوجود الهيدروكلوروثيازايد في جزلان اتش سي تي، فإنه في حال قمت بشرب الكحول أثناء تناولك هذا الدواء، قد يزداد شعورك بالدوار عند الوقوف، تحديدا بعد الوقوف من وضع الجلوس.

 

الحمل، الرضاعة والخصوبة

الحمل

يجب أن تخبري طبيبك اذا كنتِ تعتقدين بأنك حامل (او تخططين للحمل). سينصحك الطبيب عادة بالتوقف عن تناول جزلان اتش سي تي قبل ان تصبحي حامل او بمجرد ثبوت وجود الحمل خلال العلاج و سينصحك بتناول دواء آخر بديل عن جزلان اتش سي تي. لا يوصى بتناول جزلان اتش سي تي في المراحل المبكرة من الحمل، ولا ينبغي استخدامه بعد الاشهر الثلاثة الاولى من الحمل، لأنه قد يسبب أذى شديد للطفل اذا تم استخدامه بعد الشهر الثالث من الحمل.

 

الرضاعة

أخبري طبيبك اذا كنت مرضع او على وشك البدء بالرضاعة. لا يوصى بتناول جزلان اتش سي تي من قبل الامهات اللاتي يقمن بالرضاعة الطبيعية، قد يختار الطبيب دواء آخر في حال كنتِ تريدين الارضاع، خصوصا اذا كان الطفل حديث الولادة، او مولود قبل أوانه.

 

القيادة وإستخدام الآلات

من غير المرجح أن يؤثر جزلان اتش سي تي على قدرتك على القيادة او استخدام الآلات. إلا أنه قد يحدث دوار او تعب في بعض الاحيان أثناء علاج ضغط الدم المرتفع. اذا ظهرت لديك هذه الاعراض، تحدث الى طبيبك قبل القيام بالقيادة أو تشغيل الآلات.

 

معلومات هامة حول بعض مكونات جزلان اتش سي تي

تحتوي أقراص جزلان اتش سي تي على لاكتوز، إذا تم إخبارك من قبل الطبيب بأنك تعاني من عدم القدرة على تحمل بعض أنواع السكر، أخبر طبيبك قبل تناول هذا المنتج الطبي.

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تناول جزلان اتش سي تي تماما كما وصفه الطبيب لك. تحقق من طبيبك أو الصيدلي إذا لم تكن متأكدا.

 

الجرعة

الجرعة الموصى بها من جزلان اتش سي تي 150/ 12,5 هي قرص او قرصين يوميا.

الجرعة الموصى بها من جزلان اتش سي تي300/12.5 و جزلان اتش سي تي300/25 هي قرص واحد يومياً.

غالبا ما يوصيك الطبيب بتناول جزلان اتش سي تي في حال  كان العلاج السابق غير كاف لتخفيض ضغط الدم. سيخبرك الطبيب عن كيفية التحويل من علاجك السابق الى جزلان اتش سي تي.

 

طريقة الاعطاء

يؤخذ جزلان اتش سي تي عن طريق الفم. قم ببلع القرص مع كمية وافرة من السوائل (على سبيل المثال، كوب من الماء). يمكن تناول جزلان اتش سي تي مع الطعام او بدونه. حاول أن تتناول الدواء في نفس الوقت يوميا. من الضروري أن تستمر في تناول جزلان اتش سي تي إلى أن يوصيك الطبيب بغير ذلك.

يتم الحصول  على التاثير الاقصى الخافض للضغط في غضون 6-8 أسابيع من بدء العلاج.

 

·        الجرعة الزائدة من جزلان اتش سي تي

اذا تناولت كمية زائدة من الأقراص عن طريق الخطأ، اتصل بطبيبك على الفور.

 

·        يمنع استخدام جزلان اتش سي تي في الاطفال.

لا ينبغي استخدام جزلان اتش سي تي في الاطفال دون سن 18 سنة. اذا قام طفل ببلع بعض الاقراص، اتصل بطبيبك على الفور.

 

·        نسيان تناول جرعة جزلان اتش سي تي

إذا نسيت تناول الجرعة اليومية، فقط قم بتناول الجرعة التالية كالمعتاد. لا تضاعف الجرعة للتعويض عن الجرعة الفائتة.

اذا كان لديك أي اسئلة اضافية حول استخدام هذا الدواء، إسأل الطبيب او الصيدلي.

شأنه شأن الأدوية الأخرى، قد يسبب هذا الدواء أعراض جانبية، بالرغم من انها لا تظهر لدى كل المرضى.

قد تكون بعض الاعراض الجانبية خطيرة وتتطلب العناية الطبية.

تم رصد حالات نادرة من ردود الفعل التحسسية الجلدية (طفح، شرى)، بالاضافة الى تورم في الوجه، الشفاه و/أو اللسان عند تناول إربيزارتان.

إذا ظهرت لديك أي من هذه الاعراض او عانيت من قصر في التنفس، توقف عن تناول جزلان اتش سي تي و اتصل بطبيبك على الفور.

ان معدل تكرار الاعراض الجانبية المذكور في الاسفل معرف تبعاً للمصطلحات التالية:

شائع: قد يؤثر على 1 من كل 10 كحد أقصى

غير شائع: قد يؤثر على 1 من كل 100 كحد أقصى

الأعراض الجانبية عند تلقي العلاج بمزيج إربيزارتان وهيدروكلوروثيازايد:

أعراض جانبية شائعة (قد يؤثر على 1 من كل 10 كحد أقصى)

-         غثيان / قيء

-         تبول غير طبيعي

-         تعب

-         دوار (يشمل ذلك عند القيام من وضع الاستلقاء او الجلوس)

-         قد تظهر فحوصات الدم زيادة في مستويات انزيم وظيفة العضلات والقلب (انزيم الكرياتين كيناز) او ارتفاع مستويات مواد تشير الى وظيفة الكلى (نيتروجين اليوريا في الدم، الكرياتينين)

اذا سببت أي من هذه الاعراض الجانبية المشاكل، تحدث الى طبيبك.

 

أعراض جانبية غير شائعة (قد يؤثر على 1 من كل 100 كحد أقصى)

-         إسهال

-         انخفاض ضغط الدم

-         إغماء

-         زيادة ضربات القلب

-         توهج

-         تورم

-         عجز جنسي (مشاكل في الاداء الجنسي)

-         قد تظهر فحوصات الدم انخفاض في مستويات البوتاسيوم والصوديوم في الدم

اذا سببت أي من هذه الاعراض الجانبية لك المشاكل، تحدث الى طبيبك.

 

الاعراض الجانبية التي تم رصدها العلاج بمزيج إربيزارتان / هيدروكلوروثيازايد:

تم رصد بعض الاعراض الجانبية منذ بدء تسويق مزيج إربيزارتان/هيدروكلوروثيازايد. أعراض جانبية ذات معدل تكرار غير معروف هي: صداع، طنين الاذن، سعال، اضطراب التذوق، عسر الهضم، ألم في المفاصل والعضلات، اختلال في وظائف الكبد والكلى، ارتفاع مستويات البوتاسيوم في الدم و ردود فعل تحسسية مثل طفح، شرى، تورم الوجه، الشفاه، الفم، اللسان او الحلق. كما تم رصد حالات غير شائعة من اليرقان (اصفرار الجلد و/او بياض العينين).

 

شأنه شأن الادوية التي تتكون من مزيج من مادتين فعالتين، فإنه لا يمكن استبعاد الاعراض الجانبية المرتبطة بكل مادة على حدى.

 

الأعراض الجانبية المرتبطة بإربيزارتان وحده:

بالاضافة الى الاعراض الجانبية المذكورة أعلاه، تم رصد حدوث ألم في الصدر، ردود فعل تحسسية شديدة (صدمة تأقية) وانخفاض في عدد الصفائح الدموية (خلايا دموية أساسية لتجلط الدم).

 

الاعراض الجانبية المرتبطة بهيدروكلوروثيازايد وحده:

فقدان الشهية، تهيج المعدة، تشنجات المعدة، إمساك، يرقان (اصفرار الجلد و/او بياض العينين)، التهاب البنكرياس والذي يتم تمييزه بألم شديد في أعلى المعدة، غالبا مع غثيان وتقيؤ، اضطرابات النوم، اكتئاب، عدم وضوح الرؤية، نقص في خلايا الدم البيضاء، والذي قد يؤدي الى الاصابة بالعدوى بشكل متكرر، حمى، انخفاض في عدد الصفائح الدموية (خلايا الدم الضرورية لتخثر الدم)، انخفاض عدد خلايا الدم الحمراء (فقر الدم) والذي يتم تشخيصه بالشعور بتعب، صداع، قصر التنفس أثناء ممارسة التمارين، دوار وشحوب اللون، مرض في الكلى، مشاكل في الرئة تشمل التهاب الرئة او تجمع السوائل في الرئتين، زيادة حساسية الجلد تجاه اشعة الشمس، التهاب الاوعية الدموية، مرض جلدي يتم تشخيصه بحدوث تقشر للجلد في جميع انحاء الجسم، الحمى الذئبية الجلدية والتي يتم تشخيصها بوجود طفح قد يظهر على الوجه، الرقبة، وفروة الرأس، ردود فعل تحسسية، ضعف وتشنج عضلي، تغير في معدل ضربات القلب، انخفاض ضغط الدم بعد تغيير وضعية الجسم، تورم الغدد اللعابية، ارتفاع مستويات السكر في الدم، سكر في البول، زيادات في بعض انواع دهون الدم، ارتفاع مستويات حمض اليوريك في الدم، والذي قد يؤدي الى النقرس.  

غير  معروفة (لا يمكن تقدير معدل تكرارها من البيانات المتاحة): سرطان في الجلد والشفتين (سرطان الجلد غير الميلانيني)، ضعف في الرؤية أو ألم في العينين بسبب ارتفاع الضغط (علامات محتملة لتجمع السوائل في الطبقة الوعائية من العين (الانصباب المشيمي) أو جلوكوما (زرقة) الزاوية المغلقة الحادة).

من المعروف أن الاعراض الجانبية المرتبطة بهيدروكلوروثيازايد قد تزداد عند استخدام جرعات كبيرة من هيدروكلوروثيازايد.

 

اذا أصبحت أي من هذه الاعراض خطيرة، أو اذا لاحظت أي أعراض جانبية لم يتم ذكرها في هذه النشرة، تحدث الى الطبيب او الصيدلي.

·        يحفظ بعيدا عن متناول ايدي الاطفال و نظرهم.

·        يحفظ على درجة حرارة لا تزيد عن 30 درجة مئوية.

·        لا تستخدم أقراص جزلان اتش سي تي بعد تاريخ الانتهاء المذكور على العبوة الخارجية. يدل تاريخ الانتهاء على اخر يوم في الشهر المذكور.

·        يجب عدم التخلص من الأدوية في المياه العادمة أو النفايات المنزلية. إسأل الصيدلي حول الطريقة السليمة للتخلص من الأدوية التي لم تعد بحاجة إليها. سيساعد هذا في حماية البيئة.

المواد الفعالة في جزلان اتش سي تي هي إربيزارتان وهيدروكلوروثيازايد.

يحتوي كل قرص من جزلان اتش سي تي 150/12.5 على 150 ملغم إربيزارتان و 12.5 ملغم هيدروكلوروثيازايد.

يحتوي كل قرص من جزلان اتس سي تي 300/12.5 على 300 ملغم إربيزارتان و 12.5 ملغم هيدروكلوروثيازايد.

يحتوي كل قرص من جزلان اتش سي تي 300/25 على 300 ملغم إربيزارتان و 25 ملغم هيدروكلوروثيازايد.

المواد غير الفعالة الأخرى هي: لاكتوز أحادي الماء، كروس كارميلوس صوديوم، نشا مهيلم، ستيارات المغنيسيوم، سيليكا غروية لامائية، سيليلوز دقيق البلورية، هيبروميلوز، ماكروغول، ثاني أكسيد التيتانيوم، تالك،  لون أحمر (E172)، لون أصفر(E172)، يحتوي جزلان اتش سي تي 300/25 على لون أسود (E172) أيضا.

أقراص جزلان تش سي تي 150/12.5 هي أقراص مغلفة لونها وردي بيضاوية الشكل مرمزة بالرمز C109  على جهة واحدة، ملساء على الجهة الاخرى.

أقراص جزلان اتش سي تي 300/12.5 هي أقراص مغلفة لونها وردي بيضاوية الشكل مرمزة بالرمز C117 على جهة واحدة، ملساء على الجهة الاخرى.

أقراص جزلان اتش سي تي 300/25 هي أقراص مغلفة بنية الى وردية اللون بيضاوية الشكل مرمزة بالرمز C108 على جهة واحدة، ملساء على الجهة الاخرى.

تتوفر أقراص جزلان اتش سي تي في عبوات تحتوي على 30 قرص (3 أشرطة في كل منها 10 أقراص) و 500 قرص (50 شريط في كل منها 10 أقراص).

قد لا يتم تسويق جميع أنواع العبوات.

شركة دار الدواء للتنمية والإستثمار المساهمة المحدودة

شارع الأمير هاشم بن الحسين.

ناعور – عمان – الأردن.

هاتف. 132 27 57 (6 962 +)

فاكس.776 27 57 (6 962 +)

04/2021
 Read this leaflet carefully before you start using this product as it contains important information for you

Gizlan® HCT 150/12.5 mg Film Coated Tablets.

Each tablet of Gizlan® HCT 150/12.5 contains 150 mg irbesartan and 12.5 mg hydrochlorothiazide, Gizlan® HCT 150 /12.5 tablets contain 29.8 mg lactose monohydrate. For a full list of excipients, see section 6.1.

Film-Coated tablet. Gizlan® HCT 150/12.5 are pink oval – shaped film coated tablet coded C109 on one side, plain on the other side.

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

Gizlan® HCT 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:

Gizlan® HCT 150 mg/12.5 mg may be administered in patients whose blood pressure is not adequately controlled with hydrochlorothiazide or irbesartan 150 mg alone;

Gizlan® HCT 300 mg/12.5 mg may be administered in patients insufficiently controlled by irbesartan 300 mg or by Gizlan® HCT 150 mg/12.5 mg.

Gizlan® HCT 300 mg/25 mg may be administered in patients insufficiently controlled by Gizlan® HCT 300 mg/12.5 mg.

Doses higher than 300 mg irbesartan/25 mg hydrochlorothiazide once daily are not recommended.

When necessary, Gizlan® HCT 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, Gizlan® HCT 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 impairment whose renal creatinine clearance is ≥ 30 ml/min (see sections 4.3 and 4.4).

Hepatic impairment

Gizlan® HCT 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 Gizlan® HCT is necessary in patients with mild to moderate hepatic impairment (see section 4.3).

Older people

No dosage adjustment of Gizlan® HCT is necessary in older people.

Paediatric population

Gizlan® HCT 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 Gizlan® HCT with aliskiren-containing products is contraindicated in patients 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: Irbesartan/Hydrochlorothiazide have 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 Irbesartan/Hydrochlorothiazide.

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 Irbesartan/Hydrochlorothiazide, a similar effect should be anticipated.

Renal impairment and kidney transplantation: when Irbesartan/Hydrochlorothiazide are used in patients with impaired renal function, a periodic monitoring of potassium, creatinine and uric acid serum levels is recommended. There is no experience regarding the administration of Irbesartan/Hydrochlorothiazide in patients with a recent kidney transplantation. Irbesartan/Hydrochlorothiazide should not be used in patients with severe renal impairment (creatinine clearance < 30 ml/min) (see section 4.3). Thiazide diuretic-associated azotaemia 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 or aliskiren 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, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1). If dual blockade 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 Irbesartan/Hydrochlorothiazide 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 Irbesartan/Hydrochlorothiazide is not recommended.

Metabolic and endocrine effects: thiazide therapy may impair glucose tolerance. In diabetic patients dosage adjustments of insulin or oral hypoglycemic agents may be required. Latent diabetes mellitus may 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 Irbesartan/Hydrochlorothiazide, minimal or no effects were reported.

Hyperuricaemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy.

Electrolyte imbalance: as for any patient receiving diuretic therapy, periodic determination of serum electrolytes 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 are dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea or vomiting.

Although hypokalaemia may develop with the use of thiazide diuretics, concurrent therapy with irbesartan may reduce diuretic-induced hypokalaemia. The risk of hypokalaemia is greatest in patients with cirrhosis of the liver, in patients experiencing brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes and in patients receiving concomitant therapy with corticosteroids or ACTH. Conversely, due to the irbesartan component of Irbesartan/Hydrochlorothiazide hyperkalaemia might 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-sparing diuretics, potassium supplements or potassium-containing salts substitutes should be co-administered cautiously with Irbesartan/Hydrochlorothiazide (see section 4.5).

There is no evidence that irbesartan would reduce or prevent diuretic-induced hyponatraemia. Chloride deficit is generally mild and usually does not require treatment.

Thiazides may decrease urinary calcium excretion and cause an intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcaemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.

Thiazides have been shown to increase the urinary excretion of magnesium, which may result in hypomagnaesemia.

Lithium: the combination of lithium and Irbesartan/Hydrochlorothiazide are not recommended (see section 4.5).

Anti-doping test: hydrochlorothiazide contained in this medicinal product could produce a positive analytic result in an anti-doping test.

General: in patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with angiotensin converting enzyme inhibitors or angiotensin-II receptor antagonists that affect this system has been associated with acute hypotension, azotaemia, oliguria, or rarely acute renal failure (see section 4.5). As with any antihypertensive agent, excessive blood pressure decrease in patients with ischemic cardiopathy or ischemic cardiovascular disease could result in a myocardial infarction or stroke.

Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy 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 thiazide diuretics.

Cases of photosensitivity reactions have been reported with thiazides diuretics (see section 4.8). If photosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If a re-administration of the diuretic is deemed necessary, it is recommended to protect exposed areas to the sun 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 be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. 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).

Choroidal effusion, Acute Myopia and Secondary Acute Angle-Closure Glaucoma: sulfonamide drugs or sulfonamide derivative drugs can cause an idiosyncratic reaction, resulting in choroidal effusion with visual field defect, transient myopia and acute angle-closure glaucoma. While hydrochlorothiazide is a sulfonamide, only isolated cases of acute angle-closure glaucoma have been reported so far with hydrochlorothiazide. Symptoms include acute onset of 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 to discontinue drug intake as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy (see section 4.8).

Lactose: Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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).


Other antihypertensive agents: the antihypertensive effect of Irbesartan/Hydrochlorothiazide may be increased with the concomitant use of other antihypertensive agents. Irbesartan and hydrochlorothiazide (at doses up to 300 mg irbesartan/25 mg hydrochlorothiazide) have been safely administered with other antihypertensive agents including calcium channel blockers and beta-adrenergic blockers. Prior treatment with high dose diuretics may result in volume depletion and a risk of hypotension when initiating therapy with irbesartan with or without thiazide diuretics unless the volume depletion is corrected 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 associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).

Lithium: reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors. Similar effects have been very rarely reported with irbesartan so far. Furthermore, renal clearance of lithium is reduced by thiazides so the risk of lithium toxicity could be increased with Irbesartan/Hydrochlorothiazide. Therefore, the combination of lithium and Irbesartan/Hydrochlorothiazide is not recommended (see section 4.4). If the combination proves necessary, careful monitoring of serum lithium levels is recommended.

Medicinal products affecting potassium: the potassium-depleting effect of hydrochlorothiazide is attenuated by the potassium-sparing effect of irbesartan. However, this effect of hydrochlorothiazide on serum potassium would be expected to be potentiated by other medicinal products associated with potassium loss and hypokalaemia (e.g. other kaliuretic diuretics, laxatives, amphotericin, carbenoxolone, penicillin G sodium). Conversely, based on the experience with the use of other medicinal products that blunt the renin-angiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products that may increase serum potassium levels (e.g. heparin sodium) may lead to increases in serum potassium. Adequate monitoring of serum potassium in patients at risk is recommended (see section 4.4).

Medicinal products affected by serum potassium disturbances: periodic monitoring of serum potassium is recommended when Irbesartan/Hydrochlorothiazide are administered with medicinal products affected by serum potassium disturbances (e.g. digitalis glycosides, antiarrhythmics).

Non-steroidal anti-inflammatory drugs: when angiotensin II antagonists are administered simultaneously 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 effect may occur.

As with ACE inhibitors, concomitant use of angiotensin II antagonists and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor pre-existing renal function. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter.

Additional information on irbesartan interactions: in clinical studies, the pharmacokinetic of irbesartan is not affected by hydrochlorothiazide. Irbesartan is mainly metabolised by CYP2C9 and to a lesser extent by glucuronidation. No significant pharmacokinetic or pharmacodynamic interactions were observed when irbesartan was coadministered with warfarin, a medicinal product metabolised by CYP2C9. The effects of CYP2C9 inducers such as rifampicin on the pharmacokinetic of irbesartan have not been evaluated. The pharmacokinetic of digoxin was not altered by co-administration of irbesartan.

Additional information on hydrochlorothiazide interactions: when administered concurrently, the following 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 antidiabetic medicinal product may be required (see section 4.4);

Colestyramine and Colestipol resins: absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Irbesartan/Hydrochlorothiazide should be taken at least one hour before or four hours after these medications;

Corticosteroids, ACTH: electrolyte depletion, particularly hypokalaemia, may be increased;

Digitalis glycosides: thiazide induced hypokalaemia or hypomagnaesemia favour the onset of digitalis-induced cardiac arrhythmias (see section 4.4);

Non-steroidal anti-inflammatory drugs: the administration of a non-steroidal anti-inflammatory drug may 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 inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with Angiotensin II Receptor Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy 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 human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3).

Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.

Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see sections 4.3 and 4.4).

Hydrochlorothiazide

There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide its use during the second and third trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia.

Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or preeclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without a beneficial effect on the course of the disease.

Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare situations where no other treatment could be used.

Since Gizlan® HCT contains hydrochlorothiazide, it is not recommended during the first trimester of pregnancy. A switch to a suitable alternative treatment should be carried out in advance of a planned pregnancy.

Breast-feeding

Angiotensin II Receptor Antagonists (AIIRAs)

Because no information is available regarding the use of Irbesartan/Hydrochlorothiazide during breast-feeding, Gizlan® HCT is not recommended and alternative treatments with better established safety profiles during breast-feeding are 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 its metabolites in milk (for details see 5.3).

Hydrochlorothiazide

Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit the milk production. The use of Gizlan® HCT during breast feeding is not recommended. If Gizlan® HCT 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 inducing the first signs of parental toxicity (see section 5.3).


Based on its pharmacodynamic properties, Irbesartan/Hydrochlorothiazide are unlikely to affect the ability to drive and use machines. When driving vehicles or operating machines, it should be taken into account that occasionally dizziness or weariness may occur during treatment of hypertension.


Irbesartan/hydrochlorothiazide combination

Among 898 hypertensive patients who received various doses of irbesartan/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

Cardiac disorders:

Uncommon:

syncope, hypotension, tachycardia, oedema

Nervous system disorders:

Common:

dizziness

Uncommon:

orthostatic dizziness

Not known:

headache

Ear and labyrinth disorders:

Not known:

tinnitus

Respiratory, thoracic and mediastinal disorders:

Not known:

cough

Gastrointestinal disorders:

Common:

nausea/vomiting

Uncommon:

diarrhoea

Not known:

dyspepsia, dysgeusia

Renal and urinary disorders:

Common:

abnormal urination

Not known:

impaired renal function including isolated cases of renal failure in patients at risk (see section 4.4)

Musculoskeletal and connective tissue disorders:

Uncommon:

swelling extremity

Not known:

arthralgia, myalgia

Metabolism and nutrition disorders:

Not known:

hyperkalaemia

Vascular disorders:

Uncommon:

flushing

General disorders and administration site conditions:

Common:

fatigue

Immune system disorders:

Not known:

cases of hypersensitivity reactions such as angioedema, rash, urticaria

Hepatobiliary disorders:

Uncommon:

Not known:

jaundice

hepatitis, abnormal liver function

Reproductive system and breast disorders:

Uncommon:

sexual dysfunction, libido changes

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

Table 2: Adverse reactions reported with the use of irbesartan alone

Blood and lymphatic system disorders:

Not known:

thrombocytopenia

General disorders and administration site conditions:

Uncommon:

chest pain

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 hypokalaemia and hyponatraemia, see section 4.4), hyperuricaemia, glycosuria, hyperglycaemia, increases in cholesterol and triglycerides

Cardiac disorders:

Not known:

cardiac arrhythmias

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

Eye disorders:

Not known:

transient blurred vision, xanthopsia, acute myopia and secondary acute angle-closure glaucoma, choroidal effusion

Respiratory, thoracic and mediastinal disorders:

Not known:

respiratory distress (including pneumonitis and pulmonary oedema)

Gastrointestinal disorders:

Not known:

pancreatitis, anorexia, diarrhoea, constipation, gastric irritation, sialadenitis, loss of appetite

Renal and urinary disorders:

Not known:

interstitial nephritis, renal dysfunction

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, photosensitivity reactions, rash, urticaria

Musculoskeletal and connective tissue disorders:

Not known:

weakness, muscle spasm

Vascular disorders:

Not known:

postural hypotension

General disorders and administration site conditions:

Not known:

fever

Hepatobiliary disorders:

Not known:

jaundice (intrahepatic cholestatic jaundice)

Psychiatric disorders:

Not known:

depression, sleep disturbances

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Not known:

non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma)

Non-melanoma skin cancer: Based on available data from epidemiological studies, cumulative dose dependent association between HCTZ and NMSC has been observed (see also sections 4.4 and 5.1).

The dose dependent adverse events of hydrochlorothiazide (particularly electrolyte disturbances) may increase when titrating the hydrochlorothiazide.

 

To report any side effects:

o The National Pharmacovigilance Centre (NPC)

− Fax: +966-11-205-7662

− Call NPC at +966- 11-2038222, Ext 2317, 2356, 2340

− SFDA Call Centre: 19999

− Email: npc.drug@sfda.gov.sa

− Website: https://ade.sfda.gov.sa/


No specific information is available on the treatment of overdose with Irbesartan/Hydrochlorothiazide. 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.

Mechanism of action

Irbesartan/Hydrochlorothiazide 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 renin-angiotensin-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 post-dosing) 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 up titrated 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 Irbesartan/Hydrochlorothiazide 150 mg/12.5 mg were 100%. The trough to peak effects measured by cuff during office visits were 68% and 76% for Irbesartan/Hydrochlorothiazide 150 mg/12.5 mg and Irbesartan/Hydrochlorothiazide 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 irbesartan gave 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 Irbesartan/Hydrochlorothiazide, 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 Irbesartan/Hydrochlorothiazide, 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 irbesartan monotherapy. 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.

Clinical efficacy and safety

Efficacy and safety of Irbesartan/Hydrochlorothiazide as initial therapy for severe hypertension (defined as SeDBP ≥ 110 mmHg) was evaluated in a multicentre, 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 force-titrated (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 trough SeDBP < 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 (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA 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 aliskiren group 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 lip-cancer 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 the pharmacokinetics of either medicinal product.

Absorption

Irbesartan and hydrochlorothiazide are orally active agents and do not require biotransformation for their activity. Following oral administration of Irbesartan/Hydrochlorothiazide, the absolute oral bioavailability is 60-80% and 50-80% for irbesartan and hydrochlorothiazide, respectively. Food does not affect the bioavailability of Irbesartan/Hydrochlorothiazide. Peak plasma concentration occurs at 1.5-2 hours after oral administration for irbesartan and 1-2.5 hours for hydrochlorothiazide.

Distribution

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.

Linearity/non-linearity

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.

Biotransformation

Following oral or intravenous administration of 14C irbesartan, 80-85% of the circulating plasma radioactivity is attributable to unchanged irbesartan. Irbesartan is metabolised by the liver via glucuronide conjugation and oxidation. The major circulating metabolite is irbesartan glucuronide (approximately 6%). In vitro studies indicate that irbesartan is primarily oxidised by the cytochrome P450 enzyme CYP2C9; isoenzyme CYP3A4 has negligible effect.

Elimination

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 the irbesartan/hydrochlorothiazide combination after oral administration was evaluated in rats and macaques in studies lasting up to 6 months. There were no toxicological findings observed of relevance to human therapeutic use.

The following changes, observed in rats and macaques receiving the irbesartan/hydrochlorothiazide combination 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, and hyperplasia/hypertrophy of the juxtaglomerular apparatus, which are a direct consequence of the interaction 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 in a 6 months toxicity study at irbesartan 90 mg/kg/day, hydrochlorothiazide 90 mg/kg/day, and irbesartan/hydrochlorothiazide 10/10 mg/kg/day. These lesions were not observed in macaques;

▪ decreases in serum potassium due to hydrochlorothiazide and partly prevented when hydrochlorothiazide 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 the irbesartan/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 foetuses were observed. Irbesartan did not affect survival, development, or reproduction of offspring. Studies in animals indicate that the radiolabelled irbesartan is detected in rat and rabbit foetuses. 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.


Excipients:

Core:-

Lactose monohydrate 

Croscarmellose Sodium

Pregelatinized Starch 

Cellulose, microcrystaline

Magnesium Stearate

Silica colloidal anhydrous

Film Coat:-

Hypromellose

Titanium Dioxide

Talc

Macrogol

Red ferric oxide

Iron oxide yellow E-172


Not applicable


24 months.

Do not store above 30° C.


 

 

Immediate packaging

Outer packaging

Laminated aluminum strip for formpack

 

Carton

leaflet

Gizlan® HCT Tablets are available in packs of 30 (3 blisters of 10)

Not all pack sizes may be marketed.

 


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


Dar Al Dawa Development & Investment Co. Ltd. P.O. Box 9364 Na’ur - Jordan

07/04/2021
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