Тритаце®

General characteristics. Structure:

One tablet to Tritatsa 2,5 contains 2,5 mg of a ramipril as active agent.
Excipients: a gipromelloza, starch prezhelatinizirovanny, cellulose microcrystallic, the sodium stearylfumarating dye ferrous oxide yellow.
One tablet to Tritatsa 5 contains 5,0 mg of a ramipril as active agent.
Excipients: a gipromeloza, starch prezhelatinizirovanny, cellulose microcrystallic, the sodium stearylfumarating dye ferrous oxide red.
 
Description: 
To Tritatsa 2,5 - light yellow oblong tablets with dividing risky on both sides and an engraving 2,5/stylized image of a letter h and 2,5/HMR on the other hand.
To Tritatsa 5 - light pink oblong tablets with dividing risky on both sides and an engraving 5/stylized image of a letter h and 5/HMR on the other hand.

Pharmacological properties:

Pharmacodynamics. Ramiprilat, an active metabolite of a ramipril, is inhibitor of the angiotensin-converting enzyme (ACE) of long action. In a blood plasma and fabrics this enzyme catalyzes transition of angiotensin I to angiotensin II (active vasoconstrictive agent) and splitting of an active vazodilatator of bradikinin. Reduction of formation of angiotensin II and increase in activity of bradikinin leads to vasodilatation and makes the contribution to cardioprotective and endotelioprotektivny action of a ramipril.
Angiotensin II stimulates release of Aldosteronum, in this regard ramiprit causes decrease in secretion of Aldosteronum.
Reception of a ramipril leads to considerable decrease in peripheric resistance, in general without causing changes in a renal blood-groove and glomerular filtration rate. Reception of a ramipril causes a lowering of arterial pressure (ABP) both in a prone position, and in a standing position without compensatory increase in heart rate. The anti-hypertensive effect is observed in 1-2 hours after intake of a single dose of drug. The hypotensive effect remains within 24 hours. The maximum hypotensive action to Tritatsa develops usually by 3-4 week of constant administration of drug and is supported for a long time. The sudden termination of administration of drug does not lead to bystry and significant increase in the ABP.
Administration of drug reduces mortality (including sudden death), the risk of development of the expressed heart failure, reduces number of hospitalization of patients with clinical signs of chronic heart failure after an acute myocardial infarction.
At patients with the diabetic and not diabetic clinically expressed nephropathy drug reduces the speed of progressing of a renal failure, and at a preclinical stage of a diabetic and not diabetic nephropathy ramiprit reduces an albuminuria.
Drug favorably influences carbohydrate metabolism and a lipidic profile, causes decrease in the expressed hypertrophy of a myocardium and a vascular wall.

Pharmacokinetics. After intake it is quickly soaked up in digestive tract (50-60%). Food does not influence completeness of absorption, but slows down absorption.
Being pro-medicine, ramiprit is exposed to intensive presistemny metabolism (mainly in a liver by hydrolysis) as a result of which its only active metabolite - рамиприлат is formed. Except formation of this active metabolite, at a glyukuronirovaniye of a ramipril and a ramiprilat inactive metabolites are formed: ramiprit diketopiperazine and рамиприлат diketopiperazine. Ramiprilat approximately by 6 times inhibits APF more actively, than ramiprit.
The maximum concentration ramiprit and the ramiprilata is reached in a blood plasma in 1 and 3 hours, respectively. After administration of drug daily, single during the day in a dose of 5 mg steady concentration of a ramiprilat in a blood plasma is reached by 4th day. Decrease in plasma concentration of a ramiprilat happens in several stages: a phase of initial distribution and removal with an elimination half-life (T1/2) of a ramiprilat about 3 hours, then an intermediate phase with the period of T1/2 of a ramiprilat about 15 hours and a final phase with very low concentration of a ramiprilat in a blood plasma and T1/2 of a ramiprilat about 4-5 days. This final phase is connected with slow dissociation of a ramiprilat from communication with APF receptors. Despite a long final phase at reception of a ramipril single within a day in a dose of 2,5 mg and more equilibrium plasma concentration of a ramiprilat is reached approximately in 4 days of treatment. At course purpose of the drug T1/2 makes 13-17 hours.
Communication with proteins of a blood plasma makes for a ramipril 73%, and for a ramiprilat - 56%.
The volume of distribution of a ramipril and ramiprilat makes about 90 and 500 liters, respectively.
At intake about 60% of drug are removed with urine and about 40% with bile, and less than 2% are removed in an invariable look.
At renal failures removal of a ramipril and its metabolites is slowed down in proportion to decrease in the clearance of creatinine (CC). It leads to increase in plasma concentration of a ramiprilat and their slower decrease in comparison with patients with normal function of kidneys.
At the patients having liver diseases transformation of a ramipril in рамиприлат is slowed down, concentration of a ramipril in a blood plasma can increase by 3 times, at the same time the maximum concentration in a blood plasma of a ramiprilat does not change.
At heart failure increase in concentration of a ramiprilat by 1,5-1,8 times is noted. However at reception of 5 mg of a ramipril of 1 times a day by patients with heart failure after 2 weeks of treatment did not observe clinically significant accumulation of a ramipril and a ramiprilat.
At elderly people the drug pharmacokinetics significantly does not change.
In researches on animals it was shown that ramiprit gets into maternal milk.

Indications to use:

• arterial hypertension;
• chronic heart failure (as a part of a combination therapy), including, developed during the first several days after an acute myocardial infarction;
• a diabetic nephropathy and a nephropathy against the background of chronic diffusion diseases of kidneys (a chronic glomerulonephritis with the expressed proteinuria) - the preclinical and clinically expressed stages;
• decrease in risk of development of a myocardial infarction, stroke or "coronary death" at patients with coronary heart disease, with the increased risk cordial соссудистых diseases, including the patients who had a myocardial infarction, chrezkozhny transluminal coronary angioplasty, aortocoronary shunting.

Route of administration and doses:

Inside. Tablets have to be swallowed entirely (not chewed) to, in time or after food and to be washed down with enough (1/2 glasses) water. The dosage is calculated depending on the expected therapeutic effect and portability of drug the patient in each case.
At the patients who were earlier accepting diuretics it is necessary to cancel them in 2-3 days (depending on duration of effect of diuretics) before an initiation of treatment to Tritatsa or, at least, to reduce a dose of the accepted diuretics. At a renal failure (KK of 50-20 ml/min. on 1,73 sq.m of a body surface) an initial dose - 1,25 mg. The maximum daily dose - 5 mg. At an abnormal liver function the maximum daily dose - 2,5 mg. At the patients who were earlier accepting diuretics, an initial dose - 1,25 mg.
At impossibility to completely eliminate disturbance of water and electrolytic balance in cases of heavy arterial hypertension, and also at patients for whom hypotensive reaction (decrease in the ABP) represents a certain risk (for example, at reduction of a blood-groove owing to narrowing of coronary arteries of heart or vessels of a brain), an initial dose of-1,25 mg.
The clearance of creatinine can be calculated, using creatinine level indicators in blood serum on the following formula (Kokkroft's equation):

For men: 

Clcr (ml/min.) = the Body weight (kg) x (140 - age) 
-------------------------------------------------------
72 x creatinine (mg/%) 

For women: to increase the result received in the stated above equation on 0,85.
Treatment to Tritatsa usually is long and its duration in each case is defined by the doctor.
Treatment of arterial hypertension
To accept drug once a day, since a dose in 2,5 mg and, if necessary, doubling a dose in 2-3 weeks, depending on reaction of the patient to the carried-out therapy; the supporting daily dose - 2,5 - 5 mg, the maximum daily dose - 10 mg.
Treatment of chronic heart failure 
Depending on reaction of the patient the dose can be increased. Initial daily dose of-1,25 mg once. It is recommended to double it bucketed in 1-2 weeks. And more to accept once or to divide doses from 2,5 mg into 2 receptions. The maximum daily dose - 10 mg.
Treatment of chronic heart failure after a myocardial infarction
The initial dose of-5 mg divided into 2 receptions on 2,5 mg in the morning and in the evening. At intolerance her patient it is necessary to lower a dose to 1,25 mg 2 times a day within 2 days. In case of increase in a dose it is recommended to be divided into 2 receptions in the first 3 days. Afterwards the general daily dose which is originally divided into 2 receptions can be accepted as a single daily dose. The maximum daily dose - 10 mg.
The patient with heavy (the IV degree on a scale of the New York association of cardiologists) chronic heart failure after a myocardial infarction. In this case - 1,25 mg once a day. It is necessary to increase a dose with extra care.
Treatment of patients with a diabetic and not diabetic nephropathy
Initial dose - 1,25 mg of 1 times a day. A maintenance dose - 2,5 mg. At increase in a dose, it is necessary to double it at an interval of 2-3 weeks. The maximum daily dose - 5 mg.
Prevention of development of a myocardial infarction, stroke or "coronary death" 
Initial dose - 2,5 mg once a day. Increase in a dose has to happen by its doubling in 1 week of treatment. In 3 weeks the dosage can be increased still twice, as much as possible to 10 mg.

Features of use:

Treatment to Tritatsa usually is long, its duration in each case is defined by the doctor. It also demands regular medical control, in particular, from patients with the broken function of a liver and kidneys. It is usually recommended to correct dehydration, a hypovolemia or salt insufficiency prior to treatment. At emergency treatment by drug can be begun or continued only if the appropriate measures of precaution are at the same time taken for prevention of excessive decrease in the ABP and a renal failure (see the section "Route of Administration and Doses").
Observation of function of kidneys, especially within the first weeks of treatment is necessary. At the patients having a disease of vessels of kidneys (for example, at a stenosis of renal arteries still clinically not significant, or with unilateral hemodynamically significant renal artery stenosis), in cases of the renal failure which was available earlier, and also at the patients who transferred renal transplantation especially careful observation is necessary.
It is regularly necessary to control potassium concentration and sodium in blood serum. More private control of their concentration in blood serum is required from patients with a renal failure.
Control of number of leukocytes (diagnosis of a leukopenia) is necessary. Especially regular control is recommended in an initiation of treatment, and also in the risk groups specified in the section "Side effect" - to 1 time a month in the first 3-6 months of treatment at patients with the increased risk of a neutropenia - at a renal failure, general diseases of connecting fabric or the diuretics receiving high doses, and also at the first signs of development of an infection.
At confirmation of a neutropenia (the number of neutrophils are less 2000/mkl) therapy by APF inhibitors should be stopped.
At emergence of signs of disturbance of the immunity caused by a leukopenia (for example, fevers, a hyperadenosis, tonsillitis), urgent control of a picture of peripheral blood is necessary. In case of signs of bleeding (the smallest petechias, a red-brown enanthesis and mucous) also control of number of thrombocytes in peripheral blood is necessary.
To and during treatment control of the ABP, function of kidneys, hemoglobin level in peripheral blood, creatinine, urea is necessary, for concentration of electrolytes and activity of "hepatic" enzymes in blood.
It is necessary to be careful at purpose of drug to patients, being on a low-salt or electrolyte-deficient diet (the increased risk of development of arterial hypotension). At patients with a reduced volume of the circulating blood (as a result of therapy by diuretics) at sodium consumption restriction, at diarrhea and vomiting development of symptomatic arterial hypotension is possible.
Tranzitorny arterial hypotension is not a contraindication for continuation of treatment after stabilization of the ABP. In case of repeated developing of the expressed arterial hypotension it is necessary to reduce a dose or to cancel drug.
If in the anamnesis there are instructions on development of the Quincke's disease which is not connected with reception of APF inhibitors, then in such patients after all there is an increased risk of its development at reception to Tritatsa.
Safety and efficiency of use in pediatric practice: for newborns who were exposed to pre-natal influence of APF inhibitors it is recommended to conduct careful observation for detection of arterial hypotension, an oliguria and a hyperpotassemia. At an oliguria maintenance of the ABP and renal perfusion by administration of the corresponding liquids and vasoconstrictors is necessary. Newborns and babies have a risk of an oliguria and neurologic frustration, perhaps, because of decrease in a renal and brain blood-groove owing to decrease in the ABP called by APF inhibitors (received by pregnant women and after the delivery) - are recommended careful observation.
During treatment it is necessary to abstain from occupations potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions since dizziness, especially after an initial dose of APF inhibitor at the patients accepting diuretic means is possible.
It is necessary to be careful when performing physical exercises and/or hot weather because of risk of dehydration and arterial hypotension, owing to reduction of volume of liquid. It is not recommended to use ethanol. Before surgical intervention (including stomatology) it is necessary to warn the surgeon/anaesthesiologist about use of APF inhibitors.
When developing hypostases, for example in a face (lips, eyelids) of either language, or disturbance of swallowing or breath the patient has to stop administration of drug immediately. A Quincke's disease in the field of language, drinks, or throats (possible symptoms: disturbance of swallowing or breath) can threaten life and result in need of rendering acute management.
Experience of use to Tritatsa at children, at patients with the expressed renal failures (KK is lower than 20 ml/min., at a body surface of 1,73 sq.m), and also at the patients receiving treatment by a hemodialysis is insufficient.
After reception of the first dose, and also at increase in a dosage of diuretic and/or ramiprit, patients have to be within 8 hours under medical observation in order to avoid development of uncontrollable hypotensive reaction. At patients with chronic heart failure administration of drug can lead to development of the expressed arterial hypotension which in some cases is followed by an oliguria or an azotemia and is rare - development of an acute renal failure.
Patients with malignant arterial hypertension or the accompanying heavy heart failure have to begin treatment in the conditions of a hospital.
When using APF inhibitors (see also instructions of producers of membranes) the life-threatening, quickly developing, allergopodobny (anaphylactoid) hypersensitivity reactions, sometimes up to development of shock, were described at patients during a hemodialysis with use of certain high-flowing membranes (for example, polyacrylonitrile membranes). It is necessary to avoid sharing to Tritatsa and such membranes, for example, for an urgent hemodialysis or haemo filtering. In this case use of other membranes or an exception of reception of APF inhibitors is preferable. Similar reactions were observed at an afereza of lipoproteids of low density using dextran sulfate. Therefore this method should not be applied to patients at whose treatment used APF inhibitors.

Side effects:

From an urinary system
Increase in level of urea in blood serum, a giperkreatininemiya (especially at co-administration of diuretics), a renal failure, a renal failure. Seldom - a hyperpotassemia, a hyper proteinuria, a hyponatremia.
Strengthening of the existing proteinuria or increase in amount of the emitted urine.
From cardiovascular system
Seldom - the expressed decrease in the ABP, postural hypotension, ischemia of a myocardium or brain, a myocardial infarction, arrhythmia, a syncope, an ischemic stroke, passing ischemia of vessels of a brain, tachycardia, peripheral hypostases (in ankle joints)
Allergic reactions
Quincke's disease of the person, lips, century, language, glottis and/or throat.
Were observed also: reddening of integuments, feeling of heat, conjunctivitis, an itch, urticaria, other enanthesis or mucous (a makulopapulezny dieback and an enantema, a multiformny exudative erythema (including Stephens's syndrome - Johnson), a pemphigus (pempigus), a serositis, an exacerbation of psoriasis, a toxic epidermal necrolysis (Lyell's disease), онихолизис, a photosensitization, sometimes an alopecia (baldness) and development of a syndrome of Reynaud, increase in a caption of antinuclear antibodies, an eosinophilia, a vasculitis, a mialgiya, an arthralgia, arthritis.
From a respiratory organs
Often - dry, without phlegm, reflex cough. It amplifies at night when the patient is in horizontal position, most often it arises at women and at non-smoking. In certain cases APF inhibitor replacement helps. Nevertheless, the proceeding cough can force patients to stop to accept APF inhibitors absolutely. Development of cold (catarral rhinitis), sinusitis, bronchitis, a bronchospasm and диспноэ is possible.
From digestive organs
Nausea, pain in epigastric area, increase in activity of enzymes of a liver and pancreas, bilirubin, is very rare - cholestatic jaundice, digestive disturbances, vomiting, diarrhea, a lock and loss of appetite, taste change ("metal" smack), decrease in flavoring feelings and sometimes even taste loss, dryness in a mouth, stomatitis, a glossitis, pancreatitis.
Seldom - an inflammation mucous digestive tract, intestinal impassability, an abnormal liver function, with possible development of an acute liver failure.
From bodies of a hemopoiesis
In rare instances - reduction of number of erythrocytes and decrease in level of hemoglobin from a lung to considerable, thrombocytopenia and a leukopenia, sometimes - a neutropenia, an agranulocytosis, a pancytopenia, hemolitic anemia.
From the central nervous system
Balance disturbance, headache, nervousness, tremor, sleep disorder, weakness, confusion of consciousness, depression, feeling of concern, paresthesia, muscular spasms.
From sense bodys
Vestibular disturbances, disturbance of taste, sense of smell, hearing and sight, sonitus.
Influence on a fruit
Disturbance of development of kidneys of a fruit, decrease in the ABP of a fruit and newborns, renal failure, hyperpotassemia, skull hypoplasia, олигогидрамнион, contracture of extremities, deformation of a skull, hypoplasia of lungs.
Others
Decrease in an erection and sexual desire, fever.

Interaction with other medicines:

- potassium salts, kaliysberegayushchy diuretics (for example, amiloride, Triamterenum, Spironolactonum - simultaneous use leads to a hyperpotassemia (control of potassium in blood serum is necessary);
- anti-hypertensive means (in particular, diuretics) and other drugs, the reducing ABP - the concomitant use leads to strengthening of action of a ramipril;
- somnolent, narcotic and anesthetics - can cause sharp decrease in the ABP;
- angiotonic sympathomimetic drugs (Epinephrinum) and estrogen can cause weakening of action of a ramipril;
- Allopyrinolum, procaineamide, cytostatic means, immunodepressants, system corticosteroids and other drugs which can change a blood picture - in particular, to lower number of leukocytes in blood;
- lithium - increase in concentration of serumal lithium and as a result strengthening kardio-and neurotic effect of lithium;
- peroral hypoglycemic means (sulphonylurea derivatives, guanyl guanidines), insulin - strengthening of a hypoglycemia;
- non-steroidal anti-inflammatory drugs (indometacin, acetylsalicylic acid) - weakening of action of a ramipril is possible;
- heparin - possible increase in potassium concentration in blood serum;
- table salt - weakening of action of a ramipril;
- alcohol - strengthening of hypotensive effect of a ramipril.

Contraindications:

• patients with hypersensitivity to a ramipril or to any of its components (see the section "Structure");
• patients at whom according to anamnestic data the Quincke's disease (risk of bystry development of a Quincke's disease (see the section "Side effect"), including, against the background of reception of APF inhibitors was observed earlier;
• the expressed renal failure (KK less than 20 ml/min. at a body surface of 1,73 m 2);
• hemodialysis;
• pregnancy, lactation period;
• age up to 18 years (efficiency and safety are not established).
With care: the expressed abnormal liver functions and/or kidneys, a disease of connecting fabric (including, a system lupus erythematosus, a scleroderma - the risk of development of a neutropenia or agranulocytosis is increased), primary hyper aldosteronism, malignant arterial hypertension, a mitral or aortal stenosis, oppression of a marrowy hemopoiesis, a hyperpotassemia, a hyponatremia (risk of dehydration, arterial hypotension, renal failure), a bilateral stenosis of renal arteries or a stenosis of an artery of the only kidney, a state after transplantation of a kidney, the states which are followed by decrease in volume of the circulating blood (including diarrhea, vomiting), and also at the patients keeping to a diet with sodium restriction at patients of advanced age, a diabetes mellitus (because of risk of development of a hyperpotassemia), severe damages of coronary and cerebral arteries, at a concomitant use with immunodepressants and saluretics.

Pregnancy and period of feeding by a breast
Tritatsa should not apply during pregnancy. Therefore before an initiation of treatment it is necessary to be convinced of lack of pregnancy.
If the patient became pregnant during treatment, it is necessary to replace medicinal therapy to Tritatsa with other therapy as soon as possible. Otherwise there is a risk of damage of a fruit, especially in the I trimester of pregnancy.
If treatment is necessary for Tritatsa in the period of a lactation, then feeding by a breast should be stopped.

Overdose:

Symptoms: the expressed decrease in the ABP, shock, the expressed bradycardia, disturbances of water and electrolytic balance, an acute renal failure, a stupor.
Treatment: a gastric lavage, reception of adsorbents, sulfate sodium (at an opportunity within the first 30 minutes). In case of development of arterial hypotension introduction of alpha 1-adrenergic agonists (Norepinephrinum, a dopamine) and angiotensin-II can be added to therapy on completion of volume of the circulating blood and recovery of salt balance (Angiotensinamidum).

Storage conditions:

List B. At a temperature not above 25 °C and in the place, unavailable to children. Period of validity of 5 years. Not to use after the date specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets on 2,5 mg and 5 mg in blisters: on 14 tablets in the blister consisting of PVC / aluminum foil. 2 blisters together with the application instruction are placed in a cardboard pack.