Triatec - 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

TRIATEC 1.25 mg tablets
TRIATEC 2.5 mg tablets
TRIATEC 5 mg tablets
TRIATEC 10 mg tablets

Indications Why is Triatec used? What is it for?

TRITACE contains a medicine called ramipril which belongs to a group of medicines called ACE inhibitors (Angiotensin Converting Enzyme Inhibitors).

TRIATEC 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.

TRIATEC can be used:

  • To treat high blood pressure (hypertension)
  • To reduce the risk of a heart attack or stroke
  • To reduce the risk or delay the worsening of kidney problems (whether or not you have diabetes)
  • To treat your heart when it cannot pump enough blood to the rest of the body (heart failure)
  • As a treatment after a heart attack (myocardial infarction) when associated with heart failure.

Contraindications When Triatec should not be used

Do not take TRITACE:

  • If you are allergic (hypersensitive) to ramipril, other ACE inhibitor medicines or any of the other ingredients of TRITACE listed in section 6. Signs of an allergic reaction may be skin rash, difficulty swallowing or breathing, swelling of the lips, face, in the throat or tongue
  • 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 machinery being used, TRIATEC may not be suitable for you
  • 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 your blood pressure is excessively low or unstable. Your doctor will need to make this assessment
  • If you have diabetes or impaired kidney function and you are being treated with a blood pressure lowering medicine containing aliskiren.

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

Precautions for use What you need to know before taking Triatec

Check with your doctor or pharmacist before taking TRITACE:

  • 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 TRITACE 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. TRITACE 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 are taking any of the following medicines used to treat high blood pressure: - an "angiotensin II receptor antagonist" (AIIRA) (also known as sartans - for example valsartan, telmisartan, irbesartan), particularly if you have kidney problems related to diabetes - aliskiren "

Your doctor may check your kidney function, blood pressure, and the amount of electrolytes (such as potassium) in your blood at regular intervals. See also information under the heading "Do not take TRITACE".

Children

The use of TRITACE is not recommended in children and adolescents below 18 years of age because the safety and efficacy of TRITACE in children have not yet been established.

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

Interactions Which drugs or foods may change the effect of Triatec

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 TRITACE can affect the way some other medicines work.

Also some medicines can affect the way TRITACE works.

Tell your doctor if you are taking any of the following medicines. These medicines can interfere with TRITACE 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 TRITACE, 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 to treat cancer (chemotherapy)
  • 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
  • Allopurinol (used to lower the uric acid content in the blood)
  • Procainamide (for heart beat problems)
  • Take special care with TRIATEC ").

Tell your doctor if you are taking any of the following medicines. The mechanism of action of these medicines can be influenced by TRITACE:

  • Medicines for diabetes such as oral hypoglycaemics and insulin. TRITACE may lower the amount of sugar in your blood. Check your blood sugar levels carefully when taking TRITACE.
  • Lithium (for psychiatric problems). TRITACE can increase the amount of lithium in the blood. The level of lithium in your blood should be carefully checked by your doctor.

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

Taking TRITACE with food and alcohol

  • Drinking alcoholic beverages together with TRITACE may cause you to feel dizzy or lightheaded. If you want to know how much alcohol to drink while you are taking TRITACE, discuss this with your doctor, as drugs used to lower blood pressure and alcohol may have. angiotensin II receptor (AIIRA) or aliskiren (see also information under "Do not take TRITACE" and "additive effects."
  • TRIATEC can be taken with or between meals.

Warnings It is important to know that:

Pregnancy

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

You must not take TRITACE 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, please inform your doctor immediately.

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

Feeding time

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

Driving and using machines

You may feel dizzy while taking TRITACE. This is more likely when you have just started taking TRITACE 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: Posology

Always take TRITACE 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 this medicine by mouth at the same time of the day, every day
  • 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

  • The usual starting dose is 1.25 mg or 2.5 mg once a day.
  • Your doctor will adjust the amount you take until your blood pressure is under control.
  • The maximum daily dose is 10 mg.
  • If you are already taking diuretics, your doctor may stop or reduce the amount before starting treatment with TRITACE.

To reduce the risk of a heart attack or stroke

  • The starting dose is 2.5 mg once a day.
  • Your doctor may decide to increase the dosage you take
  • The usual dose is 10 mg once a day.

Treatment to reduce or prevent worsening of kidney problems

  • You may be given a starting dose of 1.25 mg or 2.5 mg once a day
  • Your doctor will adjust the amount you are taking.
  • The usual dose is 5 mg or 10 mg once a day.

Treatment of heart failure

  • The usual starting dose is 1.25 mg once a day.
  • Your doctor will adjust the amount you take.
  • The maximum dose is 10 mg per day. It is preferable to divide the dose into two daily administrations.

Treatment after a heart attack

  • The usual starting dose is 1.25 mg once daily to 2.5 mg twice daily.
  • Your doctor will adjust the amount you take.
  • The usual dose is 10 mg per day. It is preferable to divide the dose into two daily administrations.

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

If you take more TRITACE 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 TRITACE

  • 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

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

Stop taking TRITACE 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 TRITACE.
  • 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 tired feeling
  • Feeling dizzy. This is more likely to happen when TRITACE therapy has just started or the dose has just been increased
  • Weakness, hypotension (unusually low blood pressure), especially when standing or getting up quickly
  • Irritating dry cough, sinus inflammation (sinusitis) or bronchitis, shortness of breath
  • Pain in the stomach or intestines, diarrhea, indigestion, feeling unwell or being unwell
  • Skin rash with or without lumps
  • Chest pains
  • Muscle cramps or aches
  • Blood tests show a higher than normal potassium level.

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

  • 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
  • Swelling of the "gut called" intestinal angioedema "and presenting with symptoms such as abdominal pain, vomiting and diarrhea
  • Heartburn, constipation or dry mouth
  • Increased amount of urine during the day
  • More sweating than usual
  • Loss or decreased appetite (anorexia)
  • Fast or irregular heartbeat.
  • Swollen arms and legs. This may be a sign that your body is holding onto more water than usual
  • Flushes
  • Blurred vision
  • Pain in the joints
  • Fever
  • Impotence in men, reduced sexual desire in men and women
  • An increase in the number of white blood cells (eosinophilia) found in blood tests
  • Changes in the function of the liver, pancreas or kidneys shown in blood tests.

Rare (affecting less than 1 patient in every 1000 patients on therapy)

  • Feeling faint or confused
  • Swollen and red tongue
  • Severe flaking or peeling of the skin, itchy, pustular rash
  • Nail problems (such as loosening or separation of the nail from its place)
  • Skin rash or bruising
  • Spots on the skin and cold extremities
  • Red, swollen or watery or itchy eyes
  • Disturbed hearing and ringing in the ear
  • Feeling of weakness
  • Decrease in the number of red, white blood cells and platelets in the blood or in the concentration of hemoglobin, shown in blood tests.

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

  • Increased awareness of the sun.

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
  • Swelling in the mouth
  • Blood tests showing too few blood cells.
  • Blood tests showing low blood sodium
  • Fingers and toes that change color when they get cold and that tingle or hurt when heated (Raynaud's phenomenon)
  • Breast enlargement in men
  • Slowed or altered reactions
  • Burning sensation
  • Change in the perception of odors
  • Hair loss

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 after the expiry date indicated on the cartons, blisters and bottles. 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 contains

The active ingredient is ramipril

1.25 mg: Each tablet contains 1.25 mg ramipril.

2.5 mg: Each tablet contains 2.5 mg ramipril

5 mg: Each tablet contains 5 mg ramipril

10 mg: Each tablet contains 10 mg ramipril

The other ingredients of the tablets are:

1.25 mg and 10 mg tablets hypromellose, pregelatinised maize starch, microcrystalline cellulose, sodium stearyl fumarate.

2.5 mg tablets hypromellose, pregelatinised maize starch, microcrystalline cellulose, sodium stearyl fumarate, yellow iron oxide E172.

5 mg tablets hypromellose, pregelatinised maize starch, microcrystalline cellulose, sodium stearyl fumarate, red iron oxide E172.

Description of what TRIATEC looks like and contents of the pack

1.25 mg tablets Oblong, white to off-white tablets with break line, marked on the top with 1.25 and company logo and on the underside with HMN and 1.25. The score line is only to facilitate breaking by favoring swallowing and not to divide the tablet into equal doses.

2.5 mg tablets Oblong, yellow to yellowish tablets with break line, marked on the upper side with 2.5 and company logo and on the lower side with HMR and 2.5. The tablet can be divided into equal parts.

5 mg tablets Oblong, light red tablets with score line, upper side marked with 5 and company logo and lower side with HMP and 5. The tablet can be divided equally.

10 mg tablets White to off-white oblong tablets with score line, marked on the upper side with HMO / HMO. The tablet can be divided into equal parts.

Triatec 1.25 mg tablets are available in packs of 14, 15, 20, 28, 30, 50, 90, 98, 100 tablets in PVC / aluminum blisters and in packs of 500 tablets in dark glass bottles with cap.

Triatec 2.5 mg tablets are available in packs of 7, 10, 14, 15, 18, 20, 28, 30, 45, 50, 60, 90, 98, 99, 100, 300, 320, 500 tablets in PVC blisters / aluminum and in packs of 500 tablets in dark glass bottles with cap.

Triatec 5 mg tablets are available in packs of 10, 14, 15, 18, 20, 21, 28, 30, 45, 50, 56, 90, 98, 99, 100, 300, 320, 500 tablets in PVC / aluminum blisters and in packs of 500 tablets in dark glass bottles with a closure.

Triatec 10 mg tablets are available in packs of 7, 10, 14, 15, 18, 20, 28, 30, 45, 50, 56, 90, 98, 99, 100, 300, 320, 500 tablets in PVC / aluminum blisters and in packs of 28, 56, 500 tablets in dark glass bottles with cap. Not all pack sizes may be marketed

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 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 TABLETS

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Tablets

Each tablet contains 1.25 mg ramipril.

Each tablet contains 2.5 mg ramipril.

Each tablet contains 5 mg ramipril.

Each tablet contains 10 mg ramipril.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

1.25 mg tablets

White to off-white oblong tablets with score line, top side marked with 1.25 and company logo and bottom side with HMN and 1.25. The score line is only to facilitate breaking by favoring swallowing and not to divide the tablet into equal doses.

2.5 mg tablets

Yellow to yellowish oblong tablets with score line, top side with 2.5 and company logo and bottom side with HMR and 2.5. The tablet can be divided into equal parts.

5 mg tablets

Oblong, light red tablets with score line, top side with 5 and company logo and bottom side with HMP and 5. The tablet can be divided equally.

10 mg tablets

White to off-white oblong tablets with score line, marked on the upper side with HMO / HMO. The tablet can be divided into equal parts.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

- Treatment of hypertension.

- Cardiovascular prevention: reduction of cardiovascular morbidity and mortality in patients with:

• established atherothrombotic cardiovascular diseases (previous coronary heart disease or stroke, or peripheral vascular disease) or

• diabetes with at least one cardiovascular risk factor (see section 5.1)

- Treatment of kidney diseases:

• Incipient diabetic glomerular nephropathy, defined by the presence of microalbuminuria

• Overt diabetic glomerular nephropathy, defined by macroproteinuria in patients with at least one cardiovascular risk factor (see section 5.1)

• Overt glomerular non-diabetic nephropathy defined by macroproteinuria ≥3g / day (see section 5.1).

- Treatment of symptomatic heart failure.

- Secondary prevention after acute myocardial infarction: reduction of mortality after the acute phase of myocardial infarction in patients with clinical signs of heart failure when started 48 hours after the onset of acute myocardial infarction

04.2 Posology and method of administration

Oral use.

It is recommended that TRITACE be taken at the same time each day.

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

TRIATEC must be swallowed with a liquid and must not be chewed or crumbled.

Adults

Patients being treated with a diuretic

Hypotension may occur after initiation of treatment with TRITACE and is more likely in patients treated concomitantly with a diuretic. Caution is therefore recommended for these patients as they may be depleted in plasma volume and / or salts.

The diuretic should be discontinued, if possible, 2 or 3 days prior to initiation of therapy with TRITACE (see section 4.4).

In hypertensive patients in whom the diuretic has not been discontinued, therapy with TRITACE should be initiated with a dose of 1.25 mg. Renal function and serum potassium should be monitored. The subsequent dosage of TRITACE must be adjusted according to the desired blood pressure value.

Hypertension

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

TRITACE can be used alone or in combination with other classes of antihypertensive drugs (see sections 4.3, 4.4, 4.5 and 5.1).

Initial dose

Treatment with TRITACE should be started gradually, with a recommended starting dose of 2.5 mg per day.

Patients with an overactivation of the renin-angiotensin-aldosterone system may have an excessive drop in blood pressure after taking the starting dose. For these patients, a starting dose of 1.25 mg is recommended, and starting treatment under medical supervision (see section 4.4).

Titration and maintenance dose

The dose can be doubled at intervals of 2-4 weeks in order to progressively reach the required blood pressure value; the maximum dose of TRITACE is 10 mg per day. The dose is usually taken once a day.

Cardiovascular prevention

Initial dose

The recommended starting dose is 2.5 mg of TRITACE once daily.

Titration and maintenance dose

The dosage should be gradually increased in the patient based on the tolerability of the active ingredient. It is recommended to double the dose after one or two weeks of treatment and - after a further two to three weeks - to increase it until the target maintenance dose of 10 mg of TRITACE once daily is reached.

See also the posology described above for patients treated with a diuretic.

Treatment of kidney diseases

In patients with diabetes and microalbuminuria:

Initial dose

The recommended starting dose is 1.25 mg of TRITACE once daily.

Titration and maintenance dose

The dosage should be gradually increased in the patient based on the tolerability of the active ingredient.

It is recommended that the single daily dose be doubled to 2.5 mg after two weeks and a further two weeks to 5 mg.

In patients with diabetes and at least one cardiovascular risk factor

Initial dose

The recommended starting dose is 2.5 mg of TRITACE once daily.

Titration and maintenance dose

The dosage should be gradually increased in the patient based on the tolerability of the active ingredient.

It is recommended that the single daily dose be doubled to TRITACE 5 mg after one to two weeks and then to TRITACE 10 mg after a further two to three weeks. The target daily dose is 10 mg.

In patients with non-diabetic nephropathy, defined by macroproteinuria ≥3g / day

Initial dose

The recommended starting dose is 1.25 mg of TRITACE once daily.

Titration and maintenance dose

The dosage should be gradually increased in the patient based on the tolerability of the active ingredient.

It is recommended that the single daily dose be doubled to 2.5 mg after two weeks and then to 5 mg after a further two weeks.

Symptomatic heart failure

Initial dose

In patients stabilized on diuretic therapy, the recommended starting dose is 1.25 mg per day.

Titration and maintenance dose

TRITACE should be titrated by doubling the dose every one to two weeks up to a maximum daily dose of 10 mg. Two administrations per day are preferable.

Secondary prevention in patients with previous acute myocardial infarction and heart failure

Initial dose

After 48 hours of myocardial infarction, in clinically and haemodynamically stable patients, the starting dose is 2.5 mg twice daily for three days. If the starting 2.5 mg dose is not tolerated, a dose should be given. 1.25 mg twice daily for two days before increasing to 2.5 mg and 5 mg twice daily If the dose cannot be increased to 2.5 mg twice daily the treatment should be stopped.

See also the posology described above for patients treated with a diuretic.

Titration and maintenance dose

The daily dose is subsequently increased by doubling it at intervals of one to three days to a maintenance dose of 5 mg twice daily.

Whenever possible, the maintenance dose is divided into two administrations per day.

If the dose cannot be increased to 2.5mg twice daily the treatment should be stopped. There is still insufficient experience in treating patients with severe heart failure (NYHA IV) immediately following myocardial infarction. If a decision is made to treat these patients, it is recommended that therapy be initiated at 1.25 mg once daily and that particular caution be exercised in any dose increase.

Special populations

Patients with impaired renal function

The daily dose in patients with renal insufficiency should be based on creatinine clearance (see section 5.2):

• if creatinine clearance is ≥ 60 ml / min, it is not necessary to adjust the starting dose (2.5 mg / day); the maximum daily dose is 10 mg;

• if the creatinine clearance is between 30-60 ml / min it is not necessary to adjust the starting dose (2.5 mg / day); the maximum daily dose is 5 mg;

• if creatinine clearance is between 10-30 ml / min, the starting dose is 1.25 mg / day and the maximum daily dose is 5 mg;

• Ramipril is poorly dialyzable in hypertensive patients on hemodialysis; the starting dose is 1.25 mg / day and the maximum daily dose is 5 mg; the medicinal product must be administered a few hours after performing dialysis.

Patients with impaired hepatic function (see section 5.2)

In patients with hepatic insufficiency, treatment with TRITACE should only be initiated under close medical supervision and the maximum daily dose of TRITACE is 2.5 mg.

Elderly patients

The starting dose should be the lowest and the subsequent titration should be very gradual due to the increased likelihood of undesirable effects particularly in very elderly or debilitated patients. A reduced starting dose of ramipril of 1.25 mg should be considered.

Pediatric population

The safety and efficacy of ramipril in children has not yet been established. Currently available data for Triatec are described in sections 4.8, 5.1, 5.2 and 5.3 but no specific recommendation on a posology can be made.

04.3 Contraindications

• Hypersensitivity to the active substance, to any of the excipients or to other ACE inhibitors (Angiotensin Converting Enzyme inhibitors) (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 a single functioning kidney.

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

• Ramipril should not be used in patients with hypotension or haemodynamically unstable

• The concomitant use of Triatec with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR 2) (see sections 4.5 and 5.1).

04.4 Special warnings and appropriate precautions for use

Special populations

Pregnancy

Therapy with ACE inhibitors, such as ramipril or 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 therapy with an ACE inhibitor / AIIRAs is considered essential. 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 particularly at 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 deterioration of renal function due to ACE inhibition, especially when the ACE inhibitor or a concomitant diuretic is first administered. once or at the first dose increase. Relevant activation of the renin-angiotensin-aldosterone system must 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).

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

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

If dual block therapy is considered absolutely necessary, this should only be done under the supervision of a specialist and with close and frequent monitoring of kidney function, electrolytes and blood pressure.

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

Transient or persistent heart failure after myocardial infarction

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

The initial phase of treatment requires careful medical supervision.

Elderly patients

See section 4.2.

Surgery

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

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 renal impairment (see section 4.2). C "is the risk of impaired renal function, particularly in patients with congestive heart failure or after kidney transplantation.

• Angioedema

Cases of angioedema have been reported in patients receiving ACE inhibitors including ramipril (see section 4.8).

In case of angioedema, TRITACE 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 reported in patients receiving ACE inhibitors, including TRITACE (see section 4.8). These patients presented with abdominal pain (with or without nausea or vomiting).

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. Temporary discontinuation of TRITACE should be considered prior to desensitization.

Electrolyte monitoring: Hyperkalemia

Hyperkalaemia has been observed in some patients treated with ACE inhibitors including TRITACE. Patients at risk for hyperkalaemia include those with renal insufficiency, age> 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.

Neutropenia / agranulocytosis

Neutropenia / agranulocytosis, as well as thrombocytopenia and anemia, have been observed rarely, and bone marrow depression has also been reported.

It is recommended to monitor the number of white blood cells to allow the detection of a possible leukopenia.

More frequent monitoring is advised 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 those treated with drugs that can cause changes in the blood picture (see paragraphs 4.5 and 4.8).

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.

Cough

Cough has been reported 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.

04.5 Interactions with other medicinal products and other forms of interaction

Clinical trial data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) through the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events. such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single agent active on the RAAS system (see sections 4.3, 4.4 and 5.1).

Contraindicated associations

Extracorporeal treatments that lead to contact between blood and negatively charged surfaces such as dialysis or haemofiltration with 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.

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 intake, 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 (e.g. isoproterenol, dobutamide, dopamide, adrenaline) which can reduce the antihypertensive effect of TRIATEC: Blood pressure monitoring is recommended.

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 can be reduced by ACE inhibitors and therefore lithium toxicity can be increased. Serum lithium levels should be monitored.

Antidiabetic agents including insulin: Hypoglycaemic reactions may occur. Therefore, blood glucose monitoring is recommended.

Non-steroidal anti-inflammatory drugs and acetylsalicylic acid: a possible reduction in the antihypertensive effect of TRITACE 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.

04.6 Pregnancy and breastfeeding

Pregnancy

TRITACE 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 on 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 / angiortensin 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 closely monitored for hypotension, oliguria and hyperkalaemia (see also sections 4.3 and 4.4).

Feeding time

Since there is insufficient information on the use of ramipril during breastfeeding (see section 5.2), TRITACE is not recommended and alternative treatments with better established safety profiles during breastfeeding are preferable, especially when breastfeeding a newborn or infant. preterm infant.

04.7 Effects on ability to drive and use machines

Some undesirable effects (e.g. symptoms of low blood pressure such as dizziness) may interfere with the patient's ability to concentrate and react and therefore represent a risk in situations where these skills are particularly important (e.g. operating machinery or driving 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 ramipril includes persistent dry cough and reactions due to hypotension. Serious adverse reactions include angioedema, hyperkalaemia, 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 Rare Very rare Not known Cardiac pathologies Myocardial ischaemia such as angina pectoris or myocardial infarction, tachycardia, arrhythmia, palpitations, peripheral edema Disorders of the blood and lymphatic system Eosinophilia Decrease in the number of white blood cells (such as neutropenia or agranulocytosis), decrease in the number of red blood cells, decrease in hemoglobin concentration, decrease in the number of platelets. Bone marrow depression, pancytopenia, haemolytic anemia. Nervous system disorders Headache, dizziness Vertigo, paraesthesia, ageusia, dysgeusia Tremor, balance disorders Cerebral ischaemia such as ischemic stroke and transient ischemic attack, impaired psychomotor skills, burning sensation, parosmia Eye disorders Visual disturbances including blurred vision Conjunctivitis Ear and labyrinth disorders Hearing damage, tinnitus Respiratory, thoracic and mediastinal disorders Dry non-productive cough, bronchitis, sinusitis, dyspnoea Bronchospasm including aggravation of asthma, nasal congestion Gastrointestinal disorders Gastrointestinal inflammation, digestive disorders, abdominal discomfort, dyspepsia, diarrhea, nausea, vomiting Pancreatitis (very exceptionally cases with fatal outcome have been reported with ACE inhibitors), pancreatic enzymes increased, small bowel angioedema, upper abdominal pain such as gastritis, constipation, dry mouth. Glossitis Aphthae, stomatitis Renal and urinary disorders Renal impairment including acute renal failure, increased urine output, worsening of pre-existing proteinuria, increased blood urea nitrogen, increased blood creatinine Skin and subcutaneous tissue disorders Rash in particular maculo-papular Angioedema; in very exceptional cases, airway obstruction due to angioedema can be fatal; itching, hyperhidrosis. Exfoliative dermatitis, urticaria, onycholysis Photosensitization Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pemphigus, psoriasis aggravation, psoriasiform dermatitis, pemphigoid or lichenoid exanthema or enanthema, alopecia Musculoskeletal and connective tissue disorders Muscle spasms, myalgia Arthralgia Endocrine pathologies Syndrome of inappropriate antidiuretic hormone secretion (SIADH) Metabolism and nutrition disorders Increased kalaemia Anorexia, decreased appetite Decreased sodemia Vascular pathologies Hypotension, orthostatic hypotension, syncope Flushes Vascular stenosis, hypoperfusion, vasculitis Raynaud's phenomenon General disorders and administration site conditions Chest pain, fatigue Pyrexia Asthenia Disorders of the immune system Anaphylactic or anaphylactoid reactions, increased antinuclear antibodies Hepatobiliary disorders Increased liver enzymes and / or conjugated bilirubin Jaundice cholestatic, hepatocellular damage Acute liver failure, cholestatic or cytolytic hepatitis (the fatal outcome was very exceptional) Diseases of the reproductive system and breast Transient erectile impotence, decreased libido Gynecomastia Psychiatric disorders Depressed mood, anxiety, nervousness, irritability, sleep disturbances including somnolence Confusional state Attention disturbances

Pediatric population

The safety of ramipril was monitored in 325 children and adolescents, aged 2-16 years in 2 clinical studies. Although the nature and severity of adverse events are similar to those in adults, the frequency of the following events is higher in children:

Tachycardia, nasal congestion and rhinitis, "common" (i.e. ≥ 1/100,

"Common" conjunctivitis (i.e. ≥ 1/100,

Tremor and "uncommon" urticaria (i.e. ≥ 1/1000,

The overall safety profile for ramipril in pediatric patients does not differ significantly from the safety profile in adults.

04.9 Overdose

Symptoms associated with ACE inhibitor overdose may include excessive peripheral vasodilation (with marked hypotension, shock), bradycardia, electrolyte disturbance, renal failure. Patients should be carefully 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: ACE inhibitors; A.T.C code: C09AA05

Mechanism of action .

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 the degradation of the vasodilator bradykinin. The reduced formation of angiotensin II and the inhibition of the 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.

Pharmacodynamic effects .

Antihypertensive properties:

Administration of ramipril causes a marked reduction in peripheral arterial resistance. Generally neither the renal plasma flow nor the glomerular filtration undergo notable changes.

Administration of ramipril to hypertensive patients results in a reduction in blood pressure in both standing and supine positions, without compensatory increase in heart rate.

After a single oral dose, in most patients the antihypertensive action occurs after 1 or 2 hours from the 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 of treatment.

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.

Heart failure:

Ramipril has been shown to be effective, in addition to conventional therapy with diuretics and cardiac glucosides, in patients with functional classes II-IV defined by the New-York Heart Association. The drug had beneficial effects on cardiac hemodynamics (decreased filling pressure of the left and right ventricles, decreased total peripheral vascular resistance, increased cardiac output, and improved cardiac index). It also reduces neuroendocrine activation.

Clinical efficacy and safety

Cardiovascular prevention / nephroprotection:

A placebo-controlled prevention study (the HOPE study) was conducted in which ramipril was added to standard therapy in more than 9,200 patients. Patients with an increased risk of cardiovascular disease resulting from atherothrombotic cardiovascular disease (coronary artery disease, stroke or peripheral vascular disease) or diabetes mellitus with at least one additional risk factor (documented microalbuminuria, hypertension, high total cholesterol level, low HDL cholesterol level, or smoking), were included in the study.

The study showed that ramipril statistically significantly decreases the incidence of myocardial infarction, cardiovascular death and stroke, alone or combined (primary events combined).

HOPE study: main results


Ramipril Placebo relative risk (95% confidence interval) p-value % % All patients n = 4.645 n = 4.652 Combined primary event 14.0 17.8 0.78 (0.70 - 0.86) Myocardial infarction 9.9 12.3 0.80 (0.70-0.90) Death from cardiovascular causes 6.1 8.1 0.74 (0.64-0.87) Stroke 3.4 4.9 0.68 (0.56-0.84) Secondary endpoints Death for any cause 10.4 12.2 0.84 (0.75-0.95) 0.005 Need for revascularization 16.0 18.3 0.85 (0.77-0.94) 0.002 Hospitalization for unstable angina 12.1 12.3 0.98 (0.87-1.10) NS Hospitalization for heart failure 3.2 3.5 0.88 (0.70-1.10) 0.25 Complications related to diabetes 6.4 7.6 0.84 (0.72-0.98) 0.03

The MICRO-HOPE study, a predefined substudy from the HOPE study, evaluated the effect of adding ramipril 10 mg to the current regimen versus placebo in 3,577 patients aged ≥ 55 years (with no upper age limit), the majority with type 2 diabetes (and at least one other CV risk factor) normotensive or hypertensive.

The primary analysis of the results showed that 117 (6.5%) participants treated with ramipril and 149 (8.4%) treated with placebo developed overt nephropathy, which corresponds to a Relative Risk Reduction (RRR) of 24%. ; 95% CI [3-40], p = 0.027.

The REIN randomized, double-blind, parallel-group, placebo-controlled study was aimed at demonstrating the effect of ramipril treatment on the rate of decrease in glomerular function (GFR) in 352 normotensive or hypertensive patients (18-70 years). of age) with mild proteinuria (i.e. urinary protein excretion> 1 e

The main analysis of patients with the most severe proteinuria (layer prematurely separated due to the benefit seen in the ramipril group) showed that the mean rate of decrease in GFR per month was lower with ramipril than with placebo; -0, 54 vs. -0.88 mL / min / month, p = 0.038. The difference between groups was 0.34 [0.03-0.65] per month, and approximately 4 mL / min / year; on 23, 1% of patients in the ramipril group achieved the combined secondary endpoint of doubling baseline serum creatinine concentration and / or end-stage renal failure (ESRD) (need for dialysis or kidney transplantation) versus 45.5% in the group placebo (p = 0.02).

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

Two large randomized 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 antagonist of the angiotensin II receptor.

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

These studies did not demonstrate any significant beneficial effect on renal and / or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute renal injury and / or hypotension was observed compared to monotherapy.

These results are also relevant for other ACE inhibitors and angiotensin II receptor antagonists, given their similar pharmacodynamic properties.

ACE inhibitors and angiotensin II receptor antagonists should therefore not be used simultaneously in patients with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study aimed at verifying the advantage of adding aliskiren to standard therapy of an ACE inhibitor or angiotensin II receptor antagonist in patients with diabetes mellitus. type 2 and chronic kidney disease, cardiovascular disease, or both. The study was terminated early due to an increased risk of adverse events. 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 reported more frequently in the aliskiren group than in the placebo group.

Secondary prevention after acute myocardial infarction

The AIRE study included more than 2,000 patients with transient / persistent clinical signs of heart failure after documented myocardial infarction. Ramipril treatment started 3-10 days after acute myocardial infarction. The study indicated that after a mean follow-up time of 15 months the mortality in ramipril-treated patients was 16.9% while in patients treated with ramipril. treated with placebo was 22.6%, which means an absolute reduction in mortality of 5.7% and a relative risk reduction of 27% (CI of 95% [11- 40%]).

Pediatric population

In a randomized, double-blind, placebo-controlled clinical trial involving 244 pediatric patients with hypertension (73% primary hypertension), aged 6-16 years, patients received weight-based low doses, medium or high levels of ramipril to achieve plasma ramiprilat concentrations corresponding to the adult dosages of 1.25 mg, 5 mg and 20 mg. At the end of 4 weeks, ramipril was ineffective in lowering systolic blood pressure, but at the higher dose it lowered diastolic blood pressure. Both medium and high doses of ramipril showed a significant reduction in systolic and diastolic blood pressure in children with confirmed hypertension.

This effect was not observed in a randomized, double-blind, dose-escalating, clinical study stopped after 4 weeks in 218 pediatric patients aged 6-16 years (75% primary hypertension), where systolic and diastolic pressures demonstrated modest rebound, but not statistically significant return to baseline, across all three weight-tested ramipril dose levels [low dose (0.625 mg - 2.5 mg), medium dose (2.5 mg) mg - 10 mg) or high dose (5 mg - 20 mg)]. Ramipril did not show a linear dose / response relationship in the pediatric population studied.

05.2 Pharmacokinetic properties

Pharmacokinetics and Metabolism

Absorption

After oral administration, ramipril is rapidly absorbed from the gastrointestinal tract: the peak plasma concentration of ramipril 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

The excretion of the 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 elimination phase 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.

Feeding time

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.

Pediatric population

The pharmacokinetic profile of ramipril was studied in 30 hypertensive pediatric patients, aged 2 to 16 years, weighing ≥ 10 kg. After administration of doses of 0.05 to 0.2 mg / kg, ramipril was rapidly and largely metabolised to ramiprilat. Peak plasma concentrations of ramiprilat occurred within 2-3 hours. Ramiprilat clearance is highly correlated with the log of body weight (p

05.3 Preclinical safety data

Oral administration of ramipril was found to be devoid of acute toxicity in rodents and dogs. Studies involving chronic oral administration were conducted in rats, dogs and monkeys. Alterations of plasma electrolytes were detected in the three species. As an expression of the pharmacodynamic activity of ramipril, a pronounced enlargement of the juxtaglomerular apparatus was found in dogs and monkeys starting with daily doses of 250 mg / kg. Rats, dogs and monkeys tolerated daily doses of 2, 2.5 and 8 mg / kg respectively without adverse effects.

Irreversible renal damage was observed in very young rats treated with a single dose of ramipril.

Reproductive toxicology studies in rats, rabbits and monkeys revealed no teratogenic properties. Fertility was not affected in male or female rats.

Administration of ramipril to female rats during the gestation and lactation period resulted in irreversible renal damage (dilation of the renal pelvis) in the offspring at daily doses of 50 mg / kg body weight or higher.

The mutagenicity test, conducted using various test systems, did not provide evidence that ramipril possesses mutagenic or genotoxic properties.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

1.25 mg tablets

hypromellose, pregelatinised maize starch, microcrystalline cellulose, sodium stearyl fumarate.

2.5 mg tablets

hypromellose, pregelatinised maize starch, microcrystalline cellulose, sodium stearyl fumarate, yellow iron oxide E172.

5 mg tablets

hypromellose, pregelatinised maize starch, microcrystalline cellulose, sodium stearyl fumarate, red iron oxide E 172.

10 mg tablets

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

1.25 mg: packs of 14, 15, 20, 28, 30, 50, 90, 98, 100 tablets in PVC / aluminum blisters

2.5 mg: packs of 7, 10, 14, 15, 18, 20, 28, 30, 45, 50, 60, 90, 98, 99, 100, 300, 320, 500 tablets in PVC / aluminum blisters,

5 mg: packs of 10, 14, 15, 18, 20, 21, 28, 30, 45, 50, 56, 90, 98, 99, 100, 300, 320, 500 tablets in PVC / aluminum blisters

10 mg: packs of 7, 10, 14, 15, 18, 20, 28, 30, 45, 50, 56, 90, 98, 99, 100, 300, 320, 500 tablets in PVC / aluminum blisters

1.25 mg: 500 tablets in type III dark glass bottle (Eur.Ph.) with HDPE screw cap.

2.5 mg: 500 tablets in type III dark glass bottle (Eur.Ph.) with HDPE screw cap.

5 mg: 500 tablets in type III dark glass bottle (Eur.Ph.) with HDPE screw cap.

10 mg: 25, 56, 500 tablets in type III dark glass bottle (Eur.Ph.) with HDPE screw cap.

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 S.p.A. - Viale L. Bodio, 37 / B - 20158 Milan

08.0 MARKETING AUTHORIZATION NUMBER

"1.25 mg tablets" - 28 tablets in PVC / AL A.I.C. n .: 027161049

"2.5 mg tablets" - 28 divisible tablets in PVC / AL A.I.C. n .: 027161052

"2.5 mg tablets" - 320 divisible tablets in PVC / AL A.I.C. n .: 027161088

"5 mg tablets" - 14 divisible tablets in PVC / AL A.I.C. n .: 027161064

"5 mg tablets" - 320 divisible tablets in PVC / AL A.I.C. n .: 027161090 "10 mg tablets" - 28 divisible tablets in PVC / AL A.I.C.blister n .: 027161076

"10 mg tablets" - 320 divisible tablets in PVC / AL A.I.C. n .: 027161102

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION

First Authorization Date: 1 March 1990 Triatec 1.25 mg, 2.5 mg, 5 mg.

23 February 2004 Triatec 10 mg

Last renewal date: 01 June 2010

10.0 DATE OF REVISION OF THE TEXT

May 2015

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

none:  hygiene confectionery autoimmune-diseases