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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)

OLMETROL PLUS contains two active substances, olmesartan medoxomil and hydrochlorothiazide, that are used to treat high blood pressure (hypertension):

•         Olmesartan medoxomil is one of a group of medicines called angiotensin II-receptor antagonists. It lowers blood pressure by relaxing the blood vessels.

•         Hydrochlorothiazide is one of a group of medicines called thiazide diuretics (“water tablets”). It lowers blood pressure by helping the body to get rid of extra fluid by making your kidneys produce more urine. 

You will only be given Olmetrol Plus if Olmetrol (olmesartan medoxomil) alone has not adequately controlled your blood pressure. When given together, the two active substances in Olmetrol Plus help to lower blood pressure more than if either of them were given alone.

You may already be taking medicines to treat your high blood pressure, but your doctor may want you to take Olmetrol Plus to lower it more.

 High blood pressure can be controlled with medicines such as Olmetrol Plus tablets. Your doctor has probably also recommended that you make some changes in your lifestyle to help lower your blood pressure (for example losing weight, giving up smoking, reducing the amount of alcohol you drink and reducing the amount of salt in your diet). Your doctor may also have urged you to take regular exercise, such as walking or swimming. It is important to follow this advice from your doctor.


Do not take Olmetrol Plus:

 

•        if you are allergic to olmesartan medoxomil or hydrochlorothiazide, or any of the other ingredients of this medicine (listed in section 6) or substances similar to hydrochlorothiazide (sulfonamides)

•        if you are more than 3 months pregnant (It is also better to avoid Olmetrol Plus in early pregnancy – see pregnancy section)

•        if you have kidney problems

•        if you have diabetes or impaired kidney function and you are treated with a blood pressure lowering medicine containing aliskiren

•        if you suffer from low potassium, low sodium, high calcium or high uric acid levels in the blood (with symptoms of gout or kidney stones) that do not get better when treated

•        if you suffer from moderate or severe liver problems or yellowing of the skin and eyes (jaundice) or problems with drainage of the bile from the gallbladder (biliary obstruction e.g. gallstones)

 

If you think any of these apply to you, or you are unsure, do not take the tablets. Talk to your doctor first and follow the advice given.

Warnings and precautions

Talk to your doctor before using Olmetrol Plus. Before you take the tablets, tell your doctor if you are taking any of the following medicines used to treat high blood pressure:

•         an ACE-inhibitor (for example enalapril, lisinopril, ramipril), in particular if you have diabetes-related kidney problems.

•         aliskiren Your doctor may check your kidney function, blood pressure, and the amount of electrolytes (e.g. potassium) in your blood at regular intervals. See also information under the heading “Do not take Olmetrol Plus”. Before you take the tablets, tell your doctor if you have any of the following health problems:

•         Kidney transplant

•         Liver diseases

•         Heart failure or problems with your heart valves or heart muscles

•         Vomiting (being sick) or diarrhoea which is severe or it goes on for several days

•         Treatment with high doses of water tablets (diuretics) or if you are on a low salt diet

•         Problems with your adrenal glands (e.g. primary aldosteronism)

•         Diabetes

•         Lupus erythematosus (an autoimmune disease)

•         Allergies or asthma

•         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 Olmetrol Plus.

•         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 Olmetrol Plus, seek medical attention immediately.

Contact your doctor if you experience any of the following symptoms:

•         diarrhoea that is severe, persistent and causes substantial weight loss. Your doctor may evaluate your symptoms and decide on how to continue your blood pressure medication.

•        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 Olmetrol Plus. This can lead to

           permanent vision impairment, if not treated.

Your doctor may want to see you more often and do some tests if you have any of these conditions.

 Olmetrol Plus may cause a rise in blood fat levels and uric acid levels (the cause of gout – painful swelling of the joints). Your doctor will probably want to do a blood test from time to time to check these.

It may change the levels of certain chemicals in your blood called electrolytes. Your doctor will probably want to do a blood test from time to time to check these. Signs of electrolyte changes are: thirst, dryness of the mouth, muscle pain or cramps, tired muscles, low blood pressure (hypotension), feeling weak, sluggish, tired, sleepy or restless, nausea, vomiting, less need to pass urine, a rapid heart rate. Tell your doctor if you notice these symptoms.

As with any medicine which reduces blood pressure, an excessive drop in blood pressure in patients with blood flow disturbances of the heart or brain could lead to a heart attack or stroke. Your doctor will therefore check your blood pressure carefully.

If you are due to have tests for parathyroid function, you should stop taking Olmetrol Plus before these tests are carried out.

If you are a sports person, this medicine could change the results of an anti-dope test to make it positive.

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

Children and adolescents

Olmetrol Plus is not recommended for children and adolescents under the age of 18. 

Other medicines and Olmetrol Plus

Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines.

 In particular, tell your doctor or pharmacist about any of the following:

•         Other blood pressure lowering medicines (anti-hypertensives), as the effect of Olmetrol Plus can be increased.

Your doctor may need to change your dose and/or to take other precautions: If you are taking an ACE-inhibitor or aliskiren (see also information under the headings “Do not take Olmetrol Plus” and “Warnings and precautions”).

•        Medicines which may alter the levels of potassium in your blood if used at the same time as Olmetrol Plus. These include:

-        potassium supplements (as well as salt substitutes containing potassium)

-        water tablets (diuretics)

-        heparin (for thinning the blood)

-        laxatives

-        steroids

-        adrenocorticotrophic hormone (ACTH)

-        carbenoxolone (a medicine used to treat mouth and stomach ulcers)

-         penicillin G sodium (also called benzylpenicillin sodium, an antibiotic)

-         certain pain killers such as aspirin or salicylates

•        Lithium (a medicine used to treat mood swings and some types of depression) used at the same time as Olmetrol Plus may increase the toxicity of lithium. If you have to take lithium, your doctor will measure your lithium blood levels.

•        Non-steroidal anti-inflammatory (NSAIDs) medicines (medicines used to relieve pain, swelling and other symptoms of inflammation, including arthritis) used at the same time as Olmetrol Plus may increase the risk of kidney failure and the effect of

         Olmetrol Plus can be decreased by NSAIDs.

•        Sleeping tablets, sedatives and anti-depressant medicines, as using these medicines together with Olmetrol Plus may cause a sudden drop in blood pressure when standing up.

•        Certain medicines such as baclofen and tubocurarine, used to relax muscles.

•        Amifostine and some other drugs used to treat cancers, such as cyclophosphamide or methotrexate.

•        Colestyramine and colestipol, medicines for lowering blood fat levels.

•        Colesevelam hydrochloride, a drug that lowers the level of cholesterol in your blood, as the effect of Olmetrol Plus may be decreased. Your doctor may advise you to take Olmetrol Plus at least 4 hours before colesevelam hydrochloride.

•        Anticholinergic agents, such as atropine and biperiden.

•        Drugs such as thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, amisulpride, pimozide, sultopride, tiapride, droperidol or haloperidol, used to treat certain psychiatric disorders.

•        Certain medicines such as quinidine, hydroquinidine, disopyramide, amiodarone, sotalol or digitalis, used to treat heart problems.

•        Medicines such as mizolastine, pentamidine, terfenadine, dofetilide, ibutilide or erythromycin injections, which may change the heart rhythm.

•        Oral anti-diabetic medicines, such as metformin, or insulin, used to lower blood sugar.

•        Beta-blockers and diazoxide, medicines used to treat high blood pressure or low blood sugar, respectively, as Olmetrol Plus can enhance their blood-sugar-increasing effect.

•        Methyldopa, a medicine used to treat high blood pressure.

•        Medicines such as noradrenaline, used to increase blood pressure and slow heart rate.

•        Diphemanil, used to treat a slow heartbeat or reduce sweating.

•        Medicines such as probenecid, sulfinpyrazone and allopurinol, used to treat gout.

•        Calcium supplements.

•        Amantadine, an anti-viral drug.

•        Ciclosporin, a medicine used to stop rejection of organ transplants.

•        Certain antibiotics called tetracyclines or sparfloxacin.

•        Amphotericin, a medicine used to treat fungal infections.

•        Certain antacids, used to treat too much stomach acid, such as aluminium magnesium hydroxide, as the effect of Olmetrol Plus can be slightly decreased.

•        Cisapride, used to increase food movement in the stomach and gut.

•        Halofantrine, used for malaria.

 

Olmetrol Plus with food and drink

Olmetrol Plus can be taken with or without food. Take care when drinking alcohol while you are taking Olmetrol Plus, as some people feel faint or dizzy. If this happens to you, do not drink any alcohol, including wine, beer or alcopops.

Black patients

As with other similar drugs the blood pressure lowering effect of Olmetrol Plus is somewhat less in black patients.

Pregnancy and breast-feeding Pregnancy

You must tell your doctor if you think you are (or might become) pregnant. Your doctor will normally advise you to stop taking Olmetrol Plus before you become pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of Olmetrol Plus.

Olmetrol Plus is not recommended during pregnancy, and must not be taken when more than 3 months pregnant, as it may cause serious harm to your baby if it is used after the third month of pregnancy.

 Breast-feeding

Tell your doctor if you are breast-feeding or about to start breast-feeding. Olmetrol Plus is not recommended for mothers who are breast-feeding, and your doctor may choose another treatment for you if you wish to breast-feed. If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

 Driving and using machines

You may feel sleepy or dizzy while being treated for your high blood pressure. If this happens, do not drive or use machines until the symptoms wear off. Ask your doctor for advice.

 Olmetrol Plus contains lactose

This medicine contains lactose (a type of sugar). If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.


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

The recommended dose is one Olmetrol Plus 20 mg/12.5 mg tablet a day.

Swallow the tablet with water. If possible, you should take your dose at the same time each day, for example at breakfast time. It is important to continue to take Olmetrol Plus until your doctor tells you to stop.

If you take more Olmetrol Plus than you should

If you take more tablets than you should, or if a child accidentally swallows one or more, go to your doctor or nearest accident and emergency (A&E) department immediately and take your medicine pack with you.

If you forget to take Olmetrol Plus

If you forget to take a dose, take your normal dose on the following day as usual. Do not take a double dose to make up for a forgotten dose.

 If you stop taking Olmetrol Plus

It is important to continue to take Olmetrol Plus unless your doctor tells you to stop. 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.

However, the following side effects can be serious:

•        Allergic reactions that may affect the whole body, with swelling of the face, mouth and/or voice box (larynx) together with itching and rash may occur rarely. If this happens, stop taking Olmetrol Plus and contact your doctor immediately.

•        Olmetrol Plus can cause the blood pressure to fall too low in susceptible individuals or as the result of an allergic reaction. Light-headedness or fainting may occur uncommonly. If this happens, stop taking Olmetrol Plus, contact your doctor immediately

          and lie down flat.

•        Frequency not known: If you experience yellowing of the whites of the eyes, dark urine, itching of the skin, even if you started therapy with Olmetrol Plus longer time ago, contact your doctor immediately who will evaluate your symptoms and decide on

         how to continue your blood pressure medication.  

Olmetrol Plus is a combination of two active substances and the following information firstly gives the other side effects reported so far with the combination Olmetrol Plus (besides those already mentioned above) and, secondly, those which are known about for the separate active substances.

These are the other side effects known about so far with Olmetrol Plus:

If these side effects occur, they are often mild and you do not need to stop your treatment.

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

Dizziness, weakness, headache, tiredness, chest pain, swelling of ankles, feet, legs, hands or arms.

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

Fluttering of the heartbeat (palpitations), rash, eczema, vertigo, cough, indigestion, abdominal pain, nausea, vomiting, diarrhea, muscle cramps and muscular pain, pain in joints, arms and legs, back pain, erection difficulties in men, blood in urine. Some changes in blood test results have also been seen uncommonly and include: Rise in blood fat levels, rise in blood urea or uric acid, rise in creatinine, rise or decrease in blood potassium levels, rise in blood calcium levels, rise in blood sugar, increase in levels of liver function. Your doctor will know about these from a blood test and will tell you if you need to do anything.

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

 Feeling unwell, disturbances in consciousness, skin lumps (wheals), acute kidney failure.

Some changes in blood test results have also been seen in rare cases and include: Rise in blood urea nitrogen, decrease in hemoglobin and hematocrit values. Your doctor will know about these from a blood test and will tell you if you need to do anything.

Further side effects reported with use of olmesartan medoxomil or hydrochlorothiazide alone, but not with Olmetrol Plus or in a higher frequency:

Olmesartan medoxomil

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

Bronchitis, cough, runny or stuffy nose, sore throat, abdominal pain, indigestion, diarrhea, nausea, gastroenteritis, pain in the joints or bones, back pain, blood in urine, urinary tract infection, flu-like symptoms, pain. Some changes in blood test results have also been seen commonly and include: Rise in blood fat levels, rise in blood urea or uric acid, increase in levels of liver and muscle function.

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

Quick allergic reactions that may affect the whole body and may cause breathing problems as well as a rapid fall of blood pressure that may even lead to fainting (anaphylactic reactions), swelling of the face, angina (pain or uncomfortable feeling in the chest; known as angina pectoris), feeling unwell, allergic skin rash, itching, exanthema (skin eruption), skin lumps (wheals).  

Some changes in blood test results have also been seen uncommonly and include: Reduced numbers of a type of blood cell, known as platelets (thrombocytopenia).

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

Impaired kidney function, lack of energy. Some changes in blood test results have also been seen rarely and include: Increase in blood potassium.

Hydrochlorothiazide

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

 Changes in blood results including: Increase in blood fat and uric acid levels.

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

Feeling confused, abdominal pain, stomach upset, bloated feeling, diarrhea, nausea, vomiting, constipation, excretion of glucose into the urine. Some changes in blood results have also been seen and include: Increase in blood creatinine, urea, calcium and sugar levels, decrease in blood chloride, potassium, magnesium and sodium levels. Increase of serum amylase (hyperamylasemia).

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

Decreased or loss of appetite, severe difficulty breathing, anaphylactic skin reactions (hypersensitivity reactions), worsening of pre-existing myopia erythema, skin reactions to light, itching, purplish spots or patches on the skin due to small hemorrhages (purpura), skin lumps (wheals).

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

Swollen and sore salivary glands, decreased number of white blood cells, decreased number of blood platelets, anemia, bone marrow damage, restlessness, feeling ‘down’ or depressed, problems sleeping, feeling un-interested (apathy), tingling and numbness, fits (convulsions), objects you look at appearing yellow, blurred vision, dry eyes, irregular heartbeat, inflammation of the blood vessels, blood clots (thrombosis or embolism), inflammation of the lung, fluid accumulation in the lungs, inflammation of the pancreas, jaundice, infection in the gall bladder, symptoms of lupus erythematosus (such as rash, joint pains and cold hands and fingers), allergic skin reactions, peeling and blistering of the skin, non-infectious inflammation of the kidney (interstitial nephritis), fever, muscle weakness (sometimes causing impaired movement).

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

Electrolyte disturbance leading to an abnormally depleted level of chloride in the blood (hypochloraemic alkalosis), blockage in the gut (paralytic ileus). Acute respiratory distress (signs include severe shortness of breath, fever, weakness, and confusion).

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

 Decrease in vision or eye pain (possible signs of fluid accumulation in the vascular layer of the eye (choroidal effusion) or acute angle-closure glaucoma). Skin and lip cancer (Non-melanoma skin cancer).


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

-        Store below 30 C, store in original package to protect from moisture.

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

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.


Olmetrol Plus 20 mg/12.5 mg: Each film-coated tablet contains 20 mg olmesartan medoxomil and 12.5 mg hydrochlorothiazide.

 

 The other ingredients are lactose monohydrate, low substituted hydroxypropyl cellulose, hydroxy propyl cellulose, microcrystalline cellulose, magnesium stearate, hypromellose, Talc,titanium dioxide,Iron red oxid, Iron yellow oxide,
 ferrosoferric oxide and purified water.


Olmetrol Plus 20 mg/12.5 mg: Yellow colored circular biconvex, film coated tablet with (CT22) debossed on one side and plain on other side. Pack: Carton contain 3 Alu/Alu blister 10 tablets per blister (30 tablets per carton)

Medical and Cosmetic Products Company Ltd. (Riyadh Pharma)

P.O.Box 442, Riyadh 11411

Fax: +966 11 265 0505

Email: contact@riyadhpharma.com

For any information about this medicinal product, please contact the local representative of marketing Authorisation holder:

Saudi Arabia

Marketing department

Riyadh

Tel: +966 11 265 0111

Email: marketing@riyadhpharma.com


09/2022
  نشرة الدواء تحت مراجعة الهيئة العامة للغذاء والدواء (اقرأ هذه النشرة بعناية قبل البدء في استخدام هذا المنتج لأنه يحتوي على معلومات مهمة لك)

     يحتوي اولميترول بلس على مادتين فعالتين، أولميسارتان ميدوكسوميل وهيدروكلوروثيازيد، اللذان يستخدمان لعلاج ارتفاع ضغط الدم (ارتفاع ضغط الدم):

•         أولميسارتان ميدوكسوميل هو واحد من مجموعة من الأدوية تسمى مضادات مستقبلات الأنجيوتنسين 2. يخفض ضغط الدم عن طريق إرخاء الأوعية الدموية.

•         هيدروكلوروثيازيد هو أحد مجموعة الأدوية التي تسمى مدرات البول الثيازيدية ("أقراص الماء"). يخفض ضغط الدم عن طريق مساعدة الجسم على التخلص من السوائل الزائدة عن طريق جعل الكلى تنتج المزيد من البول.

سيتم إعطاؤك اولميترول بلس فقط إذا لم يتحكم (أولميسارتان ميدوكسوميل) اولميترول وحده بشكل كافٍ في ضغط الدم لديك.

عند تناولهما معًا، فإن المادتين الفعالتين في اولميترول بلس يساعدان على خفض ضغط الدم أكثر مما لو تم إعطاء أي منهما بمفرده.

قد تكون تتناول بالفعل أدوية لعلاج ارتفاع ضغط الدم لديك، ولكن قد يرغب طبيبك في وصف اولميترول لخفضه أكثر.

 يمكن السيطرة على ارتفاع ضغط الدم بأدوية مثل أقراص اولميترول بلس، قد يوصي طبيبك أيضًا بإجراء بعض التغييرات في نمط حياتك للمساعدة في خفض ضغط الدم (على سبيل المثال، خفض الوزن، والإقلاع عن التدخين، وتقليل كمية الكحول التي تتناولها وتقليل كمية الملح في نظامك الغذائي). قد يحثك طبيبك أيضًا على ممارسة التمارين الرياضية بانتظام، مثل المشي أو السباحة. من المهم اتباع هذه النصيحة من طبيبك

لا تتناول اولميترول بلس:

 

•         إذا كنت تعاني من حساسية تجاه أولميسارتان ميدوكسوميل أو هيدروكلوروثيازيد، أو أي من المكونات الأخرى لهذا الدواء (المدرجة في القسم 6) أو مواد مشابهة لهيدروكلوروثيازيد (سلفوناميدات)

•         إذا كنت حاملاً لأكثر من 3 أشهر (من الأفضل أيضًا تجنب اولميترول بلس في بداية الحمل - راجعي قسم الحمل)

•         إذا كان لديك مشاكل في الكلى

•         إذا كنت تعاني من مرض السكري أو ضعف في وظائف الكلى وتعالج بدواء لخفض ضغط الدم يحتوي على أليسكيرين

•         إذا كنت تعاني من انخفاض البوتاسيوم أو الصوديوم أو ارتفاع الكالسيوم أو ارتفاع مستويات حمض اليوريك في الدم (مع أعراض النقرس أو حصوات الكلى) التي لا تتحسن عند العلاج

•         إذا كنت تعاني من مشاكل معتدلة أو شديدة في الكبد أو اصفرار الجلد والعينين (اليرقان) أو مشاكل في تصريف الصفراء من المرارة (انسداد القنوات الصفراوية مثل حصوات المرارة)

إذا كنت تعتقد أن أيًا من هذه ينطبق عليك، أو إذا كنت غير متأكد، فلا تتناول الأقراص. تحدث إلى طبيبك أولاً واتبع النصائح المقدمة.

الاحتياطات والمحاذير

تحدث إلى طبيبك قبل استخدام اولميترول بلس. قبل تناول الأقراص، أخبر طبيبك إذا كنت تتناول أيًا 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.

•         أليسكيرين قد يقوم طبيبك بفحص وظائف الكلى وضغط الدم وكمية الشوارد (مثل البوتاسيوم) في الدم على فترات منتظمة. راجع أيضًا المعلومات الواردة تحت عنوان "لا تتناول اولميترول بلس.

 قبل تناول الأقراص، أخبر طبيبك إذا كان لديك أي من المشاكل الصحية التالية:

•         زراعة الكلى

•         أمراض الكبد

•         فشل القلب أو مشاكل في صمامات القلب أو عضلات القلب

•         القيء (المرض) أو الإسهال الشديد أو يستمر لعدة أيام

•         العلاج بجرعات عالية من أقراص الماء (مدرات البول) أو إذا كنت تتبع نظامًا غذائيًا قليل الملح

•         مشاكل في الغدد الكظرية (مثل الألدوستيرونية الأولية)

•         داء السكري

•         الذئبة الحمامية (أحد أمراض المناعة الذاتية)

•         الحساسية أو الربو

•         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 الميلانين). احمِ بشرتك من التعرض لأشعة الشمس والأشعة فوق البنفسجية أثناء تناول اولميترول بلس

 

•         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 اولميترول بلس، فعليك طلب العناية الطبية على الفور.

الأطفال والمراهقون

لا ينصح باستخدام اولميترول بلس للأطفال والمراهقين الذين تقل أعمارهم عن 18 عامًا.

 

اولمترول بلس والأدوية أخرى

أخبر طبيبك أو الصيدلي إذا كنت تستخدم أو استخدمت مؤخرًا أو قد تستخدم أي أدوية أخرى.

 على وجه الخصوص، أخبر طبيبك أو الصيدلي عن أي مما يلي:

•         أدوية أخرى لخفض ضغط الدم (مضادات ارتفاع ضغط الدم)، حيث يمكن زيادة تأثير أولمترول بلس.

قد يحتاج طبيبك إلى تغيير جرعتك و / أو اتخاذ احتياطات أخرى: إذا كنت تتناول أحد مثبطات الإنزيم المحول للأنجيوتنسين أو أليسكيرين (انظر أيضًا المعلومات الواردة تحت العناوين "لا تستعمل أولمترول بلس و "التحذيرات والاحتياطات").

 

•         الأدوية التي قد تغير مستويات البوتاسيوم في الدم إذا تم استخدامها في نفس الوقت مع أولمترول بلس. وتشمل هذه:

-          مكملات البوتاسيوم (وكذلك بدائل الملح المحتوية على البوتاسيوم)

-          أقراص الماء (مدرات البول).

-          هيبارين (لتسييل الدم).

-          أدوية مسهلة

-          المنشطات

-          هرمون قشر الكظرية(ACTH)

-          كاربينوكسولون (دواء يستعمل لعلاج تقرحات الفم والمعدة).

-          بنسيلين جي الصوديوم (يسمى أيضًا بنزيل بنسلين الصوديوم، مضاد حيوي)

-          بعض مسكنات الآلام مثل الأسبرين أو الساليسيلات

•         الليثيوم (دواء يستخدم لعلاج التقلبات المزاجية وبعض أنواع الاكتئاب) المستخدم في نفس الوقت مثل اولميترول بلس قد يزيد من سمية الليثيوم. إذا كان عليك تناول الليثيوم، فسيقيس طبيبك مستويات الليثيوم في الدم.

•         الأدوية غير الستيرويدية المضادة للالتهابات (مضادات الالتهاب غير الستيرويدية) (الأدوية المستخدمة لتخفيف الألم والتورم وأعراض الالتهاب الأخرى، بما في ذلك التهاب المفاصل) المستخدمة في نفس الوقت حيث قد يزيد اولميترول بلس من خطر الفشل الكلوي ويمكن أن يقل تأثير اولميترول بلس عن طريق مضادات الالتهاب غير الستيرويدية.

•         الأقراص المنومة والمهدئات والأدوية المضادة للاكتئاب، حيث أن استخدام هذه الأدوية مع اولميترول بلس قد يؤدي إلى انخفاض مفاجئ في ضغط الدم عند الوقوف.

•         بعض الأدوية مثل باكلوفين وتوبوكورارين، وتستخدم لإرخاء العضلات.

•         أميفوستين وبعض الأدوية الأخرى المستخدمة لعلاج السرطانات، مثل سيكلوفوسفاميد أو ميثوتريكسات.

•         كوليستيرامين وكوليستيبول، أدوية لخفض مستويات الدهون في الدم.

•         كوليسيفيلام هيدروكلوريد، وهو دواء يخفض مستوى الكوليسترول في الدم، حيث قد ينخفض ​​تأثير أولميترول بلس. قد ينصحك طبيبك بتناول أولميترول بلس قبل 4 ساعات على الأقل من هيدروكلوريد كوليسيفيلام.

•         مضادات الكولين، مثل الأتروبين والبيبيريدين.

•         أدوية مثل ثيوريدازين، كلوربرومازين، ليفوميبرومازين، تريفلوبيرازين، سياميمازين، سولبيريد، أميسولبرايد، بيموزيد، سولتوبرايد، تيابريد، دروبيريدول أو هالوبيريدول، وتستخدم لعلاج بعض الاضطرابات النفسية.

•         بعض الأدوية مثل كينيدين، هيدروكينيدين، ديسوبيراميد، أميودارون، سوتالول أو ديجيتاليس، تستخدم لعلاج مشاكل القلب.

•         الأدوية مثل حقن ميزولاستين، بنتاميدين، تيرفينادين، دوفيتيليد، إيبوتيليد أو إريثروميسين، والتي قد تغير نظم القلب.

•         الأدوية المضادة للسكري عن طريق الفم، مثل الميتفورمين، أو الأنسولين، المستخدمة لخفض نسبة السكر في الدم.

•         حاصرات بيتا وديازوكسيد، الأدوية المستخدمة لعلاج ارتفاع ضغط الدم أو انخفاض السكر في الدم، على التوالي، حيث يمكن أن يعزز أولميترول بلس تأثيرها على زيادة نسبة السكر في الدم.

•         ميثيل دوبا، دواء يستخدم لعلاج ارتفاع ضغط الدم.

•         الأدوية مثل النورأدرينالين، التي تستخدم لزيادة ضغط الدم وإبطاء معدل ضربات القلب.

•         دايفينامين، ويستخدم لعلاج بطء ضربات القلب أو تقليل التعرق.

•         الأدوية مثل البروبينسيد والسولفينبيرازون والألوبورينول المستخدمة لعلاج النقرس.

•         مكملات الكالسيوم.

•         أمانتادين، دواء مضاد للفيروسات.

•         السيكلوسبورين، دواء يستخدم لوقف رفض زراعة الأعضاء.

•         بعض المضادات الحيوية تسمى التتراسيكلين أو سبارفلوكساسين.

•         أمفوتريسين، دواء يستخدم لعلاج الالتهابات الفطرية.

•         بعض مضادات الحموضة، التي تستخدم لعلاج الكثير من حمض المعدة، مثل هيدروكسيد المغنيسيوم الألومنيوم، حيث يمكن تقليل تأثير اولميترول بلس قليلاً.

•         سيسابريد، ويستخدم لزيادة حركة الطعام في المعدة والأمعاء.

•         هالوفانترين، وتستخدم لعلاج الملاريا.

 أولميترول بلس مع الطعام والشراب

يمكن تناول اولميترول بلس مع الطعام أو بدونه. توخى الحذر عند شرب الكحول أثناء تناولك اولميترول بلس، حيث يشعر بعض الأشخاص بالإغماء أو الدوار. إذا حدث ذلك، فلا تشرب أي كحول.

 

المرضى ذوي البشرة السوداء

كما هو الحال مع الأدوية الأخرى المماثلة، يكون تأثير خفض ضغط الدم لـ أولميترول بلس أقل إلى حد ما في المرضى ذوي البشرة السوداء.

الحمل والرضاعة

يجب أن تخبري طبيبك إذا كنت تعتقدين أنك (أو قد تصبحين) حاملاً. عادةً ما ينصحك طبيبك بالتوقف عن تناول أولميترول بلس قبل الحمل أو بمجرد أن معرفتك أنك حامل، وسوف ينصحك بتناول دواء آخر بدلاً من أولميترول بلس.

لا ينصح باستخدام أولميترول بلس أثناء الحمل، ويجب عدم تناوله بعد أكثر من 3 أشهر من الحمل، لأنه قد يسبب ضررًا خطيرًا لطفلك إذا تم استخدامه بعد الشهر الثالث من الحمل.

الرضاعة الطبيعية

أخبري طبيبك إذا كنت مرضعة أو على وشك البدء في الرضاعة الطبيعية. لا ينصح باستخدام اولميترول بلس للأمهات المرضعات، وقد يختار طبيبك علاجًا آخر لك إذا كنت ترغبي في الرضاعة الطبيعية. إذا كنت حاملاً أو مرضعة، تعتقدين أنك حامل أو تخططين لإنجاب طفل، اسألي طبيبك أو الصيدلي للحصول على المشورة قبل تناول هذا الدواء.

  السياقة واستعمال المعدات

قد تشعر بالنعاس أو الدوار أثناء علاجك من ارتفاع ضغط الدم. في حالة حدوث ذلك، لا تقود السيارة أو تستخدم الآلات حتى تزول الأعراض. إسأل طبيبك للحصول على المشورة.

 يحتوي اولمترول بلس على اللاكتوز

يحتوي هذا الدواء على اللاكتوز (نوع من السكر). إذا أخبرك طبيبك أن لديك حساسية تجاه بعض السكريات، فاتصل بطبيبك قبل تناول هذا الدواء.

 

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احرص دائمًا على تناول هذا الدواء تمامًا كما أخبرك طبيبك. استشر طبيبك أو الصيدلي إذا لم تكن متأكدًا. 

الجرعة الموصى بها هي قرص واحد من اولميترول بلس 20 ملجم / 12.5 ملجم في اليوم.

ابتلع القرص مع الماء. إذا أمكن، يجب أن تأخذ جرعتك في نفس الوقت كل يوم، على سبيل المثال في وقت الإفطار. من المهم الاستمرار في تناول اولميترول بلس حتى يخبرك طبيبك بالتوقف.

إذا تناولت اولميترول بلس أكثر مما يجب

إذا تناولت أقراصًا أكثر مما ينبغي، أو إذا ابتلع طفل واحدًا أو أكثر عن طريق الخطأ، فانتقل إلى طبيبك أو أقرب قسم للحوادث والطوارئ على الفور وخذ علبة الدواء معك.

نسيان تناول اولميترول بلس

إذا نسيت تناول جرعة، فتناول جرعتك العادية في اليوم التالي كالمعتاد. لا تأخذ جرعة مضاعفة لتعويض الجرعة المنسية.

 التوقف عن تناول اولميترول بلس

من المهم الاستمرار في تناول اولميترول بلس ما لم يخبرك طبيبك بالتوقف. إذا كان لديك أي أسئلة أخرى حول استخدام هذا الدواء، اسأل طبيبك أو الصيدلي

مثل جميع الأدوية، يمكن أن يسبب هذا الدواء آثارًا جانبية، على الرغم من عدم حدوثها لدى الجميع.

ومع ذلك، يمكن أن تكون الآثار الجانبية التالية خطيرة:

•         نادرا ما تحدث تفاعلات تحسسية قد تصيب الجسم كله، مع انتفاخ في الوجه والفم و / أو صندوق الصوت (الحنجرة) مع حكة وطفح جلدي. إذا حدث هذا، توقف عن تناول اولميترول بلس واتصل بطبيبك على الفور.

•         يمكن أن يتسبب اولميترول بلس في انخفاض ضغط الدم بشكل شديد الانخفاض لدى الأفراد المعرضين للإصابة به أو نتيجة لرد فعل تحسسي. قد يحدث دوار أو إغماء بشكل غير شائع. إذا حدث هذا، توقف عن تناول اولميترول بلس، واتصل بطبيبك على الفور واستلقي.

•         التردد غير معروف: إذا كنت تعاني من اصفرار بياض العين، أو بول داكن، أو حكة في الجلد، حتى إذا بدأت العلاج بـ اولميترول بلس منذ فترة أطول، فاتصل بطبيبك على الفور الذي سيقيم الأعراض ويقرر كيفية القيام بذلك استمر في تناول دواء ضغط الدم.

اولميترول بلس هو مزيج من مادتين فعالتين، والمعلومات التالية تعطي أولاً الآثار الجانبية الأخرى التي تم الإبلاغ عنها حتى الآن مع توليفة اولميترول بلس إلى جانب تلك المذكورة أعلاه، وثانيًا، تلك المعروفة عن المواد الفعالة المنفصلة.

هذه هي الآثار الجانبية الأخرى المعروفة حتى الآن مع اولميترول بلس

في حالة حدوث هذه الآثار الجانبية، فإنها غالبًا ما تكون خفيفة ولا تحتاج إلى إيقاف العلاج.

أعراض جانبية شائعة (قد تظهر لدى حتى 1 من كل 10 أشخاص):

دوار، ضعف، صداع، إرهاق، ألم في الصدر، انتفاخ الكاحلين، القدمين، الرجلين، اليدين أو الذراعين.

 أعراض جانبية غير شائعة (قد تظهر لدى حتى 1 من كل 100 شخص):

 خفقان في القلب (خفقان)، طفح جلدي، أكزيما، دوار، سعال، عسر هضم، ألم بطني، غثيان، قيء، إسهال، تقلصات عضلية وآلام عضلية، ألم في المفاصل والذراعين والساقين، آلام الظهر، صعوبات في الانتصاب عند الرجال، دم في البول. كما لوحظت بعض التغيرات في نتائج فحص الدم بشكل غير شائع وتشمل: ارتفاع مستويات الدهون في الدم، ارتفاع اليوريا في الدم أو حمض اليوريك، ارتفاع الكرياتينين، ارتفاع أو نقص مستويات البوتاسيوم في الدم، ارتفاع مستويات الكالسيوم في الدم، ارتفاع نسبة السكر في الدم، زيادة في مستويات وظائف الكبد. سيعلم طبيبك عن هذه الأمور من خلال فحص الدم وسيخبرك إذا كنت بحاجة إلى القيام بأي شيء.

 أعراض جانبية نادرة (قد تظهر لدى حتى 1 من كل 1000 شخص):

 الشعور بتوعك، اضطرابات في الوعي، كتل جلدية (شرويه)، فشل كلوي حاد.

كما لوحظت بعض التغييرات في نتائج فحص الدم في حالات نادرة وتشمل: ارتفاع نيتروجين اليوريا في الدم، وانخفاض قيم الهيموجلوبين والهيماتوكريت. سيعلم طبيبك عن هذه الأمور من خلال فحص الدم وسيخبرك إذا كنت بحاجة إلى القيام بأي شيء.

تم الإبلاغ عن المزيد من الآثار الجانبية عند استخدام أولميسارتان ميدوكسوميل أو هيدروكلوروثيازيد بمفرده، ولكن ليس مع أولمترول بلس أو بتردد أعلى:

 

أولميسارتان ميدوكسوميل

أعراض جانبية شائعة (قد تظهر لدى حتى 1 من كل 10 أشخاص):

التهاب الشعب الهوائية، السعال، سيلان أو انسداد الأنف، التهاب الحلق، آلام البطن، عسر الهضم، الإسهال، الغثيان، التهاب المعدة والأمعاء، آلام المفاصل أو العظام، آلام الظهر، دم في البول، التهاب المسالك البولية، أعراض تشبه أعراض الأنفلونزا، ألم. كما لوحظت بعض التغيرات في نتائج فحص الدم بشكل شائع وتشمل: ارتفاع مستويات الدهون في الدم، ارتفاع اليوريا في الدم أو حمض اليوريك، زيادة في مستويات وظائف الكبد والعضلات.

أعراض جانبية غير شائعة (قد تظهر لدى حتى 1 من كل 100 شخص):

ردود فعل تحسسية سريعة قد تؤثر على الجسم كله وقد تسبب مشاكل في التنفس بالإضافة إلى انخفاض سريع في ضغط الدم قد يؤدي حتى إلى الإغماء (تفاعلات تأقيه)، تورم في الوجه، ذبحة صدرية (ألم أو شعور بعدم الراحة في الصدر؛ معروف. مثل الذبحة الصدرية)، الشعور بتوعك، طفح جلدي تحسسي، حكة، طفح جلدي (اندفاع جلدي)، كتل جلدية (شرويه).

كما لوحظت بعض التغييرات في نتائج فحص الدم بشكل غير شائع وتشمل: انخفاض عدد نوع من خلايا الدم، المعروف باسم الصفائح الدموية (قلة الصفيحات).

 

أعراض جانبية نادرة (قد تظهر لدى حتى 1 من كل 1000 شخص):

ضعف وظائف الكلى ونقص الطاقة. كما لوحظت بعض التغييرات في نتائج فحص الدم بشكل نادر وتشمل: زيادة في بوتاسيوم الدم.

هيدروكلوروثيازيد

أعراض جانبية شائعة جدًا (قد تظهر لدى أكثر من 1 من كل 10 أشخاص):

 تغيرات في نتائج الدم بما في ذلك: زيادة نسبة الدهون في الدم ومستويات حمض البوليك.

أعراض جانبية شائعة (قد تظهر لدى حتى 1 من كل 10 أشخاص):

الشعور بالارتباك، آلام في البطن، اضطراب في المعدة، شعور بالانتفاخ، إسهال، غثيان، قيء، إمساك، إفراز الجلوكوز في البول. كما لوحظت بعض التغيرات في نتائج الدم وتشمل: زيادة نسبة الكرياتينين في الدم، واليوريا، والكالسيوم، ومستويات السكر، وانخفاض مستويات كلوريد الدم، والبوتاسيوم، والمغنيسيوم، والصوديوم. زيادة إنزيم الأميلوز في الدم (فرط أميلوز الدم).

أعراض جانبية غير شائعة (قد تظهر لدى حتى 1 من كل 100 شخص):

انخفاض أو فقدان الشهية، صعوبة شديدة في التنفس، تفاعلات جلدية تأقيه (تفاعلات فرط الحساسية)، تفاقم حمامي قصر النظر الموجود مسبقًا، تفاعلات جلدية للضوء، حكة، بقع أرجوانية أو بقع على الجلد بسبب نزيف صغير، كتل الجلد (البثرات).

أعراض جانبية نادرة (قد تظهر لدى حتى 1 من كل 1000 شخص):

تورم الغدد اللعابية والتهابها ، وانخفاض عدد خلايا الدم البيضاء ، وانخفاض عدد الصفائح الدموية ، وفقر الدم ، وتلف نخاع العظام ، والأرق ، والشعور "بالإحباط" أو الاكتئاب ، ومشاكل النوم ، والشعور بعدم الاهتمام (اللامبالاة) ، والوخز والخدر ، والنوبات (تشنجات) ، الأشياء التي تنظر إليها تبدو صفراء ، عدم وضوح الرؤية ، جفاف العين ، عدم انتظام ضربات القلب ، التهاب الأوعية الدموية ، جلطات الدم (تجلط الدم أو الانسداد) ، التهاب الرئة ، تراكم السوائل في الرئتين ، التهاب البنكرياس ، اليرقان ، عدوى في المرارة ، أعراض الذئبة الحمامية (مثل الطفح الجلدي وآلام المفاصل وبرودة اليدين والأصابع) ، تفاعلات حساسية الجلد ، تقشير الجلد وتقرحاته ، التهاب الكلى غير المعدي (التهاب الكلية الخلالي) ، الحمى ، ضعف العضلات (يسبب أحيانًا ضعف الحركة).

أعراض جانبية نادرة جدًا (قد تظهر لدى حتى 1 من بين 10000 شخص):

اضطراب الكهارل الذي يؤدي إلى مستوى غير طبيعي من الكلوريد في الدم (قلاء سكر الدم)، انسداد في القناة الهضمية، الضائقة التنفسية الحادة (تشمل العلامات ضيق التنفس الشديد والحمى والضعف والارتباك).

غير معروف (لا يمكن تقدير التردد من البيانات المتاحة):

 انخفاض في الرؤية أو ألم في العين (علامات محتملة لتراكم السوائل في الطبقة الوعائية للعين (الانصباب المشيمي) أو زرق انسداد الزاوية الحاد). سرطان الجلد والشفة (سرطان الجلد غير الميلانين).

 

 

 

-        احفظ هذا الدواء بعيدًا عن أنظار ومتناول أيدي الأطفال.

-        يحفظ في درجة حرارة أقل من 30 درجة مئوية، ويحفظ في العلبة الأصلية للحماية من الرطوبة.

-        لا يجوز استعمال هذا الدواء بعد انتهاء تاريخ الصلاحية المدون على العلبة الكرتونية وعلى شريط اللويحة بعد. يشير تاريخ انتهاء الصلاحية إلى اليوم الأخير من نفس الشهر.

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.

 

أولميترول بلس 20 ملجم / 12.5 ملجم: كل قرص مغلف يحتوي على 20 ملجم أولميسارتان ميدوكسوميل و12.5 ملجم هيدروكلوروثيازيد.

المكونات الأخرى هي مونوهيدرات اللاكتوز ، هيدروكسي بروبيل السليلوز منخفض الاستبدال ،هيدروكسي بروبيل السليلوز ، مايكرو كريستالين سيليلوز ، ستيرات المغنيسيوم ،هيبروميللوز ، التلك ، ثاني أكسيد التيتانيوم ، أكسيد الحديد الأحمر ، أكسيد الحديد الأصفر، أكسيد الحديدوز فيريك والماء النقي.

 

 

أولميترول بلس 20 ملجم / 12.5 ملجم: قرص مغطى بطبقة رقيقة صفراء اللون دائرية الشكل مع (CT22) منقوش على جانب واحد وسهل على الجانب الآخر.

 

العبوة: تحتوي على 3 أشرطه المنيوم على شكل (10 أقراص لكل شريط ) 30 قرصًا في الكرتون.

شركة المنتجات الطبية والتجميلية المحدودة (الرياض فارما)

ص.ب 442 الرياض 11411

الفاكس: +966 11265 0505

البريد الالكتروني : contact@riyadhpharma.com

للحصول على أي معلومات حول هذا المنتج الطبي، يرجى الاتصال بالممثل المحلي لصاحب ترخيص التسويق:

المملكة العربية السعودية

قسم التسويق

الرياض

هاتف: +966 11265 0111

البريد الإلكتروني: marketing@riyadhpharma.com

09/2022
 Read this leaflet carefully before you start using this product as it contains important information for you

Olmesartan/Hydrochlorothiazide 40 mg/25 ,12.5 mg film-coated tablets Olmesartan/Hydrochlorothiazide 20 mg/12.5 mg film-coated tablets

Olmetrol Plus 40 mg/12.5 mg: Each film-coated tablet contains 40 mg olmesartan medoxomil and 12.5 mg hydrochlorothiazide. Olmetrol Plus 40 mg/25 mg: Each film-coated tablet contains 40 mg olmesartan medoxomil and 25 mg hydrochlorothiazide. Olmetrol Plus 20 mg/12.5 mg: Each film-coated tablet contains 20 mg olmesartan medoxomil and 12.5 mg hydrochlorothiazide. Alu/Alu blister as 10 tablets per blister (30 tablets per carton) For a full list of excipients, see Section 6.1

Film-coated tablet.

Treatment of essential hypertension.

Olmesartan/Hydrochlorothiazide 40 mg/12.5 mg and 40 mg/25 mg ,20 mg/12.5 mg fixed dose combinations are indicated in adult patients whose blood pressure is not adequately controlled on olmesartan medoxomil 40 mg alone.

 


Posology

Adults

The recommended dose of Olmesartan/Hydrochlorothiazide 40 mg/12.5 mg or Olmesartan/Hydrochlorothiazide 40 mg/25 mg is 1 tablet per day.

 The recommended dose is one Olmetrol Plus 20 mg/12.5 mg tablet a day

Olmesartan/Hydrochlorothiazide 40 mg/12.5 mg may be administered in patients whose blood pressure is not adequately controlled by olmesartan medoxomil 40 mg alone.

Olmesartan/Hydrochlorothiazide 40 mg /25 mg may be administered in patients whose blood pressure is not adequately controlled on Olmesartan/Hydrochlorothiazide 40 mg/12.5 mg fixed dose combination.

For convenience, patients receiving olmesartan medoxomil and hydrochlorothiazide from separate tablets may be switched to Olmesartan/Hydrochlorothiazide 40 mg/12.5 mg and 40 mg/25 mg tablets containing the same component doses.

This medicine can be taken with or without food.

Elderly (age 65 years or over)

In elderly people the same dosage of the combination is recommended as for adults.

Blood pressure should be closely monitored.

Renal impairment

Olmesartan/Hydrochlorothiazide is contraindicated in patients with severe renal impairment (creatinine clearance < 30 ml/min) (see section 4.3).

The maximum dose of olmesartan medoxomil in patients with mild to moderate renal impairment (creatinine clearance of 30 – 60 ml/min) is 20 mg olmesartan medoxomil once daily, owing to limited experience of higher dosages in this patient group, and periodic monitoring is advised.

Olmesartan/Hydrochlorothiazide 40 mg/12.5 mg and 40 mg/25 mg are therefore contraindicated in all stages of renal impairment (see sections 4.3, 4.4, 5.2).

Hepatic impairment

Olmesartan/Hydrochlorothiazide 40 mg/12.5 mg and 40 mg/25 mg should be used with caution in patients with mild hepatic impairment (see sections 4.4, 5.2). Close monitoring of blood pressure and renal function is advised in hepatically-impaired patients who are receiving diuretics and/or other antihypertensive agents. In patients with moderate hepatic impairment, an initial dose of 10 mg olmesartan medoxomil once daily is recommended and the maximum dose should not exceed 20 mg once daily. There is no experience of olmesartan medoxomil in patients with severe hepatic impairment. <Product Name> 40 mg/12.5 mg and 40 mg/25 mg therefore should not be used in patients with moderate and severe hepatic impairment (see sections 4.3, 5.2), as well as in cholestasis and biliary obstruction (see section 4.3).

Paediatric population

The safety and efficacy of olmesartan/hydrochlorothiazide in children and adolescents below 18 years has not been established. No data are available.

Method of administration

Olmesartan/Hydrochlorothiazide is administered once daily, with or without food. The tablet should be swallowed with a sufficient amount of fluid (e.g. one glass of water). The tablet should not be chewed and should be taken at the same time each day.

 


• Hypersensitivity to the active substances, to any of the excipients listed in section 6.1 or to other sulfonamide-derived substances (since hydrochlorothiazide is a sulfonamide-derived medicinal product). • Renal impairment (see sections 4.4 and 5.2). • Refractory hypokalaemia, hypercalcaemia, hyponatraemia and symptomatic hyperuricaemia. • Moderate and severe hepatic impairment, cholestasis and biliary obstructive disorders (see section 5.2). • 2nd and 3rd trimester of pregnancy (see sections 4.4 and 4.6). • The concomitant use of olmesartan medoxomil/hydrochlorothiazide with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see sections 4.5 and 5.1).

Non-melanoma skin cancer

An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with increasing cumulative dose of hydrochlorothiazide (HCTZ) exposure has been observed in two epidemiological studies based on the Danish National Cancer Registry. Photosensitizing actions of HCTZ could act as a possible mechanism for NMSC.

Patients taking HCTZ should be informed of the risk of NMSC and advised to regularly check their skin for any new lesions and promptly report any suspicious skin lesions. Possible preventive measures such as limited exposure to sunlight and UV rays and, in case of exposure, adequate protection should be advised to the patients in order to minimize the risk of skin cancer. Suspicious skin lesions should be promptly examined potentially including histological examinations of biopsies. The use of HCTZ may also need to be reconsidered in patients who have experienced previous NMSC (see also section 4.8).

Intravascular volume depletion

Symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be corrected before the administration of olmesartan medoxomil/hydrochlorothiazide.

Other conditions with stimulation of the renin-angiotensin-aldosterone system

In patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin- aldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with medicinal products that affect this system has been associated with acute hypotension, azotaemia, oliguria or, rarely, acute renal failure.

Renovascular hypertension

There is an increased risk of severe hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with medicinal products that affect the renin- angiotensin-aldosterone system.

Renal impairment and kidney transplantation

Olmesartan medoxomil/hydrochlorothiazide should not be used in patients with severe renal impairment (creatinine clearance < 30 ml/min).

The maximum dose of olmesartan medoxomil in patients with mild to moderate renal impairment (creatinine clearance of 30 – 60 ml/min) is 20 mg olmesartan medoxomil once daily. However, in such patients olmesartan medoxomil/hydrochlorothiazide 20 mg/12.5 mg and 20 mg/25 mg should be administered with caution and periodic monitoring of serum potassium, creatinine and uric acid levels is recommended. Thiazide diuretic- associated azotaemia may occur in patients with impaired renal function. If progressive renal impairment becomes evident, careful reappraisal of therapy is necessary, with consideration given to discontinuing diuretic therapy.

Olmesartan medoxomil/hydrochlorothiazide 40 mg/12.5 mg and 40 mg/25 mg is therefore contraindicated in all stages of renal impairment (see section 4.3).

There is no experience of the administration of olmesartan/hydrochlorothiazide in patients with a recent kidney transplantation.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1).

If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.

ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Hepatic impairment

There is currently no experience of olmesartan medoxomil in patients with severe hepatic impairment. In patients with moderate hepatic impairment, the maximum dose is 20 mg olmesartan medoxomil.

Furthermore, minor alterations of fluid and electrolyte balance during thiazide therapy may precipitate hepatic coma in patients with impaired hepatic function or progressive liver disease.

Therefore the use of olmesartan medoxomil/hydrochlorothiazide 40 mg/12.5 mg and 40 mg/25 mg in patients with moderate and severe hepatic impairment, cholestasis and biliary obstruction is contraindicated (see sections 4.3, 5.2). Care should be taken in patients with mild impairment (see section 4.2).

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy

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

Primary aldosteronism

Patients with primary aldosteronism generally will not respond to anti-hypertensive medicinal products acting through inhibition of the renin-angiotensin system. Therefore, the use of olmesartan medoxomil/hydrochlorothiazide is not recommended in such patients.

Metabolic and endocrine effects

Thiazide therapy may impair glucose tolerance. In diabetic patients dosage adjustments of insulin or oral hypoglycaemic agents may be required (see section 4.5). Latent diabetes mellitus may become manifest during thiazide therapy.

Increases in cholesterol and triglyceride levels are undesirable effects known to be associated with thiazide diuretic therapy.

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

Electrolyte imbalance

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

Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (including hypokalaemia, hyponatraemia and hypochloraemic alkalosis). Warning signs of fluid or electrolyte imbalance are dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea or vomiting (see section 4.8).

The risk of hypokalaemia is greatest in patients with cirrhosis of the liver, in patients experiencing brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes and in patients receiving concomitant therapy with corticosteroids or ACTH (see section 4.5).

Conversely, due to antagonism at the angiotensin-II receptors (AT1) through the olmesartan medoxomil component of this medicine hyperkalaemia may occur, especially in the presence of renal impairment and/or heart failure, and diabetes mellitus. Adequate monitoring of serum potassium in patients at risk is recommended.

Potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes and other medicinal products that may increase serum potassium levels (e.g. heparin) should be co-administered cautiously with olmesartan medoxomil/hydrochlorothiazide (see section 4.5).

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

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

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

Dilutional hyponatraemia may occur in oedematous patients in hot weather.

Lithium

As with other angiotensin II receptor antagonists, the coadministration of olmesartan medoxomil/hydrochlorothiazide and lithium is not recommended (see section 4.5).

Sprue-like enteropathy

In very rare cases severe, chronic diarrhoea with substantial weight loss has been reported in patients taking olmesartan few months to years after drug initiation, possibly caused by a localised delayed hypersensitivity reaction. Intestinal biopsies of patients often demonstrated villous atrophy. If a patient develops these symptoms during treatment with olmesartan, and in the absence of other apparent aetiologies, olmesartan treatment should be immediately discontinued and should not be restarted. If diarrhoea does not improve during the week after the discontinuation, further specialist (e.g. a gastro-enterologist) advice should be considered.

Choroidal Effusion, Acute Myopia and Secondary Angle-Closure Glaucoma

Hydrochlorothiazide, a sulfonamide, 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 hydrochlorothiazide 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.

Ethnic differences

As with all other angiotensin II receptor antagonist containing products, the blood pressure lowering effect of olmesartan medoxomil is somewhat less in black patients than in non-black patients, possibly because of a higher prevalence of low-renin status in the black hypertensive population.

Anti-doping test

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

Pregnancy

Angiotensin II receptor antagonists should not be initiated during pregnancy. Unless continued angiotensin II receptor antagonists 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 angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

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, this medicinal product should be withdrawn and appropriate treatment given. Hydrochlorothiazide should not be administered to patients who previously experienced ARDS following hydrochlorothiazide intake.

Other

As with any antihypertensive agent, excessive blood pressure decrease in patients with ischaemic heart disease or ischaemic cerebrovascular disease could result in a myocardial infarction or stroke.

Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history.

Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide diuretics.

This medicinal product contains lactose

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

 

Medicinal products used in the treatment of gout (e.g. probenecid, sulfinpyrazone and allopurinol)

Dosage adjustment of uricosuric medicinal products may be necessary since hydrochlorothiazide may raise the level of serum uric acid. Increase in dosage of probenecid or sulfinpyrazone may be necessary. Coadministration of a thiazide may increase the incidence of hypersensitivity reactions to allopurinol.

Amantadine

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

Cytotoxic agents (e.g. cyclophosphamide, methotrexate)

Thiazides may reduce the renal excretion of cytotoxic medicinal products and potentiate their myelosuppressive effects.

Salicylates

In case of high dosages of salicylates hydrochlorothiazide may enhance the toxic effect of the salicylates on the central nervous system.

Methyldopa

There have been isolated reports of haemolytic anaemia occurring with concomitant use of hydrochlorothiazide and methyldopa.

Cyclosporine

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

Tetracyclines

Concomitant administration of tetracyclines and thiazides increases the risk of tetracycline-induced increase in urea.

This interaction is probably not applicable to doxycycline.


Potential interactions related to both olmesartan medoxomil and hydrochlorothiazide

Concomitant use not recommended

Lithium

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors and, rarely, with angiotensin II receptor antagonists. In addition, renal clearance of lithium is reduced by thiazides and consequently the risk of lithium toxicity may be increased. Therefore use of olmesartan medoxomil/hydrochlorothiazide and lithium in combination is not recommended (see section 4.4). If use of the combination proves necessary, careful monitoring of serum lithium levels is recommended.

Concomitant use requiring caution

Baclofen

Potentiation of antihypertensive effect may occur.

Non-steroidal anti-inflammatory medicinal products

NSAIDs (i.e. acetylsalicylic acid (> 3 g/day), COX-2 inhibitors and non-selective NSAIDs) may reduce the antihypertensive effect of thiazide diuretics and angiotensin II receptor antagonists.

In some patients with compromised renal function (e.g. dehydrated patients or elderly people with compromised renal function) the co-administration of angiotensin II receptor antagonists and agents that inhibit cyclo-oxygenase may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, the combination should be administered with caution, especially in elderly people. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy and periodically thereafter.

Concomitant use to be taken into account

Amifostine

Potentiation of antihypertensive effect may occur.

Other antihypertensive agents

The blood pressure lowering effect of olmesartan medoxomil/hydrochlorothiazide can be increased by concomitant use of other antihypertensive medicinal products.

Alcohol, barbiturates, narcotics or antidepressants

Potentiation of orthostatic hypotension may occur.

Potential interactions related to olmesartan medoxomil

Concomitant use not recommended

ACE-inhibitors, angiotensin II receptor blockers 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 a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).

Medicinal products affecting potassium levels

Based on experience with the use of other medicinal products that affect the renin angiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products that may increase serum potassium levels (e.g. heparin, ACE inhibitors) may lead to increases in serum potassium (see section 4.4). If medicinal products which affect potassium levels are to be prescribed in combination with olmesartan/hydrochlorothiazide, monitoring of potassium plasma levels is advised.

Bile acid sequestering agent colesevelam

Concurrent administration of the bile acid sequestering agent colesevelam hydrochloride reduces the systemic exposure and peak plasma concentration of olmesartan and reduces t1/2. Administration of olmesartan medoxomil at least 4 hours prior to colesevelam hydrochloride decreased the drug interaction effect. Administering olmesartan medoxomil at least 4 hours before the colesevelam hydrochloride dose should be considered (see section 5.2).

Additional information

After treatment with antacid (aluminium magnesium hydroxide), a modest reduction in bioavailability of olmesartan was observed.

Olmesartan medoxomil had no significant effect on the pharmacokinetics or pharmacodynamics of warfarin or the pharmacokinetics of digoxin.

Coadministration of olmesartan medoxomil with pravastatin had no clinically relevant effects on the pharmacokinetics of either component in healthy subjects.

Olmesartan had no clinically relevant inhibitory effects on human cytochrome P450 enzymes 1A1/2, 2A6, 2C8/9, 2C19, 2D6, 2E1 and 3A4 in vitro, and had no or minimal inducing effects on rat cytochrome P450 activities. No clinically relevant interactions between olmesartan and medicinal products metabolised by the above cytochrome P450 enzymes are expected.

Potential interactions related to hydrochlorothiazide

Concomitant use not recommended

Medicinal products affecting potassium levels

The potassium-depleting effect of hydrochlorothiazide (see section 4.4) may be potentiated by the coadministration of other medicinal products associated with potassium loss and hypokalaemia (e.g. other kaliuretic diuretics, laxatives, corticosteroids, ACTH, amphotericin, carbenoxolone, penicillin G sodium or salicylic acid derivatives). Such concomitant use is therefore not recommended.

Concomitant use requiring caution

Calcium salts

Thiazide diuretics may increase serum calcium levels due to decreased excretion. If calcium supplements must be prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly.

Cholestyramine and colestipol resins

Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins.

Digitalis glycosides

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

Medicinal products affected by serum potassium disturbances

Periodic monitoring of serum potassium and ECG is recommended when olmesartan/hydrochlorothiazide is administered with medicinal products affected by serum potassium disturbances (e.g. digitalis glycosides and antiarrhythmics) and with the following torsades de pointes (ventricular tachycardia)-inducing medicinal products (including some antiarrhythmics), hypokalaemia being a predisposing factor to torsades de pointes (ventricular tachycardia):

• Class Ia antiarrhythmics (e.g. quinidine, hydroquinidine, disopyramide).

• Class III antiarrhythmics (e.g. amiodarone, sotalol, dofetilide, ibutilide).

• Some antipsychotics (e.g. thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol).

• Others (e.g. bepridil, cisapride, diphemanil, erythromycin IV, halofantrine, mizolastine, pentamidine, sparfloxacin, terfenadine, vincamine IV).

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

The effect of non-depolarising skeletal muscle relaxants may be potentiated by hydrochlorothiazide.

Anticholinergic agents (e.g. atropine, biperiden)

Increase of the bioavailability of thiazide-type diuretics by decreasing gastrointestinal motility and stomach emptying rate.

Antidiabetic medicinal products (oral agents and insulin)

The treatment with a thiazide may influence the glucose tolerance. Dosage adjustment of the antidiabetic medicinal product may be required (see section 4.4).

Metformin

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

The hyperglycaemic effect of beta-blockers and diazoxide may be enhanced by thiazides.

Pressor amines (e.g. noradrenaline)

The effect of pressor amines may be decreased.

Medicinal products used in the treatment of gout (e.g. probenecid, sulfinpyrazone and allopurinol)

Dosage adjustment of uricosuric medicinal products may be necessary since hydrochlorothiazide may raise the level of serum uric acid. Increase in dosage of probenecid or sulfinpyrazone may be necessary. Coadministration of a thiazide may increase the incidence of hypersensitivity reactions to allopurinol.

Amantadine

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

Cytotoxic agents (e.g. cyclophosphamide, methotrexate)

Thiazides may reduce the renal excretion of cytotoxic medicinal products and potentiate their myelosuppressive effects.

Salicylates

In case of high dosages of salicylates hydrochlorothiazide may enhance the toxic effect of the salicylates on the central nervous system.

Methyldopa

There have been isolated reports of haemolytic anaemia occurring with concomitant use of hydrochlorothiazide and methyldopa.

Cyclosporine

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

Tetracyclines

Concomitant administration of tetracyclines and thiazides increases the risk of tetracycline-induced increase in urea.

This interaction is probably not applicable to doxycycline


Pregnancy

Given the effects of the individual components in this combination product on pregnancy, the use of olmesartan medoxomil/hydrochlorothiazide is not recommended during the first trimester of pregnancy (see section 4.4). The use of olmesartan medoxomil/hydrochlorothiazide is contraindicated during the 2nd and 3rd trimester of pregnancy (see sections 4.3 and 4.4).

Olmesartan medoxomil

The use of angiotensin II receptor antagonists is not recommended during the first trimester of pregnancy (see section 4.4). The use of angiotensin II receptor antagonists is contraindicated during the 2nd and 3rd 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 antagonists, similar risks may exist for this class of drugs. Unless continued angiotensin receptor blocker 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 angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started.

Exposure to angiotensin II receptor antagonists therapy during the 2nd and 3rd trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see also section 5.3 “Preclinical safety data”).

Should exposure to angiotensin II receptor antagonists have occurred from the 2nd trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken angiotensin II receptor antagonists should be closely observed for hypotension (see sections 4.3 and 4.4).

Hydrochlorothiazide

There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient.

Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide its use during the 2nd and 3rd trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia.

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

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

Breast-feeding

Olmesartan medoxomil

Because no information is available regarding the use of olmesartan/hydrochlorothiazide during breast-feeding, olmesartan medoxomil/hydrochlorothiazide is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

Hydrochlorothiazide

Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit the milk production.

The use of olmesartan medoxomil/hydrochlorothiazide during breast-feeding is not recommended. If olmesartan medoxomil/hydrochlorothiazide is used during breast feeding, doses should be kept as low as possible.

 


Olmesartan medoxomil/hydrochlorothiazide can have minor or moderate influence on the ability to drive and use machines. Dizziness or fatigue may occasionally occur in patients taking antihypertensive therapy, which may impair the ability to react.


The most commonly reported adverse reactions during treatment with olmesartan medoxomil/hydrochlorothiazide are headache (2.9 %), dizziness (1.9 %) and fatigue (1.0 %).

Hydrochlorothiazide may cause or exacerbate volume depletion which may lead to electrolyte imbalance (see section 4.4).

The safety of olmesartan medoxomil/hydrochlorothiazide 40 mg/12.5 mg and 40 mg/25 mg was investigated in clinical trials in 3,709 patients receiving olmesartan medoxomil in combination with hydrochlorothiazide.

Further adverse reactions reported with the fixed dose combination of olmesartan medoxomil and hydrochlorothiazide in the lower dose strengths 20 mg/12.5 mg and 20 mg/25 mg may be potential adverse reactions with Olmesartan/Hydrochlorothiazide 40 mg/12.5 mg and 40 mg/25 mg.

Adverse reactions from olmesartan medoxomil/hydrochlorothiazide in clinical trials, post-authorisation safety studies and spontaneous reporting are summarised in the below table as well as adverse reactions from the individual components olmesartan medoxomil and hydrochlorothiazide based on the known safety profile of these substances.

The following terminologies have been used in order to classify the occurrence of adverse reactions: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data).

MedDRA

System Organ Class

Adverse reactions

Frequency

Olmesartan/HCTZ

Olmesartan

HCTZ

Infections and infestations

Sialadenitis

  

Rare

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

Non-melanomic skin cancer (Basal cell carcinoma and Squamous cell carcinoma)

  

Not known

Blood and lymphatic system disorders

Aplastic anaemia

  

Rare

Bone marrow depression

  

Rare

Haemolytic anaemia

  

Rare

Leukopenia

  

Rare

Neutropenia/Agranulocytosis

  

Rare

Thrombocytopenia

 

Uncommon

Rare

Immune system disorders

Anaphylactic reactions

 

Uncommon

Uncommon

Metabolism and nutrition disorders

Anorexia

  

Uncommon

Glycosuria

  

Common

Hypercalcaemia

  

Common

Hypercholesterolaemia

Uncommon

 

Very common

Hyperglycaemia

  

Common

Hyperkalaemia

 

Rare

 

Hypertriglyceridaemia

Uncommon

Common

Very common

Hyperuricaemia

Uncommon

Common

Very common

Hypochloraemia

  

Common

Hypochloraemic alkalosis

  

Very rare

Hypokalaemia

  

Common

Hypomagnesaemia

  

Common

Hyponatraemia

  

Common

Hyperamylasaemia

  

Common

Psychiatric disorders

Apathy

  

Rare

Depression

  

Rare

Restlessness

  

Rare

Sleep disturbance

  

Rare

Nervous system disorders

Confusional state

  

Common

Convulsions

  

Rare

Disturbances in consciousness (such as loss of consciousness)

Rare

  

Dizziness/light-headedness

Common

Common

Common

Headache

Common

Common

Rare

Loss of appetite

  

Uncommon

Paraesthesia

  

Rare

Postural dizziness

Uncommon

  

Somnolence

Uncommon

  

Syncope

Uncommon

  

Eye disorders

Lacrimation decreased

  

Rare

Transient blurred vision

  

Rare

Worsening of pre-existing myopia

  

Uncommon

Choroidal effusion, acute myopia, acute angle-closure glaucoma

  

Not known

Xanthopsia

  

Rare

Ear and labyrinth disorders

Vertigo

Uncommon

Uncommon

Rare

Cardiac disorders

Angina pectoris

 

Uncommon

 

Cardiac arrhythmias

  

Rare

Palpitations

Uncommon

  

Vascular disorders

Embolism

  

Rare

Hypotension

Uncommon

Rare

 

Necrotising angiitis (vasculitis, cutaneous vasculitis)

  

Rare

Orthostatic hypotension

Uncommon

 

Uncommon

Thrombosis

  

Rare

Respiratory, thoracic and mediastinal disorders

Acute respiratory distress syndrome (ARDS) (see section 4.4)

  

Very rare

Bronchitis

 

Common

 

Cough

Uncommon

Common

 

Dyspnoea

  

Rare

Interstitial pneumonia

  

Rare

Pharyngitis

 

Common

 

Pulmonary oedema

  

Rare

Respiratory distress

  

Uncommon

Rhinitis

 

Common

 

Gastrointestinal disorders

Abdominal pain

Uncommon

Common

Common

Constipation

  

Common

Diarrhoea

Uncommon

Common

Common

Dyspepsia

Uncommon

Common

 

Gastric irritation

  

Common

Gastroenteritis

 

Common

 

Meteorism

  

Common

Nausea

Uncommon

Common

Common

Pancreatitis

  

Rare

Paralytic ileus

  

Very rare

Vomiting

Uncommon

Uncommon

Common

Sprue-like enteropathy (see section 4.4)

 

Very rare

 

Hepatobiliary disorders

Acute cholecystitis

  

Rare

Jaundice (intrahepatic cholestatic icterus)

  

Rare

Autoimmune hepatitis*

 

Not known

 

Skin and subcutaneous tissue disorders

Allergic dermatitis

 

Uncommon

 

Anaphylactic skin reactions

  

Rare

Angioneurotic oedema

Rare

Rare

 

Cutaneous lupus erythematosus-like reactions

  

Rare

Eczema

Uncommon

  

Erythema

  

Uncommon

Exanthem

 

Uncommon

 

Photosensitivity reactions

  

Uncommon

Pruritus

 

Uncommon

Uncommon

Purpura

  

Uncommon

Rash

Uncommon

Uncommon

Uncommon

Reactivation of cutaneous lupus erythematosus

  

Rare

Toxic epidermal necrolysis

  

Rare

Urticaria

Rare

Uncommon

Uncommon

Musculoskeletal and connective tissue disorders

Arthralgia

Uncommon

  

Arthritis

 

Common

 

Back pain

Uncommon

Common

 

Muscle spasm

Uncommon

Rare

 

Muscular weakness

  

Rare

Myalgia

Uncommon

Uncommon

 

Pain in extremity

Uncommon

  

Paresis

  

Rare

Skeletal pain

 

Common

 

Renal and urinary disorders

Acute renal failure

Rare

Rare

 

Haematuria

Uncommon

Common

 

Interstitial nephritis

  

Rare

Renal insufficiency

 

Rare

 

Renal dysfunction

  

Rare

Urinary tract infection

 

Common

 

Reproductive system and breast disorders

Erectile dysfunction

Uncommon

 

Uncommon

General disorders and administration site conditions

Asthenia

Common

Uncommon

 

Chest pain

Common

Common

 

Face oedema

 

Uncommon

 

Fatigue

Common

Common

 

Fever

  

Rare

Influenza-like symptoms

 

Common

 

Lethargy

 

Rare

 

Malaise

Rare

Uncommon

 

Pain

 

Common

 

Peripheral oedema

Common

Common

 

Weakness

Uncommon

  

Investigations

Alanine aminotransferase increased

Uncommon

  

Aspartate aminotransferase increased

Uncommon

  

Blood calcium increased

Uncommon

  

Blood creatinine increased

Uncommon

Rare

Common

Blood creatine phosphokinase increased

 

Common

 

Blood glucose increased

Uncommon

  

Blood haematocrit decreased

Rare

  

Blood haemoglobin decreased

Rare

  

Blood lipids increased

Uncommon

  

Blood potassium decreased

Uncommon

  

Blood potassium increased

Uncommon

  

Blood urea increased

Uncommon

Common

Common

Blood urea nitrogen increased

Rare

  

Blood uric acid increased

Rare

  

Gamma glutamyl transferase increased

Uncommon

  

Hepatic enzymes increased

 

Common

 

*Cases of autoimmune hepatitis with a latency of few months to years have been reported post-marketing, that were reversible after the withdrawal of olmesartan.

Description of selected adverse reactions

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

Single cases of rhabdomyolysis have been reported in temporal association with the intake of angiotensin II receptor blockers.

Reporting of suspected adverse reactions

National Pharmacovigilance and Drug Safety Center (NPC)

o Fax: +966-11-205-7662

o To call the executive management of vigilance and crisis management: +966-11-2038222 ext.: 2353 – 2356 – 2317 – 2354 – 2334 – 2340

o Toll-free: 8002490000

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

o Website: www.sfda.gov.sa/npc

 

 

 


No specific information is available on the effects or treatment of olmesartan/hydrochlorothiazide overdose. The patient should be closely monitored, and the treatment should be symptomatic and supportive. Management depends upon the time since ingestion and the severity of the symptoms. Suggested measures include induction of emesis and/or gastric lavage. Activated charcoal may be useful in the treatment of overdose. Serum electrolytes and creatinine should be monitored frequently. If hypotension occurs, the patient should be placed in a supine position, with salt and volume replacements given quickly.

The most likely manifestations of olmesartan medoxomil overdose are expected to be hypotension and tachycardia; bradycardia might also occur. Overdose with hydrochlorothiazide is associated with electrolyte depletion (hypokalaemia, hypochloraemia) and dehydration resulting from excessive diuresis. The most common signs and symptoms of overdose are nausea and somnolence. Hypokalaemia may result in muscle spasm and/or accentuate cardiac arrhythmias associated with the concomitant use of digitalis glycosides or certain anti-arrhythmic medicinal products.

No information is available regarding the dialysability of olmesartan or hydrochlorothiazide.


Pharmacotherapeutic group: Angiotensin II antagonists and diuretics, ATC code: C09DA08.

Mechanism of action / Pharmacodynamic effects

Olmesartan medoxomil/hydrochlorothiazide is a combination of an angiotensin II receptor antagonist, olmesartan medoxomil, and a thiazide diuretic, hydrochlorothiazide. The combination of these ingredients has an additive antihypertensive effect, reducing blood pressure to a greater degree than either component alone.

Once daily dosing with olmesartan medoxomil/hydrochlorothiazide provides an effective and smooth reduction in blood pressure over the 24 hour dose interval.

Olmesartan medoxomil is an orally active, selective angiotensin II receptor (type AT1) antagonist. Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system and plays a significant role in the pathophysiology of hypertension. The effects of angiotensin II include vasoconstriction, stimulation of the synthesis and release of aldosterone, cardiac stimulation and renal reabsorption of sodium. Olmesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by blocking its binding to the AT1 receptor in tissues including vascular smooth muscle and the adrenal gland. The action of olmesartan is independent of the source or route of synthesis of angiotensin II. The selective antagonism of the angiotensin II (AT1) receptors by olmesartan results in increases in plasma renin levels and angiotensin I and II concentrations, and some decrease in plasma aldosterone concentrations.

In hypertension, olmesartan medoxomil causes a dose-dependent, long-lasting reduction in arterial blood pressure. There has been no evidence of first-dose hypotension, of tachyphylaxis during long-term treatment, or of rebound hypertension after abrupt cessation of therapy.

Once daily dosing with olmesartan medoxomil provides an effective and smooth reduction in blood pressure over the 24 hour dose interval. Once daily dosing produced similar decreases in blood pressure as twice daily dosing at the same total daily dose.

With continuous treatment, maximum reductions in blood pressure are achieved by 8 weeks after the initiation of therapy, although a substantial proportion of the blood pressure lowering effect is already observed after 2 weeks of treatment.

The effect of olmesartan medoxomil on mortality and morbidity is not yet known.

The Randomised Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study in 4,447 patients with type 2 diabetes, normo-albuminuria and at least one additional cardiovascular risk factor, investigated whether treatment with olmesartan could delay the onset of microalbuminuria. During the median follow-up duration of 3.2 years, patients received either olmesartan or placebo in addition to other antihypertensive agents, except ACE inhibitors or ARBs.

For the primary endpoint, the study demonstrated a significant risk reduction in the time to onset of microalbuminuria, in favour of olmesartan. After adjustment for BP differences this risk reduction was no longer statistically significant. 8.2 % (178 of 2,160) of the patients in the olmesartan group and 9.8 % (210 of 2,139) in the placebo group developed microalbuminuria.

For the secondary endpoints, cardiovascular events occurred in 96 patients (4.3 %) with olmesartan and in 94 patients (4.2 %) with placebo. The incidence of cardiovascular mortality was higher with olmesartan compared to placebo treatment (15 patients (0.7 %) vs. 3 patients (0.1 %)), despite similar rates for non-fatal stroke (14 patients (0.6 %) vs. 8 patients (0.4 %)), non-fatal myocardial infarction (17 patients (0.8 %) vs. 26 patients (1.2 %)) and non-cardiovascular mortality (11 patients (0.5 %) vs. 12 patients (0.5 %)). Overall mortality with olmesartan was numerically increased (26 patients (1.2 %) vs. 15 patients (0.7 %)), which was mainly driven by a higher number of fatal cardiovascular events.

The Olmesartan Reducing Incidence of End-stage Renal Disease in Diabetic Nephropathy Trial (ORIENT) investigated the effects of olmesartan on renal and cardiovascular outcomes in 577 randomised Japanese and Chinese type 2 diabetic patients with overt nephropathy. During a median follow-up of 3.1 years, patients received either olmesartan or placebo in addition to other antihypertensive agents including ACE inhibitors.

The primary composite endpoint (time to first event of the doubling of serum creatinine, end-stage renal disease, all cause death) occurred in 116 patients in the olmesartan group (41.1 %) and 129 patients in the placebo group (45.4 %) (HR 0.97 (95 % CI 0.75 to 1.24); p = 0.791). The composite secondary cardiovascular endpoint occurred in 40 olmesartan-treated patients (14.2 %) and 53 placebo-treated patients (18.7 %). This composite cardiovascular endpoint included cardiovascular death in 10 (3.5 %) patients receiving olmesartan versus 3 (1.1 %) receiving placebo, overall mortality 19 (6.7 %) versus 20 (7.0 %), non-fatal stroke 8 (2.8 %) versus 11 (3.9 %) and non-fatal myocardial infarction 3 (1.1 %) versus 7 (2.5 %), respectively.

Hydrochlorothiazide is a thiazide diuretic. The mechanism of the antihypertensive effect of thiazide diuretics is not fully known. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. The diuretic action of hydrochlorothiazide reduces plasma volume, increases plasma renin activity and increases aldosterone secretion, with consequent increases in urinary potassium and bicarbonate loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II and therefore coadministration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with thiazide diuretics. With hydrochlorothiazide, onset of diuresis occurs at about 2 hours and peak effect occurs at about 4 hours post-dose, whilst the action persists for approximately 6-12 hours.

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

Clinical efficacy and safety

The combination of olmesartan medoxomil and hydrochlorothiazide produces additive reductions in blood pressure which generally increase with the dose of each component.

In pooled placebo-controlled studies, administration of the 20/12.5 mg and 20/25 mg combinations of olmesartan medoxomil/hydrochlorothiazide resulted in mean placebo- subtracted systolic/diastolic blood pressure reductions at trough of 12/7 mmHg and 16/9 mmHg, respectively.

Administration of 12.5 mg and 25 mg hydrochlorothiazide in patients insufficiently controlled by olmesartan medoxomil 20 mg monotherapy gave additional reductions in 24-hour systolic/diastolic blood pressures measured by ambulatory blood pressure monitoring of 7/5 mmHg and 12/7 mmHg, respectively, compared with olmesartan medoxomil monotherapy. The additional mean systolic/diastolic blood pressure reductions at trough compared with baseline were 11/10 mmHg and 16/11 mmHg, respectively.

The effectiveness of olmesartan medoxomil/hydrochlorothiazide combination therapy was maintained over long-term (one-year) treatment. Withdrawal of olmesartan medoxomil therapy, with or without concomitant hydrochlorothiazide therapy, did not result in rebound hypertension.

The fixed combinations of olmesartan medoxomil and hydrochlorothiazide 40 mg/12.5 mg and 40 mg/25 mg were investigated in three clinical studies including 1,482 hypertensive patients.

A double-blind study with essential hypertension evaluated the effectiveness of olmesartan medoxomil/hydrochlorothiazide 40 mg/12.5 mg combination therapy versus olmesartan medoxomil monotherapy 40 mg with mean sitting diastolic blood pressure reduction being the primary efficacy parameter. Systolic/diastolic blood pressure was reduced by 31.9/18.9 mmHg in the combination group as compared to 26.5/15.8 in the monotherapy group (p < 0.0001) after 8 weeks of treatment.

In a double-blind but non-controlled second phase of this study, up-titration of non-responders from olmesartan medoxomil monotherapy 40 mg to olmesartan medoxomil/hydrochlorothiazide 40 mg/12.5 mg as well as from olmesartan medoxomil/hydrochlorothiazide 40 mg/12.5 mg to olmesartan medoxomil/hydrochlorothiazide 40 mg/25 mg resulted in a further relevant decrease in systolic/diastolic blood pressure, thus confirming that up-titration is a clinically meaningful way to improve blood pressure control.

A second double-blind, randomised, placebo-controlled study evaluated the effectiveness of adding hydrochlorothiazide to the treatment of patients not adequately controlled after 8 weeks of treatment with olmesartan medoxomil 40 mg. Patients either continued on olmesartan medoxomil 40 mg or received additional hydrochlorothiazide 12.5 mg or 25 mg respectively for another 8 weeks. A fourth group was randomised to receive olmesartan medoxomil/hydrochlorothiazide 20 mg/12.5 mg.

Adding hydrochlorothiazide 12.5 mg or 25 mg resulted in a further reduction in systolic/diastolic blood pressure of 5.2/3.4 mmHg (p < 0.0001) and 7.4/5.3 mmHg (p < 0.0001) respectively as compared to the olmesartan medoxomil 40 mg therapy alone.

A comparison between patients receiving olmesartan medoxomil/hydrochlorothiazide 20 mg/12.5 mg and patients receiving 40 mg/12.5 mg showed a statistical significant difference in systolic blood pressure reduction of 2.6 mmHg in favour of the higher dose combination (p = 0.0255) whereas for diastolic blood pressure reduction a difference of 0.9 mmHg was observed. Ambulatory blood pressure monitoring (ABPM) based on the mean changes on 24-hour, daytime and night-time diastolic and systolic blood pressure data confirmed the results of conventional blood pressure measures.

Another double-blind, randomised trial compared the effectiveness of a combination treatment with olmesartan medoxomil/hydrochlorothiazide 20 mg/25 mg and olmesartan medoxomil/hydrochlorothiazide 40 mg/25 mg in patients with inadequately controlled blood pressure after 8 weeks of treatment with olmesartan medoxomil 40 mg.

After 8 weeks of combination therapy the systolic/diastolic blood pressure was significantly reduced as compared to baseline by 17.1/10.5 mmHg in the olmesartan medoxomil/hydrochlorothiazide 20 mg/25 mg group and 17.4/11.2 mmHg in the olmesartan medoxomil/hydrochlorothiazide 40 mg/25 mg group. The difference between both treatment groups was not statistically significant when using conventional blood pressure measurement, which might be explained by the known flat dose response effect of angiotensin II receptor antagonists such as olmesartan medoxomil.

However, a clinically meaningful and statistically significant difference in favour of olmesartan medoxomil/hydrochlorothiazide 40 mg/25 mg as compared to olmesartan medoxomil/hydrochlorothiazide 20 mg/25 mg was observed in mean 24-hour, daytime and night-time ABPM on both systolic and diastolic blood pressure.

The antihypertensive effect of olmesartan medoxomil/hydrochlorothiazide was similar irrespective of age, gender or diabetes status.

Other information

Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an angiotensin II receptor blocker.

ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.

ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.

Non-melanoma skin cancer: Based on available data from epidemiological studies, cumulative dose-dependent association between HCTZ and NMSC has been observed. One study included a population comprised of 71,533 cases of BCC and of 8,629 cases of SCC matched to 1,430,833 and 172,462 population controls, respectively. High HCTZ use (≥50,000 mg cumulative) was associated with an adjusted OR of 1.29 (95% CI: 1.23-1.35) for BCC and 3.98 (95% CI: 3.68-4.31) for SCC. A clear cumulative dose response relationship was observed for both BCC and SCC. Another study showed a possible association between lip cancer (SCC) and exposure to HCTZ: 633 cases of lip-cancer were matched with 63,067 population controls, using a risk-set sampling strategy. A cumulative dose-response relationship was demonstrated with an adjusted OR 2.1 (95% CI: 1.7-2.6) increasing to OR 3.9 (3.0-4.9) for high use (~25,000 mg) and OR 7.7 (5.7-10.5) for the highest cumulative dose (~100,000 mg) (see also section 4.4).

 


Absorption and distribution

Olmesartan medoxomil

Olmesartan medoxomil is a prodrug. It is rapidly converted to the pharmacologically active metabolite, olmesartan, by esterases in the gut mucosa and in portal blood during absorption from the gastrointestinal tract. No intact olmesartan medoxomil or intact side chain medoxomil moiety have been detected in plasma or excreta. The mean absolute bioavailability of olmesartan from a tablet formulation was 25.6 %.

The mean peak plasma concentration (Cmax) of olmesartan is reached within about 2 hours after oral dosing with olmesartan medoxomil, and olmesartan plasma concentrations increase approximately linearly with increasing single oral doses up to about 80 mg.

Food had minimal effect on the bioavailability of olmesartan and therefore olmesartan medoxomil may be administered with or without food.

No clinically relevant gender-related differences in the pharmacokinetics of olmesartan have been observed.

Olmesartan is highly bound to plasma protein (99.7 %), but the potential for clinically significant protein binding displacement interactions between olmesartan and other highly bound coadministered active substances is low (as confirmed by the lack of a clinically significant interaction between olmesartan medoxomil and warfarin). The binding of olmesartan to blood cells is negligible. The mean volume of distribution after intravenous dosing is low (16 29 l).

Hydrochlorothiazide

Following oral administration of olmesartan medoxomil and hydrochlorothiazide in combination, the median time to peak concentrations of hydrochlorothiazide was 1.5 to 2 hours after dosing. Hydrochlorothiazide is 68 % protein bound in the plasma and its apparent volume of distribution is 0.83 - 1.14 l/kg.

Biotransformation and elimination

Olmesartan medoxomil

Total plasma clearance of olmesartan was typically 1.3 l/h (CV, 19 %) and was relatively slow compared to hepatic blood flow (ca. 90 l/h). Following a single oral dose of 14C-labelled olmesartan medoxomil, 10 16 % of the administered radioactivity was excreted in the urine (the vast majority within 24 hours of dose administration) and the remainder of the recovered radioactivity was excreted in the faeces. Based on the systemic availability of 25.6 %, it can be calculated that absorbed olmesartan is cleared by both renal excretion (ca. 40 %) and hepato-biliary excretion (ca. 60 %). All recovered radioactivity was identified as olmesartan. No other significant metabolite was detected. Enterohepatic recycling of olmesartan is minimal. Since a large proportion of olmesartan is excreted via the biliary route, use in patients with biliary obstruction is contraindicated (see section 4.3).

The terminal elimination half-life of olmesartan varied between 10 and 15 hours after multiple oral dosing. Steady state was reached after the first few doses and no further accumulation was evident after 14 days of repeated dosing. Renal clearance was approximately 0.5 0.7 l/h and was independent of dose.

Hydrochlorothiazide

Hydrochlorothiazide is not metabolised in man and is excreted almost entirely as unchanged active substance in urine. About 60 % of the oral dose is eliminated as unchanged active substance within 48 hours. Renal clearance is about 250 - 300 ml/min. The terminal elimination half-life of hydrochlorothiazide is 10 - 15 hours.

Olmesartan medoxomil/hydrochlorothiazide

The systemic availability of hydrochlorothiazide is reduced by about 20 % when co-administered with olmesartan medoxomil, but this modest decrease is not of any clinical relevance. The kinetics of olmesartan are unaffected by the co-administration of hydrochlorothiazide.

Pharmacokinetics in special populations

Elderly (age 65 years or over)

In hypertensive patients, the olmesartan AUC at steady state was increased by ca. 35 % in elderly people (65-75 years old) and by ca. 44 % in very elderly people (≥ 75 years old) compared with the younger age group (see section 4.2).

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

Renal impairment

In renally impaired patients, the olmesartan AUC at steady state increased by 62 %, 82 % and 179 % in patients with mild, moderate and severe renal impairment, respectively, compared to healthy controls (see sections 4.2, 4.4).

The maximum dose of olmesartan medoxomil in patients with mild to moderate renal impairment (creatinine clearance of 30 60 ml/min) is 20 mg olmesartan medoxomil once daily. The use of olmesartan medoxomil in patients with severe renal impairment (creatinine clearance of < 30 ml/min) is not recommended.

The half-life of hydrochlorothiazide is prolonged in patients with impaired renal function.

Hepatic impairment

After single oral administration, olmesartan AUC values were 6 % and 65 % higher in mildly and moderately hepatically impaired patients, respectively, than in their corresponding matched healthy controls. The unbound fraction of olmesartan at 2 hours post-dose in healthy subjects, in patients with mild hepatic impairment and in patients with moderate hepatic impairment was 0.26 %, 0.34 % and 0.41 %, respectively. Following repeated dosing in patients with moderate hepatic impairment, olmesartan mean AUC was again about 65 % higher than in matched healthy controls. Olmesartan mean Cmax values were similar in hepatically-impaired and healthy subjects.

In patients with moderate hepatic impairment, an initial dose of 10 mg olmesartan medoxomil once daily is recommended and the maximum dose should not exceed 20 mg once daily. Olmesartan medoxomil has not been evaluated in patients with severe hepatic impairment (see sections 4.2, 4.3, 4.4).

Hepatic impairment does not significantly influence the pharmacokinetics of hydrochlorothiazide.

Drug interactions

Bile acid sequestering agent colesevelam

Concomitant administration of 40 mg olmesartan medoxomil and 3,750 mg colesevelam hydrochloride in healthy subjects resulted in 28 % reduction in Cmax and 39 % reduction in AUC of olmesartan. Lesser effects, 4 % and 15 % reduction in Cmax and AUC respectively, were observed when olmesartan medoxomil was administered 4 hours prior to colesevelam hydrochloride. Elimination half-life of olmesartan was reduced by 50 52 % irrespectively of whether administered concomitantly or 4 hours prior to colesevelam hydrochloride (see section 4.5).


The toxic potential of olmesartan medoxomil/hydrochlorothiazide combinations was evaluated in repeated dose oral toxicity studies for up to six months in rats and dogs.

As for each of the individual substances and other medicinal products in this class, the main toxicological target organ of the combination was the kidney. The combination of olmesartan medoxomil/hydrochlorothiazide induced functional renal changes (increases in serum urea nitrogen and in serum creatinine). High dosages caused tubular degeneration and regeneration in the kidneys of rats and dogs, probably via a change in renal haemodynamics (reduced renal perfusion resulting from hypotension with tubular hypoxia and tubular cell degeneration). In addition the olmesartan medoxomil/hydrochlorothiazide combination caused a decrease in red blood cell parameters (erythrocytes, haemoglobin and haematocrit) and a reduction in heart weight in rats.

These effects have also been observed for other AT1 receptor antagonists and for ACE inhibitors and they seem to have been induced by the pharmacological action of high dosages of olmesartan medoxomil and seem to be not relevant to humans at the recommended therapeutic doses.

Genotoxicity studies using combined olmesartan medoxomil and hydrochlorothiazide as well as the individual components have not shown any signs of a clinically relevant genotoxic activity.

The carcinogenic potential of a combination of olmesartan medoxomil and hydrochlorothiazide was not investigated as there was no evidence of relevant carcinogenic effects for the two individual components under conditions of clinical use.

There was no evidence of teratogenicity in mice or rats treated with olmesartan medoxomil/hydrochlorothiazide combinations. As expected from this class of medicinal product, foetal toxicity was observed in rats, as evidenced by significantly reduced foetal body weights, when treated with olmesartan medoxomil/hydrochlorothiazide combinations during gestation (see sections 4.3, 4.6).

 


lactose monohydrate

 Low substituted hydroxypropyl cellulose H-21

magnesium stearate

 talc

 and purified water


Not applicable.


3 years

Store below 30 C, store in original package to protect from moisture.


Olmetrol Plus 40 mg/12.5 mg: Yellow colored oblong biconvex, film coated tablet with (CT23) debossed on one side and plain on other side.

 

Olmetrol Plus 40 mg/25 mg: Pink colored oblong biconvex, film coated tablet with (CT24) debossed on one side and plain on other side.  

 

Olmetrol Plus 20 mg/12.5 mg: Yellow colored circular biconvex, film coated tablet with (CT22) debossed on one side and plain on other side.

Pack: Alu/Alu blister as 10 tablets per blister (30 tablets per carton)

 


 Not applicable.


Marketing Authorisation Holder and Manufacturer Medical and Cosmetic Products Company Ltd. (Riyadh Pharma) P.O.Box 442, Riyadh 11411 Fax: +966 11 265 0505 Email: contact@riyadhpharma.com For any information about this medicinal product, please contact the local representative of marketing authorisation holder: Saudi Arabia Marketing department Riyadh Tel: +966 11 265 0111 Email: marketing@riyadhpharma.com

09/2022
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