Triatec hct - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf life and Storage Composition and pharmaceutical form

Active ingredients: Ramipril, Hydrochlorothiazide

Triatec HCT 2.5 mg + 12.5 mg tablets
Triatec HCT 5 mg + 25 mg tablets

Why is Triatec hct used? What is it for?

Triatec HCT is a combination of two medicines called ramipril and hydrochlorothiazide.

Ramipril belongs to a group of medicines called "ACE inhibitors" (Angiotensin Converting Enzyme Inhibitors). It acts:

  • By decreasing the body's production of substances that can cause blood pressure to rise
  • Relaxing and widening your blood vessels
  • Making it easier for your heart to pump blood around your body

Hydrochlorothiazide belongs to a group of drugs called "thiazide diuretics" or oral diuretics. It works by increasing the amount of water (urine) that is produced. This lowers blood pressure.

Triatec HCT is used to treat high blood pressure (hypertension). The two active ingredients work together to lower blood pressure. They are used in combination when treatment with one component alone does not work.

Contraindications When Triatec hct is not to be used

Do not take Triatec HCT:

  • If you are allergic (hypersensitive) to ramipril, other ACE inhibitor medicines or any of the other ingredients of Triatec HCT (see section 6).
  • If you are allergic (hypersensitive) to medicines similar to Triatec HCT (other ACE inhibitors or medicines derived from sulphonamide) .Signs of an allergic reaction may be skin rash, difficulty swallowing or breathing, swelling of the lips, face, throat or language
  • If you have ever had a severe allergic reaction called 'angioedema'. The signs include itching, rash (hives), red spots on the hands, feet and throat, swelling of the throat and tongue, swelling around the eyes and lips, difficulty in breathing and swallowing
  • If you are on dialysis or doing some other type of blood filtration. Depending on the machine being used, Triatec HCT may not be suitable for you
  • If you have severe liver problems.
  • If you have abnormal levels of salts (calcium, potassium, sodium) in your blood.
  • If you have kidney problems due to insufficient blood supply to the kidney (renal artery stenosis).
  • During the last 6 months of pregnancy (see section under "Pregnancy and breastfeeding")
  • If you are breast-feeding (see section under "Pregnancy and breast-feeding").
  • If you are taking a blood pressure medicine containing aliskiren and have diabetes.
  • If you are taking a blood pressure medicine containing aliskiren and suffer from kidney problems.

Do not take Triatec HCT if any of the above conditions apply. If you are not sure, ask your doctor before taking Triatec HCT.

Precautions for use What you need to know before taking Triatec hct

Check with your doctor or pharmacist before taking Triatec HCT:

  • If you have heart, liver or kidney problems
  • If you have lost a lot of salts or body fluids (due to being unwell such as vomiting, diarrhea, excessive sweating, or following a low-salt diet, or from taking diuretics for a long period of time or having undergone a dialysis)
  • If you are about to undergo treatment to reduce allergy to bee or wasp stings (desensitization)
  • If you are about to undergo anesthesia. This may be given for surgery or dental work. You may need to stop taking Triatec HCT the day before; ask your doctor for advice
  • If you have a high amount of potassium in your blood (shown in a blood test)
  • You are taking medicines or have conditions such that your blood sodium levels may fall. Your doctor may order blood tests at regular intervals, especially to check your blood sodium levels, especially if you are elderly
  • If you have a vascular collagen disease such as scleroderma or systemic lupus erythematosus.
  • You should tell your doctor if you think you are (or might become) pregnant. Triatec HCT is not recommended in the first 3 months of pregnancy and can cause serious harm to the baby after 3 months of pregnancy (see section under "Pregnancy and breastfeeding")
  • If you have decreased vision or eye pain, especially if you are at risk of developing a condition called glaucoma or having an 'allergy to drugs containing penicillin or sulphonamide.

Children

Triatec HCT is not recommended for children and young people under the age of 18 because this medicine has never been used in this age group.

If any of the above apply to you (or you are not sure), ask your doctor before taking Triatec HCT.

Interactions Which drugs or foods can modify the effect of Triatec hct

Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription (including herbal medicines). This is because Triatec HCT can affect the way some other medicines work.

Also some medicines can affect the way Triatec HCT works.

Tell your doctor if you are taking any of the following medicines. These medicines can interfere with Triatec HCT by altering its action:

  • Medicines used to relieve pain and inflammation (e.g. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) such as ibuprofen, indomethacin, aspirin)
  • Medicines used to treat low blood pressure, shock, heart failure, asthma or allergies such as ephedrine, noradrenaline or adrenaline. Your doctor will need to check your blood pressure.

Tell your doctor if you are taking any of the following medicines. These medicines, when taken with Triatec HCT, can increase the likelihood of side effects:

  • Medicines used to relieve pain and inflammation (e.g. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) such as ibuprofen, indomethacin, aspirin)
  • Medicines that can lower the amount of potassium in the blood. These include medicines for constipation, diuretics, amphotericin B (used in fungal infections) and adrenocortic hormone cotropus (used to check if your adrenal glands are working properly)
  • Medicines to treat cancer (chemotherapy)
  • Medicines for heart problems, including heart beat problems
  • Medicines to avoid organ rejection after transplantation such as cyclosporine
  • Diuretics such as furosemide
  • Medicines that can increase the amount of potassium in the blood such as spironolactone, triamterene, amiloride, potassium salts and heparin (used to thin the blood)
  • Steroid medicines for the treatment of inflammation such as prednisolone
  • Calcium supplements
  • Allopurinol (used to lower the uric acid content in the blood)
  • Procainamide (for heart beat problems)
  • Cholestyramine (to reduce the amount of fat in the blood)
  • Carbamazepine (for the treatment of epilepsy)
  • Aliskiren (to treat high blood pressure)
  • Heparin (to thin the blood)
  • Vildagliptin (for the treatment of type 2 diabetes).

Tell your doctor if you are taking any of the following medicines. The way these medicines work can be affected by Triatec HCT:

  • Medicines for diabetes such as oral hypoglycaemics and insulin. Triatec HCT can lower the amount of sugar in your blood. Check your blood sugar carefully when taking Triatec HCT.
  • Lithium (for psychiatric problems). Triatec HCT can increase the amount of lithium in the blood. The level of lithium in your blood should be carefully checked by your doctor.
  • Muscle relaxant drugs
  • Quinine (for the treatment of malaria)
  • Medicines that contain iodine, these can be used in the hospital before an X-ray or scan exam
  • Penicillin (to treat infections)
  • Medicines that thin the blood to be taken by mouth (oral anticoagulants) such as warfarin.

If any of the above apply to you (or you are not sure), ask your doctor before taking Triatec HCT.

Checks

Tell your doctor or pharmacist before taking this medicine.

  • If you are having a check for parathyroid function. Triatec HCT could alter the control results
  • If you are a sportsman who has to carry out a doping control. Triatec HCT could give a positive result.

Taking Triatec HCT with food and alcohol

  • Drinking alcoholic beverages together with Triatec HCT may cause you to feel dizzy or lightheaded. If you want to know how much alcohol you can drink while taking Triatec HCT, please discuss this with your doctor. In fact, alcohol increases the effects of blood pressure medications. Giotensin II (AIIRA) or aliskiren (see also information under "Do not take Triatec HCT" and "additive effects."
  • Triatec HCT can be taken with or between meals.

Warnings It is important to know that:

Pregnancy and breastfeeding

You should tell your doctor if you think you are (or might become) pregnant.

You must not take Triatec HCT in the first 12 weeks of pregnancy and you must not take it at all after the 13th week as its use during pregnancy may be harmful to the baby.

If you become pregnant while taking Triatec HCT, please inform your doctor immediately.

Before planning a pregnancy, a switch to another more suitable drug should be made.

You should not take Triatec HCT if you are breastfeeding. Ask your doctor or pharmacist before taking any medicine.

Driving and using machines

You may feel dizzy while taking Triatec HCT. This is more likely when you have just started taking Triatec HCT or have just increased your dose. If this happens, do not drive or use any tools or machines.

Dose, Method and Time of Administration How to use Triatec hct: Posology

Always take Triatec HCT exactly as your doctor has told you. You should seek the advice of your doctor or pharmacist if you are not sure.

Taking this medicine

  • Take the medicine by mouth at the same time of the day each day, usually in the morning.
  • Swallow the tablets whole with liquid.
  • Do not break the tablets or chew them.

How much do you have to take

Treatment of high blood pressure

Your doctor will adjust the amount you take until your blood pressure is under control.

Senior citizens

Your doctor will reduce the starting dose and adjust your treatment more slowly.

Overdose What to do if you have taken too much Triatec hct

If you take more Triatec HCT than you should

Tell your doctor or go to the emergency room of the nearest hospital. Do not drive to the hospital, have someone accompany you or call an ambulance. Take the box of medicine with you. This is because your doctor needs to know what you have hired.

If you forget to take Triatec HCT

  • If you miss a dose, take your normal dose when it is time for it.
  • Do not take a double dose to make up for a forgotten tablet.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Side Effects What are the side effects of Triatec hct

Like all medicines, Triatec HCT can cause side effects, although not everybody gets them.

Stop taking Triatec HCT and see your doctor immediately if you notice any serious side effects - you may need urgent medical treatment:

  • Swelling of the face, lips or throat that make it difficult to swallow or breathe, as well as itching or rash. This could be a sign of a severe allergic reaction to Triatec HCT.
  • Severe skin reactions including rash, mouth ulcers, worsening of a pre-existing skin condition, redness, blistering and peeling of the skin (such as Stevens-Johnson Syndrome, toxic epidermal necrolysis or erythema multiforme).

Tell your doctor immediately if you experience:

  • Faster heart rate, irregular or strengthened heartbeat (palpitations), chest pain, tightness in the chest, or more serious problems including heart attack and stroke
  • Shortness of breath or cough. These can be signs of lung problems
  • Bruising easier, bleeding longer than normal, any signs of bleeding (e.g. bleeding gums) purple spots on the skin or easier onset of infections, throat irritation and fever, feeling tired, weakness, dizziness or pale skin . These can be signs of blood or bone marrow problems
  • Severe stomach pain which can extend to the back. This can be a sign of pancreatitis (inflammation of the pancreas)
  • Fever, chills, tiredness, loss of appetite, stomach pain, feeling sick, yellowing of the skin or eyes (jaundice). These may be signs of liver problems such as hepatitis (inflammation of the liver) or liver damage. .

Other side effects include:

Tell your doctor if any of the conditions described below become severe or persist for longer than a few days:

Common (affecting less than 1 patient in every 10 patients on therapy)

  • Headache or a feeling of weakness or tiredness
  • Feeling dizzy. This is more likely to happen when Triatec HCT therapy has just started or the dose has just been increased
  • Irritating dry cough or bronchitis
  • Blood tests show a higher than normal sugar level. If you have diabetes, this could make it worse
  • Blood tests show a higher than normal level of uric acid or fat
  • Painful, red and swollen joints

Uncommon (affecting less than 1 patient in every 100 patients on therapy)

  • Skin rash with or without lumps
  • Flushing, weakness, hypotension (unusually low blood pressure), especially when standing or getting up quickly
  • Balance problems (dizziness)
  • Itching and unusual skin sensations such as numbness, tingling, burning, stinging or rubbing (paraesthesia)
  • Loss or change in taste
  • Sleep problems
  • Depressed mood, anxiety, more nervousness than usual or irritability
  • Stuffed nose, difficulty breathing or worsening of asthma
  • Inflammation of the gums (gingivitis), swelling of the mouth
  • Red, swollen or watery or itchy eyes
  • Ringing in the ear
  • Blurred vision
  • Hair loss
  • Chest pain
  • Muscular pain
  • Constipation, pain in the stomach or intestines
  • Indigestion or feeling unwell
  • Increased amount of urine during the day
  • More sweating or feeling thirsty than usual
  • Loss or decrease of appetite (anorexia), less feeling of hunger
  • Fast or irregular heartbeat
  • Swollen arms and legs. This may be a sign that your body is holding onto more water than usual
  • Fever
  • Impotence in the male
  • Decrease in the number of red, white blood cells and blood platelets or in the concentration of hemoglobin, shown in blood tests
  • Changes in the function of the liver, pancreas or kidneys shown in blood tests.
  • Blood tests show a lower than normal potassium level.

Very rare (affecting less than 1 patient in 10,000 patients on therapy)

  • Feeling sick, causing diarrhea or heartburn
  • Red swollen tongue or dry mouth
  • Blood tests show a higher than normal potassium level.

Other side effects found:

Tell your doctor if any of the conditions described below become severe or persist for longer than a few days.

  • Difficulty concentrating, feeling agitated or confused
  • Fingers and toes that change color when they get cold and that tingle and hurt when heated (Raynaud's phenomenon)
  • Breast enlargement in men
  • Blood clots
  • Hearing disturbances
  • Eyes less moist than normal
  • Objects appear yellow
  • Dehydration
  • Swelling, pain and redness of the cheeks (inflammation of a salivary gland)
  • Swelling of the "gut called" intestinal angioedema "which presents with symptoms such as abdominal pain, vomiting and diarrhea
  • Increased sensitivity to the sun
  • Severe flaking or peeling of the skin, itching, rash or other skin reactions such as redness of the face or forehead
  • Skin rash or bruising
  • Spots on the skin and cold extremities
  • Nail problems (such as loosening or separation of the nail from its place)
  • Musculoskeletal stiffness or inability to move the jaw (tetanus)
  • Muscle weakness or cramps
  • Reduction of sexual desire in men and women
  • Presence of blood in the urine. This could be a sign of a kidney problem (interstitial nephritis)
  • More sugar in the urine than normal
  • An increase in the number of certain white blood cells in the blood (eosinophilia) found in blood tests
  • Too low number of blood cells shown in blood tests (pancytopenia)
  • Change in the level of salts such as sodium, calcium, magnesium and chlorine in the blood shown in blood tests
  • Slowed or altered reactions
  • Change in the perception of odors
  • Breathing difficulties or worsening of asthma
  • Severe eye pain, blurred vision or haloed vision, headache, diffuse tearing or nausea and vomiting which can be a condition called glaucoma.

If you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

Expiry and Retention

Keep this medicine out of the reach and sight of children. Do not use Triatec HCT after the expiry date stated on the cartons and blisters. The expiry date refers to the last day of the month indicated.

This medicine does not require any special storage conditions.

Medicines should not be disposed of via wastewater or household waste.

Ask your pharmacist how to throw away medicines you no longer use.

This will help protect the environment.

Composition and pharmaceutical form

What Triatec HCT contains

Each tablet contains 2.5 mg of rampipril and 12.5 mg of hydrochlorothiazide Each tablet contains 5 mg of ramipril and 25 mg of hydrochlorothiazide

The other ingredients are hypromellose, pregelatinised maize starch, microcrystalline cellulose and sodium stearyl fumarate.

What Triatec HCT looks like and contents of the pack

The 2.5 mg + 12.5 mg tablets are oblong, white to off-white, with a break line, marked on both sides with "HNV and company logo". The tablet can be divided into equal parts

Triatec HCT 2.5 mg + 12.5 mg tablets are available in packs of 10, 14, 18, 20, 28, 30, 45, 50, 56, 60, 98, 99, 100, 300 tablets in PVC / aluminum blisters

The 5 mg + 25 mg tablets are oblong, white to off-white, scored, marked on both sides with "HNW and company logo". The tablet can be divided into equal parts

Triatec HCT 5 mg + 25 mg tablets are available in packs of 10, 14, 18, 20, 28, 30, 45, 50, 56, 98, 99, 100, 300 tablets in PVC / aluminum blisters

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

Further information on Triatec hct can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction 04.6 Pregnancy and lactation 04.7 Effects on ability to drive and use machines 04.8 Undesirable effects 04.9 Overdose 05.0 PHARMACOLOGICAL PROPERTIES 05.1 Pharmacodynamic properties 05.2 Pharmacokinetic properties 05.3 Preclinical safety data 06.0 PHARMACEUTICAL PARTICULARS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the primary packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER 08.0 MARKETING AUTHORIZATION NUMBER CIO 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIO DRUGS, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON PREPARATION AND QUALITY CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

TRIATEC HCT TABLETS

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 2.5 mg of ramipril and 12.5 mg of hydrochlorothiazide.

Each tablet contains 5 mg of ramipril and 25 mg of hydrochlorothiazide.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

2.5 mg + 12.5 mg tablets

White to off-white oblong tablets with score line, marked on both sides with HNV and company logo. The tablet can be divided into equal parts

Tablets 5 mg + 25 mg

White to off-white oblong tablets with score line, marked on both sides with HNW and company logo.The tablet can be divided into equal parts

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Treatment of hypertension.

This fixed dose combination is indicated in patients whose blood pressure is not adequately controlled with ramipril alone or hydrochlorothiazide alone.

Oral use.

It is recommended that Triatec HCT be taken once a day at the same time, usually in the morning.

Triatec HCT can be taken before, during or after meals, because food intake does not change its bioavailability (see section 5.2).

Triatec HCT must be swallowed with liquid and must not be chewed or crumbled.

Adults

The dose should be individualized according to the patient profile (see section 4.4) and blood pressure control.

Administration of the fixed combination of ramipril and hydrochlorothiazide is usually recommended after dose titration with one of the single components.

Triatec HCT should be started at the lowest available dosage. If necessary, the dose can be progressively increased to reach the required blood pressure value; the maximum permitted doses are 10 mg of ramipril and 25 mg of hydrochlorothiazide per day.

04.2 Posology and method of administration

Special populations

Patients treated with diuretics

Caution is advised in patients already being treated with diuretics, as hypotension may occur after initiation of treatment. Dose reduction or discontinuation of the diuretic should be considered before initiating treatment with Triatec HCT.

If withdrawal is not possible, it is recommended to start treatment with the lowest possible dose of ramipril (1.25 mg daily) not in combination. A switch to a maximum initial daily dose of 2.5 mg ramipril / 12.5 mg hydrochlorothiazide is recommended thereafter.

Patients with impaired renal function

Triatec HCT is contraindicated in patients with severe renal impairment due to the presence of hydrochlorothiazide (creatinine clearance

Patients with impaired renal function may require reduced doses of Triatec HCT. Patients with creatinine clearance between 30 and 60 ml / min should only be treated with the lowest dose of the fixed combination of rampiril and hydrochlorothiazide after administration of ramipril alone. The maximum permitted doses are 5 mg of ramipril and 25 mg of hydrochlorothiazide. per day.

Patients with impaired liver function

In patients with mild to moderate hepatic impairment, treatment with Triatec HCT should only be initiated under close medical supervision and the maximum permitted daily doses are 2.5 mg of ramipril and 12.5 mg of hydrochlorothiazide.

Triatec HCT is contraindicated in patients with severe hepatic impairment (see section 4.3).

Elderly patients

The starting dose should be the lowest and subsequent titration should be more gradual due to the increased likelihood of side effects particularly in very elderly or debilitated patients.

Pediatric population

The use of Triatec HCT in children and adolescents under 18 years of age is not recommended due to lack of sufficient data on safety and efficacy.

04.3 Contraindications

• Hypersensitivity to the active substance, to other ACE inhibitors (Angiotensin Converting Enzyme inhibitors), to hydrochlorothiazide, to other thiazide diuretics, to sulphonamides or to any of the excipients (see section 6.1).

• History of angioedema (hereditary, idiopathic or previous angioedema with ACE inhibitors or AIIRAs).

• Extracorporeal treatments that bring blood into contact with negatively charged surfaces (see section 4.5).

• Significant bilateral renal artery stenosis or unilateral stenosis in patients with only one functioning kidney.

• Second and third trimester of pregnancy (see sections 4.4 and 4.6).

• Breastfeeding (see section 4.6).

• Severe renal impairment with creatinine clearance less than 30 ml / min in patients not on dialysis.

• Clinically relevant electrolyte changes that may worsen following treatment with Triatec HCT (see section 4.4).

• Severe hepatic insufficiency

• Hepatic encephalopathy

• In combination with aliskiren-containing medicines in patients with diabetes mellitus or moderate to severe renal impairment (creatinine clearance

04.4 Special warnings and appropriate precautions for use

Special populations

Pregnancy: Therapy with ACE inhibitors, such as ramipril, or with Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy.

For patients planning pregnancy, alternative antihypertensive treatments with a proven safety profile for use in pregnancy should be used unless continued ACE inhibitor / AIIRA therapy is considered essential. When diagnosed with an ACE inhibitor / AIIRA. pregnancy, treatment with ACE inhibitors / AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

Patients with particular risk of hypotension

- Patients with overactivation of the renin-angiotensin-aldosterone system

Patients with overactivation of the renin-angiotensin-aldosterone system are at risk of an acute notable drop in blood pressure and worsening of renal function due to ACE inhibition, especially when an ACE inhibitor or diuretic, in combination, is administered for the first time or at first dose increase. Relevant activation of the renin-angiotensin-aldosterone system should be expected and medical supervision including blood pressure monitoring is required, for example in:

• patients with severe hypertension;

• patients with decompensated congestive heart failure;

• patients with haemodynamically significant obstacle to left ventricular inflow or outflow (eg aortic or mitral valve stenosis);

• patients with unilateral renal artery stenosis with a functioning second kidney;

• patients in whom fluid or salt depletion exists or may develop (including patients on diuretics);

• patients with liver cirrhosis and / or ascites;

• during major surgery or during anesthesia with drugs that cause hypotension.

It is generally recommended to correct dehydration, hypovolaemia or salt depletion before starting treatment (however in patients with heart failure this corrective action should be carefully weighed against the risk of overload).

Surgery

If possible, it is recommended that treatment with angiotensin converting enzyme inhibitors such as ramipril be discontinued one day before surgery.

- Patients at risk of cardiac or cerebral ischaemia in case of acute hypotension

The initial phase of treatment requires "careful medical supervision.

Primary hyperaldosteronism

The combination of ramipril and hydrochlorothiazide is not a treatment of choice for primary aldosteronism. If the combination ramipril and hydrochlorothiazede is used in a patient with primary aldosteronism, careful monitoring of plasma potassium levels is required.

Elderly patients

See section 4.2.

Patients with liver disease

Electrolyte disturbances due to diuretic therapy including hydrochlorothiazide may cause hepatic encephalopathy in patients with hepatic disease.

Monitoring of renal function

Renal function should be evaluated before and during treatment and the dose should be adjusted particularly in the first weeks of treatment. Particularly careful monitoring is required in patients with impaired renal function (see section 4.2). There is a risk of renal impairment, particularly in patients with congestive heart failure or after kidney transplantation or with renovascular disease including patients with haemodynamically relevant unilateral renal artery stenosis.

Impaired renal function

In patients with renal disease, thiazides may aggravate uremia. In patients with impaired renal function, cumulative effects of the active substance may develop. a careful re-evaluation of therapy, and discontinuation of diuretic therapy should be considered (see section 4.3).

Electrolyte imbalance

As with any patient on diuretic therapy, periodic monitoring of serum electrolytes should be performed at appropriate intervals. Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (hypokalaemia, hyponatremia and hypochloraemic alkalosis).

Although hypokalaemia may develop with the use of thiazide diuretics, concomitant therapy with ramipril may reduce diuretic-induced hypokalaemia. The risk of hypokalaemia is greater in patients with liver cirrhosis, in patients with rapid diuresis, in patients receiving inadequate electrolyte supplementation and in patients receiving concomitant corticosteroid or ACTH therapy (see section 4.5).

The first assessment of plasma potassium levels should be done in the first week after starting treatment. If low potassium levels are found, correction is required.

Dilutional hyponatraemia may occur. Reduction in sodium levels may initially be asymptomatic, and regular monitoring is therefore essential. Monitoring should be more frequent in elderly and cirrhotic patients. Thiazides have been shown to increase urinary excretion of magnesium, which can lead to hypomagnesaemia.

Electrolyte monitoring: Hyperkalemia

Hyperkalaemia has been observed in some patients treated with ACE inhibitors including Triatec HCT. Patients at risk of developing hyperkalaemia include those with renal insufficiency, aged> 70 years, with uncontrolled diabetes mellitus or those using potassium salts, potassium-sparing diuretics, or other active substances that increase plasma potassium or conditions such as dehydration, acute heart failure, metabolic acidosis.

If the use of any of the above substances is deemed necessary, regular monitoring of serum potassium is recommended (see section 4.5).

Electrolyte monitoring: Hyponatremia

Syndrome of inappropriate anti-diuretic hormone secretion (SIADH) and subsequent hyponatremia has been observed in some patients treated with ramipril. It is recommended that serum sodium levels are regularly monitored in elderly patients and in other patients at risk for hyponatremia.

Hepatic encephalopathy

In patients with liver disease, electrolyte disturbances due to therapy with diuretics including hydrochlorothiazide can cause hepatic encephalopathy. If hepatic encephalopathy develops, treatment should be stopped immediately.

Hypercalcemia

Hydrochlorothiazide stimulates renal calcium reabsorption and can cause hypercalcemia. It can interfere with tests for parathyroid function.

Angioedema

Cases of angioedema have been reported in patients receiving ACE inhibitors including ramipril (see section 4.8). In the event of angioedema, Triatec HCT should be discontinued.

Emergency treatment should be instituted promptly. Patients should be kept under observation for at least 12-24 hours and discharged only after complete resolution of symptoms.

Intestinal angioedema has been observed in patients receiving ACE inhibitors, including Triatec HCT (see section 4.8). These patients presented with abdominal pain (with or without nausea or vomiting). Symptoms of intestinal angioedema resolved after discontinuation of the ACE inhibitor.

Anaphylactic reactions during desensitizing therapies

The likelihood and severity of anaphylactic or anaphylactoid reactions following contact with insect venom or other allergens are increased during therapy with ACE inhibitors. A temporary withdrawal of Triatec HCT should be considered prior to desensitization.

Neutropenia / agranulocytosis

Neutropenia / agranulocytosis has been rarely observed, and bone marrow depression has also been reported. Monitoring of white blood cell counts is recommended to allow for detection of possible leukopenia.

More frequent monitoring is recommended in the initial phase of treatment and in patients with impaired renal function, in patients with concomitant collagen disorders (e.g. lupus erythematosus or scleroderma) and in all those treated with drugs that can cause changes in the blood picture ( see sections 4.5 and 4.8).

Acute myopia and closed-angle glaucoma

Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute narrow-angle glaucoma. Symptoms include acute onset of decreased vision intensity or eye pain and usually occur within hours to weeks of "initiation of drug administration. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The main treatment is to discontinue hydrochlorothiazide as soon as possible. If intraocular pressure remains uncontrolled, rapid medical or surgical treatment may need to be considered. History of allergy to sulfonamides or penicillins may be considered risk factors for the development of acute angle glaucoma Closed.

Ethnic differences

ACE inhibitors cause a higher incidence of angioedema in black patients than in non-black patients.

Like other ACE inhibitors, ramipril may be less effective in lowering blood pressure in black populations than in non-black populations, possibly due to a higher prevalence of low-renin hypertension in black populations.

Athletes

Hydrochlorothiazide can determine positive anti-doping tests.

Metabolic and endocrine effects

Thiazide therapy can impair glucose tolerance. In diabetic patients, adjustment of the dosage of insulin or oral hypoglycemic drugs may be required. Latent diabetes mellitus may become manifest during thiazide therapy.

Increases in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy. Hyperuricaemia or worsening of overt gout may occur in some patients taking thiazides.

Cough

Cough has been observed with the use of ACE inhibitors. Typically, cough is nonproductive, persistent and resolves upon discontinuation of therapy. ACE inhibitor cough should be considered in the differential diagnosis of cough.

Others

Sensitization reactions may occur in patients with or without a history of allergy or bronchial asthma. The possibility of worsening of systemic lupus erythematosus has been reported.

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

As a consequence of the inhibition of the renin-angiotensin-aldosterone system, hypotension, syncope, hyperkalaemia and alterations in renal function (including acute renal failure) have been reported in susceptible individuals, especially when combined with medicinal products affecting this system. dual blockade of the renin-angiotensin-aldosterone system (eg by administration of ramipril with other blockers of the renin-angiotensin-aldosterone system) is therefore not recommended.Careful monitoring of renal function is advisable if co-administration is considered necessary.

The use of ramipril in combination with aliskiren is contraindicated in patients with diabetes mellitus or renal insufficiency (creatinine clearance

04.5 Interactions with other medicinal products and other forms of interaction

Contraindicated associations

Extracorporeal treatments that bring blood into contact with negatively charged surfaces such as dialysis or haemofiltration with some high-flux membranes (eg polyacrylonitrile membranes) or low-density lipoprotein apheresis by means of dextran sulphate are contraindicated due to the increased risk of severe anaphylactoid reactions (see section 4.3). If this type of treatment is required, the use of different dialysis membranes or a different class of antihypertensive agents should be considered.

Medicines containing aliskiren: The combination of ramipril with aliskiren-containing products is contraindicated in patients with diabetes mellitus or moderate to severe renal impairment and is not recommended in other patients (see sections 4.3 and 4.4).

Precautions for use

Potassium salts, heparin, potassium-sparing diuretics and other active substances that increase blood potassium levels (including Angiotensin II antagonists, trimethoprim, tacrolimus, cyclosporine):

Hyperkalaemia may occur, therefore careful monitoring of serum potassium levels is required.

Antihypertensive drugs (e.g. diuretics) and other drugs with potential antihypertensive effect (e.g. nitrates, tricyclic antidepressants, anesthetics, alcohol, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin): a possible potentiation of the risk of hypotension should be anticipated (see section 4.2 for diuretics).

Sympathomimetic vasopressors and other substances (adrenaline) that can reduce the antihypertensive effect of ramipril: Blood pressure monitoring is recommended.Furthermore, the effect of sympathomimetic vasopressors can be attenuated by hydrochlorothiazide.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics and other drugs that can alter the blood picture: increased risk of haematological reactions (see section 4.4).

Salts of lithium: Lithium excretion may be reduced by ACE inhibitors and therefore lithium toxicity may be increased. Serum lithium levels should be monitored. Concomitant use of thiazide diuretics may increase the risk of lithium toxicity and increase the risk already increased lithium toxicity with ACE inhibitors. The combination of ramipril and hydrochlorothiazide with lithium is therefore not recommended.

Antidiabetic agents including insulin: Hypoglycaemic reactions may occur. Hydrochlorothiazide may attenuate the effects of antidiabetic medicinal products. Therefore, careful glycemic monitoring is recommended in the initial phase of co-administration.

Non-steroidal anti-inflammatory drugs and acetylsalicylic acid: A possible reduction in the antihypertensive effect of Triatec HCT should be anticipated. In addition, concomitant therapy with ACE inhibitors and NSAIDs may lead to an increased risk of worsening of renal function and an increase in kalaemia.

Oral anticoagulants: The effect of oral anticoagulants may be diminished by the concomitant use of hydrochlorothiazide.

Corticosteroids, ACTH, amphotericin B, carbenoxolone, high amounts of licorice, laxatives (in case of prolonged use) and other substances with kaliuretic effect or which decrease plasma potassium: increased risk of hypokalaemia.

Preparations based on digitalis, known active substances that prolong the QT interval and antiarrhythmics: their proarrhythmic toxicity may be increased or their antiarrhythmic effects decreased in the presence of electrolyte disturbances (eg hypokalaemia, hypomagnesaemia).

Methyldopa: possible haemolysis.

Colestyramine and other enteric administered ion exchangers: reduced absorption of hydrochlorothiazide. Sulfonamide diuretics should be taken at least 1 hour before or 4-6 hours after these medicines.

Curaric-type muscle relaxants: possible intensification and prolongation of muscle relaxing effects.

Calcium salts and medicinal products that increase plasma calcium levels: an increase in serum calcium concentration can be expected in case of concomitant administration of hydrochlorothiazide; therefore careful monitoring of serum calcium is required.

Carbamazepine: risk of hyponatraemia due to additive effects with hydrochlorothiazide.

Iodine contrast mediaIn case of diuretic induced dehydration including hydrochlorothiazide, there is a risk of acute renal failure, particularly with the use of large doses of iodinated contrast media.

Penicillin: hydrochlorothiazide is excreted in the distal tubule, and reduces the excretion of penicillin.

Quinine: hydrochlorothiazide reduces the excretion of quinine.

Heparin: Possible increase in serum potassium concentration.

Vildagliptin: An increased incidence of angioedema was observed in patients treated with ACE inhibitors and vildagliptin.

04.6 Pregnancy and breastfeeding

The use of Triatec HCT is not recommended during the first trimester of pregnancy (see section 4.4) and is contraindicated during the second and third trimester of pregnancy (see section 4.3).

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.

For patients planning pregnancy, alternative antihypertensive treatments with a proven safety profile for use in pregnancy should be used unless continued ACE inhibitor therapy is considered essential.

When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately and, if appropriate, alternative therapy should be started.

Exposure to ACE inhibitors / Angiotensin II Receptor Antagonists (AIIRAs) during the second and third trimesters in women is known to induce fetal toxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity ( renal failure, hypotension, hyperkalaemia) (see section 5.3 "Preclinical safety data").

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

Neonates whose mothers have taken ACE inhibitors should be carefully observed for hypotension, oliguria and hyperkalaemia (see sections 4.3 and 4.4).

Hydrochlorothiazide, in case of prolonged exposure during the third trimester of pregnancy, can cause feto-placental ischaemia and the risk of growth retardation. In addition, rare cases of hypoglycaemia and thrombocytopenia in neonates have been reported with near term exposure. Hydrochlorothiazide can reduce plasma volume and uteroplacental blood flow.

Triatec HCT is contraindicated during breastfeeding.

Ramipril and hydrochlorothiazide are excreted in breast milk in quantities such that effects on the nursing infant are likely if therapeutic doses of ramipril and hydrochlorothiazide are administered to breastfeeding women.

Insufficient information is available regarding the use of ramipril during breastfeeding, and an alternative treatment with an established safety profile for breastfeeding, especially of the newborn or preterm infant, is preferred.

Hydrochlorothiazide is excreted in human milk. The intake of thiazides during lactation in nursing mothers has been associated with a decrease or even suppression of lactation.

Hypersensitivity to sulphonamide-derived active substances, hypokalaemia and nuclear jaundice may occur. Because of the possibility of serious reactions from both active substances in nursing infants, a decision must be made whether to discontinue breastfeeding or to discontinue therapy, taking into account the importance of the therapy to the mother.

04.7 Effects on ability to drive and use machines

Some undesirable effects (e.g. some symptoms of low blood pressure such as dizziness) may interfere with the patient's ability to concentrate and react and therefore pose a risk in situations where these abilities are particularly important (e.g. maneuvering machines or driving. of vehicles).

This may particularly occur at the start of treatment or when substituting for another therapy. After the first dose or dose increase it is not recommended to drive or operate machinery for several hours.

04.8 Undesirable effects

The safety profile of the ramipril and hydrochlorothiazide combination includes adverse reactions occurring in the context of hypotension and / or fluid depletion due to increased diuresis. The active ingredient ramipril can induce persistent dry cough, while the active ingredient hydrochlorothiazide can lead to a worsening of the metabolism of glucose, lipids and uric acid. The two active ingredients have opposite effects on plasma potassium. Serious adverse reactions include angioedema or anaphylactic reactions, hepatic or renal impairment, pancreatitis, severe skin reactions and neutropenia / agranulocytosis.

The frequency of undesirable effects is defined using the following convention:

Very common (≥ 1/10); common (≥ 1/100,

Within the frequency groups, undesirable effects are listed in descending order of severity.


System and organ classification Common Uncommon Very rare Not known Cardiac pathologies Myocardial ischaemia including: angina pectoris, tachycardia, arrhythmia, palpitations, peripheral edema Myocardial infarction Disorders of the blood and lymphatic system Decreased number of white blood cells, decreased number of red blood cells, decreased hemoglobin, haemolytic anemia, decreased platelet count Bone marrow depression, neutropenia with agranulocytosis, pancytopenia, eosinophilia Haemoconcentration in the context of fluid depletion. Nervous system disorders Headache, dizziness Vertigo, paraesthesia, tremor, balance disorder, burning sensation, dysgeusia ageusia. Cerebral ischaemia including ischemic stroke and transient ischemic attack, impaired psychomotor skills, parosmia Eye disorders Visual disturbance including blurred vision, conjunctivitis Xanthopsia, decreased lacrimation due to hydrochlorothiazide, acute angle-closure glaucoma due to hydrochlorothiazide Ear and labyrinth disorders Tinnitus Damage to hearing Respiratory, thoracic and mediastinal disorders Dry non-productive cough, bronchitis. Sinusitis, dyspnoea, nasal congestion Bronchospasm with worsening of asthma Allergic alveolitis, non-cardiogenic pulmonary edema due to hydrochlorothiazide Gastrointestinal disorders Gastrointestinal inflammation, digestive disturbances, abdominal discomfort, dyspepsia, gastritis, nausea, constipation. Gingivitis due to hydrochlorothiazide Vomiting, aphthous stomatitis, glossitis, diarrhea, pain in the upper abdomen, dry mouth. Pancreatitis (very exceptionally cases with fatal outcome have been reported with ACE inhibitors), increase in pancreatic enzymes, angioedema of the small intestine. Sialoadenitis due to hydrochlorothiazide Renal and urinary disorders Renal impairment including acute renal failure, increased diuresis, increased blood urea, increased blood creatinine worsening of pre-existing proteinuria Interstitial nephritis due to hydrochlorothiazide Skin and subcutaneous tissue disorders Angioedema: in very exceptional cases, the obstruction of the airways due to angioedema can be fatal; psoriasiform dermatitis, hyperhidrosis, rash, especially maculo-papular, pruritus, alopecia Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pemphigus, psoriasis aggravated, exfoliative dermatitis, photosensitivity reactions, onycholysis, pemphigoid or lichenoid rash or enanthema, urticaria Lupus erythematosus due to hydrochlorothiazide Musculoskeletal and connective tissue disorders Myalgia Arthralgia, muscle spasmsMuscle weakness, musculoskeletal stiffness, tetany due to hydrochlorothiazide Endocrine pathologies Syndrome of inappropriate antidiuretic hormone secretion (SIADH) Metabolism and nutrition disorders Inadequate control of diabetes mellitus, decreased glucose tolerance, increased blood glucose, increased blood uric acid, aggravated gout, increased blood cholesterol and / or triglycerides due to hydrochlorothiazide Anorexia, decreased appetite, decreased blood potassium, thirst caused by hydrochlorothiazide Blood potassium increased due to ramipril Blood sodium decreased, Glycosuria, metabolic alkalosis, hypochloraemia, hypomagnesaemia, hypercalcaemia, dehydration due to hydrochlorothiazide Vascular pathologies Hypotension, orthostatic hypotension, syncope, flushing Thrombosis in the context of severe fluid depletion, vascular stenosis, hypoperfusion, Raynaud's phenomenon, vasculitis General disorders and changes related to the administration site Fatigue, asthenia Chest pain, pyrexia Disorders of the immune system Anaphylactic or anaphylactoid reactions to ramipril or anaphylactic reactions to hydrochlorothiazide, antinuclear antibodies increased Hepatobiliary disorders cholestatic or cytolytic hepatitis (fatal outcome was very exceptional), increased liver enzymes and / or conjugated bilirubin Gallbladder stones due to hydrochlorothiazide Acute liver failure, cholestatic jaundice, hepatocellular damage Diseases of the reproductive system and breast Transient erectile impotence Decreased libido, gynecomastia Psychiatric disorders Depressed mood, apathy, anxiety, nervousness, sleep disturbances including somnolence Confusional state, restlessness, attention disturbance

04.9 Overdose

Symptoms associated with ACE inhibitor overdose may include excessive peripheral vasodilation (with marked hypotension, shock), bradycardia, electrolyte disturbances, renal failure, cardiac arrhythmia, impaired consciousness including coma, cerebral seizures, paresis and paralytic ileus.

In predisposed patients (e.g. prostatic hyperplasia) overdose of hydrochlorothiazide can lead to acute urinary retention.

Patients should be closely monitored and treatment should be symptomatic and supportive. The main measures suggested include detoxification (gastric lavage, administration of adsorbents) and measures to restore haemodynamic stability, including administration of alpha 1 adrenal agonists or angiotensin II (angiotensinamide). Ramiprilat, the active metabolite of ramipril, is poorly removed from the general circulation by hemodialysis.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: ramipril and diuretics; ATC code: C09BA05

Mechanism of action

Ramipril

ramiprilat, the active metabolite of the prodrug ramipril, inhibits the dipeptidylcarboxypeptidase I enzyme (synonyms: angiotensin converting enzyme; kininase II). This enzyme, at plasma and tissue level, determines the conversion of angiotensin I into the vasoconstrictor substance angiotensin II , and degradation of the vasodilator bradykinin. Reduced formation of angiotensin II and inhibition of degradation of bradykinin lead to vasodilation.

Since angiotensin II also stimulates the release of aldosterone, ramiprilat causes a reduction in the secretion of aldosterone. The mean response to ACE inhibitors of black (Afro-Caribbean) hypertensive patients (usually this hypertensive population has a low renin level) is lower than that of non-black patients.

Hydrochlorothiazide

Hydrochlorothiazide is a thiazide diuretic. The mechanism of the antihypertensive effect of thiazide diuretics is not fully understood. Hydrochlorothiazide inhibits the reabsorption of sodium and chlorine in the distal tubule. The increased renal excretion of these ions is accompanied by an increase in urine production (due to the osmotic binding of water). The excretion of potassium and magnesium increased, the excretion of uric acid decreased. Possible mechanisms of the antihypertensive action of hydrochlorothiazide could be: modification of the sodium balance, reduction of extracellular water and plasma volume, modification of renal vascular resistance as well as a reduced response to noradrenaline and angiotensin II.

Pharmacodynamic effects

Ramipril

Administration of ramipril causes a marked reduction in peripheral arterial resistance. Generally, neither the renal plasma flow nor the glomerular filtration index undergo noticeable changes. Administration of ramipril to hypertensive patients causes a reduction in blood pressure both in the standing position and in the supine position, without compensatory increase in heart rate.

After a single oral dose, in most patients the antihypertensive action occurs 1-2 hours after intake, reaches its maximum effect after 3-6 hours and lasts for at least 24 hours.

The maximum antihypertensive effect of continuous treatment with ramipril is generally achieved after 3-4 weeks.

It has been shown that the antihypertensive effect is maintained for prolonged therapy up to 2 years.

Abrupt discontinuation of therapy does not cause a rapid rebound increase in blood pressure.

Hydrochlorothiazide

With hydrochlorothiazide, the onset of diuresis occurs in 2 hours, and the peak of the effect occurs at about 4 hours, while the action lasts for about 6-12 hours.

The onset of the antihypertensive effect occurs after 3-4 days and can last up to a week after discontinuation of therapy.

The blood pressure lowering effect is accompanied by a slight increase in the filtration fraction, renal vascular resistance and plasma renin activity.

Concomitant administration of ramipril-hydrochlorothiazide

In clinical trials, the combination resulted in a greater reduction in blood pressure than either product given alone. Presumably through blockade of the renin-angiotensin-aldosterone system, co-administration of ramipril with hydrochlorothiazide tends to compensate for the loss. associated with these diuretics. The combination of an ACE inhibitor with a thiazide diuretic produces a synergistic effect and also decreases the risk of hypokalaemia caused by the diuretic alone.

05.2 Pharmacokinetic properties

Pharmacokinetics and Metabolism

Ramipril

Absorption

After oral administration ramipril is rapidly absorbed from the gastrointestinal tract; peak plasma ramipril concentration is reached within one hour. Based on urinary recovery, absorption is at least 56% and is not significantly affected by the presence of food in the gastrointestinal tract. The bioavailability of the active metabolite ramiprilat after oral administration of 2.5 mg and 5 mg of ramipril is 45%.

Peak plasma concentrations of ramiprilat, the only active metabolite of ramipril, are reached 2-4 hours after ramipril intake. Steady-state plasma concentrations of ramiprilat after once daily administration of the usual daily doses of ramipril are reached by the fourth day of treatment approx.

Distribution

The serum protein binding of ramipril is approximately 73% and that of ramiprilat is approximately 56%.

Metabolism

Ramipril is almost completely metabolised to ramiprilat and the diketopiperazine ester, the acid form of diketopiperazine and the glucuronides of ramipril and ramiprilat.

Elimination

Excretion of metabolites is mainly via the kidney. Plasma concentrations of ramiprilat decrease in a polyphasic manner. Due to its potent and saturable binding to ACE and slow dissociation from the enzyme, ramiprilat exhibits a prolonged terminal phase of elimination at very low plasma concentrations.

After multiple daily doses of ramipril, the effective half-life of ramiprilat concentrations was 13-17 hours for the 5-10 mg doses and longer for the lower 1.25-2.5 mg doses. This difference is related to the saturable ability of the enzyme to bind ramiprilat. A single oral dose of ramipril produced an undetectable level of ramipril and its metabolite in breast milk. However, the effect of multiple dose administration is not known.

Patients with renal insufficiency (see section 4.2)

The renal excretion of ramiprilat is reduced in patients with renal insufficiency and the renal clearance of ramiprilat is proportional to the creatinine clearance. This results in elevated plasma concentrations of ramiprilat which decline more slowly than in patients with normal renal function.

Patients with hepatic insufficiency (see section 4.2)

In patients with impaired hepatic function, the metabolization of ramipril to ramiprilat is delayed due to decreased activity of hepatic esterases; in these patients the plasma levels of ramipril are increased. Peak concentrations of ramiprilat in these patients, however, they are not different from those seen in subjects with normal liver function.

Hydrochlorothiazide

Absorption

After oral administration approximately 70% of hydrochlorothiazide is absorbed from the gastrointestinal tract. Peak plasma concentrations of hydrochlorothiazide are reached within 1.5 - 5 hours.

Distribution

Plasma protein binding of hydrochlorothiazide is 40%.

Metabolism

Hydrochlorothiazide has negligible hepatic metabolism.

Elimination

Hydrochlorothiazide is eliminated almost completely (> 95%) unchanged by the kidney: between 50 and 70% of a single oral dose is eliminated within 24 hours. The elimination half-life is 5-6 hours.

Patients with renal insufficiency (see section 4.2)

Renal excretion of hydrochlorothiazide is reduced in patients with renal insufficiency and renal clearance of hydrochlorothiazide is proportional to creatinine clearance. This results in elevated plasma concentrations of hydrochlorothiazide which decline more slowly than in patients with normal renal function.

Patients with hepatic insufficiency (see section 4.2)

The pharmacokinetics of hydrochlorothiazide are not significantly changed in patients with liver cirrhosis. The pharmacokinetics of hydrochlorothiazide have not been studied in patients with heart failure.

Ramipril and hydrochlorothiazide

Concomitant administration of ramipril and hydrochlorothiaizde does not change their bioavailability. The combination product can be considered bioequivalent to products containing the individual components.

05.3 Preclinical safety data

In rats and mice the combination of ramipril and hydrochlorothiazide did not produce acute toxicity up to 10,000 mg / kg. Repeated dose administration studies in rats and monkeys revealed only alterations in electrolyte balance.

Mutagenicity and carcinogenicity studies have not been conducted with the combination as studies with the individual components showed no risk.

Reproduction studies in rats and rabbits have shown that the combination is slightly more toxic than either of the individual components but no studies have shown a teratogenic effect of the combination.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

2.5 mg + 12.5 mg tablets

Hypromellose

Pregelatinised maize starch

Microcrystalline cellulose

Sodium stearyl fumarate

Tablets 5 mg + 25 mg

Hypromellose

Pregelatinised maize starch

Microcrystalline cellulose

Sodium stearyl fumarate

06.2 Incompatibility

Not relevant.

06.3 Period of validity

3 years.

06.4 Special precautions for storage

This medicine does not require any special storage conditions

06.5 Nature of the immediate packaging and contents of the package

2.5 mg + 12.5 mg: packs of 10, 14, 18, 20, 28, 30, 45, 50, 56, 60, 98, 99, 100, 300, 320 tablets in PVC / aluminum blisters

5 mg + 25 mg: packs of 10, 14, 18, 20, 28, 30, 45, 50, 56, 98, 99, 100, 300, 320 tablets in PVC / aluminum blisters

Not all pack sizes may be marketed

06.6 Instructions for use and handling

Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.

07.0 MARKETING AUTHORIZATION HOLDER

sanofi-aventis S.p.A.

Viale L. Bodio, 37 / B - Milan

08.0 MARKETING AUTHORIZATION NUMBER

2.5 mg + 12.5 mg tablets 14 tablets AIC n. 028531010

2.5 mg + 12.5 mg tablets 320 tablets AIC n. 028531174

5 mg + 25 mg tablets 14 tablets AIC n. 028531022

5 mg + 25 mg tablets 320 tablets AIC n. 028531186

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION

Date of first authorization: 31 October 1994

Last renewal date: November 15th 2004

10.0 DATE OF REVISION OF THE TEXT

September 2014

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY

12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL

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