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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-Diovan film-coated tablets contain two active substances called valsartan and hydrochlorothiazide. Both of these substances help to control high blood pressure (hypertension).

·         Valsartan belongs to a class of medicines known as “angiotensin II receptor antagonists”, which help to control high blood pressure. Angiotensin II is a substance in the body that causes vessels to tighten, thus causing your blood pressure to increase. Valsartan works by blocking the effect of angiotensin II. As a result, blood vessels relax and blood pressure is lowered.

·         Hydrochlorothiazide belongs to a group of medicines called thiazide diuretics (also known as “water tablets”). Hydrochlorothiazide increases urine output, which also lowers blood pressure.

Co-Diovan is used to treat high blood pressure which is not adequately controlled by a single substance alone.

High blood pressure increases the workload of the heart and arteries. If not treated, it can damage the blood vessels of the brain, heart, and kidneys, and may result in a stroke, heart failure or kidney failure. High blood pressure increases the risk of heart attacks. Lowering your blood pressure to normal reduces the risk of developing these disorders.


 o                  Do not take Co-Diovan

·         If you are allergic (hypersensitive) to valsartan, hydrochlorothiazide, sulphonamide derivatives (substances chemically related to hydrochlorothiazide) or to any of the other ingredients of this medicine (listed in section 6).

·         If you are more than 3 months pregnant, (it is also better to avoid Co-Diovan in early pregnancy – see pregnancy section).

·         If you have severe liver disease, destruction of the small bile ducts within the liver (biliary cirrhosis) leading to the build up of bile in the liver (cholestasis).

·         If you have severe kidney disease.

·         If you are unable to produce urine (anuria).

·         If you are treated with an artificial kidney.

·         If the level of potassium or sodium in your blood is lower than normal, or if the level of calcium in your blood is higher than normal despite treatment.

·         If you have gout.

·         If you have diabetes or impaired kidney function and you are treated with a blood pressure lowering medicine containing aliskiren.

 

If any of the above apply to you, tell your doctor and do not take Co-Diovan.

 

o                  Take special care with Co-Diovan

·         if you are taking potassium-sparing medicines, potassium supplements, salt substitutes containing potassium or other medicines that increase the amount of potassium in your blood such as heparin. Your doctor may need to check the amount of potassium in your blood regularly.

·         if you have low levels of potassium in your blood.

·         if you have diarrhoea or severe vomiting.

·         if you are taking high doses of water tablets (diuretics).

·         if you have severe heart disease.

·         if you are suffering from heart failure or have experienced a heart attack. Follow your doctor’s instruction for the starting dose carefully. Your doctor may also check your kidney function.

·         if you suffer from a narrowing of the kidney artery.

·         if you have recently received a new kidney.

·         if you suffer from hyperaldosteronism. This is a disease in which your adrenal glands make too much of the hormone aldosterone. If this applies to you, the use of Co-Diovan is not recommended.

·         if you have liver or kidney disease.

·         if you have ever experienced swelling of the tongue and face caused by an allergic reaction called angioedema when taking another drug (including ACE inhibitors), tell your doctor. If these symptoms occur when you are taking Co-Diovan, stop taking Co-Diovan immediately and never take it again. See also section 4, “Possible side effects”.

·         if you have fever, rash and joint pain, which may be signs of systemic lupus erythematosus (SLE, a so-called autoimmune disease).

·         if you have diabetes, gout, high levels of cholesterol or triglycerides in your blood.

·         if you have had allergic reactions with the use of other blood pressure-lowering agents of this class (angiotensin II receptor antagonists) or if you have allergy or asthma.

·         if you experience a decrease in vision or eye pain. These could be symptoms of fluid accumulation in the vascular layer of the eye (choroidal effusion) or an increase of pressure in your eye and can happen within hours to weeks of taking Co-Diovan. This can lead to permanent vision loss, if not treated. If you earlier have had a penicillin or sulphonamide allergy you can be at higher risk of developing this.

·         if you are taking any of the following medicines used to treat high blood pressure:

o                  an ACE inhibitors (for example enalapril, lisinopril, Ramipril), in particular if you have diabetes-related kidney problems. 

o                  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 Co-Diovan.

·         if you experienced breathing or lung problems (including inflammation or fluid in the lungs) following hydrochlorothiazide intake in the past. If you develop any severe shortness of breath or difficulty breathing after taking Co-Diovan, seek medical attention immediately.

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-Diovan”

Co-Diovan may cause increased sensitivity of the skin to sun.

The use of Co-Diovan in children and adolescents (below the age of 18 years) is not recommended.

You must tell your doctor if you think you are (or might become) pregnant. Co-Diovan 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).

 

o                  Taking other medicines, herbal or dietary supplements

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

The effect of the treatment can be influenced if Co-Diovan is taken together with certain other medicines. It may be necessary to change the dose, to take other precautions, or in some cases to stop taking one of the medicines. This especially applies to the following medicines:

·                lithium, a medicine used to treat some types of psychiatric diseases.

·                medicines or substances that may increase the amount of potassium in your blood. These include potassium supplements or salt substitutes containing potassium, potassium-sparing medicines and heparin.

·                medicines that may reduce the amount of potassium in your blood, such as diuretics (water tablets), corticosteroids, laxatives, carbenoxolone, amphotericin or penicillin G.

·                some antibiotics (rifamycin group), a drug used to protect against transplant rejection (ciclosporin) or an antiretroviral drug used to treat HIV/AIDS infection (ritonavir). These drugs may increase the effect of Co-Diovan.

·                medicines that may induce “torsades de pointes” (irregular heart beat), such as antiarrhythmics (medicines used to treat heart problems) and some antipsychotics.

·                medicines that may reduce the amount of sodium in your blood, such as antidepressants, antipsychotics, antiepileptics.

·                medicines for the treatment of gout, such as allopurinol, probenecid, sulfinpyrazone.

·                therapeutic vitamin D and calcium supplements.

·                medicines for the treatment of diabetes (oral agents such as metformin or insulins).

·                other medicines to lower your blood pressure including methyldopa, ACE inhibitors (such as enalapril, lisinopril, etc.) or aliskiren (see also information under the headings “Do not take Co-Diovan” and “Warnings and precautions”).

·                medicines to increase blood pressure, such as noradrenaline or adrenaline.

·                digoxin or other digitalis glycosides (medicines used to treat heart problems).

·                medicines that may increase blood sugar levels, such as diazoxide or beta blockers.

·                cytotoxic medicines (used to treat cancer), such as methotrexate or cyclophosphamide.

·                pain killers such as non-steroidal anti-inflammatory agents (NSAIDs), including selective cyclooxygenase-2 inhibitors (Cox-2 inhibitors) and acetylsalicylic acid > 3 g.

·                muscle relaxing medicines, such as tubocurarine.

·                anti-cholinergic medicines (medicines used to treat a variety of disorders such as gastrointestinal cramps, urinary bladder spasm, asthma, motion sickness, muscular spasms, Parkinson's disease and as an aid to anaesthesia).

·                amantadine (medicine used to treat Parkinson’s disease and also used to treat or prevent certain illnesses caused by viruses).

·                cholestyramine and colestipol (medicines used mainly to treat high levels of lipids in the blood).

·                ciclosporin, a medicine used for organ transplant to avoid organ rejection.

·                alcohol, sleeping pills and anaesthetics (medicines with sleeping or painkilling effect used for example during surgery).

·                 iodine contrast media (agents used for imaging examinations).

 

o                  Taking Co-Diovan with food and drink

Avoid taking alcohol until you have talked to your doctor. Alcohol may make your blood pressure fall more and/or increase the risk of you becoming dizzy or feeling faint.

 

o                  Pregnancy and breast-feeding

·         You must tell your doctor if you think that you are (or might become) pregnant

Your doctor will normally advise you to stop taking Co-Diovan before you become pregnant or as soon as you know you are pregnant, and will advise you to take another medicine instead of Co-Diovan. Co-Diovan 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 it is used after the third month of pregnancy.

 

·         Tell your doctor if you are breast-feeding or about to start breast-feeding

Co-Diovan 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

Before you drive a vehicle, use tools, or operate machines or carry out other activities that require concentration, make sure you know how Co-Diovan affects you. Like many other medicines used to treat high blood pressure, Co-Diovan may occasionally cause dizziness and affect the ability to concentrate


Always take Co-Diovan exactly as your doctor or health care provider has told you.

You should check with your doctor, health care provider or pharmacist if you are not sure.

People with high blood pressure often do not notice any signs of this problem. Many may feel quite normal. This makes it all the more important for you to keep your appointments with your doctor even if you are feeling well.

Your doctor will tell you exactly how many tablets of Co-Diovan to take. Depending on how you respond to the treatment, your doctor may suggest a higher or lower dose.

·         The recommended dose of Co-Diovan is one tablet per day.

·         Do not change the dose or stop taking the tablets without consulting your doctor.

·         The medicine should be taken at the same time each day, usually in the morning.

·         You can take Co-Diovan with or without food.

·         Swallow the tablet with a glass of water.

 

o                  If you take more Co-Diovan than you should

If you experience severe dizziness and/or fainting, lie down and contact your doctor immediately.

If you have accidentally taken too many tablets, contact your doctor, pharmacist or hospital.

 

o                  If you forget to take Co-Diovan

If you forget to take a dose, take it as soon as you remember. However, if it is almost time for your next dose, skip the dose you missed.

Do not take a double dose to make up for a forgotten dose.

 

o                  If you stop taking Co-Diovan

Stopping your treatment with Co-Diovan may cause your high blood pressure to get worse. Do not stop taking your medicine unless your doctor tells you to.

 

o                  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 side effects can be serious and need immediate medical attention:

·         You should see your doctor immediately if you experience symptoms of angioedema, such as:

·         swollen face, tongue or pharynx

·         difficulty in swallowing

·         hives and difficulties in breathing

·         Severe skin disease that causes rash, red skin, blistering of the lips, eyes or mouth, skin peeling, fever (toxic epidermal necrolysis)

·         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)

·         Fever, sore throat, more frequent infections (agranulocytosis)

·         Severe shortness of breath, fever, weakness, and confusion (acute respiratory distress syndrome)

These side effects are very rare or of frequency not known.

 

If you get any of these symptoms, stop taking Co-Diovan and contact your doctor straight away (see also section 2 “Before you take Co-Diovan”).

Side effects include:

Uncommon (may affect up to 1 in 100 people):

·         cough

·         low blood pressure

·         light-headedness

·         dehydration (with symptoms of thirst, dry mouth and tongue, infrequent urination, dark colored urine, dry skin)

·         muscle pain

·         tiredness

·         tingling or numbness

·         blurred vision

·         noises (e.g. hissing, buzzing) in ears

 

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

·         dizziness

·         diarrhoea

·         joint pain

 

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

·         breathing difficulty

·         severely decreased urine output

·         low level of sodium in the blood (which can trigger tiredness, confusion, muscle twitching and / or  convulsions in severe cases)

·         low level of potassium in the blood (sometimes with muscle weakness, muscle spasms, abnormal heart rhythm)

·         low level of white cells in the blood (with symptoms such as fever, skin infections, sore throat or mouth ulcers due to infections, weakness)

·         the level of bilirubin increased in blood (which can, in severe cases, trigger yellow skin and eyes)

·         the level of blood urea nitrogen and creatinine increased in blood (which can indicate abnormal kidney function)

·         the level of uric acid in blood increased (which can, in severe cases, trigger gout)

·         syncope (fainting)

·             choroidal effusion in the eyes.

 

The following side effects have been reported with products containing valsartan or hydrochlorothiazide alone:

 

Valsartan

 

Uncommon (may affect up to 1 in 100 people):

·         spinning sensation

·         abdominal pain

 

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

·         blistering skin (sign of dermatitis bullous)

·         skin rash with or without itching together with some of the following signs or symptoms: fever, joint pain, muscle pain, swollen lymph nodes and/or flu-like symptoms

·         rash, purplished-red spots, fever, itching (symptoms of inflammation of blood vessels)

·         low level of blood platelets (sometimes with unusual bleeding or bruising)

·         high level of potassium in the blood (sometimes with muscle spasms, abnormal heart rhythm)

·         allergic reactions (with symptoms such as rash, itching, hives, difficulty breathing or swallowing, dizziness)

·         swelling mainly of the face and throat; rash; itching

·         elevation of liver function values

·         the level of haemoglobin decreased and the percentage of red cells decreased in the blood (which both can, in severe cases, trigger an anaemia).

·         kidney failure

·         low level of sodium in the blood (which can trigger tiredness, confusion, muscle twitching and/or convulsions in severe cases)

 

Hydrochlorothiazide

 

Very common (may affect more than 1 in 10 people):

·         low level of potassium in the blood

·         increase of lipids in the blood

 

Common (may affect up to 1 in 10 people):

·         low level of sodium in the blood

·         low level of magnesium in the blood

·         high level of uric acid in the blood

·         itchy rash and other types of rash

·         reduced appetite

·         mild nausea and vomiting

·         dizziness, fainting on standing up

·         inability to achieve or maintain erection

 

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

·         swelling and blistering of the skin (due to increased sensitivity to sun)

·         high level of calcium in the blood

·         high level of sugar in the blood

·         sugar in the urine

·         worsening of diabetic metabolic state

·         constipation, diarrhoea, discomfort of the stomach or bowels, liver disorders which can occur together with yellow skin and eyes

·         irregular heart beat

·         headache

·         sleep disturbances

·         sad mood (depression)

·         low level of blood platelets (sometimes with bleeding or bruising underneath the skin)

·         dizziness

·         tingling or numbness

·         vision disorder

 

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

·         inflammation of blood vessels with symptoms such as rash, purplish-red spots, fever (vasculitis)

·         rash, itching, hives, difficulty breathing or swallowing, dizziness (hypersensitivity reactions)

·         facial rash, joint pain, muscle disorder, fever (lupus erythematosus)

·         severe upper stomach pain (pancreatitis)

·         difficulty breathing with fever, coughing, wheezing, breathlessness (respiratory distress including pneumonitis and pulmonary oedema)

·         pale skin, tiredness, breathlessness, dark urine (haemolytic anaemia)

·         fever, sore throat or mouth ulcers due to infections (leucopenia)

·         confusion, tiredness, muscle twitching and spasm, rapid breathing (hypochloraemic alkalosis)

 

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

·         weakness, bruising and frequent infections (aplastic anemia)

·         severely decreased urine output (possible signs of renal disorder or renal failure)

·         rash, red skin, blistering of the lips, eyes or mouth, skin peeling, fever (possible signs of erythema multiforme)

·         muscle spasm

·         fever (pyrexia)

·         weakness (asthenia)

·         skin and lip cancer (non-melanoma skin cancer


·         Keep out of the reach and sight of children.

·         Do not store above 30°C

·         Store your tablets in the original package.

·         Do not take Co-Diovan after the expiry date shown on the pack. The expiry date refers to the last day of that month.

·         Do not use this medicine if you notice that the pack is damaged or shows signs of tampering.

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


·         The active substances of Co-Diovan are valsartan (80 mg, 160 mg or 320 mg) and

hydrochlorothiazide (12.5 mg or 25 mg)

·         The other ingredients are microcrystalline cellulose, hydroxypropyl methylcellulose, silicon dioxide, crospovidone, polyethylene glycol, talc, magnesium stearate, titanium dioxide (E171). In addition, the

80/12.5 mg tablets contain red iron oxide (E172) and yellow iron oxide (E172). The 160/12.5 mg tablets contain only red iron oxide (E172) additionally. The 160/25 mg tablets contain in addition red iron oxide (E172), yellow iron oxide (E172) and black iron oxide (E172). The 320/12.5 mg tablets contain in addition black iron oxide (E172) and red iron oxide (E172). The 320/25 mg tablets contain in addition only yellow iron oxide (E172).

 

This information might differ in some countries.


Co-Diovan is supplied as film-coated-tablets in five strengths: Co-Diovan film-coated tablets, (80/12.5 mg) containing 80 mg valsartan and 12.5 mg hydrochlorothiazide. They are ovaloid, slightly convex, non-divisible, film-coated tablets measuring approximately 10.2 mm in length and approximately 5.4 mm in width, and weighing approximately 156 mg. The tablets are colored light orange and debossed “HGH” on one side and “CG” on the other side. Co-Diovan film-coated tablets, (160/12.5 mg) containing 160 mg valsartan and 12.5 mg hydrochlorothiazide. They are ovaloid, slightly convex, non-divisible, film-coated tablets measuring approximately 15.2 mm in length and approximately 6.2 mm in width, and weighing approximately 312 mg. The tablets are colored dark red and debossed “HHH” on one side and “CG” on the other side. Co-Diovan film-coated tablets, (160/25 mg) containing 160 mg valsartan and 25 mg hydrochlorothiazide. They are ovaloid, slightly convex, non-divisible, film-coated tablets measuring approximately 14.2 mm in length and approximately 5.7 mm in width, and weighing approximately 310 mg. The tablets are colored brown-orange and debossed “HXH” on one side and “NVR” on the other side. Co-Diovan film-coated tablets, (320/12.5 mg) containing 320 mg valsartan and 12.5 mg hydrochlorothiazide. They are ovaloid slightly convex, non-divisible, film-coated tablets measuring approximately 17.6 mm in length and approximately 8.2 mm in width, and weighing approximately 608 mg. The tablets are colored pink and debossed “HIL” on one side and “NVR” on the other side. Co-Diovan film-coated tablets, (320/25 mg) containing 320 mg valsartan and 25 mg hydrochlorothiazide. They are ovaloid, slightly convex, non-divisible, film-coated tablets measuring approximately 17.7 mm in length and approximately 8.2 mm in width, and weighing approximately 620 mg. The tablets are colored yellow and debossed CTI on one side and NVR on the other side. This information might differ in some countries.

The Marketing Authorization Holder for this Product is Novartis Pharma AG.

www.Novartis.com


This leaflet was last approved by United Kingdom in 03/2022 e. To report any side effect(s): • Saudi Arabia The National Pharmacovigilance Centre (NPC): o Fax: +966-11-205-7662 o SFDA call center: 19999 o E-mail: npc.drug@sfda.gov.sa o Website: https://ade.sfda.gov.sa Patient Safety Department Novartis Consulting AG - Saudi Arabia: o Toll Free Number: 8001240078 o Phone: +966112658100 o Fax: +966112658107 o Email: adverse.events@novartis.com • Other GCC States: - Please contact the relevant competent authority. This is a Medicament o Medicament is a product which affects your health and its consumption contrary to instructions is dangerous for you. o Follow strictly the doctor’s prescription, the method of use and the instructions of the pharmacist who sold the medicament. o The doctor and the pharmacist are the experts in medicines, their benefits and risks. o Do not by yourself interrupt the period of treatment prescribed for you. o Do not repeat the same prescription without consulting your doctor. o Keep all medicaments out of reach of children. Council of Arab Health Ministers Union of Arab Pharmacists f. This patient information leaflet is approved by the Saudi Food and Drug Authority
  نشرة الدواء تحت مراجعة الهيئة العامة للغذاء والدواء (اقرأ هذه النشرة بعناية قبل البدء في استخدام هذا المنتج لأنه يحتوي على معلومات مهمة لك)

تحتوي أقراص كوديوفان على مادتين فعالتين تسمى فالسارتان وهيدروكلوروثيازيد. تساعد هاتان المادتان في السيطرة على ارتفاع ضغط الدم.

•  فالسارتان ينتمي إلى فئة من الأدوية تعرف باسم "مضادات مستقبلات الأنجيوتنسين 2" ، والتي تساعد على التحكم في ارتفاع ضغط الدم، أنجيوتنسين 2 مادة في الجسم تتسبب في شد الأوعية ، مما يؤدي إلى زيادة ضغط الدم، يعمل فالسارتان عن طريق منع تأثير أنجيوتنسين 2. نتيجة لذلك ، تسترخي الأوعية الدموية وينخفض ​​ضغط الدم.

•  هيدروكلوروثيازيد ينتمي إلى مجموعة من الأدوية تسمى مدرات البول الثيازيدية (المعروفة أيضًا باسم "أقراص الماء"). يزيد هيدروكلوروثيازيد من إنتاج البول ، مما يؤدي أيضًا إلى خفض ضغط الدم.

 

يستخدم كوديوفان لعلاج ارتفاع ضغط الدم الذي لا يتم التحكم فيه بشكل كاف بواسطة مادة واحدة بمفردها.

 

يؤدي ارتفاع ضغط الدم إلى زيادة عبء عمل القلب والشرايين. إذا لم يتم علاجه ، فإنه يمكن أن يتلف الأوعية الدموية في الدماغ والقلب والكلى ، وقد يؤدي إلى السكتة الدماغية أو فشل القلب أو الفشل الكلوي. يزيد ارتفاع ضغط الدم من خطر الإصابة بالنوبات القلبية. يقلل خفض ضغط الدم إلى المعدل الطبيعي من خطر الإصابة بهذه الاضطرابات.

‌أ.         موانع استعمال عقار كوديوفان

o        إذا كنت تُعاني من حساسية (فرط الحساسية) تجاه فالسارتان أو هيدروكلوروثيازيد أو مشتقات السلفوناميد (مواد ذات صلة بهيدروكلوروثيازيد من النَّاحية الكيميائية) أو أيٍّ من المكونات الأخرى بهذا الدَّواء (المُدرجة في قسم 6).

o        إذا تجاوز حملكِ الشهر الثالث (من الأفضل أيضًا تجنُّب تناول عقار كوديوفان في مراحل الحمل المُبكرة - انظري قسم: "الحمل").

o        إذا كنت تُعاني من مرض شديد بالكبد، تلف القنوات الصفراوية الصغيرة داخل الكبد (تليُّف القنوات المرارية) مما يُؤدي إلى تراكم الصفراء في الكبد (الركود الصفراوي).

o        إذا كنت تُعاني من مرض كلوي شديد.

o        إذا لم تكن قادرًا على التبوُّل (انقطاع البول).

o        إذا كنت تُعالَج بكُلية اصطناعية.

o        إذا كان مستوى البوتاسيوم أو الصوديوم في دمك أقل من الطبيعي، أو إذا كان مستوى الكالسيوم في دمك أعلى من الطبيعي على الرَّغم من تلقي العلاج.

o        إذا كنت مُصابًا بالنّقْرِس.

o        إذا كنت مصابًا بمرض السُّكَّري أو بقصورٍ بوظائف الكُلى وتخضع للعلاج بدواء خافض لضغط الدَّم يحتوي على أليسكيرين.

 

إذا انطبق عليك أي من الوارد أعلاه، فأخبِر طبيبك ولا تتناول عقار كوديوفان.

 

‌ب.     الاحتياطات عند استعمال عقار كوديوفان

o        إذا كنت تتناول أدوية تحافظ على مستوى البوتاسيوم أو مكملات البوتاسيوم أو بدائل الملح التي تحتوي على البوتاسيوم أو أدوية أخرى تزيد من كمية البوتاسيوم في الدم مثل الهيبارين. قد يحتاج طبيبك إلى فحص كمية البوتاسيوم في دمك بانتظام.

o        إذا كان لديك مستويات منخفضة من البوتاسيوم في دمك.

o        إذا كنت تعاني من الإسهال أو القيء الشديد.

o        إذا كنت تتناول جرعات عالية من أقراص الماء (مدرات البول).

o        إذا كنت تعاني من مرض قلبي شديد.

o        إذا كنت تعاني من قصور في القلب أو من نوبة قلبية. اتبع تعليمات طبيبك لجرعة البدء بعناية. قد يقوم طبيبك أيضًا بفحص وظائف الكلى.

o        إذا كنت تعاني من تضيق في شريان الكلى.

o        إذا كنت قد قمت مؤخرًا بعملية زراعة للكلية.

o        إذا كنت تعاني من فرط الألدوستيرونية. هذا مرض تصنع فيه الغدد الكظرية الكثير من هرمون الألدوستيرون. إذا كان هذا ينطبق عليك ، لا ينصح باستخدام كوديوفان.

o        إذا كنت تعاني من أمراض الكبد أو الكلى.

o        إذا كنت قد عانيت من قبل من تورم في اللسان والوجه ناجم عن رد فعل تحسسي يسمى الوذمة الوعائية عند تناول دواء آخر (بما في ذلك مثبطات الإنزيم المحول للأنجيوتنسين) ، أخبر طبيبك. إذا حدثت هذه الأعراض أثناء تناول كوديوفان ، فتوقف عن تناول كوديوفان على الفور ولا تتناوله مرة أخرى. انظر أيضًا القسم 4 ، "الآثار الجانبية المحتملة".

o        إذا كنت تعاني من الحمى والطفح الجلدي وآلام المفاصل ، والتي قد تكون علامات على الذئبة الحمامية الجهازية (وهو ما يسمى بأمراض المناعة الذاتية).

o        إذا كنت تعاني من مرض السكري أو النقرس أو ارتفاع مستويات الكوليسترول أو الدهون الثلاثية في الدم.

o        إذا كان لديك تفاعلات حساسية مع استخدام أدوية أخرى لخفض ضغط الدم من هذه الفئة (مضادات مستقبلات الأنجيوتنسين 2) أو إذا كنت تعاني من حساسية أو ربو.

o        إذا كنت تعاني من انخفاض في الرؤية أو ألم في العين. قد تكون هذه أعراض تراكم السوائل في الطبقة الوعائية للعين (الانصباب المشيمي) أو زيادة الضغط في عينك ويمكن أن تحدث في غضون ساعات إلى أسابيع من تناول كوديوفان. هذا يمكن أن يؤدي إلى فقدان دائم للبصر ، إذا لم يتم علاجه. إذا كنت قد عانيت في وقت سابق من حساسية من البنسلين أو السلفوناميد ، فقد تكون أكثر عرضة للإصابة بهذا.

o        إذا كنت تتناول أي من الأدوية التالية المستخدمة لعلاج ارتفاع ضغط الدم:

§         مثبطات الإنزيم المحول للأنجيوتنسين (على سبيل المثال إنالابريل ، ليزينوبريل ، راميبريل) ، خاصة إذا كنت تعاني من مشاكل في الكلى مرتبطة بمرض السكري.

§         اليسكيرين

o        إذا كنت قد أصبت بسرطان الجلد أو إذا أصبت بآفة جلدية غير متوقعة أثناء العلاج. قد يؤدي العلاج بهيدروكلوروثيازيد ، وخاصة الاستخدام طويل الأمد بجرعات عالية ، إلى زيادة خطر الإصابة ببعض أنواع سرطان الجلد والشفتين (سرطان الجلد غير الميلانيني). احمي بشرتك من التعرض لأشعة الشمس والأشعة فوق البنفسجية أثناء تناول كوديوفان.

o        إذا كنت تعاني من مشاكل في التنفس أو الرئة (بما في ذلك الالتهاب أو السوائل في الرئتين) بعد تناول هيدروكلوروثيازيد في الماضي. إذا كنت تعاني من ضيق شديد في التنفس أو صعوبة في التنفس بعد تناول كوديوفان ، فاطلب العناية الطبية على الفور.

 

قد يفحص طبيبك وظائف الكلى وضغط الدم وكمية الإلكتروليت (مثل البوتاسيوم) في دمك على فترات منتظمة.

 

انظر أيضًا المعلومات الواردة تحت عنوان "موانع استعمال عقار كوديوفان"

 

قد يتسبب كوديوفان في زيادة حساسية الجلد للشمس.

 

لا ينصح باستخدام كوديوفان في الأطفال والمراهقين (أقل من 18 عامًا).

 

يجب أن تخبر طبيبك إذا كنت تعتقدين أنك (أو قد تصبحين) حاملاً. لا ينصح باستخدام كوديوفان في بداية الحمل ، ويجب عدم تناوله إذا كنت حاملاً أكثر من 3 أشهر ، لأنه قد يسبب ضررًا خطيرًا لطفلك إذا تم استخدامه في تلك المرحلة (انظر قسم ‌"الحمل والرضاعة الطبيعية").

 

‌ج.      التداخلات الدَّوائية من أخذ هذا المستحضر مع أدوية أخرى أو أعشاب أو مكملات غذائية

أخبر طبيبك أو الصيدلي إذا كنت تتناول ، أو تناولت مؤخرًا أي أدوية أخرى ، أو قد تتناول أي أدوية أخرى.

يمكن أن تتأثر فعالية العلاج إذا تم تناول كوديوفان مع بعض الأدوية الأخرى. قد يكون من الضروري تغيير الجرعة ، أو اتخاذ احتياطات أخرى ، أو في بعض الحالات التوقف عن تناول أحد الأدوية. هذا ينطبق بشكل خاص على الأدوية التالية:

• الليثيوم وهو دواء يستخدم لعلاج بعض أنواع الأمراض النفسية.

• الأدوية أو المواد التي قد تزيد من كمية البوتاسيوم في الدم. وتشمل مكملات البوتاسيوم أو بدائل الملح التي تحتوي على البوتاسيوم والأدوية التي تحافظ على مستوى البوتاسيوم والهيبارين.

• الأدوية التي قد تقلل من كمية البوتاسيوم في الدم ، مثل مدرات البول (أقراص الماء) ، والكورتيكوستيرويدات ، والملينات ، والكاربينوكسولون ، والأمفوتريسين ، والبنسلين ج.

• بعض المضادات الحيوية (مجموعة ريفاميسين) ، وهو دواء يستخدم للوقاية من رفض زراعة الأعضاء (سيكلوسبورين) أو أحد الأدوية المضادة للفيروسات القهقرية المستخدمة لعلاج عدوى فيروس نقص المناعة البشرية / الإيدز (ريتونافير). قد تزيد هذه الأدوية من تأثيرعقار  كوديوفان.

• الأدوية التي قد تسبب " تورسادس دي بوانت" (عدم انتظام ضربات القلب) ، مثل مضادات اضطراب ضربات القلب (الأدوية المستخدمة لعلاج مشاكل القلب) وبعض مضادات الذهان.

• الأدوية التي قد تقلل من كمية الصوديوم في الدم مثل مضادات الاكتئاب ومضادات الذهان ومضادات الصرع.

• أدوية لعلاج النقرس مثل الوبيورينول ، البروبينسيد ، سلفينبيرازون.

• فيتامين د العلاجي ومكملات الكالسيوم.

• أدوية لعلاج مرض السكر (عوامل فموية مثل الميتفورمين أو الأنسولين).

• أدوية أخرى لخفض ضغط الدم بما في ذلك ميثيل دوبا ، مثبطات الإنزيم المحول للأنجيوتنسين (مثل إنالابريل ، ليزينوبريل ، إلخ) أو أليسكيرين (انظر أيضًا المعلومات الواردة تحت العناوين "موانع استعمال عقار كوديوفان" و "الاحتياطات عند استعمال عقار كوديوفان").

• الأدوية التي ترفع ضغط الدم مثل النورأدرينالين أو الأدرينالين.

• الديجوكسين أو جليكوسيدات الديجيتال الأخرى (الأدوية المستخدمة لعلاج مشاكل القلب).

• الأدوية التي قد تزيد من مستويات السكر في الدم ، مثل ديازوكسيد أو حاصرات بيتا.

• الأدوية السامة للخلايا (المستخدمة لعلاج السرطان) ، مثل ميثوتريكسات أو سيكلوفوسفاميد.

• مسكنات الآلام مثل مضادات الالتهاب غير الستيرويدية (NSAIDs) ، بما في ذلك مثبطات انزيمات الأكسدة الحلقية -2 الانتقائية (مثبطات Cox-2) وحمض أسيتيل الساليسيليك > 3 جم.

• أدوية إرخاء العضلات ، مثل توبوكورارين.

• الأدوية المضادة للكولين (الأدوية المستخدمة لعلاج مجموعة متنوعة من الاضطرابات مثل تقلصات الجهاز الهضمي ، وتشنج المثانة البولية ، والربو ، ودوار الحركة ، والتشنجات العضلية ، ومرض باركنسون وكمادة مساعدة للتخدير).

• أمانتادين (دواء يستخدم لعلاج مرض باركنسون ويستخدم أيضًا لعلاج أو منع بعض الأمراض التي تسببها الفيروسات).

• كوليستيرامين وكوليستيبول (أدوية تستخدم بشكل رئيسي لعلاج المستويات العالية من الدهون في الدم).

• السيكلوسبورين ، وهو دواء يستخدم في زراعة الأعضاء لتجنب رفض العضو.

• الكحول والحبوب المنومة والمخدرات (الأدوية التي لها تأثير منوم أو مسكن للألم تستخدم على سبيل المثال أثناء الجراحة).

• وسائط اليود للتباين (عوامل تستخدم في فحوصات التصوير).

 

‌د.        تناوُل عقار كوديوفان مع الأطعمة والمشروبات

تجنب تناول الكحول. قد يتسبب الكحول في انخفاض ضغط الدم أكثر و / أو يزيد من خطر إصابتك بالدوار أو الشعور بالإغماء.

‌ه.        الحمل والرضاعة الطبيعية

o        يجب عليكِ إخبار طبيبكِ إذا كنت تعتقدين أنك حامل (أو قد تصبحين حاملًا)

سينصحكِ طبيبكِ عادةً بالتَّوقُّف عن تناوُل عقار كوديوفان قبل أن تُصبِحي حاملًا، أَو بِمجرّد أَن تعلمي أنكِ حامل، وسينصحكِ بِتناوُل دواء آخر بدلًا من عقار كوديوفان. لا يُوصى باستخدام عقار كوديوفان في مراحل الحمل المبكرة، ويجب ألا يتم تناوُله إذا تجاوز حملكِ الشهر الثالث؛ حيث إنه قد يُسبب أضرارًا خطيرة لطفلك إذا تم استخدامه بعد الشهر الثالث من الحمل.

o        أخبري طبيبك إذا كنتِ مرضعًا، أو إذا كنتِ على وشك البدء في ممارسة الرضاعة الطبيعيَّة

لا يُوصى باستخدام عقار كوديوفان من قِبَل الأمهات المُرضعات، وقد يختار لكِ طبيبك علاجًا آخر إذا كنتِ ترغبين في الإرضاع، خاصةً إذا كان طفلكِ حديث الولادة، أو مبتسرًا.

 

‌و.       القيادة واستخدام الآلات

قبل أن تقوم بقيادة مركبة أو استخدام أدوات أو تشغيل آلات أو قبل أن تقوم بأنشطة أخرى تتطلب تركيزًا، تأكَّد من معرفة تأثير عقار كوديوفان عليك. مثله مثل العديد من الأدوية الأخرى التي تُستَخدَم لعلاج ارتفاع ضغط الدَّم، قد يُسبب عقار كوديوفان أحيانًا دوخة وقد يُؤثر في القدرة على التَّركيز.

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تناول دائمًا عقار كوديوفان كما أخبرك طبيبك أو مقدم الرعاية الصحية الخاص بك بالضبط.

يجب مراجعة طبيبك أو مقدم الرعاية الصحية أو الصيدلي الخاص بك إذا لم تكن متأكدًا من كيفية الاستخدام.

لا يلاحظ الأشخاص المُصابون بارتفاع ضغط الدَّم غالبًا أي علامات لهذه المشكلة. وكثيرون منهم قد لا يشكون من أي شيء. ولهذا السبب، يُعتبر حفاظك على مواعيدك مع طبيبك غايةً في الأهمية حتى إذا كنت تشعر بأنك على ما يُرام.

 

سيخبرك طبيبك بالضبط بعدد الأقراص التي ستتناولها من عقار كوديوفان. قد يصف لك طبيبك جرعة أعلى أو أقل، وفقًا لكيفية استجابتك للعلاج.

 

o        الجرعة الموصى بها من عقار كوديوفان هي قرص واحد يوميًّا.

o        لا تغير الجرعة أو توقف تناوُل الأقراص بدون استشارة طبيبك.

o        يجب تناوُل الدَّواء في الوقت نفسه من كل يوم، عادةً في الصباح.

o        يمكنك تناول عقار كوديوفان مع الطعام أو دونه.

o        ابتلع القرص مع كوب من الماء.

 

‌أ.         الجرعة الزَّائدة من عقار كوديوفان

إذا تعرَّضت لدوخة شديدة و/أو إغماء، فاستلقِ واتصل بطبيبك فورًا.

إذا تناوُلت كمية أكبر من اللازم من الأقراص بطريق الخطأ، فاتصل بطبيبك أو الصيدلي الخاص بك أو المستشفى.

 

‌ب.      نسيان تناول جرعة من عقار كوديوفان

إذا أغفلت تناول إحدى الجرعات، فتناولها بمجرد تذكرك لها. مع ذلك، إذا كان موعد الجرعة التَّالية قد اقترب، فتجاوز الجرعة التي أغفلتها.

لا تتناول جرعة مضاعفة لتعويض جرعة أغفلتها.

 

‌ج.      التَّوقف عن تناول عقار كوديوفان

قد يُؤدي إيقاف علاجك بعقار كوديوفان إلى تفاقم ارتفاع ضغط الدَّم لديك. لا تتوقف عن تناول دوائك ما لم يخبرك طبيبك بذلك.

 

‌د.        إذا كانت لديك أية أسئلة إضافية حول استخدام هذا الدَّواء، فاستشر طبيبك أو الصيدلي الخاص بك.

مثله مثل كافة الأدوية، قد يُسبب هذا الدَّواء أعراضًا جانبية، على الرَّغم من عدم حدوثها لدى الجميع.

 

بعض الأعراض الجانبية قد تكون خطيرة وتحتاج إلى عناية طبية فورية:

 

·         عليك رؤية طبيبك فورًا إذا تعرضت لأعراض الوذمة الوعائية، مثل:

·                تورُّم الوجه أو اللسان أو البلعوم.

·                صعوبة في البلع.

·                شرى وصعوبات في التنفس.

·         مرض جلدي شديد يُسبب ظهور طفح جلدي، واحمرارًا بالجلد، وظهور بثور على الشفتين أو العينين أو الفم، وتقشُّر الجلد، وحُمى (انحلال البشرة النخري التَّسَمُّمِيّ).

·         انخفاض في الرؤية أو ألم في عينيك بسبب ارتفاع الضغط (علامات محتملة لتراكم السوائل في الطبقة الوعائية للعين (الانصباب المشيمي) أو الزَّرَق ضيق الزاوية).

·         حُمّى، التهاب الحلق، الإصابة بالعدوى بصورة أكثر تكرارًا (ندرة خلايا المحببات).

·         ضيق شديد في التنفس وحمى وضعف وارتباك (متلازمة الضائقة التنفسية الحادة)

 

هذه الأعراض الجانبية هي أعراض نادرة جدًّا أو مُعدَّل تكرارها غير معروف.

 

إذا أُصِبت بأي من هذه الأعراض، فتوقف عن تناوُل عقار كوديوفان واتصل بطبيبك فورًا (انظر أيضًا قسم 2 "قبل القيام بتناول عقار كوديوفان").

 

تشمل الأعراض الجانبية ما يلي:

 

غير شائعة (قد تؤثر على ما يصل إلى شخص واحد من بين كل 100 شخص):

·         سعالًا.

·         انخفاض ضغط الدَّم.

·         شعورًا بخفة الرأس.

·         جفافًا (مع أعراض تتمثل في العطش، وجفاف الفم واللسان، وندرة التبوُّل، وبولًا داكن اللون، وجفاف الجلد).

·         ألمًا في العضلات.

·         تعبًا.

·         وخزًا أو تنميلًا.

·         عدم وضوح الرؤية.

·         سماع ضوضاء في الأذنين (على سبيل المثال، هسهسة أو طنين).

 

نادرة جدًّا (قد تُؤثر على ما يصل إلى شخص واحد من بين كل 10000 شخص):

·         دوخة.

·         إِسْهالًا.

·         ألمًا بالمفاصل.

 

غير معروفة  (لا يمكن تقدير معدل التكرار من واقع البيانات المتاحة):

·         صعوبة في التَّنفس.

·         انخفاضًا شديدًا في إنتاج البول.

·         انخفاض مستوى الصوديوم في الدَّم (وهو ما قد يُؤدي إلى التَّعب و/أو الارتباك و/أو الانتفاض العضلي و/أو التشنجات في الحالات الشديدة).

·         انخفاض مستوى البوتاسيوم في الدَّم (في بعض الأحيان يكون ذلك مصحوبًا بضعف عضلي أو تقلصات عضلية أو اضطراب بالنَّظْم القلبي).

·         انخفاض مستوى خلايا الدَّم البيضاء (مع أعراض مثل: الحُمّى، أو عدوى الجلد، أو التهاب الحلق أو قُرَح الفم بسبب العدوى، أو الضعف).

·         ارتفاع مستوى البيليروبين في الدَّم (وهو ما قد يُؤدي في حالاته الشديدة إلى اصفرار الجلد والعينين).

·         ارتفاع مستوى نيتروجين يوريا الدَّم والكرياتينين في الدَّم (وهو ما قد يدل على اضطراب وظائف الكُلى).

·         ارتفاع مستوى حمض اليوريك (وهو ما قد يؤدي في الحالات الشديدة إلى الإصابة بالنقرس).

·         غشيًا (إغماء).

·         الانصباب المشيمي في العين.

 

تم الإبلاغ عن الأعراض الجانبية التالية مع المنتجات التي تحتوي على فالسارتان وحده أو هيدروكلوروثيازيد وحده:

 

فالسارتان

 

غير شائعة (قد تُؤثر على ما يصل إلى شخص واحد من بين كل 100 شخص):

·         شعورًا بالدوران.

·         ألمًا بالبطن.

 

غير معروفة (لا يمكن تقدير معدل التكرار من واقع البيانات المتاحة):

·         بثورًا على الجلد (علامة على الإصابة بالتهاب الجلد الفقاعي).

·         طفحًا جلديًّا مع أو بدون حكة جنبًا إلى جنب مع بعض العلامات أو الأعراض التَّالية: حُمّى و/أو ألم بالمفاصل و/أو ألم عضلي و/أو تورُّم العقد الليمفاوية و/أو أعراض شبيهة بأعراض الأنفلونزا.

·         طفح جلدي، بقع حمراء مائلة إلى اللون الأرجواني، حُمّى، حكة (أعراض التهاب الأوعية الدَّموية).

·         انخفاض مستوى الصفائح الدَّموية (في بعض الأحيان يكون ذلك مصحوبًا بنزيف أو كدمات غير مُعتادة).

·         ارتفاع مستوى البوتاسيوم في الدَّم (في بعض الأحيان يكون ذلك مصحوبًا بتقلصات عضلية واضطراب بالنَّظْم القلبي).

·         تفاعلات حساسية (مع أعراض مثل: الطفح الجلدي، أو الحكة، أو الشرى، أو صعوبة التنفس أو البلع، أو الدوخة).

·         تورُّم بشكل أساسي في الوجه والحَلْق، طفح جلدي، حكة.

·         ارتفاع قيم وظائف الكبد.

·         انخفاض مستوى الهيموجلوبين ونسبة خلايا الدَّم الحمراء في الدَّم (وكلاهما قد يؤدي -في الحالات الشَّديدة- إلى الإصابة بفقر الدَّم).

·         فشل كُلوي.

·         انخفاض مستوى الصوديوم في الدَّم (وهو ما قد يُؤدي إلى التعب و/أو الارتباك و/أو الانتفاض العضلي و/أو التشنجات في الحالات الشديدة).

 

هيدروكلوروثيازيد

 

شائعة جدًّا (قد تُؤثر على أكثر من شخص واحد من بين كل 10 أشخاص):

·         انخفاض مستوى البوتاسيوم في الدَّم.

·         ارتفاع مستوى الدهون في الدَّم.

 

شائعة (قد تُؤثر على ما يصل إلى شخص واحد من بين كل 10 أشخاص):

·         انخفاض مستويات الصوديوم بالدَّم.

·         انخفاض مستوى الماغنسيوم في الدَّم.

·         ارتفاع مستوى حمض اليوريك في الدَّم.

·         طفحًا جلديًّا مثير للحكة وأنواع أخرى من الطفح الجلدي

·         انخفاض الشَّهية.

·         الغثيان الطفيف والقيء.

·         دوخة، إغماء عند النهوض.

·         عدم القدرة على تحقيق الانتصاب أو الوصول إليه.

 

نادرة  (قد تُؤثر على ما يصل إلى شخص واحد من بين كل 1000 شخص):

·         تورُّم الجلد وظهور بثور عليه (بسبب زيادة الحساسية لأشعة الشمس).

·         ارتفاع مستوى الكالسيوم في الدَّم.

·         ارتفاع مستوى السُّكَّرِ في الدَّم.

·         وجود سكر بالبول.

·         تفاقم الحالة الاستقلابية لمرض السُّكَّرِي.

·         إمساكًا، إسهالًا، شعورًا غير مريح بالمعدة أو الأمعاء، اضطرابات الكبد التي قد تحدث بمصاحبة اصفرار الجلد والعينين.

·         عدم انتظام ضربات القلب.

·         الصداع.

·         اضطرابات النوم.

·         حالة مزاجية حزينة (اكتئاب).

·         انخفاض مستوى الصفائح الدَّموية (في بعض الأحيان يكون ذلك مصحوبًا بنزيف أو كدمات أسفل الجلد).

·         دوخة.

·         الوخز أو التنميل.

·         اضطراب الرؤية.

 

نادرة جدًّا (قد تؤثر على ما يصل إلى شخص واحد من بين كل 10000 شخص):

·         التهاب الأوعية الدَّموية مع أعراض مثل: الطفح الجلدي، بقع حمراء مائلة إلى اللون الأرجواني، حُمّى (التهاب الأوعية الدَّموية).

·         طفحًا جلديًّا، حكة، شرى، صعوبة التنفس أو البلع، دوخة (تفاعلات فرط الحساسية).

·         طفحًا جلديًّا بالوجه، ألمًا بالمفاصل، اضطرابًا عضليًّا، حُمّى (الذئبة الحمامية).

·         ألمًا شديدًا بأعلى المعدة (علامة على الإصابة بالتهاب البنكرياس).

·         صعوبة بالتنفس مع حُمّى، سعال، أزيز بالصدر، عُسْر التَّنَفُّس (أزمة تنفسية بما في ذلك الالتهاب الرئوي والوذمة الرئوية).

·         بشرة شاحبة، تعبًا، عُسْر التَّنَفُّس، بولًا داكنًا (فقر الدَّم الانحلالي).

·         حُمى، التهاب الحلق أو الإصابة بقُرَح في الفم بسبب العدوى (نقص كريات الدَّم البيضاء).

·         ارتباكًا، تعبًا، انتفاضًا وتقلصًا عضليًّا، معدل تنفس سريع (قلاء نقص كلوريد الدَّم).

 

غير معروفة  (لا يمكن تقدير معدل التكرار من واقع البيانات المتاحة):

·         ضعفًا وكدمات وإصابة بالعدوى بشكلٍ متكرر (فقر الدَّم غير التنسجي).

·         انخفاضًا شديدًا في إنتاج البول (علامات مُحتَمَلة على الإصابة باضطراب كُلوي أو فشل كُلوي).

·         طفحًا جلديًّا، احمرار الجلد، ظهور بثور على الشفتين أو العينين أو الفم، تقشُّر الجلد، حُمى (علامات محتملة للاحمرار متعدد الأشكال).

·         تقلصات عضلية.

·         حُمى (ارتفاع درجة الحرارة).

·         الضعف (الوهن).

·         سرطان الجلد والشفة (سرطان الجلد غير الميلانيني).

·         يُحفظ بعيدًا عن مُتناوَل ورؤية الأطفال.

·         لا يُخزَّن في درجة حرارة تتعدى 30 درجة مئوية

·         تُحفظ الأقراص داخل العبوة الأصلية.

·         لا يُستخدم عقار كوديوفان بعد انتهاء تاريخ الصلاحية الموضح على العبوة. يُشير تاريخ انتهاء الصَّلاحية إلى اليوم الأخير من ذلك الشهر.

·         لا تستخدم هذا الدواء إذا لاحظت أن العبوة تالفة أو تظهر عليها علامات العبث.

·         لا تتخلص من الأدوية في مياه الصرف الصحي أو النفايات المنزلية، اسأل الصيدلي عن كيفية التخلص من الأدوية التي لم تعد تستخدمها، ستساعد هذه الإجراءات في حماية البيئة.

·         المواد الفعَّالة بعقار كوديوفان هي فالسارتان (80 مجم أو 160 مجم أو 320 مجم) وهيدروكلوروثيازيد (12.5 مجم أو 25 مجم)

·         المكونات الأخرى هي سليلوز دقيق التَّبلور، هيدروكسي بروبيل ميثيل السليلوز، ثاني أكسيد السيليكون، كروسبوفيدون، بولي إيثيلين الجلايكول، تلك، ستيرات الماغنسيوم، ثاني أكسيد التيتانيوم (E171). بالإضافة إلى ذلك، تحتوي

الأقراص التي قدرها 80/12.5 مجم على أكسيد الحديد الأحمر (E172) وأكسيد الحديد الأصفر (E172). تحتوي الأقراص التي قدرها 160/12.5 مجم على أكسيد الحديد الأحمر (E172) فقط بالإضافة إلى المكونات الأخرى. تحتوي الأقراص التي قدرها 160/25 مجم على أكسيد الحديد الأحمر (E172) وأكسيد الحديد الأصفر (E172) وأكسيد الحديد الأسود (E172) بالإضافة إلى المكونات الأخرى. تحتوي الأقراص التي قدرها 320/12.5 مجم على أكسيد الحديد الأسود (E172) وأكسيد الحديد الأحمر (E172) بالإضافة إلى المكونات الأخرى. تحتوي الأقراص التي قدرها 320/25 مجم على أكسيد الحديد الأصفر (E172) فقط بالإضافة إلى المكونات الأخرى.

 

قد تختلف هذه المعلومات في بعض الدول.

يتوفر عقار كوديوفان في هيئة أقراص مغلَّفة بخمسة تركيزات:

 

أقراص عقار كوديوفان المغلَّفة، (80/12.5 مجم) تحتوي على 80 مجم فالسارتان و12.5 مجم

هيدروكلوروثيازيد. هي عبارة عن

أقراص مغلفة بيضاوية محدبة قليلًا، غير قابلة للانقسام، ويبلغ طولها 10.2 مللي متر تقريبًا وعرضها 5.4 مللي متر تقريبًا، ويبلغ وزنها 156 مجم تقريبًا.

 الأقراص لونها برتقالي فاتح ومحفور على أحد جانبيها أحرف "HGH" وحرفا "CG" على الجانب الآخر.

 

أقراص عقار كوديوفان المغلَّفة، (160/12.5 مجم) تحتوي على 160 مجم فالسارتان و12.5 مجم

هيدروكلوروثيازيد. هي عبارة عن

أقراص مغلفة بيضاوية محدبة قليلًا، غير قابلة للانقسام، ويبلغ طولها 15.2 مللي متر تقريبًا وعرضها 6.2 مللي متر تقريبًا، ويبلغ وزنها 312 مجم تقريبًا.

 الأقراص لونها أحمر داكن ومحفور على أحد جانبيها أحرف "HHH" وحرفا "CG" على الجانب الآخر.

 

أقراص عقار كوديوفان المغلَّفة، (160/25 مجم) تحتوي على 160 مجم فالسارتان، و25 مجم

هيدروكلوروثيازيد. هي عبارة عن

أقراص مغلفة بيضاوية محدبة قليلًا، غير قابلة للانقسام، ويبلغ طولها 14.2 مللي متر تقريبًا وعرضها 5.7 مللي متر تقريبًا، ويبلغ وزنها 310 مجم تقريبًا.

 الأقراص لونها برتقالي مائل إلى اللون البني ومحفور على أحد جانبيها أحرف "HXH" وأحرف "NVR" على الجانب الآخر.

 

أقراص عقار كوديوفان المغلَّفة، (320/12.5 مجم) تحتوي على 320 مجم فالسارتان و12.5 مجم

هيدروكلوروثيازيد. هي عبارة عن

أقراص مغلفة بيضاوية محدبة قليلًا، غير قابلة للانقسام، ويبلغ طولها 17.6 مللي متر تقريبًا وعرضها 8.2 مللي متر تقريبًا، ويبلغ وزنها 6.8مجم تقريبًا.

 الأقراص لونها وردي ومحفور على أحد جانبيها أحرف "HIL" وأحرف "NVR" على الجانب الآخر.

 

أقراص عقار كوديوفان المغلَّفة، (320/25 مجم) تحتوي على 320 مجم فالسارتان و25 مجم

هيدروكلوروثيازيد. هي عبارة عن

أقراص مغلفة بيضاوية محدبة قليلًا، غير قابلة للانقسام، ويبلغ طولها 17.7مللي متر تقريبًا وعرضها 8.2 مللي متر تقريبًا، ويبلغ وزنها 620 مجم تقريبًا.

 الأقراص لونها أصفر ومحفور على أحد جانبيها أحرف "CTI" وأحرف "NVR" على الجانب الآخر.

قد تختلف هذه المعلومات في بعض الدول.

مالك حق التَّسويق لهذا المنتج هي شركة نوفارتس فارما إيه جي.

www.Novartis.com

‌تم اعتماد هذه النَّشرة قِبَل المملكة المتحدة في 03/2022 جـ. للإبلاغ عن الأعراض الجانبية : المملكة العربية السعودية - المركز الوطني للتيقظ والسلامة الدوائية (NPC) • الفاكس: +966112057662 • مركز اتصال الهيئة السعودية للغذاء والدواء: 19999 • البريد الالكتروني: npc.drug@sfda.gov.sa • الموقع الالكتروني: https://ade.sfda.gov.sa - شركة نوفارتس - السعودية - قسم سلامة المرضى: • الهاتف المجاني: 8001240078 • الهاتف: +966112658100 • الفاكس: +966112658107 • البريد الالكتروني: adverse.events@novartis.com دول مجلس التَّعاون الخليجي الأخرى: - يُرجى الاتصال بسلطات الاختصاص المعنية هذا مُنتَج دوائي o الدَّواء مستحضر يُؤثر على صحتك واستهلاكه خلافًا للتَّعليمات يعرضك للخطر. o اتبع بدقة وصفة الطبيب وطريقة الاستعمال المنصوص عليها وتعليمات الصيدلي الذي صرفها لك. o إنَّ الطبيب والصيدلي هما الخبيران في الدَّواء وفي نفعه وضرره. o لا تقطع مدة العلاج المحددة لك من تلقاء نفسك. o لا تكرر صرف الدَّواء بدون استشارة الطبيب. o لا تترك الأدوية في مُتناوَل أيدي الأطفال. مجلس وزراء الصحة العرب اتحاد الصيادلة العرب ‌ح. تم اعتماد نشرة معلومات المريض هذه من قبل الهيئة السعودية العامة للغذاء والدَّواء.
 Read this leaflet carefully before you start using this product as it contains important information for you

Co-Diovan 80/12.5 Film-coated tablets Co-Diovan 160/12.5 Film-coated tablets Co-Diovan 160/25 Film-coated tablets Co-Diovan 320/12.5 Film-coated tablets Co-Diovan 320/25 Film-coated tablets

Co-Diovan 80/12.5 Film-coated tablets containing 80 mg valsartan and 12.5 mg hydrochlorothiazide. Excipients: Tableting excipients. Ovaloid, slightly convex non-divisible, pale orange film-coated tablets Imprinted with HGH on one side and CG on the other side. Co-Diovan 160/12.5 Film-coated tablets containing 160 mg valsartan and 12.5 mg hydrochlorothiazide. Ovaloid, slightly convex, non-divisible, dark red film-coated tablets. Imprinted with HHH on one side and CG on the other side. Excipients: Tableting excipients. Co-Diovan 160/25 Film-coated tablets containing 160 mg valsartan and 25 mg hydrochlorothiazide. Ovaloid, slightly convex, non-divisible, brown-orange film-coated tablets. Imprinted with HXH on one side and NVR on the other side. Excipients: Tableting excipients. Co-Diovan 320/12.5 Film-coated tablets containing 320 mg valsartan and 12.5 mg hydrochlorothiazide. Ovaloid, slightly convex, non-divisible, pink film-coated tablets imprinted with HIL on one side and NVR on the other side. Excipients: Tableting excipients. Co-Diovan 320/25 Film-coated tablets containing 320 mg valsartan and 25 mg hydrochlorothiazide. Ovaloid, slightly convex, non-divisible, yellow film-coated tablets imprinted with CTI on one side and NVR on the other side. Excipients: Tableting excipients. For a full list of excipients, see section 6.1.

Co-Diovan 80/12.5 Film-coated tablets Ovaloid, slightly convex non-divisible, pale orange film-coated tablets Imprinted with HGH on one side and CG on the other side. Co-Diovan 160/12.5 Film-coated tablets Ovaloid, slightly convex, non-divisible, dark red film-coated tablets. Imprinted with HHH on one side and CG on the other side. Co-Diovan 160/25 Film-coated tablets Ovaloid, slightly convex, non-divisible, brown-orange film-coated tablets. Imprinted with HXH on one side and NVR on the other side. Co-Diovan 320/12.5 Film-coated tablets Ovaloid, slightly convex, non-divisible, pink film-coated tablets imprinted with HIL on one side and NVR on the other side. Co-Diovan 320/25 Film-coated tablets Ovaloid, slightly convex, non-divisible, yellow film-coated tablets imprinted with CTI on one side and NVR on the other side. Co-Diovan FCT cannot be divided into equal doses.

Treatment of essential hypertension in adults.

 

Co-Diovan fixed-dose combination is indicated in patients whose blood pressure is not adequately controlled on valsartan or hydrochlorothiazide monotherapy.


Posology

The recommended dose of Co-Diovan 80/12.5mg is one film-coated tablet once daily. Dose titration with the individual components is recommended. In each case, up-titration of individual components to the next dose should be followed in order to reduce the risk of hypotension and other adverse events. 

 

When clinically appropriate direct change from monotherapy to the fixed combination may be considered in patients whose blood pressure is not adequately controlled on valsartan or hydrochlorothiazide monotherapy, provided the recommended dose titration sequence for the individual components is followed.

 

The clinical response to Co-Diovan should be evaluated after initiating therapy and if blood pressure remains uncontrolled, the dose may be increased by increasing either one of the components to a maximum dose of Co-Diovan 320 mg/25 mg.

 

The antihypertensive effect is substantially present within 2 weeks.

 

In most patients, maximal effects are observed within 4 weeks. However, in some patients, 4-8 weeks treatment may be required.  This should be taken into account during dose titration.

 

Method of administration

Co-Diovan may be taken without regard to meals. It should be taken with Water.

 

Special populations

 

Patients with renal impairment

No dose adjustment is required for patients with mild to moderate renal impairment (Glomerular Filtration Rate (GFR) ³ 30 ml/min). Due to the hydrochlorothiazide component, Co-Diovan is contraindicated in patients with severe renal impairment (GFR < 30 mL/min) and anuria (see sections 4.3, 4.4 and 5.2).

 

 

Patients with hepatic impairment

In patients with mild to moderate hepatic impairment without cholestasis the dose of valsartan should not exceed 80 mg (see section 4.4). No adjustment of the hydrochlorothiazide dose is required for patients with mild to moderate hepatic impairment. Due to the valsartan component, Co-Diovan is contraindicated in patients with severe hepatic impairment or with biliary cirrhosis and cholestasis (see sections 4.3, 4.4 and 5.2).

 

Older people

No dose adjustment is required in elderly patients.

 

Paediatric patients

Co-Diovan is not recommended for use in children below the age of 18 years due to a lack of data on safety and efficacy


 Hypersensitivity to active substances, other sulfonamide-derived medicinal products or to any of the excipients listed in section 6.1.  Second and third trimester of pregnancy (section 4.4 and 4.6).  Severe hepatic impairment, biliary cirrhosis and cholestasis.  Severe renal impairment (creatinine clearance < 30 ml/min), anuria.  Refractory hypokalaemia, hyponatraemia, hypercalcaemia, and symptomatic hyperuricaemia.  Concomitant use of Co-Diovan with aliskiren containing products in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73m2) (see sections 4.5 and 5.1).

Serum electrolyte changes

 

Valsartan

Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other agents that may increase potassium levels (heparin, etc.) is not recommended.  Monitoring of potassium should be undertaken as appropriate.

 

Hydrochlorothiazide

Hypokalaemia has been reported under treatment with thiazide diuretics, including hydrochlorothiazide. Frequent monitoring of serum potassium is recommended.

Treatment with thiazide diuretics, including hydrochlorothiazide, has been associated with hyponatraemia and hypochloraemic alkalosis. Thiazides, including hydrochlorothiazide, increase the urinary excretion of magnesium, which may result in hypomagnesaemia. Calcium excretion is decreased by thiazide diuretics. This may result in hypercalcaemia.

As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals.

 

Sodium and/or volume-depleted patients

Patients receiving thiazide diuretics, including hydrochlorothiazide, should be observed for clinical signs of fluid or electrolyte imbalance.

 

In severely sodium-depleted and/or volume-depleted patients, such as those receiving high doses of diuretics, symptomatic hypotension may occur in rare cases after initiation of therapy with Co-Diovan. Sodium and/or volume depletion should be corrected before starting treatment with Co-Diovan.

 

Patients with severe chronic heart failure or other conditions with stimulation of the renin-angiotensin-aldosterone-system

In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure), treatment with angiotensin converting enzyme inhibitors has been associated with oliguria and/or progressive azotaemia, and in rare cases with acute renal failure and/or death. Evaluation of patients with heart failure or post-myocardial infarction should always include assessment of renal function. The use of Co-Diovan in patients with severe chronic heart failure has not been established.

 

Hence it cannot be excluded that because of the inhibition of the renin-angiotensin-aldosterone system the application of Co-Diovan as well may be associated with impairment of the renal function. Co-Diovan should not be used in these patients.

 

Renal artery stenosis

Co-Diovan should not be used to treat hypertension in patients with unilateral or bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, since blood urea and serum creatinine may increase in such patients.

 

Primary hyperaldosteronism

Patients with primary hyperaldosteronism should not be treated with Co-Diovan as their renin-angiotensin system is not activated.

 

Aortic and mitral valve stenosis, hypertrophic obstructive cardiomyopathy

As with all other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or hypertrophic obstructive cardiomyopathy (HOCM).

 

Renal impairment

No dosage adjustment is required for patients with renal impairment with a creatinine clearance ³30 ml/min (see section 4.2). Periodic monitoring of serum potassium, creatinine and uric acid levels is recommended when Co-Diovan is used in patients with renal impairment.

 

Kidney transplantation

There is currently no experience on the safe use of Co-Diovan in patients who have recently undergone kidney transplantation.

 

 

Hepatic impairment

In patients with mild to moderate hepatic impairment without cholestasis, Co-Diovan should be used with caution (see sections 4.2 and 5.2). 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.

 

History of angioedema

Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swelling of the face, lips, pharynx, and/or tongue has been reported in patients treated with valsartan; some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Co-Diovan should be immediately discontinued in patients who develop angioedema, and Co-Diovan should not be re-administered (see section 4.8).

 

Systemic lupus erythematosus

Thiazide diuretics, including hydrochlorothiazide, have been reported to exacerbate or activate systemic lupus erythematosus.

 

Other metabolic disturbances

Thiazide diuretics, including hydrochlorothiazide, may alter glucose tolerance and raise serum levels of cholesterol, triglycerides and uric acid. In diabetic patients dosage adjustments of insulin or oral hypoglycaemic agents may be required.

 

Thiazides may reduce 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 underlying hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.

 

Photosensitivity

Cases of photosensitivity reactions have been reported with thiazide 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 AIIRAs therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive 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).

 

General

Caution should be exercised in patients who have shown prior hypersensitivity to other angiotensin II receptor antagonists. Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with allergy and asthma.

 

Choroidal effusion, acute myopia and secondary acute Angle-Closure Glaucoma:

Sulfonamide or sulfonamide derivative drugs can cause an idiosyncratic reaction resulting in choroidal effusion with visual field defect, transient myopia and acute angle-closure glaucoma. 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.

 

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 the RAAS through the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see section 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.

 

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 exposure has been observed in two epidemiological studies based on the Danish National Cancer Registry. Photosensitising actions of hydrochlorothiazide could act as a possible mechanism for NMSC.

 

Patients taking hydrochlorothiazide 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 hydrochlorothiazide may also need to be reconsidered in patients who have experienced previous NMSC (see also section 4.8).

 

Acute respiratory toxicity

Very rare severe cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), have been reported after taking hydrochlorothiazide. Pulmonary oedema typically develops within minutes to hours after hydrochlorothiazide intake. At the onset, symptoms include dyspnoea, fever, pulmonary deterioration and hypotension. If diagnosis of ARDS is suspected, Diovan Comp should be withdrawn, and appropriate treatment given. Hydrochlorothiazide should not be administered to patients who previously experienced ARDS following hydrochlorothiazide intake.


Interactions related to both valsartan and hydrochlorothiazide

 

Concomitant use not recommended

Lithium

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors, angiontensin II receptor antagonist or thiazides, including hydrochlorothiazide. Since renal clearance of lithium is reduced by thiazides, the risk of lithium toxicity may presumably be increased further with Co-Diovan. If the combination proves necessary, a careful monitoring of serum lithium levels is recommended.

 

Concomitant use requiring caution

Other antihypertensive agents

Co-Diovan may increase the effects of other agents with antihypertensive properties (e.g. guanethidine, methyldopa, vasodilators, ACEI, ARBs, beta-blockers, calcium channel blockers and DRIs).

 

Pressor amines (e.g. noradrenaline, adrenaline)

Possible decreased response to pressor amines. The clinical significance of this effect is uncertain and not sufficient to preclude their use.

 

Non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX2) inhibitors, acetylsalicylic acid (>3 g/day), and non-selective NSAIDs:

NSAIDS can attenuate the antihypertensive effect of both angiotensin II antagonists and hydrochlorothiazide when administered simultaneously. Furthermore, concomitant use of Co-Diovan and NSAIDs may lead to worsening of renal function and an increase in serum potassium. Therefore, monitoring of renal function at the beginning of the treatment is recommended, as well as adequate hydration of the patient.

 

Interactions related to Valsartan

Dual blockade of the renin-angiotensin-aldosterone system with ARBs, ACEIs or aliskiren:

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 s single RAAS-acting agent (see section 4.3, 4.4 and 5.1).

 

Concomitant use not recommended

Potassium -sparing diuretics, potassium supplements, salt substitutes containing potassium and other substances that may increase potassium levels.

If a medicinal product that affects potassium levels is considered necessary in combination with valsartan, monitoring of potassium plasma levels is advised.

Transporters:

In vitro studies with human liver tissue indicate that valsartan is a substrate of the hepatic uptake transporter OATP1B1 and the hepatic efflux transporter MRP2. The clinical relevance of this finding is unknown. Co-administration of inhibitors of the uptake transporter (eg. rifampin, ciclosporin) or efflux transporter (eg. ritonavir) may increase the systemic exposure to valsartan. Exercise appropriate care when initiating or ending concomitant treatment with such drugs.

 

No interaction

In drug interaction studies with valsartan, no interactions of clinical significance have been found with valsartan or any of the following substances: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glibenclamide. Digoxin and indomethacin could interact with the hydrochlorothiazide component of Co-Diovan (see interactions related to hydrochlorothiazide).

Interactions related to Hydrochlorothiazide

 

Concomitant use requiring caution

Medicinal products affecting serum potassium or serum magnesium levels:

The hypokalaemic effect of hydrochlorothiazide may be increased by concomitant administration of kaliuretic diuretics, corticosteroids, laxatives, ACTH, amphotericin, carbenoxolone, penicillin G, salicylic acid and derivatives.

 

If these medicinal products are to be prescribed with the hydrochlorothiazide-valsartan combination, monitoring of potassium plasma levels is advised (see section 4.4).

 

Medicinal products that could induce torsades de pointes:

Due to the risk of hypokalaemia, hydrochlorothiazide should be administered with caution when associated with medicinal products that could induce torsades de pointes, in particular Class Ia and Class III antiarrhythmics and some antipsychotics.

 

Medicinal products affecting serum sodium level

The hyponatraemic effect of diuretics may be intensified by concomitant administration of drugs such as antidepressants, antipsychotics, antiepileptics, etc. Caution is advised in long-term administration of these drugs.

 

Digitalis glycosides

 Thiazide-induced hypokalaemia or hypomagnesaemia may favour the onset of digitalis-induced cardiac arrhythmias.

 

Calcium salts and vitamin D

Administration of thiazide diuretics, including hydrochlorothiazide, with vitamin D or with calcium salts may potentiate the rise in serum calcium. Concomitant use of thiazide type diuretics with calcium salts may cause hypercalcaemia in patients pre-disposed for hypercalcaemia (e.g. hyperparathyroidism, malignancy or vitamin-D-mediated conditions) by increasing tubular calcium reabsorption.

 

Anti-diabetic agents (oral agents and insulin):

Thiazides may alter glucose tolerance. Dose adjustment of the antidiabetic medicinal product may be necessary.

 

Metformin should be used with caution because of the risk of lactic acidosis induced by possible functional renal failure linked to hydrochlorothiazide.

 

Beta blockers and diazoxide

Concomitant use of thiazide diuretics, including hydrochlorothiazide, with beta blockers may increase the risk of hyperglycaemia. Thiazide diuretics, including hydrochlorothiazide, may enhance the hyperglycaemic effect of diazoxide

 

Medicinal products used in the treatment of gout (probenecid, sulfinpyrazone and Allopurinol):

Dose adjustment of uricosuric medications may be necessary as hydrochlorothiazide may raise the level of serum uric acid. Increase of dosage of probenecid or sulfinpyrazone may be necessary. Co-administration of thiazide diuretics, including hydrochlorothiazide, may increase the incidence of hypersensitivity reactions to allopurinol.

 

Anticholinergic agents and other medicinal products affecting gastric motility

The bioavailability of thiazide-type diuretics may be increased by anticholinergic agents (e.g. atropine, biperiden), apparently due to a decrease in gastrointestinal motility and the stomach emptying rate. Conversely, it is anticipated that prokinetic drugs such as cisapride may decrease the bioavailability of thiazide-type diuretics.

 

Amantadine:

Thiazides, including hydrochlorothiazide, may increase the risk of adverse effects caused by amantadine.

 

Ion exchange resins: 

Absorption of thiazide diuretics, including hydrochlorothiazide, is decreased by cholestyramine or colestipol. This could result in sub-therapeutic effects of thiazide diuretics. This could result in sub-therapeutic effects of thiazide diuretics. However, staggering the dosage of hydrochlorothiazide and resin such that hydrochlorothiazide is administered at least 4 h before or 4-6 h after the administration of resins would potentially minimise the interaction.

 

Cytotoxic agents

Thiazides, including hydrochlorothiazide, may reduce renal excretion of cytotoxic agents (e.g. cyclophosamide, methotrexate) and potentiate their myelosuppressive effects.

 

Non-depolarising skeletal muscle relaxants (e.g. tubocurarine)

Thiazides, including hydrochlorothiazide, potentiate the action of skeletal muscle relaxants such as curare derivatives.

 

Ciclosporin:

 Concomitant treatment with ciclosporin may increase the risk of hyperuricaemia and gout-type complications.

 

Alcohol, barbiturates or narcotics:

Concomitant administration of thiazide diuretics with substances that also have a blood pressure lowering effect (e.g. by reducing sympathetic central nervous system activity or direct vasodilatation activity) may potentiate orthostatic hypotension.

Methyldopa:

 There have been isolated reports of haemolytic anaemia in patients receiving concomitant treatment with methyldopa and hydrochlorothiazide.

 

 

Iodine contrast media

In case of diuretic-induced dehydration, there is an increased risk of acute renal failure, especially with high doses of the iodine product. Patients should be rehydrated before the administration.


Pregnancy

Valsartan

The use of Angiotensin II Receptor Antagonists (AIIRAs) is not recommended during first trimester of pregnancy (see section 4.4). The use of AIIRAs is contra-indicated during the second and third trimester 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 Inhibitors (AIIRAs), similar risks may exist for this class of drugs. Unless continued AIIRAs therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive 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.

 

AIIRAs therapy exposure during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see also 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 also section 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.

 

Breast-feeding

No information is available regarding the use of valsartan during breastfeeding. Hydrochlorothiazide is excreted in human milk.. Therefore the use of Co-Diovan during breast feeding is not recommended. Alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.


No studies on the effect of Co-Diovan, on the ability to drive and use machines have been performed. When driving vehicles or operating machines it should be taken into account that occasionally dizziness or weariness may occur.


Adverse drug reactions reported in clinical trials and laboratory findings occurring more frequently with valsartan plus hydrochlorothiazide versus placebo and individual postmarketing reports are presented below according to system organ class. Adverse drug reactions known to occur with each component given individually but which have not been seen in clinical trials may occur during treatment with valsartan/ hydrochlorothiazide.

 

Adverse Drug Reactions

Adverse drug reactions are ranked by frequency, the most frequent first, using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (frequency cannot be estimated from the available data).

Within each frequency grouping, adverse drug reactions are ranked in order of decreasing seriousness.

 

Table 1. Frequency of adverse reactions with valsartan/hydrochlorothiazide

 

Metabolism and nutrition disorders

Uncommon: Dehydration.

Nervous system disorders

Very rare: Dizziness

Uncommon: Paraesthesia

Not known: Syncope.

Eye disorders

Uncommon: Vision blurred.

Not known: choroidal effusion

Ear and labyrinth disorders

Uncommon: Tinnitus.

Vascular disorders

Uncommon: Hypotension.

Respiratory, thoracic and mediastinal disorders

Uncommon: Cough.

Not known: Non-cardiogenic pulmonary oedema.

Gastrointestinal disorders

Very rare: Diarrhoea.

Musculoskeletal and connective tissue disorders

Uncommon: Myalgia.

Very rare: Arthralgia

Renal and urinary disorders

Not known: Impaired renal function

General disorders and administration site conditions:

Uncommon: Fatigue

Investigations:

Not known: Serum uric acid increased, Serum bilirubin and Serum creatinine increased, Hypokalaemia, Hyponatraemia, Elevation of Blood Urea Nitrogen, Neutropenia

 

Additional information on the individual components

Adverse reactions previously reported with one of the individual components may be potential undesirable effects with Co-Diovan as well, even if not observed in clinical trials or during postmarketing period.

Frequency of adverse reaction with Valsartan

Other adverse events reported in clinical studies with valsartan, irrespective of their causal relationship, were as follows:

Blood and lymphatic system disorders:

Not known: Decrease in haemoglobin, decrease in haematocrit, thrombocytopenia

Immune system disorders:

Not known: Other hypersensitivity/allergic reactions including serum sickness

Metabolism and nutrition disorders:

Not known: Increase of serum potassium, hyponatraemia

Ear and labyrinth disorders:

Uncommon: Vertigo

Vascular disorders:

Not known: Vasculitis

Gastrointestinal disorders

Uncommon: Abdominal pain

Hepatobiliary disorders

Not known: Elevation of liver function values

Skin and subcutaneous tissue disorders

Not known: Angioedema, dermatitis bullous, rash, pruritus

Renal and urinary disorders

Not known: Renal failure

 

Frequency of adverse reaction with Hydrochlorothiazide

Hydrochlorothiazide has been extensively prescribed for many years, frequently in higher doses than those administered with Co-Diovan. The following adverse reactions have been reported in patients treated with monotherapy of thiazide diuretics, including hydrochlorothiazide:

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

Not known: Non-melanoma skin cancer (Basal cell carcinoma and Squamous cell carcinoma)

Blood and lymphatic system disorders

Rare: Thrombocytopenia sometimes with purpura.

Very rare: Agranulocytosis, leucopenia, haemolytic anaemia, bone marrow failure

Not known: Aplastic anemia

Immune system disorders

Very rare: hypersensitivity reactions.

Metabolism and nutrition disorders

Very common: Hypokalaemia, blood lipids increased (mainly at higher doses)

Common: Hyponatraemia, hypomagnesaemia, hyperuricaemia

Rare: Hypercalcaemia, hyperglycaemia, glycosuria and worsening of diabetic metabolic state

Very rare: Hypochloraemic alkalosis.

Psychiatric disorders

Rare: Depression, Sleep disorders

Nervous system disorders

Rare: Headache, dizziness, paraesthesia.

Eye disorders

Rare: Visual impairment.

Not known: Choroidal effusion, acute angle-closure glaucoma

Cardiac disorders

Rare: Cardiac arrhythmias.

Vascular disorders

Common: Postural hypotension.

Respiratory, thoracic and mediastinal disorders

Very rare: Acute respiratory distress syndrome (ARDS) (see section 4.4), respiratory distress including pneumonitis and pulmonary oedema.

Gastrointestinal disorders

Common: Loss of appetite, mild nausea and vomiting.

Rare: Constipation, gastrointestinal discomfort, diarrhoea

Very rare: Pancreatitis.

Hepatobiliary disorders

Rare: Intrahepatic Cholestasis or jaundice.

Renal and urinary disorders

Not known: Renal dysfunction, acute renal failure

Skin and subcutaneous tissue disorders

Common: Urticaria and other forms of rash.

Rare: Photosensitivity.

Very rare: Necrotising vasculitis and toxic epidermal necrolysis, cutaneous lupus-erythematosus-like skin reactions, reactivation of cutaneous lupus erythematosus.

Not known: Erythema multiforme

General disorders and administration site conditions:

Not known: Pyrexia, asthenia

Musculoskeletal and connective tissue disorders:

Not known: Muscle spasm

Reproductive system and breast disorders

Common: Impotence.

 

 

Description of selected adverse reactions

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

 

Cases of choroidal effusion with visual field defect have been reported after the use of thiazide and thiazide-like diuretics. If cases are to be reported for these substances in the future, the appropriate procedure should be used to update the product information accordingly.

 

- To report any side effect(s):

Saudi Arabia

The National Pharmacovigilance Centre (NPC):

o Fax: +966-11-205-7662

o SFDA call center: 19999

o E-mail: npc.drug@sfda.gov.sa

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

Patient Safety Department Novartis Consulting AG - Saudi Arabia:

o Toll Free Number: 8001240078

o Phone: +966112658100

o Fax: +966112658107

o Email: adverse.events@novartis.com

•    Other GCC States:

-  Please contact the relevant competent authority.


Symptoms

Overdose with valsartan may result in marked hypotension, which could lead to depressed level of consciousness, circulatory collapse and/or shock.  In addition, the following signs and symptoms may occur due to an overdose of the hydrochlorothiazide component: nausea, somnolence, hypovolaemia, and electrolyte disturbances associated with cardiac arrhythmias and muscle spasms. 

 

Treatment

The therapeutic measures depend on the time of ingestion and the type and severity of the symptoms, stabilisation of the circulatory condition being of prime importance.

 

If hypotension occurs, the patient should be placed in the supine position and salt and volume supplementation should be given rapidly.

 

Valsartan cannot be eliminated by means of haemodialysis because of its strong plasma binding behaviour whereas clearance of hydrochlorothiazide will be achieved by dialysis.


- Pharmacotherapeutic group: Angiotensin II antagonists and diuretics, valsartan and diuretics; ATC code: C09DA03

 

Valsartan/hydrochlorothiazide

In a double-blind, randomised, active-controlled trial in patients not adequately controlled on hydrochlorothiazide 12.5 mg, significantly greater mean systolic/diastolic BP reductions were observed with the combination of valsartan/hydrochlorothiazide 80/12.5 mg (14.9/11.3 mmHg) compared to hydrochlorothiazide 12.5 mg (5.2/2.9 mmHg) and hydrochlorothiazide 25 mg (6.8/5.7 mmHg). In addition, a significantly greater percentage of patients responded (diastolic BP <90 mmHg or reduction ≥10 mmHg) with valsartan/hydrochlorothiazide 80/12.5 mg (60%) compared to hydrochlorothiazide 12.5 mg (25%) and hydrochlorothiazide 25 mg (27%).

 

In a double-blind, randomised, active-controlled trial in patients not adequately controlled on valsartan 80 mg, significantly greater mean systolic/diastolic BP reductions were observed with the combination of valsartan/hydrochlorothiazide 80/12.5 mg (9.8/8.2 mmHg) compared to valsartan 80 mg (3.9/5.1 mmHg) and valsartan 160 mg (6.5/6.2 mmHg). In addition, a significantly greater percentage of patients responded (diastolic BP <90 mmHg or reduction ≥10 mmHg) with valsartan/hydrochlorothiazide 80/12.5 mg (51%) compared to valsartan 80 mg (36%) and valsartan 160 mg (37%).

 

In a double-blind, randomised, placebo-controlled, factorial design trial comparing various dose combinations of valsartan/hydrochlorothiazide to their respective components, significantly greater mean systolic/diastolic BP reductions were observed with the combination of valsartan/hydrochlorothiazide 80/12.5 mg (16.5/11.8 mmHg) compared to placebo (1.9/4.1 mmHg) and both hydrochlorothiazide 12.5 mg (7.3/7.2 mmHg) and valsartan 80 mg (8.8/8.6 mmHg). In addition, a significantly greater percentage of patients responded (diastolic BP <90 mmHg or reduction ≥10 mmHg) with valsartan/hydrochlorothiazide 80/12.5 mg (64%) compared to placebo (29%) and hydrochlorothiazide (41%).

 

Dose-dependent decreases in serum potassium occurred in controlled clinical studies with valsartan + hydrochlorothiazide. Reduction in serum potassium occurred more frequently in patients given 25 mg hydrochlorothiazide than in those given 12.5 mg hydrochlorothiazide. In controlled clinical trials with valsartan/hydrochlorothiazide the potassium lowering effect of hydrochlorothiazide was attenuated by the potassium-sparing effect of valsartan.

 

Beneficial effects of valsartan in combination with hydrochlorothiazide on cardiovascular mortality and morbidity are currently unknown.

 

Epidemiological studies have shown that long-term treatment with hydrochlorothiazide reduces the risk of cardiovascular mortality and morbidity.

 

Valsartan

Valsartan is an orally active and specific angiotensin II (Ang II) receptor antagonist.  It acts selectively on the AT1 receptor subtype, which is responsible for the known actions of angiotensin II.  The increased plasma levels of Ang II following AT1 receptor blockade with valsartan may stimulate the unblocked AT2 receptor, which appears to counterbalance the effect of the AT1 receptor. Valsartan does not exhibit any partial agonist activity at the AT1 receptor and has much (about 20,000 fold) greater affinity for the AT1 receptor than for the AT2 receptor.  Valsartan is not known to bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

 

Valsartan does not inhibit ACE, also known as kininase II, which converts Ang I to Ang II and degrades bradykinin.  Since there is no effect on ACE and no potentiation of bradykinin or substance P, angiotensin II antagonists are unlikely to be associated with coughing.  In clinical trials where valsartan was compared with an ACE inhibitor, the incidence of dry cough was significantly (P <0.05) lower in patients treated with valsartan than in those treated with an ACE inhibitor (2.6% versus 7.9% respectively).  In a clinical trial of patients with a history of dry cough during ACE inhibitor therapy, 19.5% of trial subjects receiving valsartan and 19.0% of those receiving a thiazide diuretic experienced cough compared to 68.5% of those treated with an ACE inhibitor (P <0.05). 

 

Administration of valsartan to patients with hypertension results in reduction of blood pressure without affecting pulse rate.  In most patients, after administration of a single oral dose, onset of antihypertensive activity occurs within 2 hours, and the peak reduction of blood pressure is achieved within 4-6 hours.  The antihypertensive effect persists over 24 hours after dosing.  During repeated dosing, the maximum reduction in blood pressure with any dose is generally attained within 2-4 weeks and is sustained during long-term therapy.  Combined with hydrochlorothiazide, a significant additional reduction in blood pressure is achieved.

 

Abrupt withdrawal of valsartan has not been associated with rebound hypertension or other adverse clinical events.

 

In hypertensive patients with type 2 diabetes and microalbuminuria, valsartan has been shown to reduce the urinary excretion of albumin. The MARVAL (Micro Albuminuria Reduction with Valsartan) study assessed the reduction in urinary albumin excretion (UAE) with valsartan (80‑160 mg/od) versus amlodipine (5‑10 mg/od), in 332 type 2 diabetic patients (mean age: 58 years; 265 men) with microalbuminuria (valsartan: 58 µg/min; amlodipine: 55.4 µg/min), normal or high blood pressure and with preserved renal function (blood creatinine <120 µmol/l). At 24 weeks, UAE was reduced (p <0.001) by 42% (–24.2 µg/min; 95% CI: –40.4 to –19.1) with valsartan and approximately 3% (–1.7 µg/min; 95% CI: –5.6 to 14.9) with amlodipine despite similar rates of blood pressure reduction in both groups. The Diovan Reduction of Proteinuria (DROP) study further examined the efficacy of valsartan in reducing UAE in 391 hypertensive patients (BP=150/88 mmHg) with type 2 diabetes, albuminuria (mean=102 µg/min; 20–700 µg/min) and preserved renal function (mean serum creatinine = 80 µmol/l). Patients were randomised to one of 3 doses of valsartan (160, 320 and 640 mg/od) and treated for 30 weeks. The purpose of the study was to determine the optimal dose of valsartan for reducing UAE in hypertensive patients with type 2 diabetes. At 30 weeks, the percentage change in UAE was significantly reduced by 36% from baseline with valsartan 160 mg (95%CI: 22 to 47%), and by 44% with valsartan 320 mg (95%CI: 31 to 54%). It was concluded that 160‑320 mg of valsartan produced clinically relevant reductions in UAE in hypertensive patients with type 2 diabetes.

 

Other: 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.

 

Hydrochlorothiazide

The site of action of thiazide diuretics is primarily in the renal distal convoluted tubule.  It has been shown that there is a high-affinity receptor in the renal cortex as the primary binding site for the thiazide diuretic action and inhibition of NaCl transport in the distal convoluted tubule.  The mode of action of thiazides is through inhibition of the Na+Cl- symporter perhaps by competing for the Cl- site, thereby affecting electrolyte reabsorption mechanisms:directly increasing sodium and chloride excretion to an approximately equal extent, and indirectly by this diuretic action reducing plasma volume, with consequent increases in plasma renin activity, aldosterone secretion and urinary potassium loss, and a decrease in serum potassium.  The renin-aldosterone link is mediated by angiotensin II, so with co-administration of valsartan the reduction in serum potassium is less pronounced as observed under monotherapy with hydrochlorothiazide.

 

Non-melanoma skin cancer:

Based on available data from epidemiological studies, cumulative dose-dependent association between hydrochlorothiazide 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 hydrochlorothiazide use (≥50,000 mg cumulative) was associated with an adjusted Odds Ratio (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 hydrochlorothiazide: 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).


Valsartan/hydrochlorothiazide

The systemic availability of hydrochlorothiazide is reduced by about 30% when co-administered with valsartan. The kinetics of valsartan are not markedly affected by the co-administration of hydrochlorothiazide. This observed interaction has no impact on the combined use of valsartan and hydrochlorothiazide, since controlled clinical studies have shown a clear anti-hypertensive effect, greater than that obtained with either drug given alone or placebo.

 

Valsartan

Absorption

Following oral administration of valsartan alone, peak plasma concentrations of valsartan are reached in 2–4 hours.  Mean absolute bioavailability is 23%.  Food decreases exposure (as measured by AUC) to valsartan by about 40% and peak plasma concentration (Cmax) by about 50%, although from about 8 h post dosing plasma valsartan concentrations are similar for the fed and fasted groups. This reduction in AUC is not, however, accompanied by a clinically significant reduction in the therapeutic effect, and valsartan can therefore be given either with or without food.

 

Distribution

 

The steady-state volume of distribution of valsartan after intravenous administration is about 17 litres, indicating that valsartan does not distribute into tissues extensively. 

 

Valsartan is highly bound to serum proteins (94 – 97%), mainly serum albumin. 

 

Biotransformation

Valsartan is not biotransformed to a high extent, as only about 20% of the dose is recovered as metabolites. A hydroxy metabolite has been identified in plasma at low concentrations (less than 10% of the valsartan AUC). This metabolite is pharmacologically inactive.

 

Elimination

Valsartan shows multiexponential decay kinetics (t½α <1 h and t½ß about 9 h). Valsartan is primarily eliminated in faeces (about 83% of dose) and urine (about 13% of dose), mainly as unchanged drug. Following intravenous administration, plasma clearance of valsartan is about 2 l/h and its renal clearance is 0.62  l/h (about 30% of total clearance). The half-life of valsartan is 6 hours.

 

Hydrochlorothiazide

Absorption

The absorption of hydrochlorothiazide after an oral dose is rapid (tmax approx. 2 hours). The increase in mean AUC is linear and dose-proportional in the therapeutic range.

The effect of food on hydrochlorothiazide absorption, if any, has little clinical significance.

Absolute bioavailability of hydrochlorothiazide is around 70% after oral administration.

 

Distribution

The apparent volume of distribution is 4 to 8 litres/kg. Circulating hydrochlorothiazide is bound to serum proteins (40 to 70%), mainly serum albumin. Hydrochlorothiazide also accumulates in erythrocytes at approximately 3 times the level in plasma.

 

Elimination

Hydrochlorothiazide is eliminated predominantly as unchanged drug. Hydrochlorothiazide is eliminated from plasma with a mean half-life of 6 to 15 hours in the terminal elimination phase. There is no change in the kinetics of hydrochlorothiazide on repeated dosing and accumulation is minimal when dosed once daily.

More than 95% of the absorbed dose is excreted as unchanged compound in the urine.

The renal clearance is composed of passive filtration and active secretion into the renal tubule.

 

Special populations

Older people

A somewhat higher systemic exposure to valsartan  was observed in some elderly subjects than in young subjects; however, this has not been shown to have any clinical significance.

 

Limited data suggest that the systemic clearance of hydrochlorothiazide is reduced in both healthy and hypertensive elderly subjects compared to young healthy volunteers.

 

Renal impairment

At the recommended dose of Co-Diovan  no dose adjustment is required for patients with a Glomerular Filtration Rate (GFR) of 30–70 ml/min.

 

In patients with severe renal impairment (GFR <30 ml/min) and patients undergoing dialysis no data are available for Co-Diovan. Valsartan is highly bound to plasma protein and is not to be removed by dialysis, whereas clearance of hydrochlorothiazide will be achieved by dialysis.

 

In the presence of renal impairment, mean peak plasma levels and AUC values of hydrochlorothiazide are increased and the urinary excretion rate is reduced. In patients with mild to moderate renal impairment, a 3-fold increase in hydrochlorothiazide AUC has been observed. In patients with severe renal impairment an 8-fold increase in AUC has been observed. Hydrochlorothiazide is contraindicated in patients with severe renal impairment (see section 4.3).

 

Patients with hepatic dysfunction

In a pharmacokinetics trial in patients with mild (n=6) to moderate (n=5) hepatic dysfunction, exposure to valsartan was increased approximately 2-fold compared with healthy volunteers (see sections 4.2 and 4.4).

 

There is no data available on the use of valsartan in patients with severe hepatic dysfunction (see section 4.3). Hepatic disease does not significantly affect the pharmacokinetics of hydrochlorothiazide.


The potential toxicity of the valsartan - hydrochlorothiazide combination after oral administration was investigated in rats and marmosets in studies lasting up to six months. No findings emerged that would exclude the use of therapeutic doses in man.

 

The changes produced by the combination in the chronic toxicity studies are most likely to have been caused by the valsartan component. The toxicological target organ was the kidney, the reaction being more marked in the marmoset than the rat. The combination led to kidney damage (nephropathy with tubular basophilia, rises in plasma urea, plasma creatinine and serum potassium, increases in urine volume and urinary electrolytes from 30 mg/kg/day valsartan + 9 mg/kg/day hydrochlorothiazide in rats and 10 + 3 mg/kg/d in marmosets), probably by way of altered renal haemodynamics. These doses in rat, respectively, represent 0.9 and 3.5–times the maximum recommended human dose (MRHD) of valsartan and hydrochlorothiazide on a mg/m2 basis. These doses in marmoset, respectively, represent 0.3 and 1.2–times the maximum recommended human dose (MRHD) of valsartan and hydrochlorothiazide on a mg/m2 basis. (Calculations assume an oral dose of 320 mg/day valsartan in combination with 25 mg/day hydrochlorothiazide and a 60-kg patient.)

 

High doses of the valsartan - hydrochlorothiazide combination caused falls in red blood cell indices (red cell count, haemoglobin, haematocrit, from 100 + 31 mg/kg/d in rats and 30 + 9 mg/kg/d in marmosets). These doses in rat, respectively, represent 3.0 and 12 times the maximum recommended human dose (MRHD) of valsartan and hydrochlorothiazide on a mg/m2 basis. These doses in marmoset, respectively, represent 0.9 and 3.5 times the maximum recommended human dose (MRHD) of valsartan and hydrochlorothiazide on a mg/m2 basis. (Calculations assume an oral dose of 320 mg/day valsartan in combination with 25 mg/day hydrochlorothiazide and a 60-kg patient).

 

In marmosets, damage was observed in the gastric mucosa (from 30 + 9 mg/kg/d). The combination also led in the kidney to hyperplasia of the afferent aterioles (at 600 + 188 mg/kg/d in rats and from 30 + 9 mg/kg/d in marmosets). These doses in marmoset, respectively, represent 0.9 and 3.5 times the maximum recommended human dose (MRHD) of valsartan and hydrochlorothiazide on a mg/m2 basis. These doses in rat, respectively, represent 18 and 73 times the maximum recommended human dose (MRHD) of valsartan and hydrochlorothiazide on a mg/m2 basis. (Calculations assume an oral dose of 320 mg/day valsartan in combination with 25 mg/day hydrochlorothiazide and a 60-kg patient).

 

The above mentioned effects appear to be due to the pharmacological effects of high valsartan doses (blockade of angiotensin II-induced inhibition of renin release, with stimulation of the renin-producing cells) and also occur with ACE inhibitors. These findings appear to have no relevance to the use of therapeutic doses of valsartan in humans.

 

The valsartan - hydrochlorothiazide combination was not tested for mutagenicity, chromosomal breakage or carcinogenicity, since there is no evidence of interaction between the two substances. However, these tests were performed separately with valsartan and hydrochlorothiazide, and produced no evidence of mutagenicity, chromosomal breakage or carcinogenicity.

 

In rats, maternally toxic doses of valsartan (600 mg/kg/day) during the last days of gestation and lactation led to lower survival, lower weight gain and delayed development (pinna detachment and ear-canal opening) in the offspring (see section 4.6). These doses in rats (600 mg/kg/day) are approximately 18 times the maximum recommended human dose on a mg/m2 basis (calculations assume an oral dose of 320 mg/day and a 60-kg patient). Similar findings were seen with valsartan/hydrochlorothiazide in rats and rabbits. In embryo-fetal development (Segment II) studies with valsartan/hydrochlorothiazide in rat and rabbit, there was no evidence of teratogenicity; however, fetotoxicity associated with maternal toxicity was observed.


Co-Diovan 80/12.5 Film-coated tablets:

- Microcrystaline Cellulose

- Crospovidone

- Colloidal silicon Dioxide

- Magnesium Stearate

Co-Diovan 160/12.5 Film-coated tablets:

- Microcrystalline Cellulose

- Crospovidone

- Colloidal Silicon Dioxide

- Magnesium Stearate

Co-Diovan 160/25 Film-coated tablets:

- Microcrystalline Cellulose

- Crospovidone

- Colloidal Silicon Dioxide

- Magnesium Stearate

Co-Diovan 320/12.5 Film-coated tablets:

- Microcrystalline Cellulose

- Crospovidone

- Colloidal Silicon Dioxide

- Magnesium Stearate

Co-Diovan 320/25 Film-coated tablets:

- Microcrystalline Cellulose

- Crospovidone

- Colloidal Silicon Dioxide

- Magnesium Stearate


Not applicable.


3 years.

Do not store above 30°C.

Store in the original package in order to protect from moisture


PVC/PE/PVDC, PVC/PVDC aluminium blister packs


No special requirements.


The Marketing Authorization Holder for this Product is Novartis Pharma AG. www.Novartis.com

by United Kingdom in 03/2022
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