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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)

MILORA HCT tablets contain three substances called amlodipine, valsartan and hydrochlorothiazide. All of these substances help to control high blood pressure.

Amlodipine belongs to a group of substances called “calcium channel blockers”. Amlodipine stops calcium from moving into the blood vessel wall, which stops the blood vessels from tightening.

Valsartan belongs to a group of substances called “angiotensin-II receptor antagonists”. Angiotensin II is produced by the body and makes the blood vessels tighten, thus increasing the blood pressure. Valsartan works by blocking the effect of angiotensin II.

Hydrochlorothiazide belongs to a group of substances called “thiazide diuretics”. Hydrochlorothiazide increases urine output, which also lowers blood pressure.

As a result of all three mechanisms, the blood vessels relax and blood pressure is lowered.

MILORA HCT is used to treat high blood pressure in adult patients whose blood pressure is already controlled while taking amlodipine, valsartan and hydrochlorothiazide and who may benefit from taking one tablet containing all three substance


Do not take MILORA HCT

- If you are more than 3 months pregnant. (It is also recommended to avoid MILORA HCT in early pregnancy – see Pregnancy section.)

- If you are allergic to amlodipine or to any other calcium channel blockers, valsartan, hydrochlorothiazide, sulphonamide-derived medicines (medicines used to treat chest or urinary infections), or any of the other ingredients of this medicine (listed in section 6). If you think you may be allergic, do not take MILORA HCT and talk to your doctor.

- If you have liver disease, destruction of the small bile ducts within the liver (biliary cirrhosis) leading to the buildup of bile in the liver (cholestasis).

- If you have severe kidney problems or if you are having dialysis.

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

- If the level of potassium or sodium in your blood is too low despite treatment to increase the potassium or sodium levels in your blood.

- If the level of calcium in your blood is too high despite treatment to reduce the calcium levels in your blood.

- If you have gout (uric acid crystals in the joints).

- If you have severe low blood pressure (hypotension).

- If you have narrowing of the aortic valve (aortic stenosis) or cardiogenic shock (a condition where your heart is unable to supply enough blood to the body).

- If you suffer from heart failure after a heart attack.

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

- If any of the above applies to you, do not take MILORA HCT and talk to your doctor.

Warning and precautions

Talk to your doctor or pharmacist before taking MILORA HCT

- If you have a low level of potassium or magnesium in your blood (with or without symptoms such as muscle weakness, muscle spasms, abnormal heart rhythm).

- If you have a low level of sodium in your blood (with or without symptoms such as tiredness, confusion, muscle twitching, convulsions).

- If you have a high level of calcium in your blood (with or without symptoms such as nausea, vomiting, constipation, stomach pain, frequent urination, thirst, muscle weakness and twitching).

- If you have kidney problems, have had a kidney transplant or if you had been told that you have a narrowing of your kidney arteries.

- If you have liver problems.

- If you have or have had heart failure or coronary artery disease.

- If you have experienced a heart attack. Follow your doctor’s instructions for the starting dose carefully. Your doctor may also check your kidney function.

- If your doctor has told you that you have a narrowing of the valves in your heart (called “aortic or mitral stenosis”) or that the thickness of your heart muscle is abnormally increased (called “obstructive hypertrophic cardiomyopathy”).

- If you suffer from aldosteronism. This is a disease in which the adrenal glands make too much of the hormone aldosterone If this applies to you, the use of MILORA HCT is not recommended.

- If you suffer from a disease called systemic lupus erythematosus (also called “lupus” or “SLE”).

- If you have diabetes (high level of sugar in your blood).

- If you have high levels of cholesterol or triglycerides in your blood.

- If you experience skin reactions such as rash after sun exposure.

- If you had an allergic reaction to other high blood pressure medicines or diuretics (a type of medicine also known as “water tablets”), especially if you suffer from asthma and allergies - if you have been sick (vomiting or diarrhoea).

- If you have experienced swelling, particularly of the face and throat, while taking other medicines (including angiotensin converting enzyme inhibitors). If you get these symptoms, stop taking MILORA HCT and contact your doctor straight away. You should never take MILORA HCT again.

-  If you experience dizziness and/or fainting during treatment with MILORA HCT, tell your doctor as soon as possible.

-  If you experience a decrease in vision or eye pain. These could be symptoms of an increase of pressure in your eye and can happen within hours to a week of taking Arvavasc HCT. This can lead to permanent vision impairment, if not treated.

- 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 MILORA HCT”.

If any of these apply to you, talk to your doctor.

Children and adolescents

The use of MILORA HCT in children and adolescents under 18 years of age is not recommended.

Elderly people (age 65 years and older)

MILORA HCT can be used by people aged 65 years and over at the same dose as for other adults and in the same way as they have already taken the three substances called amlodipine, valsartan and hydrochlorothiazide. Elderly patients, should have their blood pressure checked regularly.

Other medicines and MILORA HCT

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. Your doctor may need to change your dose and/or to take other precautions. In some cases you may have to stop using one of the medicines. This is especially important if you are using any of the medicines listed below:

Do not take together with:

• lithium (a medicine used to treat some types of depression);

• medicines or substances that increase the amount of potassium in your blood. These include potassium supplements or salt substitutes containing potassium, potassiumsparing medicines and heparin;

 • ACE inhibitors or aliskiren (see also information under the headings “Do not take MILORA HCT” and “Warnings and precautions”).

Caution should be used with:

• alcohol, sleeping pills and anaesthetics (medicines allowing patients to undergo surgery and other procedures);

• amantadine (anti-Parkinson therapy, also used to treat or prevent certain illnesses caused by viruses); • anticholinergic agents (medicines used to treat a variety of disorders such as gastrointestinal cramps, urinary bladder spasm, asthma, motion sickness, muscular spasms, Parkinson's disease and as an aid to anaesthesia);

• anticonvulsant medicines and mood-stabilising medicines used to treat epilepsy and bipolar disorder (e.g. carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone);

• cholestyramine, colestipol or other resins (substances used mainly to treat high levels of lipids in the blood); • simvastatin (a medicine used to control high cholesterol levels);

 • ciclosporin (a medicine used in transplantation to prevent organ rejection or for other conditions, e.g: rheumatoid arthritis or atopic dermatitis);

 • cytotoxic medicines (used to treat cancer), such as methotrexate or cyclophosphamide;

 • digoxin or other digitalis glycosides (medicines used to treat heart problems);

 • verapamil, diltiazem (heart medicines);

 • iodine contrast media (agents used for imaging examinations);

 • medicines for the treatment of diabetes (oral agents such as metformin or insulins);

 • medicines for the treatment of gout, such as allopurinol;

 • medicines that may increase blood sugar levels (beta blockers, diazoxide);

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

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

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

 • medicines to increase blood pressure such as adrenaline or noradrenaline;

 • medicines used for HIV/AIDS (e.g. ritonavir, indinavir, nelfinavir);

 • medicines used to treat fungal infections (e.g. ketoconazole, itraconazole);

 • medicines used for oesophageal ulceration and inflammation (carbenoxolone);

 • medicines used to relieve pain or inflammation, especially non-steroidal anti-inflammatory agents (NSAIDs), including selective cyclooxygenase-2 inhibitors (Cox-2 inhibitors);

 • muscle relaxants (medicines to relax the muscles which are used during operations);

 • nitroglycerin and other nitrates, or other substances called “vasodilators”;

 • other medicines to treat high blood pressure, including methyldopa;

 • rifampicin (used, for example, to treat tuberculosis);

 • St. John’s wort;

 • dantrolene (infusion for severe body temperature abnormalities);

 • vitamin D and calcium salts.

MILORA HCT with food, drink and alcohol

Grapefruit and grapefruit juice should not be consumed by people who are prescribed MILORA HCT. This is because grapefruit and grapefruit juice can lead to an increase in the blood levels of the active substance amlodipine, which can cause an unpredictable increase in the blood pressure lowering effect of MILORA HCT. Talk to your doctor before drinking alcohol. Alcohol may make your blood pressure fall too much and/or increase the possibility of dizziness or fainting.

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 MILORA HCT before you become pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of MILORA HCT. MILORA HCT is not recommended in early pregnancy and must not be taken when more than 3 months pregnant, as it may cause serious harm to your baby if used after the third month of pregnancy. Breast-feeding Tell your doctor if you are breast-feeding or about to start breast-feeding. MILORA HCT is not recommended for mothers who are breast-feeding, and your doctor may choose another treatment for you if you wish to breast-feed, especially if your baby is a newborn, or was born prematurely. Ask your doctor or pharmacist for advice before taking any medicine.

Breast-feeding

Tell your doctor if you are breast-feeding or about to start breast-feeding. MILORA HCT is not recommended for mothers who are breast-feeding, and your doctor may choose another treatment for you if you wish to breast-feed, especially if your baby is a newborn, or was born prematurely.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

This medicine may make you feel dizzy, drowsy, nauseous or have a headache. If you experience these symptoms, do not drive or use tools or machines.


Always take this medicine exactly as your doctor has told you. Check with your doctor if you are not sure. This will help you get the best results and lower the risk of side effects.

The usual dose of MILORA HCT is one tablet per day

It is best to take the tablet at the same time each day. Morning is the best time.

Swallow the tablet whole with a glass of water.

You can take MILORA HCT with or without food. Do not take MILORA HCT with grapefruit or grapefruit juice.

Depending on how you respond to the treatment, your doctor may suggest a higher or lower dose.

Do not exceed the prescribed dose.

If you take more MILORA HCT than you should

 If you have accidentally taken too many MILORA HCT tablets, talk to a doctor immediately.You may require medical attention.

If you forget to take MILORA HCT

If you forget to take a dose of this medicine, take it as soon as you remember and then take the next dose at its usual time. If it is almost time for your next dose you should simply take the next tablet at the usual time. Do not take a double dose (two tablets at once) to make up for a forgotten tablet.

 

If you stop taking MILORA HCT

Stopping your treatment with MILORA HCT may cause your disease to get worse. Do not stop taking your medicine unless your doctor tells you to.

Always take this medicine, even if you are feeling well

People who have high blood pressure often do not notice any signs of the problem. Many feel normal. It is very important that you take this medicine exactly as your doctor tells you to get the best results and reduce the risk of side effects. Keep your appointments with the doctor even if you are feeling well.

 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.

As for any combination containing three active substances, side effects associated with each individual component cannot be excluded. The side effects reported with MILORA HCT or one of its three active substances (amlodipine, valsartan and hydrochlorothiazide) are listed below and may occur with the use of MILORA HCT.

Some side effects can be serious and need immediate medical attention.

 

Consult a doctor immediately if you experience any of the following serious side effects after taking this medicine:

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

• dizziness

• low blood pressure (feeling of faintness, lightheadedness, sudden loss of consciousness)

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

• severely decreased urine output (decreased kidney function)

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

• spontaneous bleeding

• irregular heart beat

• liver disorder

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

• sudden wheeziness, chest pain, shortness of breath or difficulty breathing

• swelling of eyelids, face or lips

• swelling of the tongue and throat which causes great difficulty breathing

•severe skin reactions including intense skin rash, hives, reddening of the skin over your whole body, severe itching, blistering, peeling and swelling of the skin, inflammation of the mucous membranes (Stevens-Johnson syndrome) or other allergic reactions

• heart attack

• inflamed pancreas, which may cause severe abdominal and back pain accompanied with feeling of being very unwell

• weakness, bruising, fever and frequent infections

• stiffness

Other side effects may include:

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

• low level of potassium in the blood

• increase of lipids in the blood

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

• sleepiness

• palpitations (awareness of your heart beat)

• flushing

• ankle swelling (oedema)

• abdominal pain

• stomach discomfort after meal

• tiredness

• headache

• frequent urination

• high level of uric acid in the blood

• low level of magnesium in the blood

• low level of sodium in the blood

• dizziness, fainting on standing up

• reduced appetite

• nausea and vomiting

• itchy rash and other types of rash

• inability to achieve or maintain erection

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

• fast heart beat

• spinning sensation

• vision disorder

• stomach discomfort

• chest pain

• increase of urea nitrogen, creatinine and uric acid in the blood

• high level of calcium, fat or sodium in the blood

• decrease of potassium in the blood

• breath odour

• diarrhoea

• dry mouth

• weight increase

• loss of appetite

• disturbed sense of taste

• back pain

• joint swelling

• muscle cramps/weakness/pain

• pain in extremity

• inability to either stand or walk in a normal manner

• weakness

• abnormal coordination

• dizziness on standing up or after exercising

• lack of energy

• sleep disturbances

• tingling or numbness

• neuropathy

• sudden, temporary loss of consciousness

• low blood pressure on standing up

• cough

• breathlessness

• throat irritation

• excessive sweating

• itching

• swelling, reddening and pain along a vein

• skin reddening

• trembling

• mood changes

• anxiety

• depression

• sleeplessness

• taste abnormalities

• fainting

• loss of pain sensation

• visual disturbances

• visual impairment

• ringing in the ears

• sneezing/runny nose caused by inflammation of the lining of the nose (rhinitis)

• altered bowel habits

• indigestion

• hair loss

• itchy skin

• skin discolouration

• disorder in passing urine

• increased need to urinate at night

• increased number of times of passing urine

• discomfort or enlargement of the breasts in men

• pain

• feeling unwell

• weight decrease

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

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

• sugar in the urine

• high level of sugar in the blood

• worsening of the diabetic metabolic state

• abdominal discomfort

• constipation

• liver disorders which can occur together with yellow skin and eyes, or dark-coloured urine (haemolytic anaemia)

• increased sensitivity of skin to sun

• purple skin patches

• kidney disorders

• confusion

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

• decreased number of white blood cells

• decrease in blood platelets which may result in unusual brusing or easy bleeding (red blood cell damage)

• swelling of the gums

• abdominal bloating (gastritis)

• inflammation of the liver (hepatitis)

• yellowing of the skin (jaundice)

• liver enzyme increase which may have an effect on some medical tests

• increased muscle tension

• inflammation of blood vessels often with skin rash

• sensitivity to light

• disorders combining rigidity, tremor and/or movement disorders

• fever, sore throat or mouth ulcers, more frequent infections (lack or low level of white blood cells)

• pale skin, tiredness, breathlessness, darkcoloured urine (haemolytic anaemia, abnormal breakdown of red blood cells either in the blood vessels or elsewhere in the body)

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

• severe upper stomach ache (inflammation of the pancreas)

• difficulty breathing with fever, coughing, wheezing, breathlessness (respiratory distress, pulmonary oedema, pneumonitis)

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

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

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

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

• changes in blood tests for kidney function, increase of potassium in your blood, low level of red blood cells

• abnormal red blood cell test

• low level of a certain type of white blood cell and blood platelet

• increase of creatinine in the blood

• abnormal liver function test

• severely decreased urine output

• inflammation of blood vessels

• weakness, bruising and frequent infections (aplastic anaemia)

• decrease in vision or pain in your eyes due to high pressure (possible signs of acute angleclosure glaucoma)

• breathlessness

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

• severe skin disease that causes rash, red skin, blistering of the lips, eyes or mouth, skin peeling, fever (erythema multiforme)

• muscle spasm

• fever (pyrexia)

• blistering skin (sign of a condition called dermatitis bullous)

 


Keep out of reach and sight of children.

Store below 30  C. 

Do not use MILORA HCT after the expiry date which is stated on the carton and blister 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


What MILORA HCT contains

Tha active ingredients are:

MILORA HCT (12.5/5/160) contains Valsartan 160mg, Amlodipine 5mg (as Besylate) and Hydrochlorothiazide 12.5 mg

MILORA HCT (25/5/160) contains Valsartan 160mg, Amlodipine 5mg and Hydrochlorothiazide 25 mg

MILORA HCT (12.5/10/160) contains Valsartan 160mg, Amlodipine 10mg and Hydrochlorothiazide 12.5 mg

MILORA HCT (25/10/160) contains Valsartan 160mg, Amlodipine 10mg and Hydrochlorothiazide 25 mg

The other ingredients are: Microcrystalline cellulose, Crospovidone, Colloidal Silicon Dioxide, Magnesium Stearate, Opadry

 


MILORA HCT 12.5/5/160 mg is White Oval shaped biconvex core tablet embossed with SJ523 from one side MILORA HCT 25/5/160 mg is Yellow Oval shaped biconvex core tablet embossed with SJ527 from one side MILORA HCT 12.5/10/160 mg is Pale yellow oval shaped biconvex film coated tablet embossed with SJ525 in one side MILORA HCT 25/10/160 mg is Brownish yellow oval shaped biconvex film coated tablet embossed with SJ531 in one side Alu/Alu blisters of 28 tablets contained in a carton.

Pharco International pharmaceutical company- Al Madina Almonawara, Saudi Arabia

TEL: +966 112349763

 

Manufacturer

SAJA Pharmaceuticals

Saudi Arabian Japanese pharmaceutical company limited

Jeddah – Saudi Arabia

 

For any information about MILORA HCT, please contact:

Pharco International pharmaceutical company- Al Madina Almonawara, Saudi Arabia

Tel: +966 112349763


This leaflet was last revised in {October/2019}; version number {00}
  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 عقار ميلورا إتش سى تى أقراص على ثلاث مواد تُسمى أملوديبين وفالسارتان وهيدروكلوروثيازيد. تُساعد كل هذه المواد على التحكُّم في ضغط الدَّم المرتفع.

ينتمي أملوديبين إلى مجموعة من المواد تُسمى: "حاصرات قنوات الكالسيوم". يوقف أملوديبين الكالسيوم عن التَّحرك إلى داخل جدار الأوعية الدَّموية، الأمر الذي يوقف الأوعية الدَّموية عن التَّضيّق وبالتَّالي يُخفِّض أيضًا ضغط الدَّم.

ينتمي فالسارتان إلى مجموعة من المواد تُسمى: "مناهضات مستقبلات الأنجيوتنسين 2". ينتج الجسم هرمون الأنجيوتنسين-2 ويُسبب تضيُّق الأوعية الدَّموية، وبالتَّالي زيادة ضغط الدَّم لديك.  يعمَل فالسارتان عن طريق حصر تأثير أنجيوتنسين-2.

ينتمي هيدروكلوروثيازيد، إلى مجموعة من المواد تُسمى: "مدرات البول الثيازيدية". يُزيد هيدروكلوروثيازيد إخراج البول، مما يُخفِّض أيضًا ضغط الدَّم.

نتيجة لذلك، ترتخي الأوعية الدَّموية، فيقل ضغط الدَّم لديك.

يُستَخدَم عقار ميلورا إتش سى تى لعلاج ارتفاع ضغط الدَّم في المرضى من البالغين الذين يتم التَّحكُّم بالفعل في ضغط الدَّم لديهم أثناء تناوُل أملوديبين وفالسارتان وهيدروكلوروثيازيد والذين قد يستفيدون من تناوُل قرص واحد يحتوي على الثلاث مواد جميعهم.

 

لا تتناول عقار ميلورا إتش سى تى في الحالات الآتية:

- إذا كنتِ حاملًا لأكثر من 3 أشهر. (من الأفضل أيضًا تجنُّب تناوُل عقار ميلورا إتش سى تى في مراحل الحمل المبكرة - انظري قسم: "الحمل").

- إذا كنت تُعاني من فرط الحساسية تجاه أملوديبين، أي من حاصرات قنوات الكالسيوم، فالسارتان، هيدروكلوروثيازيد، أي من الأدوية المشتقة من السالفونيميدات (أدوية لعلاج عدوى الصدر أو المسالك البولية) أو أيٍّ من المكونات الأخرى بهذا الدَّواء (المُدرجة في قسم 6). إذا كنت تعتقد أنَّ لديك حساسية، فتحدَّث إلى طبيبك قبل تناوُل عقار ميلورا إتش سى تى.

- إذا كنت تُعاني من مرض شديد بالكبد، فقد يحدث تدمير للقنوات الصفراوية الصغيرة داخل الكبد (تليف الكبد الصفراوي) مما يُؤدي إلى تراكم العصارة الصفراوية في الكبد (ركود صفراوي).

- إذا كان لديك مشاكل شديدة في الكلى أو تقوم بغسيل الكلى.

- إذا كنت غير قادر على إخراج البول (انقطاع البول).

- إذا كان مستوى البوتاسيوم أو الصوديوم في دمك منخفضًا للغاية على الرغم من تلقي العلاج فعليك زيادة مستويات البوتاسيوم أو الصوديوم في دمك.

- إذا كان مستوى الكالسيوم في دمك مرتفعًا للغاية على الرغم من تلقي العلاج فعليك خفض مستويات الكالسيوم في دمك.

- إذا كنت مُصابًا بمرض النّقرس (بلورات حمض اليوريك في المفاصل).

- إذا كنت تعاني من انخفاض ضغط الدَّم (هبوط).

- إذا كان لديك تضيُّق في الصمام الأورطي أو صدمة قلبية المنشأ (حالة يكون فيها القلب غير قادر على إمداد الجسم بكمية كافية من الدَّم).

- إذا كنت تعاني من هبوط (فشل) القلب.

- إذا كنت مصابًا بمرض السُّكَّري أو تُعاني من قصور في وظائف الكُلى، ويتم علاجك بدواء خافض لضغط الدَّم يحتوي على أليسكيرين.

 إذا انطبق عليك أي مما سبق، فلا تتناول عقار ميلورا إتش سى تى وتحدَّث إلى طبيبك.

 

تحذيرات واحتياطات

تحدَّث إلى الطبيب أو الصيدلي الخاص بك قبل تناول عقار ميلورا إتش سى تى.

- إذا كان لديك انخفاض في مستوى البوتاسيوم أو الماغنسيوم في دمك (مع أو بدون أعراض مثل ضعف العضلات، تقلصات عضلية، اضطراب النّظْم القلبي).

 إذا كان لديك مستوى منخفض من الصوديوم في دمك (مع أو بدون أعراض مثل: التَّعب، الارتباك، الانتفاض العضلي، التشنُّجات).

- إذا كان لديك مستوى مرتفع من الكالسيوم في دمك (مع أو بدون أعراض مثل: الغثيان والقيء والإمساك وألم المعدة والتبوُّل المتكرر والعطش وضعف العضلات والانتفاض العضلي).

- إذا كان لديك مشاكل بالكُلى أو خضعت لعملية زرع كُلى أو إذا تم إخبارك أنه لديك تضيُّق في شرايين الكُلى.

- إذا كنت تعاني من مشاكل بالكبد.

- إذا كنت مُصابًا أو قد أُصِبت من قبل بفشل القلب أو مرض بالشريان التَّاجي.

- إذا تعرَّضت لنوبة قلبية. اتبع تعليمات طبيبك الخاصة بجرعة البدء بعناية. قد يفحص طبيبك أيضًا وظائف الكُلى لديك.

- إذا أخبرك طبيبك أن لديك تضيُّقًا في صمام القلب (يُسمى "تضيُّق الشريان الأورطي أو الميترالي") أو زيادة سمك عضلة القلب بشكل غير طبيعي (يُسمى: "اعتلال عضلة القلب التضخُّمي الانسدادي").

 إذا كنت تعاني من فرط الألدوستيرونية. يُعَد هذا مرضًا تقوم فيه الغدة الكظرية بصُنع كمية كبيرة جدًّا من هرمون الألدوستيرون. إذا انطبق ذلك عليك، لا يوصى باستخدام عقار ميلورا إتش سى تى.

- إذا كنت تُعاني من مرض يُسمى الذئبة الحمامية الجهازية (يُسمى أيضًا "الذئبة" "SLE").

- إذا كنت مصابًا بمرض السكري (ارتفاع مستوى السكر في الدَّم).

- إذا كنت مصابًا بارتفاع مستويات الكوليسترول أو الدهون الثلاثية في دمك.

-  إذا تعرَّضت لتفاعلات جلدية مثل: الطفح الجلدي بعد التعرُّض لأشعة الشمس.

- إذا أُصِبت بتفاعلات حساسية تجاه أدوية علاج ارتفاع ضغط الدَّم الأخرى أو مُدِرات البول (نوع من الأدوية ويُعرف أيضًا باسم: "أقراص الماء")، لا سيِّما إذا كنت تُعاني من الربو والحساسية - إذا كنت مُصابًا بإعياء (قيء أو إسهال).

- إذا تعرَّضت لتورُّم، لا سيِّما بالوجه والحَلْق، أثناء تناوُل أدوية أخرى (بما في ذلك مثبطات الإنزيم المُحوِّل للأنجيوتنسين). إذا أُصِبت بهذه الأعراض، فتوقف عن تناوُل عقار ميلورا إتش سى تى واتصل بطبيبك فورًا. يجب ألا تتناول عقار ميلورا إتش سى تى ثانيةً.

- إذا تعرَّضت لدوخة و/أو إغماء أثناء العلاج بعقار ميلورا إتش سى تى، فأخبِر طبيبك بأسرع ما يُمكِن.

- إذا كنت قد تعرضت لانخفاض في الرؤية أو ألم بالعين. يمكن أن تكون هذه أعراض لزيادة ضغط العين، وقد تحدث في غضون ساعات إلى أسابيع من تناول عقار ميلورا إتش سى تى. يمكن أن يُؤدي ذلك إلى ضعف دائم بالإبصار، إذا لم يتم علاجه.

- إذا كنت تتناول أيًّا من الأدوية التَّالية التي تُستَخدَم لعلاج ارتفاع ضغط الدَّم: - مثبط الإنْزيم المُحَوِّل للأَنْجيُوتَنْسينِ (على سبيل المثال: إنالابريل، ليزينوبريل، راميبريل)، لا سيما إذا كنت تُعاني من مشاكل بالكُلى متعلقة بمرض السُّكَّري. - أليسكيرين. قد يُجري لك طبيبك فحصًا لوظائف الكُلى وضغط الدَّم وكمية الكهارل (على سبيل المثال: البوتاسيوم) في دمك على فترات منتظمة. انظر أيضًا المعلومات تحت عنوان: "لا تتناول عقار ميلورا إتش سى تى".

إذا كان أيٌّ من ذلك ينطبق عليك، فيُرجى التحدُّث إلى طبيبك.

 

الأطفال والمراهقون

لا يُنصح بتناوُل عقار ميلورا إتش سى تى في الأطفال والمراهقين الذين تقل أعمارهم عن 18 عامًا.

كبار السن ( من عمر 65 عامًا فأكثر)

يُمكِن أن يُستَخدَم عقار ميلورا إتش سى تى من قِبَل الأشخاص بعُمْر 65 عامًا فأكثر بالجرعة نفسها الخاصة بغيرهم من البالغين وبنفس الطريقة التي تناولوا بها بالفعل المواد الثلاثة (أملوديبين وفالسارتان وهيدروكلوروثيازيد). يجب خضوع المرضى من كبار السن، لفحص ضغط الدَّم بصفة منتظمة.

 

تناوُل عقار ميلورا إتش سى تى مع أدوية أخرى

يُرجى إبلاغ الطبيب أو الصيدلي الخاص بك إذا كنت تتناول أو تناولت مؤخرًا أو قد تتناول أيَّة أدوية أخرى.  قد يحتاج طبيبك لتغيير جرعتك و/أو اتخاذ احتياطات أخرى: وفي بعض الحالات، قد تكون مضطرًّا للتوقف عن تناول أحد الأدوية.  يُعَد هذا مُهِمًّا بشكل خاص إذا كنت تستخدم أيًّا من الأدوية المُدرَجة أدناه:

لا تتناوله بمصاحبة:

•  الليثيوم (دواء يُستَخدَم لعلاج بعض أنواع من الاكتئاب).

• الأدوية أو المواد التي قد تُزيد كمية البوتاسيوم في دمك. تشمل هذه الأدوية مكملات البوتاسيوم، أو بدائل الملح التي تحتوي على البوتاسيوم، أو الأدوية الموفرة للبوتاسيوم والهيبارين.

• إذا كنت تتناول مثبط الإنْزيم المُحَوِّل للأَنْجيُوتَنْسينِ أو أليسكيرين (انظر أيضًا المعلومات الواردة تحت العناوين: "لا تتناول عقار ميلورا إتش سى تى"، و"تحذيرات واحتياطات").

يجب توخي الحذر:

• الكحوليات وأقراص النوم وأدوية التخدير (الأدوية التي تسمح بخضوع المرضى للجراحة والإجراءات الأخرى).

•أمانتادين (علاج لمرض باركنسون، يستخدم أيضًا لعلاج أو الوقاية من أمراض فيروسية معينة).

الأدوية المضادة للكولين (الأدوية التي تُستخدَم لعلاج العديد من الاضطرابات مثل: تقلصات المعدة والأمعاء وتقلص المثانة والربو ودوار الحركة وتشنجات العضلات ومرض باركنسون وكعامل مساعد في التخدير).

الأدوية المضادة للتشنُّجات والأدوية المُثبِّتة للحالة المزاجية التي تُستَخدَم لعلاج الصَّرَع والاضْطِّراب ثنائي القطب (على سبيل المثال: كَرْبامازِيبين، فينوباربيتال، فينيتوين، فوسفينيتوين، بريميدون).

كولستيرامين أو كوليستيبول أو الراتنجات الأخرى (مواد تُستَخدَم بشكل أساسي لعلاج المستويات المرتفعة من الدهون في الدَّم).

• سيمفاستاتين (دواء يُستَخدَم للتحكم في مستويات الكوليسترول في المرتفعة).

• سيكلوسبورين (دواء يُستَخدَم في عمليات الزَّرع لمنع رفض العضو أو لحالات أخرى، على سبيل المثال: التهاب المفاصل أو التهاب الجلد التَّأَتُّبِيّ).

• الأدوية السامة للخلايا (التي تستخدم لعلاج السرطان)، مثل: ميثوتريكسات أو سيكلوفوسفاميد.

• ديجوكسِين أو جليكوزيدات الديجيتاليس (الأدوية التي تُستخدَم لعلاج مشاكل القلب).

• فيراباميل، ديلتِيازِيم (أدوية القلب).

• صبغات التباين المحتوية على اليود (عوامل تُستخدَم لفحوصات الأشعة).

• أدوية علاج مرض السُّكَّري (الأدوية التي يتم تناوُلها عن طريق الفم مثل: ميتفورمين أو الأنسولين).

• أدوية علاج النقرس: مثل ألوبيورينول.

• الأدوية التي قد تزيد من مستويات السكر في الدَّم (حاصرات مستقبلات البيتا، الديازوكسيد).

• الأدوية التي قد تُسبب "التفاف النقاط (إحدى العلامات برسم القلب)" (عدم انتظام ضربات القلب)، مثل: الأدوية المضادة لاضطرابات النظم القلبي وبعض مضادات الذهان.

• الأدوية التي قد تقلل كمية الصوديوم في دمك، مثل: مضادات الاكتئاب، مضادات الذهان، مضادات الصرع.

• الأدوية التي قد تخفض كمية البوتاسيوم في دمك، مثل: مدرات البول (أقراص الماء)، الكورتيكوستيرويدات، المُليّنات، أَمْفُوتيريسين أو البنيسللين جي.

• أدوية لرفع ضغط الدَّم، مثل: نورادرينالين أو أدرينالين.

الأدوية التي تُستَخدَم لعلاج فيروس نقص المناعة البشري/ الإيدز (على سبيل المثال: ريتونافير، إندينافير، نيلفينافير).

• أدوية تستخدم لعلاج الالتهابات الفطرية (مثل: كيتوكونازول وإتراكونازول).

• الأدوية التي تُستَخدَم لعلاج تقرُّح والتهاب المريء (كَرْبينُوكْسُولُون).

• الأدوية التي تخفف الألم والالتهاب خاصة مضادات الالتهاب غير الستيرويدية بما في ذلك مثبطات سيكلو أوكسجينيز-2 (COX-2) الانتقائية.

• مُرخيات العضلات (أدوية لإرخاء العضلات تُستَخدَم أثناء العمليات الجراحية).

• النِّتْروجليسِرين والنترات الأخرى، أو المواد الأخرى التي تُسمى: "مُوسِّعات الأوعية الدَّموية".

• أدوية أخرى لعلاج ارتفاع ضغط الدَّم، بما في ذلك ميثيل دوبا.

• ريفامبيسين (يستخدم في علاج السل).

• نبتة سانت جونز.

• دانتُرولِين (تسريب لعلاج الاضطرابات الشَّديدة في درجة حرارة الجسم).

• فيتامين "د" العلاجي ومكملات الكالسيوم.

تناوُل عقار ميلورا إتش سى تى مع الأطعمة والمشروبات والكحوليات

يجب ألا يتناول عصير الجريب فروت والجريب فروت من قبل الأشخاص الذين يتناولون عقار ميلورا إتش سى تى. هذا لأن الجريب فروت وعصير الجريب فروت يُمكِن أن يُؤديا إلى ارتفاع في مستويات المادة الفعَّالة، أملوديبين في الدَّم، الأمر الذي يُمكِن أن يُسبب ارتفاعًا غير مُتوقَّع في تأثير عقار ميلورا إتش سى تى الخافض لضغط الدَّم. تحدَّث إلى طبيبك قبل تناول الكحوليات.  قد تُؤدي الكحوليات إلى هبوط ضغط الدَّم لديك بشكل كبير للغاية و/أو تُزيد احتمالية حدوث دوخة أو إغماء.

 

الحمل والرضاعة الطبيعية

الحمل

يجب عليكِ إخبار طبيبكِ إذا كنتِ تعتقدين أنكِ حامل أو قد تصبحين حاملًا. سينصحكِ طبيبكِ في العادة بالتوقف عن تناوُل عقار ميلورا إتش سى تى قبل أن تصبِحي حاملًا أَو بِمجرّد أَن تعلمي بِأنكِ حامل، وسينصحك بِتناوُل دواء آخر بدلًا من عقار ميلورا إتش سى تى. لا ينصح باستخدام عقار ميلورا إتش سى تى في وقت مبكر من الحمل، ويجب ألا يتم تناوله إذا تعدى حملك الشهر الثالث؛ حيث إنه قد يُسبب أضرار خطيرة لطفلك إذا تم استخدامه بعد الشهر الثالث من الحمل.  أخبري طبيبك إذا كنتِ تُرضعين طفلك طبيعيًّا، أو على وشك البدء في إرضاعه طبيعيًّا.  لا يُوصى باستخدام ميلورا إتش سى تى من قبل الأمهات اللاتي ترضعن طبيعيًّا، وقد يختار لكِ طبيبكِ علاجًا آخر إذا كنتِ ترغبين في الرضاعة الطبيعيَّة، خاصة إذا كان طفلك حديث الولادة، أو مبتسرًا. استشيري الطبيب أو الصيدلي الخاص بك قبل تناول أي دواء.

الرضاعة الطبيعية

أخبري طبيبكِ إذا كنتِ تُرضعين طفلك طبيعيًّا، أو على وشك البدء في إرضاعه طبيعيًّا. لا يوصى باستخدام ميلورا إتش سى تى من قبل الأمهات اللاتي ترضعن طبيعيًّا، وقد يختار لكِ طبيبكِ علاجًا آخر إذا كنتِ ترغبين في الرضاعة الطبيعيَّة، خاصة إذا كان طفلك حديث الولادة، أو مبتسرًا.

استشيري الطبيب أو الصيدلي الخاص بك قبل تناول أي دواء.

 

القيادة واستخدام الآلات

قد يجعلك هذا الدَّواء تشعر بالدوخة أو النُّعاس أو الغثيان أو الصُّداع. إذا واجهت هذه الأعراض، فلا تمارس القيادة أو تستخدم الأدوات أو الآلات.

https://localhost:44358/Dashboard

تناوَل دائمًا هذا الدَّواء كما أخبرك طبيبك بالضبط. يُرجى مراجعة طبيبك إذا لم تكن متأكدًا من كيفية التناول.  سيُساعدك هذا في الحصول على أفضل النتائج ولتقليل خطر الإصابة بالآثار الجانبية.

 الجرعة المُعتادة من ميلورا إتش سى تى هي قرص واحد في اليوم.

- حاول أن تتناول القرص في نفس الوقت من كل يوم.  الصباح هو الوقت الأفضل.

- ابتلع الأقراص كاملة مع كوب من الماء.

- يمكنك تناول ميلورا إتش سى تى مع الطعام أو دونه. لا تتناول عقار ميلورا إتش سى تى مع الجريب فروت أو عصير الجريب فروت.

-قد يصف لك طبيبك جرعة أعلى أو أقل وفقًا إلى كيفية استجابتك للعلاج.

- لا تتجاوز الجرعات التي تم وصفها لك.

 

إذا تناولت كمية أكثر مما يجب من ميلورا إتش سى تى

 إذا تناولت بطريق الخطأ كمية كبيرة للغاية من عقار ميلورا إتش سى تى، فتحدَّث إلى الطبيب فورًا. قد تحتاج إلى العناية الطبية.

إذا أغفلت تناوُل عقار ميلورا إتش سى تى

إذا أغفلت تناول جرعة فتناولها بمجرد تذكرها وتناول الجرعة التَّالية في موعدها المعتاد. إذا اقترب موعد جرعتك التَّالية فما عليك سوى تناوُل القرص التَّالي في الوقت المُعتاد. لا تتناول جرعة مضاعفة لتعويض جرعة أغفلتها.

إذا توقفت عن تناول عقار ميلورا إتش سى تى

التَّوقف عن تناوُل ميلورا إتش سى تى قد يُسبب لك تفاقم ارتفاع ضغط الدَّم. لا تتوقف عن تناول دوائك ما لم يخبرك الطبيب بذلك.

تناول دائمًا هذا الدَّواء، حتى إذا كنت تشعر أنك على ما يُرام

الأشخاص المصابون بارتفاع ضغط الدَّم غالبًا لا يُلاحظون أي علامات على هذه المشكلة. قد يشعر الكثير بأن الأمور طبيعية تمامًا. من الهَام للغاية أن تتناول هذا الدَّواء بالضبط كما أخبرك طبيبك؛ للحصول على أفضل نتائج ولتقليل خطر الإصابة بآثار جانبية. حافظ على مواعيدك مع الطبيب حتى إذا كنت تشعر بأنك على ما يُرام.

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

 

مثل كافة الأدوية، قد يُسبب هذا الدَّواء آثارًا جانبية، على الرغم من عدم حدوثها لدى الجميع.

 بالنسبة لأي تركيبة تحتوي على ثلاث مواد فعَّالة، لا يُمكِن استبعاد حدوث الآثار الجانبية المصاحبة لكل مُكوِّن من الثلاثة مُكوِّنات. مُدرَج أدناه الآثار الجانبية التي تم الإبلاغ عنها مع عقار ميلورا إتش سى تى أو إحدى مواده الفعَّالة الثلاث (أملوديبين وفالسارتان وهيدروكلوروثيازيد)، وقد تحدث مع استخدام عقار ميلورا إتش سى تى.

 

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

أخبر طبيبك فورًا إذا كنت تواجه أيًّا من الآثار الجانبية الخطيرة التَّالية بعد تناول هذا الدَّواء:

 

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

• دوخة.

• انخفاض ضغط الدَّم (الشعور بالإغماء، الشعور بدوار بالرَّأس، فقدان الوعي المفاجئ).

 

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

• انخفاض إخراج البول بشكل شديد (ضعف وظائف الكلى).

 

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

• نزيف تلقائي.

• ضربات قلب غير منتظمة.

• اضطراب في الكبد.

 

نادرة جدًّا (قد تُؤثر في ما يصل إلى 1 من كل 10000 شخص):

• أزيز مفاجئ بالصدر، ألم في الصدر، ضيق أو صعوبة بالتَّنفس. 

• تورم الجفنين أو الوجه أو الشفتين.

• تورُّم اللسان والحَلْق مما قد يُسبب صعوبة كبيرة في التَّنفس.

• تفاعلات حساسية شديدة تشمل: الطفح الجلدي الشديد، الشرى (الأرتكاريا)، احمرار جلد الجسم بالكامل، حكة شديدة، ظهور نفطات، تقشُّر وتورُّم الجلد، التهاب الأغشية المخاطية (متلازمة ستيفنز جونسون) أو غيرها من تفاعلات الحساسية.

• نوبة قلبية.

• التهاب البنكرياس، الذي قد يُسبب ألمًا شديدًا بالبطن والظهر مصحوبًا بشعور بالتوعُّك الشديد.

• ضعف، تكدُّم، حُمى وعدوى متكررة الحدوث.

• تصلُّب (تيبُّس).

 

تشمل الآثار الجانيبة الأخرى التَّالي: 

شائعة جدًّا (قد تُؤثر على أكثر من 1 من بين كل 10 أشخاص):

• انخفاض مستوى البوتاسيوم بالدَّم.

• ارتفاع نسبة الدهون في الدَّم.

 

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

• النُّعاس.

• خفقان (إدراك ضربات القلب).

• احمرار الجلد.

• تورُّم الكاحل (وذمة).

• ألم بالبطن.

• شعور غير مريح بالمعدة بعد تناوُل الوجبات.

• تعب.

• الصداع.

• التبوُّل بصفة متكررة.

• ارتفاع مستوى حمض اليوريك في الدَّم.

• انخفاض مستوى الماغنسيوم بالدَّم.

• انخفاض مستوى الصوديوم في الدَّم.

• دوخة، إغماء عند الوقوف.

• انخفاض الشهية.

 

• غثيان وقيء.

• طفح جلدي مصحوب بحكة وأنواع أخرى من الطفح الجلدي.

• عدم القدرة على الحصول على انتصاب أو المحافظة عليه.

 

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

• تسارع ضربات القلب.

• شعور بالدوران.

• اضطراب الرؤية.

• ضيق بالمعدة.

• ألم في الصدر.

• زيادة مستوى النيتروجين يوريا والكرياتينين وحمض اليوريك في الدَّم.

• ارتفاع مستوى الكالسيوم، الدهون أو الصوديوم في الدَّم.

• انخفاض مستوى البوتاسيوم بالدَّم.

• وجود رائحة للنَّفس.

• الإسْهال.

• جفاف الفم.

• زيادة الوزن.

• فقدان الشهية.

• اضطراب حاسة التذوُّق

• آلام الظهر.

• تورم المفاصل.

• ألم/ ضعف/ تقلصات بالعضلات.

• ألم بالأطراف.

• عدم القدرة على الوقوف أو المشي بشكل طبيعي.

• ضعف.

• اضطرابات التَّنسيق.

• دوخة عند الوقوف أو بعد ممارسة التمارين.

• نقص الطاقة والضعف.

• اضطرابات النوم.

• وخز أو تنميل.

• اعتلال الأعصاب.

• فقدان الوعي المفاجئ أو المؤقت.

• انخفاض ضغط الدَّم عند الوقوف.

• سعال.

• ضيق التَّنَفُّس.

• تهيُّج الحلق.

• فرط التَّعرق.

• حكة بالجلد.

• تورُّم واحمرار وألم بطول الوريد.

• احمرار الجلد.

• ارتجاف.

• تغيرات مزاجية.

• القلق.

• الاكتئاب.

• عدم القدرة على النوم (أرق).

• اضطرابات التَّذوق.

• الإغماء.

• فقدان الإحساس بالألم.

• اضطرابات بصرية.

• ضعف البصر. 

• "رنين" في الأذنين (طنين).

• عطس/ سيلان الأنف ناجم عن التهاب في بطانة الأنف (التهاب الأنف).

• تغير في طبيعة الأمعاء المعتادة.

• عسر الهضم.

• تساقط الشعر. 

• حكة بالجلد.

• تغيير لون الجلد.

• اضطراب في التبوُّل.

• زيادة الحاجة إلى التبوُّل أثناء الليل.

• زيادة عدد مرات التبوُّل.

• الشعور بالانزعاج أو تضخُّم الثدي لدى الرجال.

• ألم.

• شعور بالإعياء (توعُّك).

• انخفاض الوزن.

 

نادرة (قد تؤثر في ما يصل إلى شخص واحد من بين كل 1000 شخص):

• انخفاض مستوى الصفائح الدَّموية (أحيانًا مع نزيف أو كدمات أسفل الجلد).

• وجود سكر بالبول.

• ارتفاع مستوى السكر في الدَّم.

• تفاقم الحالة الاستقلابية لمرض السكري.

• انتفاخ البطن.

• إمساك.

• اضطرابات الكبد التي قد تحدث مع اصفرار الجلد والعينين، أو بول داكن اللون (فقر الدَّم الانحلالي).

• زيادة حساسية الجلد تجاه أشعة الشمس.

• بقع بنفسجية على الجلد.

• اضطرابات الكلى.

• ارتباك.

 

نادرة جدًّا (قد تؤثر في ما يصل إلى 1 من كل 10000 شخص):

• انخفاض عدد كريات الدَّم البيضاء:

• انخفاض الصفائح الدَّموية الذي قد يُؤدي إلى تكدُّم غير مُعتاد أو سهولة النزيف (تلف خلايا الدَّم الحمراء).

• تورُّم اللثة.

• انتفاخ البطن (التهاب المعدة).

• التهاب الكبد.

• اصفرار الجلد (يرقان).

• زيادة إنزيمات الكبد مما قد يكون له تأثير على نتائج بعض الاختبارات الطبية.

• زيادة توتر العضلات.

• التهاب الأوعية الدَّموية المصحوب غالبًا بطفح جلدي.

• الحساسية للضوء.

• اضطرابات تشمل: التصلُّب، الارتعاش و/أو اضطرابات الحركة.

حُمى، التهاب الحَلْق أو قُرَح الفم، عدوى تحدث بشكل أكثر تكرارًا (نقص أو انخفاض مستوى خلايا الدَّم البيضاء).

• شحوب الجلد، تعب، عُسْر التَّنَفُّس، بول داكن اللون (فقر الدَّم الانحلالي، تكسير خلايا الدَّم الحمراء غير الطبيعي سواء في الأوعية الدَّموية أو في أي مكان آخر بالجسم).

• ارتباك، تعب، انتفاض وتقلص العضلات، تنفس سريع (قلوية ناتجة عن نقص كلوريد الدَّم).

ألم شديد أعلى المعدة (التهاب البنكرياس).

• صعوبة في التَّنفس، مع حمى، سعال، أزيز بالصدر، ضيق التنفس (أزمة تنفسية تشمل الالتهاب الرئوي والوذمة الرئوية).

• طفح جلدي بالوجه، ألم بالمفاصل، اضطراب بالعضلات، حُمى (الذئبة الحمراء الجهازية).

التهاب الأوعية الدَّموية المصحوب بأعراض مثل: طفح جلدي، بقع حمراء تميل إلى القرمزي، حُمى (التهاب الأوعية الدَّموية).

• مرض شديد بالجلد يُسبب طفحًا جلديًّا، احمرار الجلد، نفطات بالشفتين أو العينين أو الفم، تقشُّر الجلد، حُمى (انحلال البشرة النخري التَّسَمُّمِيّ).

 

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

• تغيُّرات في نتائج اختبارات الدَّم لفحص وظائف الكُلى، ارتفاع مستوى البوتاسيوم في الدَّم، انخفاض مستوى خلايا الدَّم الحمراء.

• نتائج غير طبيعية لاختبار خلايا الدَّم الحمراء.

• انخفاض مستويات أحد أنواع خلايا الدَّم البيضاء والصفائح الدموية.

• ارتفاع مستوى الكرياتينين في الدَّم.

• نتائج غير طبيعية باختبارات وظائف الكبد. 

• انخفاض إخراج البول بشكل شديد.

• التهاب الأوعية الدَّموية.

• ضعف، كدمات وعدوى متكررة (فقر الدَّم اللاتنسجي).

• انخفاض في الرؤية أو ألم في عينيك بسبب ارتفاع ضغط الدَّم (علامات مُحتمَلة للإصابة بالزَّرَق ضيق الزاوية الحاد).

• ضيق التَّنَفُّس.

• انخفاض إخراج البول بشكل شديد (علامات مُحتمَلة للإصابة باضطراب أو فشل الكُلى).

• مرض شديد بالجلد يُسبب طفحًا جلديًّا، احمرار الجلد، نفطات بالشفتين أو العينين أو الفم، تقشُّر الجلد، حُمى (احمرار متعدد الأشكال).

• تقلصات عضلية.

• حمى.

• ظهور نفطات على الجلد (علامة على حالة تُسمى التهاب الجلد الفقاعي).

 

يحفظ بعيدًا عن متناول ورؤية الأطفال.

يُحفَظ في درجة حرارة أقل من 30 درجة مئوية. 

لا تستعمل عقار ميلورا إتش سى تى بعد تاريخ انتهاء الصلاحية المدون على العبوة والشريط بعد كلمة "EXP". يُشير تاريخ انتهاء الصلاحية إلى اليوم الأخير من ذلك الشهر.

لا تتخلص من الأدوية عن طريق إلقائها في مياه الصرف أو مع المخلفات المنزلية. استشر الصيدلي الخاص بك عن كيفية التَّخلص من الأدوية التي لم تَعُد تستخدمها. سوف تُساعد هذه الإجراءات في الحفاظ على البيئة

ما هي محتويات عقار ميلورا إتش سى تى

المواد الفعَّالة هي:

يحتوي عقار ميلورا إتش سى تى (160/5/12.5) على فالسارتان 160 ملج، بيزيلات الأملوديبين 5 ملج وهيدروكلوروثيازيد 12.5 ملج

يحتوي عقار ميلورا إتش سى تى (160/5/25) على فالسارتان 160 ملج، بيزيلات الأملوديبين 5 ملج وهيدروكلوروثيازيد 25 ملج

يحتوي عقار ميلورا إتش سى تى (160/10/12.5) على فالسارتان 160 ملج، بيزيلات الأملوديبين 10 ملج وهيدروكلوروثيازيد 12.5 ملج

يحتوي عقار ميلورا إتش سى تى (160/10/25) على فالسارتان 160 ملج، بيزيلات الأملوديبين 10 ملج وهيدروكلوروثيازيد 25 ملج

المكونات الأخرى هي: سليلوز دقيق التَّبلور، كروسبوفيدون، ثاني أكسيد السيليكون الغروي، ستيرات الماغنسيوم، أوبادري

عقار ميلورا إتش سى تى 160/5/12.5 ملج عبارة عن أقراص بيضاء اللون وبيضاوية الشكل وثنائية التحدُّب منقوش على أحد وجهيها "SJ523".

عقار ميلورا إتش سى تى 160/5/25 ملج عبارة عن أقراص صفراء اللون وبيضاوية الشكل وثنائية التحدُّب منقوش على أحد وجهيها "SJ527".

عقار ميلورا إتش سى تى 160/10/12.5 ملج عبارة عن أقراص مُغلَّفة ذات لون أصفر شاحب وبيضاوية الشكل وثنائية التحدُّب منقوش على أحد وجهيها "SJ525".

عقار ميلورا إتش سى تى 160/10/25 ملج عبارة عن أقراص مُغلَّفة ذات لون أصفر مائل إلى البني وبيضاوية الشكل وثنائية التحدُّب منقوش على أحد وجهيها "SJ531".

 

مالك حق التَّسويق

شركة أدوية فاركو انترناشونال - المدينة المنورة - المملكة العربية السعودية

هاتف رقم: 763 9 234 11 966+

 

جهة التَّصنيع

ساجا الصيدلانية

جدة – المملكة العربية السعودية

للحصول على أية معلومات حول هذا الدواء، يُرجى الاتصال بـ

شركة أدوية فاركو انترناشونال - المدينة المنورة - المملكة العربية السعودية

هاتف رقم: 763 9 234 11 966+

 

للإبلاغ عن أية آثار جانبية:

• المملكة العربية السعودية

 

المركز الوطني للتَّيقظ الدَّوائي والسلامة الدَّوائية

فاكس: 7662-205-11-966+

اتصل بالمركز الوطني للتَّيقظ الدَّوائي على رقم 2038222-11-966+، أرقام الهاتف الداخلي: 2340-2334-2354-2353-2356-2317

الرقم المجاني: 8002490000

البريد الإلكتروني: npc.drug@sfda.gov.sa

الموقع الإلكتروني: www.sfda.gov.sa/npc

• دول مجلس التعاون الخليجي الأخرى:

  يُرجى التَّواصل مع السلطات المعنية المختصة.

 

هذا مُنتَج دوائي

الدَّواء منتج يُؤثر على صحتك وتناوله على نحو مخالف للتعليمات يعرضك للخطر. 

اتبع وصفة الطبيب بشكل صارم وطريقة الاستعمال وتعليمات الصيدلي الذي باعك الدَّواء.

الطبيب والصيدلي هما خبيران في الأدوية وفوائدها ومخاطرها.

لا تقطع فترة العلاج الموصوفة لك من تلقاء نفسك.

لا تكرر الوصفة الطبية دون استشارة طبيبك.

احفظ جميع الأدوية بعيدًا عن مُتناوَل الأطفال.

تمت آخر مراجعة لهذه النَّشرة في {أكتوبر/ 2019}، إصدار رقم {00}
 Read this leaflet carefully before you start using this product as it contains important information for you

MILORA HCT film-coated tablets

• MILORA HCT (160/5/12.5) contains Valsartan 160mg, Amlodipine 5mg (as Besylate) and Hydrochlorothiazide 12.5 mg

Film Coated Tablet

Treatment of essential hypertension as substitution therapy in adult patients whose blood pressure is adequately controlled on the combination of amlodipine, valsartan and hydrochlorothiazide (HCT), taken either as three single-component formulations or as a dual-component and a single-component formulation


Posology

The recommended dose of MILORA HCT is one tablet per day, to be taken preferably in the morning.

Before switching to MILORA HCT patients should be controlled on stable doses of the monocomponents taken at the same time. The dose of MILORA HCT should be based on the doses of the individual components of the combination at the time of switching.

The maximum recommended dose of MILORA HCT is 10 mg/320 mg/25 mg.

Special populations Renal impairment

Due to the hydrochlorothiazide component, MILORA HCT is contraindicated for use in patients with anuria (see section 4.3) and in patients with severe renal impairment (glomerular filtration rate (GFR)

<30 ml/min/1.73 m2) (see sections 4.3, 4.4 and 5.2).

No adjustment of the initial dose is required for patients with mild to moderate renal impairment (see sections 4.4 and 5.2).

Hepatic impairment

Due to the valsartan component, MILORA HCT is contraindicated in patients with severe hepatic impairment (see section 4.3). In patients with mild to moderate hepatic impairment without cholestasis, the maximum recommended dose is 80 mg valsartan and therefore MILORA HCT is not suitable in this group of patients (see sections 4.3, 4.4 and 5.2). Amlodipine dose recommendations have not been established in patients with mild to moderate hepatic impairment. When switching eligible hypertensive patients (see section 4.1) with hepatic impairment to MILORA HCT, the lowest available dose of the amlodipine component should be used.

Heart failure and coronary artery disease

There is limited experience with the use of MILORA HCT, particulary at the maximum dose, in patients with heart failure and coronary artery disease. Caution is advised in patients with heart failure and coronary artery disease, particularly at the maximum dose of MILORA HCT, 10 mg/320 mg/25 mg.

Elderly (age 65 years or over)

Caution, including more frequent monitoring of blood pressure, is recommended in elderly patients, particularly at the maximum dose of MILORA HCT, 10 mg/320 mg/25 mg, since available data in this patient population are limited. When switching eligible elderly hypertensive patients (see section 4.1)

Posology

The recommended dose of MILORA HCT is one tablet per day, to be taken preferably in the morning.

Before switching to MILORA HCT patients should be controlled on stable doses of the monocomponents taken at the same time. The dose of MILORA HCT should be based on the doses of the individual components of the combination at the time of switching.

The maximum recommended dose of MILORA HCT is 10 mg/320 mg/25 mg.

Special populations Renal impairment

Due to the hydrochlorothiazide component, MILORA HCT is contraindicated for use in patients with anuria (see section 4.3) and in patients with severe renal impairment (glomerular filtration rate (GFR)

<30 ml/min/1.73 m2) (see sections 4.3, 4.4 and 5.2).

No adjustment of the initial dose is required for patients with mild to moderate renal impairment (see sections 4.4 and 5.2).

Hepatic impairment

Due to the valsartan component, MILORA HCT is contraindicated in patients with severe hepatic impairment (see section 4.3). In patients with mild to moderate hepatic impairment without cholestasis, the maximum recommended dose is 80 mg valsartan and therefore MILORA HCT is not suitable in this group of patients (see sections 4.3, 4.4 and 5.2). Amlodipine dose recommendations have not been established in patients with mild to moderate hepatic impairment. When switching eligible hypertensive patients (see section 4.1) with hepatic impairment to MILORA HCT, the lowest available dose of the amlodipine component should be used.

Heart failure and coronary artery disease

There is limited experience with the use of MILORA HCT, particulary at the maximum dose, in patients with heart failure and coronary artery disease. Caution is advised in patients with heart failure and coronary artery disease, particularly at the maximum dose of MILORA HCT, 10 mg/320 mg/25 mg.

Elderly (age 65 years or over)

Caution, including more frequent monitoring of blood pressure, is recommended in elderly patients, particularly at the maximum dose of MILORA HCT, 10 mg/320 mg/25 mg, since available data in this patient population are limited. When switching eligible elderly hypertensive patients (see section 4.1)


− Hypersensitivity to the active substances, to other sulphonamide derivatives, to dihydropyridine derivatives, or to any of the excipients listed in section 6.1. − Second and third trimesters of pregnancy (see sections 4.4 and 4.6). − Hepatic impairment, biliary cirrhosis or cholestasis. − Severe renal impairment (GFR <30 ml/min/1.73 m2), anuria and patients undergoing dialysis. − Concomitant use of MILORA HCT with aliskiren-containing products in patients with diabetes mellitus or renal impairment (GFR <60 ml/min/1.73 m2) (see sections 4.5 and 5.1). − Refractory hypokalaemia, hyponatraemia, hypercalcaemia, and symptomatic hyperuricaemia. − Severe hypotension. − Shock (including cardiogenic shock). − Obstruction of the outflow tract of the left ventricle (e.g. hypertrophic obstructive cardiomyopathy and high grade aortic stenosis). − Haemodynamically unstable heart failure after acute myocardial infarction.

The safety and efficacy of amlodipine in hypertensive crisis have not been established. Sodium- and/or volume-depleted patients

Excessive hypotension, including orthostatic hypotension, was seen in 1.7% of patients treated with the maximum dose of MILORA HCT (10 mg/320 mg/25 mg) compared to 1.8% of valsartan/hydrochlorothiazide (320 mg/25 mg) patients, 0.4% of amlodipine/valsartan (10 mg/320 mg) patients, and 0.2% of hydrochlorothiazide/amlodipine (25 mg/10 mg) patients in a controlled trial in patients with moderate to severe uncomplicated hypertension.

 

In sodium-depleted and/or volume-depleted patients, such as those receiving high doses of diuretics, symptomatic hypotension may occur after initiation of treatment with MILORA HCT. MILORA HCT should be used only after correction of any pre-existing sodium and/or volume depletion.

 

If excessive hypotension occurs with MILORA HCT, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. Treatment can be continued once blood pressure has been stabilised.

 

Serum electrolyte changes

 

Amlodipine/valsartan/hydrochlorothiazide

 

In the controlled trial of MILORA HCT, the counteracting effects of valsartan 320 mg and hydrochlorothiazide 25 mg on serum potassium approximately balanced each other in many patients. In other patients, one or the other effect may be dominant. Periodic determinations of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.

 

Periodic determination of serum electrolytes and potassium in particular should be performed at appropriate intervals to detect possible electrolyte imbalance, especially in patients with other risk factors such as impaired renal function, treatment with other medicinal products or history of prior electrolyte imbalances.

 

Valsartan

 

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

 

Hydrochlorothiazide

 

Treatment with MILORA HCT should only start after correction of hypokalaemia and any coexisting hypomagnesaemia. Thiazide diuretics can precipitate new onset hypokalaemia or exacerbate pre- existing hypokalaemia. Thiazide diuretics should be administered with caution in patients with conditions involving enhanced potassium loss, for example salt-losing nephropathies and prerenal (cardiogenic) impairment of kidney function. If hypokalaemia develops during hydrochlorothiazide therapy, MILORA HCT should be discontinued until stable correction of the potassium balance.

 

Thiazide diuretics can precipitate new onset hyponatraemia and hypochloroaemic alkalosis or  exacerbate pre-existing hyponatraemia. Hyponatraemia, accompanied by neurological symptoms (nausea, progressive disorientation, apathy) has been observed. Treatment with hydrochlorothiazide should only be started after correction of pre-existing hyponatraemia. In case severe or rapid hyponatraemia develops during MILORA HCT therapy, the treatment should be discontinued until normalisation of natraemia.

 

All patients receiving thiazide diuretics should be periodically monitored for imbalances in electrolytes, particularly potassium, sodium and magnesium.

 

Renal impairment

Thiazide diuretics may precipitate azotaemia in patients with chronic kidney disease. When MILORA HCT is used in patients with renal impairment periodic monitoring of serum electrolytes (including potassium), creatinine and uric acid serum levels is recommended. MILORA HCT is contraindicated in patients with severe renal impairment, anuria or undergoing dialysis (see section 4.3).

 

No dose adjustment of MILORA HCT is required for patients with mild to moderate renal impairment

(GFR ≥30 ml/min/1.73 m2). Renal artery stenosis

MILORA HCT should be used with caution to treat hypertension in patients with unilateral or bilateral renal artery stenosis or stenosis to a solitary kidney since blood urea and serum creatinine may increase in such patients.

 

Kidney transplantation

 

To date there is no experience of the safe use of MILORA HCT in patients who have had a recent kidney transplantation.

 

Hepatic impairment

 

Valsartan is mostly eliminated unchanged via the bile. The half-life of amlodipine is prolonged and AUC values are higher in patients with impaired liver function; dose recommendations have not been established. In patients with mild to moderate hepatic impairment without cholestasis, the maximum recommended dose is 80 mg valsartan, and therefore, MILORA HCT is not suitable in this group of patients (see sections 4.2, 4.3 and 5.2).

 

Angioedema

 

Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swelling of the face, lips, pharynx, and/or tongue, has been reported in patients treated with valsartan. Some of these patients previously experienced angioedema with other medicinal products including ACE inhibitors. MILORA HCT should be discontinued immediately in patients who develop angioedema and should not be re-administered.

 

Heart failure and coronary artery disease/post-myocardial infarction

 

As a consequence of the inhibition of the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotaemia and (rarely) with acute renal failure and/or death. Similar outcomes have been reported with valsartan. Evaluation of patients with heart failure or post-myocardial infarction should always include assessment of renal function.

 

In a long-term, placebo-controlled study (PRAISE-2) of amlodipine in patients with NYHA (New York Heart Association Classification) III and IV heart failure of non-ischaemic aetiology, amlodipine was associated with increased reports of pulmonary oedema despite no significant difference in the incidence of worsening heart failure as compared to placebo.

 

Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of future cardiovascular events and mortality.

 

Caution is advised in patients with heart failure and coronary artery disease, particularly at the maximum dose of MILORA HCT, 10 mg/320 mg/25 mg, since available data in these patient populations is limited.

 

Aortic and mitral valve stenosis

 

As with all other vasodilators, special caution is indicated in patients with mitral stenosis or significant aortic stenosis that is not high grade.

 

Pregnancy

 

Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

 

Primary hyperaldosteronism

 

Patients with primary hyperaldosteronism should not be treated with the angiotensin II antagonist valsartan as their renin-angiotensin system is not activated. Therefore, MILORA HCT is not recommended in this population.

 

Systemic lupus erythematosus

 

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

 

Other metabolic disturbances

 

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

 

Due to the hydrochlorothiazide component, MILORA HCT is contraindicated in symptomatic hyperuricaemia. Hydrochlorothiazide may raise the serum uric acid level due to reduced clearance of uric acid and may cause or exacerbate hyperuricaemia as well as precipitate gout in susceptible patients.

Thiazides reduce urinary calcium excretion and may cause intermittant and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. MILORA HCT is contraindicated in patients with hypercalcaemia and should only be used after correction of any pre-existing hypercalcaemia. MILORA HCT should be discontinued if hypercalcaemia develops during treatment. Serum levels of calcium should be periodically monitored during treatment with thiazides. Marked hypercalcaemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.

 

Photosensitivity

 

Cases of photosensitivity reactions have been reported with thiazide diuretics (see section 4.8). If photosensitivity reaction occurs during treatment with MILORA HCT, it is recommended to stop the treatment. If a readministration of the diuretic is deemed necessary, it is recommended to protect exposed areas to the sun or to artificial UVA.

 

Acute angle-closure glaucoma

 

Hydrochlorothiazide, a sulphonamide, has been associated with an idiosyncratic reaction resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to a week of treatment 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 treatment may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle closure glaucoma may include a history of sulphonamide or penicillin allergy.

 

General

 

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

 

Elderly (age 65 years or over)

 

Caution, including more frequent monitoring of blood pressure, is recommended in elderly patients, particularly at the maximum dose of MILORA HCT, 10 mg/320 mg/25 mg, since available data in this patient population are limited.

 

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

 

There is evidence that the concomitant use of ACE inhibitors, ARBs 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, ARBs 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 ARBs should not be used concomitantly in patients with diabetic nephropathy.

 


No formal interaction studies with other medicinal products have been performed with MILORA HCT. Thus, only information on interactions with other medicinal products that are known for the individual active substances is provided in this section.

 

However, it is important to take into account that MILORA HCT may increase the hypotensive effect of other antihypertensive agents.

 

Concomitant use not recommended

 

MILORA HCT

individual component

Known interactions with the following agents

Effect of the interaction with other medicinal products

Valsartan and HCT

Lithium

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors, angiotensin II receptor antagonists including valsartan or thiazides.

Since renal clearance of lithium is reduced by thiazides, the risk of lithium toxicity may presumably be increased further with MILORA HCT. Therefore careful monitoring of serum lithium concentrations is recommended during concomitant use.

Valsartan

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

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

Amlodipine

Grapefruit or grapefruit juice

Administration of amlodipine with grapefruit or grapefruit juice is not recommended as bioavailability may be increased in some patients, resulting in increased blood pressure lowering effects.

 

Caution required with concomitant use

 

MILORA HCT

individual component

Known interactions with the following agents

Effect of the interaction with other medicinal products

Amlodipine

CYP3A4 inhibitors

Concomitant use of amlodipine with strong or moderate

CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides like erythromycin or clarithromycin, verapamil

 

(i.e. ketoconazole, itraconazole, ritonavir)

or diltiazem) may give rise to significant increase in amlodipine exposure. The clinical translation of these pharmacokinetic variations may be more pronounced in the elderly. Clinical monitoring and dose adjustment may thus be required.

CYP3A4

inducers (anticonvulsant agents [e.g. carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone], rifampicin, Hypericum perforatum[St. John's wort])

There is no data available regarding the effect of CYP3A4 inducers on amlodipine. The concomitant use of CYP3A4 inducers (e.g. rifampicin, Hypericum perforatum) may give a lower plasma concentration of amlodipine.

Amlodipine should be used with caution together with CYP3A4 inducers.

Simvastatin

Co-administration of multiple doses of 10 mg amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone. It is recommended to limit the dose of simvastatin to 20 mg daily in patients on amlodipine.

Dantrolene (infusion)

In animals, lethal ventricular fibrillation and cardiovascular collapse are observed in association with hyperkalaemia after administration of verapamil and intravenous dantrolene. Due to risk of hyperkalaemia, it is recommended that the co-administration of calcium channel blockers such as amlodipine be avoided in patients susceptible to malignant hyperthermia and in the management of malignant hyperthermia.

Valsartan and HCT

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

NSAIDS can attenuate the antihypertensive effect of both angiotensin II antagonists and hydrochlorothiazide when administered simultaneously. Furthermore, concomitant use of MILORA HCT and NSAIDs may lead to worsening of renal function and an increase in serum potassium.

Therefore, monitoring of renal function at the beginning of the treatment is recommended, as well as adequate hydration of the patient.

Valsartan

Inhibitors of the uptake transporter (rifampicin, ciclosporin) or efflux transporter (ritonavir)

The results of an in vitro study with human liver tissue indicate that valsartan is a substrate of the hepatic uptake transporter OATP1B1 and of the hepatic efflux transporter MRP2. Co-administration of inhibitors of the uptake transporter (rifampicin, ciclosporin) or efflux transporter (ritonavir) may increase the systemic exposure to valsartan.

HCT

Alcohol, barbiturates or narcotics

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

Amantadine

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

Anticholinergic agents and

The bioavailability of thiazide-type diuretics may be

 

 

other medicinal products affecting gastric motility

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

Antidiabetic agents (e.g. insulin and oral antidiabetic agents)

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

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

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

Ciclosporin

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

Cytotoxic agents

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

Digitalis glycosides

Thiazide-induced hypokalaemia or hypomagnesaemia may occur as undesirable effects, favouring the onset of digitalis-induced cardiac arrhythmias.

Iodine contrasting agents

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

Ion exchange resins

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

Medicinal products affecting serum potassium level

The hypokalaemic effect of hydrochlorothiazide may be increased by concomitant administration of kaliuretic diuretics, corticosteroids, laxatives, adrenocorticotropic hormone (ACTH), amphotericin, carbenoxolone, penicillin G and salicylic acid derivatives or antiarrhythmics. If these medicinal products are to be prescribed with the amlodipine /valsartan

/hydrochlorothiazide combination, monitoring of potassium plasma levels is advised.

Medicinal products affecting

The hyponatraemic effect of diuretics may be intensified

 

 

serum sodium level

by concomitant administration of medicinal products such as antidepressants, antipsychotics, antiepileptics, etc.

Caution is indicated in long-term administration of these medicinal products.

Medicinal products that could induce torsades de pointes

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

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

Dose adjustment of uricosuric medicinal products may be necessary as hydrochlorothiazide may raise the level of serum uric acid. Increase of dose of probenecid or sulfinpyrazone may be necessary.

 

Co-administration of thiazide diuretics, including hydrochlorothiazide, may increase the incidence of hypersensitivity reactions to allopurinol.

Methyldopa

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

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

Thiazides, including hydrochlorothiazide, potentiate the action of curare derivatives.

Other anti-hypertensive medicinal products

Thiazides potentiate the antihypertensive action of other antihypertensive drugs (e.g. guanethidine, methyldopa, beta-blockers, vasodilators, calcium channel blockers, ACE inhibitors, ARBs and Direct Renin Inhibitors [DRIs]).

Pressor amines (e.g. noradrenaline, adrenaline)

Hydrochlorothiazide may reduce the response to pressor amines such as noradrenaline. The clinical significance of this effect is uncertain and not sufficient to preclude their use.

Vitamin D and calcium salts

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

 

Dual blockade of the RAAS with ARBs, ACE inhibitors or aliskiren

 

Clinical trial data have shown that dual blockade of the RAAS through the combined use of ACE inhibitors, ARBs 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).

 


Pregnancy Category: D

 

Pregnancy

 

Amlodipine

 

The safety of amlodipine in human pregnancy has not been established. In animal studies, reproductive toxicity was observed at high doses (see section 5.3). Use in pregnancy is only recommended when there is no safer alternative and when the disease itself carries greater risk for the mother and foetus.

 

 
  

 


Valsartan

 

CThe use of Angiotensin II Receptor Antagonists (AIIRAs) is not recommended during the first trimester of pregnancy (see section 4.4). The use of AIIRAs is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 and 4.4).

 

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with Angiotensin II Receptor Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and if appropriate, alternative therapy should be started.

 

Exposure to AIIRAs therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see section 5.3).

 

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

 

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

 

Hydrochlorothiazide

 

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

 

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

Amlodipine/valsartan/hydrochlorothiazide

 

There is no experience on the use of MILORA HCT in pregnant women. Based on the existing data with the components, the use of MILORA HCT is not recommended during first trimester and contra-indicated during the second and third trimester of pregnancy (see sections 4.3 and 4.4).

 

Breast-feeding

 

No information is available regarding the use of valsartan and/or amlodipine during breast-feeding. Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit milk production. The use of MILORA HCT during breast-feeding is not recommended. If MILORA HCT is used during breast-feeding, doses should be kept as low as possible. Alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

 

Fertility

 

There are no clinical studies on fertility with MILORA HCT.

 

Valsartan

 

Valsartan had no adverse effects on the reproductive performance of male or female rats at oral doses up to 200 mg/kg/day. This dose is 6 times the maximum recommended human dose on a mg/m2 basis (calculations assume an oral dose of 320 mg/day and a 60-kg patient).

 

Amlodipine

 

Reversible biochemical changes in the head of spermatozoa have been reported in some patients treated by calcium channel blockers. Clinical data are insufficient regarding the potential effect of amlodipine on fertility. In one rat study, adverse effects were found on male fertility (see section 5.3).

 


Patients taking MILORA HCT and driving vehicles or using machines should take into account that dizziness or weariness may occasionally occur.

 

Amlodipine can have mild or moderate influence on the ability to drive and use machines. If patients taking MILORA HCT suffer from dizziness, headache, fatigue or nausea the ability to react may be impaired.

 


The safety profile of MILORA HCT presented below is based on clinical studies performed with MILORA HCT and the known safety profile of the individual components amlodipine, valsartan and hydrochlorothiazide.

A. Summary of the safety profile

 

The safety of MILORA HCT has been evaluated at its maximum dose of 10 mg/320 mg/25 mg in one controlled short-term (8 weeks) clinical study with 2,271 patients, 582 of whom received valsartan in combination with amlodipine and hydrochlorothiazide. Adverse reactions were generally mild and transient in nature and only infrequently required discontinuation of therapy. In this active controlled clinical trial, the most common reasons for discontinuation of therapy with MILORA HCT were dizziness and hypotension (0.7%).

 

In the 8-week controlled clinical study, no significant new or unexpected adverse reactions were observed with triple therapy treatment compared to the known effects of the monotherapy or dual therapy components.

 

In the 8-week controlled clinical study, changes in laboratory parameters observed with the combination of MILORA HCT were minor and consistent with the pharmacological mechanism of action of the monotherapy agents. The presence of valsartan in the triple combination attenuated the hypokalaemic effect of hydrochlorothiazide.

 

B.  Tabulated list of adverse reactions

 

The following adverse reactions, listed by MedDRA System Organ Class and frequency, concern MILORA HCT (amlodipine/valsartan/HCT) and amlodipine, valsartan and HCT individually.

 

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

 

 

 

MILORA HCT

Amlodipine

Valsartan

HCT

Blood and lymphatic system disorders

Agranulocytosis, bone marrow failure

--

--

--

Very rare

Haemoglobin and haematocrit decreased

--

--

Not known

--

Haemolytic anaemia

--

--

--

Very rare

Leukopenia

--

Very rare

--

Very rare

Neutropenia

--

--

Not known

--

Thrombocytopenia, sometimes with purpura

--

Very rare

Not known

Rare

Aplastic anaemia

--

--

--

Not known

Immune system disorders

Hypersensitivity

--

Very rare

Not known

Very rare

Metabolism and nutrition disorders

Anorexia

Uncommon

--

--

--

Hypercalcaemia

Uncommon

--

--

Rare

Hyperglycaemia

--

Very rare

--

Rare

 

Hyperlipidaemia

Uncommon

--

--

--

Hyperuricaemia

Uncommon

--

--

Common

Hypochloraemic alkalosis

--

--

--

Very rare

Hypokalaemia

Common

--

--

Very common

Hypomagnesaemia

--

--

--

Common

Hyponatraemia

Uncommon

--

--

Common

Worsening of diabetic metabolic state

--

--

--

Rare

Psychiatric disorders

Depression

--

Uncommon

--

Rare

Insomnia/sleep disorders

Uncommon

Uncommon

--

Rare

Mood swings

--

Uncommon

--

 

Confusion

--

Rare

--

--

Nervous system disorders

Coordination abnormal

Uncommon

--

--

--

Dizziness

Common

Common

--

Rare

Dizziness postural, dizziness exertional

Uncommon

--

--

--

Dysgeusia

Uncommon

Uncommon

--

--

Extrapyramidal syndrome

--

Not known

--

--

Headache

Common

Common

--

Rare

Hypertonia

--

Very rare

--

--

Lethargy

Uncommon

--

--

--

Paraesthesia

Uncommon

Uncommon

--

Rare

Peripheral neuropathy, neuropathy

Uncommon

Very rare

--

--

Somnolence

Uncommon

Common

--

--

Syncope

Uncommon

Uncommon

--

--

Tremor

--

Uncommon

--

--

Hypoesthesia

--

Uncommon

--

--

Eye disorders

Acute angle-closure glaucoma

--

--

--

Not known

Visual disturbance

--

Uncommon

--

--

Visual impairment

Uncommon

Uncommon

--

Rare

Ear and labyrinth disorders

Tinnitus

--

Uncommon

--

--

Vertigo

Uncommon

--

Uncommon

--

 

Cardiac disorders

Palpitations

--

Common

--

--

Tachycardia

Uncommon

--

--

--

Arrhythmias (including bradycardia, ventricular tachycardia, and atrial fibrillation)

--

Very rare

--

Rare

Myocardial infarction

--

Very rare

--

--

Vascular disorders

Flushing

--

Common

--

--

Hypotension

Common

Uncommon

--

--

Orthostatic hypotension

Uncommon

--

--

Common

Phlebitis, thrombophlebitis

Uncommon

--

--

--

Vasculitis

--

Very rare

Not known

--

Respiratory, thoracic and mediastinal disorders

Cough

Uncommon

Very rare

Uncommon

--

Dyspnoea

Uncommon

Uncommon

--

--

Respiratory distress, pulmonary oedema, pneumonitis

--

--

--

Very rare

Rhinitis

--

Uncommon

--

--

Throat irritation

Uncommon

--

--

--

Gastrointestinal disorders

Abdominal discomfort, abdominal pain upper

Uncommon

Common

Uncommon

Rare

Breath odour

Uncommon

--

--

--

Change of bowel habit

--

Uncommon

--

--

Constipation

--

--

--

Rare

Decreased appetite

--

--

--

Common

Diarrhoea

Uncommon

Uncommon

--

Rare

Dry mouth

Uncommon

Uncommon

--

--

Dyspepsia

Common

Uncommon

--

--

Gastritis

--

Very rare

--

--

Gingival hyperplasia

--

Very rare

--

--

Nausea

Uncommon

Common

--

Common

Pancreatitis

--

Very rare

--

Very rare

Vomiting

Uncommon

Uncommon

--

Common

Hepatobiliary disorders

Liver function test abnormal, including blood bilirubin

--

Very rare**

Not known

--

 

increase

 

 

 

 

Hepatitis

--

Very rare

--

--

Intrahepatic cholestasis, jaundice

--

Very rare

--

Rare

Skin and subcutaneous tissue disorders

Alopecia

--

Uncommon

--

 

Angioedema

--

Very rare

Not known

--

Dermatitis bullous

--

--

Not known

--

Cutaneous lupus erythematosus-like reactions, reactivation of cutaneous lupus erythematosus

--

--

--

Very rare

Erythema multiforme

--

Very rare

--

Not known

Exanthema

--

Uncommon

--

--

Hyperhidrosis

Uncommon

Uncommon

--

--

Photosensitivity reaction*

--

Very rare

--

Rare

Pruritus

Uncommon

Uncommon

Not known

--

Purpura

--

Uncommon

--

Rare

Rash

--

Uncommon

Not known

Common

Skin discoloration

--

Uncommon

--

--

Urticaria and other forms of rash

--

Very rare

--

Common

Vasculitis necrotising and toxic epidermal necrolysis

--

--

--

Very rare

Exfoliative dermatitis

--

Very rare

--

--

Stevens-Johnson syndrome

--

Very rare

--

--

Quincke oedema

--

Very rare

--

--

Musculoskeletal and connective tissue disorders

Arthralgia

--

Uncommon

--

--

Back pain

Uncommon

Uncommon

--

--

Joint swelling

Uncommon

--

--

--

Muscle spasm

Uncommon

Uncommon

--

Not known

Muscular weakness

Uncommon

--

--

--

Myalgia

Uncommon

Uncommon

Not known

--

Pain in extremity

Uncommon

--

--

--

Ankle swelling

--

Common

--

--

Renal and urinary

Blood creatinine increased

Uncommon

--

Not known

--

 

disorders

Micturition disorder

 

Uncommon

 

 

Nocturia

--

Uncommon

--

--

Pollakiuria

Common

Uncommon

 

 

Renal dysfunction

--

--

--

Not known

Acute renal failure

Uncommon

--

--

Not known

Renal failure and impairment

--

--

Not known

Rare

Reproductive system and breast disorders

Impotence

Uncommon

Uncommon

--

Common

Gynaecomastia

 

Uncommon

--

--

General disorders and administration site conditions

Abasia, gait disturbance

Uncommon

--

--

--

Asthenia

Uncommon

Uncommon

--

Not known

Discomfort, malaise

Uncommon

Uncommon

--

--

Fatigue

Common

Common

Uncommon

--

Non cardiac chest pain

Uncommon

Uncommon

--

--

Oedema

Common

Common

--

--

Pain

--

Uncommon

--

--

Pyrexia

--

--

--

Not known

Investigations

Lipids increased

 

--

 

Very common

Blood urea nitrogen increased

Uncommon

--

--

--

Blood uric acid increased

Uncommon

--

--

 

Glycosuria

 

 

 

Rare

Blood potassium decreased

Uncommon

--

--

--

Blood potassium increased

--

--

Not known

--

Weight increase

Uncommon

Uncommon

--

--

Weight decrease

--

Uncommon

--

--

 

* See section 4.4 Photosensitivity

 

** Mostly consistent with cholestasis

 

A.  Description of selected Side effects

 

Not Applicable

 

B.   Special population:

Renal impairment

 

Due to the hydrochlorothiazide component, MILORA HCT is contraindicated for use in patients with anuria (see section 4.3) and in patients with severe renal impairment (glomerular filtration rate (GFR) <30 ml/min/1.73 m2) (see sections 4.3, 4.4 and 5.2).

 

No adjustment of the initial dose is required for patients with mild to moderate renal impairment (see sections 4.4 and 5.2).

 

Hepatic impairment

 

Due to the valsartan component, MILORA HCT is contraindicated in patients with severe hepatic impairment (see section 4.3). In patients with mild to moderate hepatic impairment without cholestasis, the maximum recommended dose is 80 mg valsartan and therefore MILORA HCT is not suitable in this group of patients (see sections 4.3, 4.4 and 5.2). Amlodipine dose recommendations have not been established in patients with mild to moderate hepatic impairment. When switching eligible hypertensive patients (see section 4.1) with hepatic impairment to MILORA HCT, the lowest available dose of the amlodipine component should be used.

 

Heart failure and coronary artery disease

 

There is limited experience with the use of MILORA HCT, particulary at the maximum dose, in patients with heart failure and coronary artery disease. Caution is advised in patients with heart failure and coronary artery disease, particularly at the maximum dose of MILORA HCT, 10 mg/320 mg/25 mg.

 

Elderly (age 65 years or over)

 

Caution, including more frequent monitoring of blood pressure, is recommended in elderly patients, particularly at the maximum dose of MILORA HCT, 10 mg/320 mg/25 mg, since available data in this patient population are limited. When switching eligible elderly hypertensive patients (see section 4.1) to MILORA HCT, the lowest available dose of the amlodipine component should be used.

A.  Paediatric population

 

There is no relevant use of MILORA HCT in the paediatric population (patients below age 18 years) for the indication of essential hypertension.

 

 

Reporting of suspected adverse reactions

·Saudi Arabia

The National Pharmacovigilance and Drug Safety Centre (NPC) o Fax: +966-11-205-7662

o Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.

o  Toll free phone: 8002490000

o  E-mail: npc.drug@sfda.gov.sa

o  Website: www.sfda.gov.sa/npc

 

·Other GCC States:

Please contact the relevant competent authority.

 


Symptoms

 

There is no experience of overdose with MILORA HCT. The major symptom of overdose with valsartan is possibly pronounced hypotension with dizziness. Overdose with amlodipine may result in excessive peripheral vasodilation and, possibly, reflex tachycardia. Marked and potentially prolonged systemic hypotension, including shock with fatal outcome, have been reported with amlodipine.

 

Treatment

 

Amlodipine/Valsartan/Hydrochlorothiazide

 

Clinically significant hypotension due to MILORA HCT overdose calls for active cardiovascular support, including frequent monitoring of cardiac and respiratory function, elevation of extremities, and attention to circulating fluid volume and urine output. A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade.

 

Amlodipine

 

If ingestion is recent, induction of vomiting or gastric lavage may be considered. Administration of activated charcoal to healthy volunteers immediately or up to two hours after ingestion of amlodipine has been shown to significantly decrease amlodipine absorption.

 

Amlodipine is unlikely to be removed by haemodialysis.

 

Valsartan

 

Valsartan is unlikely to be removed by haemodialysis.

 

Hydrochlorothiazide

 

Overdose with hydrochlorothiazide is associated with electrolyte depletion (hypokalaemia, hypochloraemia) and hypovolaemia resulting from excessive diuresis. The most common signs and symptoms of overdose are nausea and somnolence. Hypokalaemia may result in muscle spasms and or accentuate arrhythmia associated with the concomitant use of digitalis glycosides or certain anti-

arrhythmic medicinal products.

 

The degree to which hydrochlorothiazide is removed by haemodialysis has not been established.

 


Pharmacotherapeutic group: Agents acting on the renin-angiotensin system, angiotensin II antagonists, other combinations, ATC code: C09DX01.

 

Mechanism of action

 

MILORA HCT combines three antihypertensive compounds with complementary mechanisms to control blood pressure in patients with essential hypertension: amlodipine belongs to the calcium antagonist class and valsartan to the angiotensin II antagonist class of medicines and hydrochlorothiazide belongs to the thiazide diuretics class of medicines. The combination of these substances has an additive antihypertensive effect.

 

Amlodipine/Valsartan/Hydrochlorothiazide

 

Clinical efficacy and safety

 

MILORA HCT was studied in a double-blind, active controlled study in hypertensive patients. A total of 2,271 patients with moderate to severe hypertension (mean baseline systolic/diastolic blood pressure was 170/107 mmHg) received treatments of amlodipine/valsartan/hydrochlorothiazide 10 mg/320 mg/25 mg, valsartan/hydrochlorothiazide 320 mg/25 mg, amlodipine/valsartan 10 mg/320 mg, or hydrochlorothiazide/amlodipine 25 mg/10 mg. At study initiation patients were assigned lower doses of their treatment combination and were titrated to their full treatment dose by week 2.

 

At week 8, the mean reductions in systolic/diastolic blood pressure were 39.7/24.7 mmHg with MILORA HCT, 32.0/19.7 mmHg with valsartan/hydrochlorothiazide, 33.5/21.5 mmHg with amlodipine/valsartan, and 31.5/19.5 mmHg with amlodipine/hydrochlorothiazide. The triple combination therapy was statistically superior to each of the three dual combination treatments in reduction of diastolic and systolic blood pressures. The reductions in systolic/diastolic blood pressure with MILORA HCT were 7.6/5.0 mmHg greater than with valsartan/hydrochlorothiazide, 6.2/3.3 mmHg greater than with amlodipine/valsartan, and 8.2/5.3 mmHg greater than with amlodipine/hydrochlorothiazide. The full blood pressure lowering effect was achieved 2 weeks after being on their maximal dose of MILORA HCT. Statistically greater proportions of patients achieved blood pressure control (<140/90 mmHg) with MILORA HCT (71%) compared to each of the three dual combination therapies (45-54%) (p<0.0001).

 

In a subgroup of 283 patients focusing on ambulatory blood pressure monitoring, clinically and statistically superior reductions in 24-hour systolic and diastolic blood pressures were observed with the triple combination compared to valsartan/hydrochlorothiazide, valsartan/amlodipine, and

 

hydrochlorothiazide/amlodipine. Amlodipine

Mechanism of action

 

The amlodipine component of MILORA HCT inhibits the transmembrane entry of calcium ions into cardiac and vascular smooth muscle. The mechanism of the antihypertensive action of amlodipine is due to a direct relaxant effect on vascular smooth muscle, causing reductions in peripheral vascular resistance and in blood pressure.

 

Pharmacodynamic effects

 

Experimental data suggest that amlodipine binds to both dihydropyridine and non-dihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels.

 

Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation, resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing.

 

Plasma concentrations correlate with effect in both young and elderly patients.

 

In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and increases in glomerular filtration rate and effective renal plasma flow, without change in filtration fraction or proteinuria.

 

As with other calcium channel blockers, haemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In haemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and humans, even when co-administered with beta blockers to humans.

 

Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or humans. In clinical studies in which amlodipine was administered in combination with beta blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed.

 

Amlodipine has been studied in patients with chronic stable angina, vasospastic angina and angiographically documented coronary artery disease.

 

Clinical efficacy and safety

 

Use in patients with hypertension

A randomised double-blind morbidity-mortality study called the Antihypertensive and Lipid- Lowering treatment to prevent Heart Attack Trial (ALLHAT) was performed to compare newer therapies: amlodipine 2.5-10 mg/day (calcium channel blocker) or lisinopril 10-40 mg/day (ACE- inhibitor) as first-line therapies to that of the thiazide-diuretic, chlorthalidone 12.5-25 mg/day in mild to moderate hypertension.

 

A total of 33,357 hypertensive patients aged 55 or older were randomised and followed for a mean of

4.9 years. The patients had at least one additional coronary heart disease risk factor, including: previous myocardial infarction or stroke (>6 months prior to enrollment) or documentation of other atherosclerotic cardiovascular disease (overall 51.5%), type 2 diabetes (36.1%), high density lipoprotein - cholesterol <35 mg/dl or <0.906 mmol/l (11.6%), left ventricular hypertrophy diagnosed by electrocardiogram or echocardiography (20.9%), current cigarette smoking (21.9%).

 

The primary endpoint was a composite of fatal coronary heart disease or non-fatal myocardial infarction. There was no significant difference in the primary endpoint between amlodipine-based therapy and chlorthalidone-based therapy: risk ratio (RR) 0.98 95% CI (0.90-1.07) p=0.65. Among secondary endpoints, the incidence of heart failure (component of a composite combined cardiovascular endpoint) was significantly higher in the amlodipine group as compared to the chlorthalidone group (10.2% versus 7.7%, RR 1.38, 95% CI [1.25-1.52] p<0.001). However, there was no significant difference in all-cause mortality between amlodipine-based therapy and chlorthalidone-based therapy RR 0.96 95% CI [0.89-1.02] p=0.20.

 

Valsartan

 

Mechanism of action

 

Valsartan is an orally active, potent and specific angiotensin II receptor antagonist. It acts selectively on the receptor subtype AT1, which is responsible for the known actions of angiotensin II.

 

Clinical efficacy and safety

 

Administration of valsartan to patients with hypertension results in a drop in blood pressure without affecting pulse rate.

 

In most patients, after administration of a single oral dose, onset of antihypertensive activity occurs within 2 hours, and the peak drop in blood pressure is achieved within 4-6 hours. The antihypertensive effect persists over 24 hours after administration. During repeated administration, the maximum reduction in blood pressure with any dose is generally attained within 2-4 weeks.

 

Hydrochlorothiazide

 

Mechanism of action

 

The site of action of thiazide diuretics is primarily in the renal distal convoluted tubule. It has been shown that there is a high-affinity receptor in the renal cortex as the primary binding site for the

 

thiazide diuretic action and inhibition of NaCl transport in the distal convoluted tubule. The mode of action of thiazides is through inhibition of the Na+Cl- symporter perhaps by competing for the Cl- site, thereby affecting electrolyte reabsorption mechanisms: directly increasing sodium and chloride excretion to an approximately equal extent, and indirectly, by this diuretic action, reducing plasma volume, with consequent increases in plasma renin activity, aldosterone secretion and urinary potassium loss, and a decrease in serum potassium.

 

Paediatric population

 

The European Medicines Agency has waived the obligation to submit the results of studies with MILORA HCT in all subsets of the paediatric population in essential hypertension (see section 4.2 for information on paediatric use).

 

Other: dual blockade of the renin-angiotensin-aldosterone system (RAAS)

 

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

 

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 ARBs.

 

ACE inhibitors and ARBs should therefore not be used concomitantly in patients with diabetic nephropathy (see section 4.4).

 

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 ARB 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.

 


Linearity

 

Amlodipine, valsartan and hydrochlorothiazide exhibit linear pharmacokinetics

Amlodipine/valsartan/hydrochlorothiazide

 

Following oral administration of MILORA HCT in normal healthy adults, peak plasma concentrations of amlodipine, valsartan and hydrochlorothiazide are reached in 6-8 hours, 3 hours, and 2 hours, respectively. The rate and extent of absorption of amlodipine, valsartan and hydrochlorothiazide from MILORA HCT are the same as when administered as individual dosage forms.

 

Amlodipine

 

Absorption

 

After oral administration of therapeutic doses of amlodipine alone, peak plasma concentrations of amlodipine are reached in 6-12 hours. Absolute bioavailability has been calculated as between 64% and 80%. Amlodipine bioavailability is unaffected by food ingestion.

 

Distribution

 

Volume of distribution is approximately 21 l/kg. In vitro studies with amlodipine have shown that approximately 97.5% of circulating drug is bound to plasma proteins.

 

Biotransformation

 

Amlodipine is extensively (approximately 90%) metabolised in the liver to inactive metabolites.

 

Elimination

 

Amlodipine elimination from plasma is biphasic, with a terminal elimination half-life of approximately 30 to 50 hours. Steady-state plasma levels are reached after continuous administration for 7-8 days. Ten per cent of original amlodipine and 60% of amlodipine metabolites are excreted in urine.

 

Valsartan

 

Absorption

 

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

 

Distribution

 

The steady-state volume of distribution of valsartan after intravenous administration is about 17 litres, indicating that valsartan does not distribute into tissues extensively. Valsartan is highly bound to serum proteins (94-97%), mainly serum albumin.

 

Biotransformation

 

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

 

Elimination

 

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

 

Hydrochlorothiazide

 

Absorption

 

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

 

The effect of food on hydrochlorothiazide absorption, if any, has little clinical significance. Absolute bioavailability of hydrochlorothiazide is 70% after oral administration.

 

Distribution

 

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

 

Biotransformation

 

Hydrochlorothiazide is eliminated predominantly as unchanged compound.

 

Elimination

 

Hydrochlorothiazide is eliminated from plasma with a half-life averaging 6 to 15 hours in the terminal elimination phase. There is no change in the kinetics of hydrochlorothiazide on repeated dosing, and accumulation is minimal when dosed once daily. More than 95% of the absorbed dose is being excreted as unchanged compound in the urine. The renal clearance is composed of passive filtration and active secretion into the renal tubule.

Special populations

 

Paediatric patients (age below 18 years)

 

No pharmacokinetic data are available in the paediatric population.

 

Elderly (age 65 years or over)

 

Time to peak plasma amlodipine concentrations is similar in young and elderly patients. In elderly patients, amlodipine clearance tends to decline, causing increases in the area under the curve (AUC) and elimination half-life. Mean systemic AUC of valsartan is higher by 70% in the elderly than in the young, therefore caution is required when increasing the dosage.

 

Systemic exposure to valsartan is slightly elevated in the elderly as compared to the young, but this has not been shown to have any clinical significance.

 

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

 

Since the three components are equally well tolerated in younger and elderly patients, normal dose regimens are recommended (see section 4.2).

 

Renal impairment

 

The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. As expected for a compound where renal clearance accounts for only 30% of total plasma clearance, no correlation was seen between renal function and systemic exposure to valsartan.

 

Patients with mild to moderate renal impairment may therefore receive the usual initial dose (see sections 4.2 and 4.4).

 

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

 

Hepatic impairment

 

Very limited clinical data are available regarding amlodipine administration in patients with hepatic impairment. Patients with hepatic impairment have decreased clearance of amlodipine with resulting increase of approximately 40–60% in AUC. On average, in patients with mild to moderate chronic liver disease, exposure (measured by AUC values) to valsartan is twice that found in healthy volunteers (matched by age, sex and weight). Due to the valsartan component, MILORA HCT is

contraindicated in patients with hepatic impairment (see sections 4.2 and 4.3).

 


Amlodipine/Valsartan/Hydrochlorothiazide

 

In a variety of preclinical safety studies conducted in several animal species with amlodipine, valsartan, hydrochlorothiazide, valsartan/hydrochlorothiazide, amlodipine/valsartan and amlodipine/valsartan/hydrochlorothiazide (MILORA HCT), there was no evidence of systemic or target organ toxicity that would adversely affect the development of MILORA HCT for clinical use in humans.

 

Preclinical safety studies of up to 13 weeks in duration were conducted with amlodipine/ valsartan/hydrochlorothiazide in rats. The combination resulted in expected reduction of red blood cell mass (erythrocytes, haemoglobin, haematocrit, and reticulocytes), increase in serum urea, increase in serum creatinine, increase in serum potassium, juxtaglomerular (JG) hyperplasia in the kidney and focal erosions in the glandular stomach in rats. All these changes were reversible after a 4- week recovery period and were considered to be exaggerated pharmacological effects.

 

The amlodipine/valsartan/hydrochlorothiazide combination was not tested for genotoxicity or carcinogenicity as there was no evidence of any interaction between these substances, which have been on the market for a long time. However, amlodipine, valsartan and hydrochlorothiazide have been tested individually for genotoxicity and carcinogenicity with negative results.

 

Amlodipine

 

Reproductive toxicology

 

Reproductive studies in rats and mice have shown delayed date of delivery, prolonged duration of labour and decreased pup survival at dosages approximately 50 times greater than the maximum recommended dosage for humans based on mg/kg.

 

Impairment of fertility

 

There was no effect on the fertility of rats treated with amlodipine (males for 64 days and females 14 days prior to mating) at doses up to 10 mg/kg/day (8 times* the maximum recommended human dose of 10 mg on a mg/m2 basis). In another rat study in which male rats were treated with amlodipine besilate for 30 days at a dose comparable with the human dose based on mg/kg, decreased plasma follicle-stimulating hormone and testosterone were found as well as decreases in sperm density and in the number of mature spermatids and Sertoli cells.

 

Carcinogenesis, mutagenesis

 

Rats and mice treated with amlodipine in the diet for two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 mg/kg/day showed no evidence of carcinogenicity. The highest dose (for mice, similar to, and for rats twice* the maximum recommended clinical dose

of 10 mg on a mg/m2 basis) was close to the maximum tolerated dose for mice but not for rats. Mutagenicity studies revealed no drug related effects at either the gene or chromosome levels.

* Based on patient weight of 50 kg Valsartan

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.

 

In rats, maternally toxic doses (600 mg/kg/day) during the last days of gestation and lactation led to lower survival, lower weight gain and delayed development (pinna detachment and ear-canal opening) in the offspring (see section 4.6). These doses in rats (600 mg/kg/day) are approximately 18 times the maximum recommended human dose on a mg/m2 basis (calculations assume an oral dose of 320 mg/day and a 60-kg patient).

 

In non-clinical safety studies, high doses of valsartan (200 to 600 mg/kg body weight) caused in rats a reduction of red blood cell parameters (erythrocytes, haemoglobin, haematocrit) and evidence of changes in renal haemodynamics (slightly raised blood urea nitrogen, and renal tubular hyperplasia and basophilia in males). These doses in rats (200 and 600 mg/kg/day) are approximately 6 and 18 times the maximum recommended human dose on a mg/m2 basis (calculations assume an oral dose of 320 mg/day and a 60-kg patient).

 

In marmosets at comparable doses, the changes were similar though more severe, particularly in the kidney where the changes developed to a nephropathy including raised blood urea nitrogen and creatinine.

 

Hypertrophy of the renal juxtaglomerular cells was also seen in both species. All changes were considered to be caused by the pharmacological action of valsartan which produces prolonged hypotension, particularly in marmosets. For therapeutic doses of valsartan in humans, the hypertrophy of the renal juxtaglomerular cells does not seem to have any relevance


·Microcrystalline cellulose

·Crospovidone

·Colloidal Silicon Dioxide

·Magnesium Stearate

·Opadry


Not applicable.

 


2 Years

Keep out of reach and sight of children. Store below 30°C.

Do not use MILORA HCT after the expiry date which is stated on the carton and blister 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.


MILORA HCT 160/5/12.5 mg is White Oval shaped biconvex core tablet embossed with SJ523 from one side packed in Alu/Alu blister

MILORA HCT 160/5/25 mg is Yellow Oval shaped biconvex core tablet embossed with SJ527 from one side packed in Alu/Alu blister

MILORA HCT 160/10/12.5 mg is Pale yellow oval shaped biconvex film coated tablet embossed with SJ525 in one side packed in Alu/Alu blister

MILORA HCT 160/10/25 mg is Brownish yellow oval shaped biconvex film coated tablet embossed with SJ531 in one side packed in Alu/Alu blister

 


No special requirements


Pharco International pharmaceutical company- Al Madina Almonawara, Saudi Arabia For more information, please contact Pharco International pharmaceutical company- Al Madina Almonawara, Saudi Arabia Tel: +966 112349763

October 2019
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