Pharmacological properties

Pharmacodynamics. ramiprit treats pro-drugs, after absorption it is metabolized in a liver with formation of the ramiprilat. ramiprilat is powerful inhibitor apf with long action. apf catalyzes transformation of angiotensin i to vasoconstrictive substance — ii angiotensin. apf is a kininaza analog — enzyme which catalyzes bradykinin disintegration. oppression of activity apf leads to decrease in concentration in ii angiotensin blood plasma, to increase in concentration of renin, strengthening of effect of bradykinin and decrease in secretion of Aldosteronum. the last can cause increase in level of potassium in blood serum. at patients with ag the hypotensive effect of a ramipril and its influence on a hemodynamics are caused by expansion of resistant vessels and reduction opss, leading hell to gradual decrease. chss usually does not change. at long treatment there is a reduction of expressiveness of a hypertrophy of a left ventricle without influence on function of heart. the hypotensive effect is shown in 1–2 h after reception of a single dose, reaches a maximum within 3–6 h and lasts usually for 24 h

Ramipril is also effective at treatment of chronic heart failure. Its use for patients with clinical signs of chronic heart failure after a myocardial infarction reduces risk of sudden death, progressing of heart failure to heavy or resistant to therapy, and reduces the frequency of hospitalization concerning heart failure.

ramiprit

According to the published data considerably reduces the frequency of a myocardial infarction, stroke and cardiovascular diseases mortality at patients with the increased risk in connection with these diseases (for example an active stage of an ischemic heart disease, the had stroke or diseases of peripheral vessels) or diabetes, at patients at least with one accessory factor of risk (microalbuminuria, AG, increase in the general level XC, the LPVP low level, smoking).

Drug also reduces the general mortality and the need for carrying out revascularization and also the beginning and progressing of chronic heart failure detains. Ramipril considerably reduces the probability of a microalbuminuria and risk of development of a nephropathy at patients with diabetes and also other patients.

Pharmacokinetics. Ramipril is quickly soaked up in a GIT. Absorption is 50–60% and does not depend on meal. The C _max in blood plasma is reached for 1 h after reception. The ramiprila makes T _½ 1 h

Ramipril is metabolized in a liver. The main metabolite is ramiprilat which activity as APF inhibitor is 6 times higher in comparison with ramiprily. Except the ramiprilat, also inactive metabolites (diketopiperazine ether and diketopiperazine acid and also connections) are revealed.

C _max ramiprilat in blood plasma is reached in 2–4 h after reception, equilibrium concentration in blood plasma is reached in 4 days.

About 73% of a ramipril and 56% of the ramiprilat contact proteins of blood plasma.

Ramipril and ramiprilat are generally removed by

with urine (about 60%), mainly in the form of metabolites, and 2% of the accepted dose are removed in the form of not changed ramipril.

Removal of the ramiprilat has several phases. After reception of a ramipril in a therapeutic dose final T _½ makes 13–17 h

Research on animals showed that this medicament gets into breast milk. Researches with participation of healthy volunteers aged from 65 up to 76 years showed that the kinetics ramiprit also the ramiprilat in this category same, as well as among young healthy volunteers.

elimination ramiprit

At patients with a renal failure, the ramiprilat and their metabolites is slowed down therefore the dose needs to be korrigirovat depending on function of kidneys (see USE).

At patients with a liver failure (perhaps, because of decrease of the activity of hepatic esterases) metabolic transformation of a ramipril in ramiprilat can slow down, and ramiprit concentration in blood plasma — to raise.

Indication

Treatment, including as a part of complex therapy:

arterial hypertension;

stagnant heart failure;

patients with clinical signs of chronic heart failure in the first few days after an acute myocardial infarction;

a diabetic or not diabetic nephropathy.

Reduction of risk of a myocardial infarction, stroke and cardiovascular mortality at patients with high risk of cardiovascular diseases, including an ischemic heart disease (irrespective of presence of a myocardial infarction in the anamnesis), a stroke and a disease of peripheral arteries.

Use

Dosing and duration of treatment depend on a condition of the patient, requirement and possible use of other medicines therefore define individually.

Treatment of arterial hypertension. The recommended initial dose ramiprit for patients who do not accept diuretics and who have no heart failure, makes 2.5 mg of 1 times a day. Depending on the corresponding treatment response a dose it is possible to raise twice each 2–3 weeks. The usual maintenance dose makes 2.5-5 mg/days, and the maximum daily dose — 10 mg.

If the patient accepts diuretic, it it is necessary at an opportunity to cancel or at least to lower a dose at least in 2–3 days prior to treatment ramiprily.

Initial dose ramiprit

for sick AG which accepted diuretic prior to treatment and also for patients with AG and heart failure with a renal failure or without makes 1.25 mg of 1 times a day. Treatment is begun in a hospital under careful medical control.

Treatment of stagnant heart failure. The recommended initial dose ramiprit for the patients with a stable state accepting diuretics makes 1.25 mg of 1 times a day. Depending on the corresponding treatment response a dose it is possible to raise twice each 1–2 weeks. If the necessary dose makes 2.5 mg of a ramipril above, it can be accepted once or to distribute on 2 receptions. The maximum daily dose makes 10 mg.

If the patient accepts diuretic in a high dose, it is necessary to lower a dose prior to treatment ramiprily.

Treatment after a myocardial infarction. Treatment ramiprily can be begun only in a hospital during the period between the 3rd and 10th day after a heart attack. The recommended initial dose of a ramipril makes 2.5 mg 2 times a day (in the morning and in the evening); in 2 days the dose is raised to 5 mg by 2 times a day (in the morning and in the evening). The usual maintenance dose of a ramipril makes 2.5-5 mg 2 times a day.

If the patient badly transfers this initial dose (for example there is arterial hypotension), it is necessary to lower it to 1.25 mg 2 times a day. In 2 days this dose can be raised to 2.5 mg 2 times again a day, and every 1-3 day it is possible to raise a dose to 5 mg 2 times a day. The maximum daily dose makes 10 mg.

If the patient badly transfers increase in a dose to 2.5 mg 2 times to day, treatment ramiprily needs to be stopped.

with heavy (degree of the IV in classification NYHA) heart failure right after a myocardial infarction is not enough

Experience of treatment of patients. If, despite this, it is decided to treat such patients this medicine, it is recommended to begin therapy with the lowest effective daily dose (1.25 mg of a ramipril of 1 times a day) and to carry out any its increase with extreme care.

Treatment of a diabetic or not diabetic nephropathy. The recommended initial dose makes 1.25 mg of 1 times a day. This dose needs to be raised to 5 mg of 1 times a day in each 2–3 weeks depending on tolerance of drug. The maximum daily dose makes 5 mg of 1 times a day.

Reduction of risk of a myocardial infarction, stroke and cardiovascular mortality. The recommended initial dose makes 1.25 mg of 1 times a day. Depending on the corresponding treatment response the dose needs to be raised gradually. It is recommended to raise a dose twice within the first week of treatment and in 2–3 weeks to raise it to usual supporting — 10 mg of 1 times a day.

during controlled clinical trials use of a dose more than 20 mg of a ramipril of 1 times a day were studied by

insufficiently.

Dosing in a renal failure. Patients with clearance of creatinine have 0.5 ml / with (30 ml/min.) dose adjustments it is not required. Patients with clearance of creatinine have 0.5 ml / with (30 ml/min.) the initial dose has to make 1.25 mg, and the maximum daily dose — 5 mg.

Dosing in an abnormal liver function. The initial dose of a ramipril makes 1.25 mg of 1 times a day, and the maximum daily dose — 2.5 mg.

Especially careful control is necessary for

at patients of advanced age (65 years are more senior), patients who accept diuretics, patients with heart failure and a renal failure or a liver. The dose of a ramipril has to be modified according to desirable decrease in the ABP. The recommended initial dose makes 1.25 mg of a ramipril of 1 times a day. Whole needs to swallow of a tablet, washing down with enough liquid (approximately ¹ / ₂ a glass). Tablets should not be chewed or crushed. A pill can be taken to, in time or after meal.

Contraindication

Hypersensitivity to a ramipril or any other component of medicament and also to other inhibitors apf, to medicament components, presence of a Quincke's disease in the anamnesis, a renal artery stenosis (bilateral or a stenosis of an artery of the only kidney), arterial hypotension or hemodynamically unstable states, primary hyper aldosteronism.

Should avoid Ampril's use or other APF inhibitors in a combination with methods of extracorporal therapy which can cause engagement of blood with negatively charged surfaces as at the same time there is a risk of development of heavy anaphylactoid reaction that can sometimes lead to a heavy acute anaphylaxis.

Thus, at Ampril's reception it is impossible to carry out the procedure of dialysis or haemo filtration with use weed (acrylonitrile, sodium-2-metilsulfonatnykh) membranes with high ultrafiltrational activity (for example AN69) and the procedure of an aferez of LDL using a sulfate dextran.

Side effects

from a cardiovascular system: tachycardia, peripheral hypostases, rushes of blood suit, heart consciousness, disturbance of orthostatic regulation, stenocardia, cardiac arrhythmias, heavy arterial hypotension, ischemia of a myocardium or brain, a myocardial infarction, a short-term ischemic attack, an ischemic stroke, aggravation of the disturbances of blood circulation caused by a stenosis of vessels, acceleration or strengthening of manifestations of a phenomenon of Reynaud.

from nervous system: headache, balance disturbance, weakness, drowsiness, dizziness or delay of reaction, fatigue, excitability, depression, suppressed mood, tremor, concern, sleep disorders, confusion of consciousness, feeling of alarm, faint, paresthesias.

from an organ of sight: disorder of vision.

from an organ of hearing: a ring in ears, a hearing disorder.

from an urinary system: increase in level of urea and creatinine in blood serum (probability increases at additional use of diuretics), deterioration in function of kidneys, increase in potassium concentration in blood serum, decrease in level of sodium and also strengthening of already existing proteinuria (in spite of the fact that APF inhibitors usually reduce a proteinuria) or increase in amount of urine (in connection with improvement of warm activity). In isolated cases of a renal failure can progress.

from a respiratory system: the dry (unproductive) tickling cough (cough often worsens at night and during rest (for example in a prone position) and more often arises at women and at persons who do not smoke), congestion of a nose, sinusitis, bronchitis, a bronchospasm and dispnoe.

from the immune system, skin and hypodermic cellulose: a Quincke's disease (the Quincke's disease caused by APF inhibitors arises at patients of negroid race in comparison with patients of other races more often), heavy anaphylactic or anaphylactoid reactions, a rash, an itching, urticaria, makulopapulezny rashes, a bladderwort, exacerbation of psoriasis, a psoriazoformny, pemfigoidny or lichenoid dieback and an enantema, a multiformny erythema, Stephens's syndrome — Johnson, a toxic epidermal necrolysis, an alopecia, onikholizis or photosensitivity.

Probability of emergence and weight of anaphylactic and anfilaktoidny reactions to poison of insects at inhibition of APF increase. Consider that such effect can be observed also concerning other allergens.

from a digestive tract and a gepatobiliarny system: nausea, increase in serumal levels of enzymes of a liver and/or bilirubin, cholestatic jaundice, dryness in a mouth, a glossitis, inflammatory reactions in an oral cavity and a digestive tract, sensation of discomfort in an abdominal cavity, a stomach ache (including pain, similar that in gastritis), digestion disturbances, dyspepsia, a constipation, diarrhea, vomiting and increase in enzymes of a pancreas, pancreatitis, injury of a liver (including an acute liver failure), hepatitis, intestinal impassability.

from blood and lymphatic system: reduction of quantity of erythrocytes and hemoglobin, quantity of leukocytes and thrombocytes, agranulocytosis, pancytopenia and oppression of function of marrow. Possible symptoms of an agranulocytosis — fever, a hyperadenosis and inflammation of a throat. Petechias and also a purpura or an odontorrhagia which is heavy for stopping can be signs of a tendency to bleeding in view of thrombocytopenia.

Hematologic reactions action APF inhibitors more often arise at patients with disturbance of function of kidneys and at patients with accompanying collagenoses (for example a system lupus erythematosus or a scleroderma), or at those who use other medicaments which can cause changes in composition of blood. In isolated cases the hemolytic anemia can develop.

Other effects: conjunctivitis, spasms of muscles, decrease in a libido, loss of appetite, disturbance of perception of a smell and taste (for example metal smack in a mouth) or partial, sometimes total loss of feeling of taste, increased fatigue, temporary erectile dysfunction, the increased sweating. In isolated cases the vasculitis, myalgia, an arthralgia, fervescence, fever and an eosinophilia and also increase in credits of anti-nuclear antibodies are observed.

Special instructions

Quincke's disease. at patients who were treated by inhibitors apf cases of a Quincke's disease of the face, extremities, lips, language, a glottis or throat were observed. in case of developing of a Quincke's disease the treatment ramiprily should be stopped immediately. urgent treatment of a life-threatening Quincke's disease provides immediate administration of epinephrine (p / to or slowly in / c), along with control of the ECG and hell. hospitalization, observation of the patient for 12–24 h at least is recommended, and it is possible to write out it only after symptoms completely disappear. at patients who were treated by inhibitors apf cases of a Quincke's disease of intestines were observed. these patients complained of an abdominal pain (with or without nausea or vomiting).

Caution. In an initiation of treatment it is necessary to control function of kidneys. Observation of function of kidneys needs to be carried out during treatment, especially at patients with disturbance of functional activity of kidneys, with heart failure, a bilateral stenosis of renal arteries or a stenosis of an artery of the only kidney and also at patients to whom carried out transplantation of a kidney.

Risk of emergence of hypersensitivity reactions, allergic (anaphylactic) reactions increases at patients to whom together with treatment APF inhibitors carry out a hemodialysis at use of polyacrylonitrile membranes. If the hemodialysis is necessary, the patient at first should be transferred to medicament from other group which is shown for this nosology, or it is necessary to apply other type of membranes in the dialyzer.

Similar reactions were observed by

throughout treatment by means of an aferez of LDL with dextran sulfate therefore this method of treatment is not recommended to be applied at patients who accept APF inhibitors. Throughout treatment ramiprily increase in concentration of urea and creatinine in blood serum can also happen and at patients to normal function of kidneys, especially if they at the same time accept diuretics. In that case treatment can be continued at introduction of a smaller dose of a ramipril or to stop use of this drug. At patients with a renal failure the risk of development of a hyperpotassemia increases. At patients with an abnormal liver function the metabolism of a ramipril and formation of an active metabolite can slow down because of reduction of activity of hepatic esterases. Therefore treatment of such patients can be begun only under careful medical observation. After the beginning of use of a ramipril by patients with uncomplicated hypertensia the symptomatic hypotension can sometimes develop.

Patients with superactivity system renin-angiotenzinovoy. At treatment of patients at whom the activity renin-angiotenzinovoy of a system is increased it is necessary to observe extra care. Such patients have a risk of the unexpected and significant decrease in the ABP and deterioration in function of kidneys as a result of APF inhibition, especially when APF inhibitor or the accompanying diuretic are appointed for the first time or for the first time in higher dose. At the beginning of use of medicament or at increase in a dose it is necessary to carry out careful control of the ABP until there is a risk of its sharp decrease. The superactivity renin-angiotenzinovoy of a system can be expected, in particular:

• at patients with heavy, and especially malignant hypertensia. On an initial phase of treatment the special medical control is necessary;
• at patients with heart failure, especially with heavy or such which was treated by other medicaments which can lower the arterial blood pressure. In case of heavy heart failure on an initial phase of treatment the special medical observation is necessary;
• at patients with hemodynamically significant disturbance of inflow or outflow of blood from a left ventricle (for example because of a stenosis of an aorta or a stenosis of the mitral valve or a hypertrophic cardiomyopathy). On an initial phase of treatment the special medical observation is necessary;
• at patients with hemodynamically significant renal artery stenosis. On an initial phase of treatment the special medical observation is necessary. There can be a need to stop the begun treatment by diuretics;
• at patients who accepted previously diuretics. If the termination of reception or a dose decline of diuretic is impossible, on an initial phase of treatment the special medical observation is necessary;
• at patients at whom the lack of liquid or salt as a result of unsatisfactory consumption of liquid or salt, or, for example, because of diarrhea, vomiting or excessive sweating exists or can develop, in cases when compensation of a lack of liquid and salt is insufficient. In general correction of conditions of dehydration, a hypovolemia or lack of salt prior to treatment is recommended (however for patients with heart failure such remedial measures should be estimated carefully in terms of possible risk of a volume overload). At clinically significant states the treatment by Ampril can be begun or continued only when the relevant activities for prevention of excessive decrease in the ABP and deterioration in function of kidneys at the same time are accepted.

Patients with liver diseases. Patients with an abnormal liver function can have an expressiveness of the response to treatment by Ampril either is increased, or reduced. Besides, at patients with heavy cirrhosis with hypostases and/or ascites activity renin-angiotenzinovoy of a system can be essentially raised; therefore during treatment of these patients it is necessary to observe extra care.

Patients with considerable decrease in the ABP get into group of extra risk. Special medical control is necessary for patients for whom considerable decrease in the ABP represents extra risk (for example patients with hemodynamically significant stenosis of the coronary arteries or vessels supplying a brain with blood) on an initial phase of treatment.

Elderly person. Elderly people can have more expressed reaction to APF inhibitors. At the beginning of their treatment assessment of function of kidneys is recommended.

Monitoring of function of kidneys. It is recommended to carry out monitoring of function of kidneys, first of all in the first weeks of treatment by APF inhibitor. Especially careful control is necessary for patients with:

• heart failure;
• a renovascular disease, including patients with hemodynamically significant unilateral renal artery stenosis. In the last group of patients even slight increase of level of creatinine in blood serum can demonstrate unilateral deterioration in function of kidneys;
• deterioration in function of kidneys;
• transplantirovanny kidney.

Monitoring of balance of electrolytes. It is recommended to exercise regular control of potassium concentration in blood serum. More frequent monitoring of level of potassium in blood serum is necessary at patients with a renal failure.

Hematologic monitoring. It is recommended to carry out monitoring of quantity of white blood cells for the purpose of early detection of a possible leukopenia. More frequent monitoring is recommended on an initial phase of treatment at patients with a renal failure, with the accompanying collagenic disease (for example a system lupus erythematosus or a scleroderma) or those who were treated by other medicaments which can be the cause of changes of a picture of blood.

Use during pregnancy and feeding by a breast. Use of APF inhibitors is contraindicated throughout pregnancy. In case pregnancy is confirmed, treatment by Ampril should be stopped immediately and to pass as soon as possible to alternative therapeutic means.

Epidemiological conclusions concerning risk of teratogenecity after influence of APF inhibitors throughout the I trimester of pregnancy are ambiguous

; however it is impossible to exclude small increase in risk. If therapy continuation APF inhibitors is not considered important, patients who plan pregnancy should be transferred to alternative antihypertensive treatment which has the approved profile of safety of use during pregnancy. If pregnancy is established, treatment by APF inhibitors should be stopped immediately, and if it is possible, to begin alternative therapy. It is known that use of APF inhibitors during II and III trimester of pregnancy can cause development of a fetotoksichnost (depression of function of kidneys, oligogidramnion, delay of ossification of a skull) and neonatal toxicity (renal failure, hypotension, a hyperpotassemia).

to

If needs use of APF inhibitors in the II trimester of pregnancy, it is recommended to carry out ultrasonography of function of kidneys of an embryo and a skull of an embryo. Babies whose mothers accepted APF inhibitors should be examined carefully regarding arterial hypotension.

Research on animals was shown that ramiprit gets into breast milk. As it is unknown whether gets ramiprit in breast milk of the person, use of medicament is contraindicated during feeding by a breast.

Children. Use of a ramipril for children was not studied therefore medicament is not recommended to use at treatment of children.

Ability to influence speed of response at control of vehicles and work with other mechanisms. Some side effects (certain symptoms of decrease in the ABP, for example dizziness or vertigo) can affect ability to control of vehicles or work with other mechanisms. Patients are recommended to avoid similar types of activity before clarification of individual treatment response by drug.

Interaction

At simultaneous use of a ramipril and other antihypertensive medicaments (for example diuretics) or other medicaments lowering arterial blood pressure (for example nitrates, tricyclic antidepressants, anesthetics), the hypotensive effect of a ramipril can amplify. at the patients accepting diuretics it is necessary to control sodium level in blood serum.

Simultaneous use of a ramipril and medicaments of potassium or kaliysberegayushchy diuretics can cause a hyperpotassemia. Therefore at simultaneous use of these medicaments it is regularly necessary to control potassium level in blood serum.

Angiotonic sympathomimetics (for example epinephrine, Norepinephrinum) can reduce hypotensive effect of a ramipril therefore at simultaneous use of these medicaments the thicket needs to control the ABP level.

Simultaneous introduction of a ramipril and Allopyrinolum, immunodepressants, GKS, procaineamide, tsitostatik or other medicaments capable to change blood indicators increases the probability of change of these indicators.

Other APF inhibitors can reduce lithium discharge and by that to cause increase in its level in blood plasma with risk of development of toxic effects. Therefore at simultaneous use of medicaments of lithium and a ramipril it is required to control lithium level in blood plasma.

APF Inhibitors can enhance effect of anti-diabetic means (for example insulin or derivatives of sulphonylurea) that in some cases can cause development of a hypoglycemia. Therefore at the beginning of such combination therapy it is necessary to control especially strictly glucose level in blood.

Simultaneous use of a ramipril and some NPVP (for example acetylsalicylic acid or indometacin) can reduce hypotensive effect of a ramipril. Besides, simultaneous use of these medicaments can cause development of a hyperpotassemia and increase risk of a renal failure.

Combined introduction of a ramipril and heparin can cause a hyperpotassemia.

Overdose

Overdose can cause an excessive peripheral vazodilatation (which is followed by the profound arterial hypotension, shock), bradycardia, disturbance of electrolytic balance and a renal failure.

At appearance of hypotension of the patient needs to be turned to horizontal position with slightly raised lower extremities. If necessary it is recommended to increase blood plasma volume infusion of 0.9% of solution of sodium of chloride. In case of considerable overdose it is recommended to carry out gastric lavage, to enter adsorbents and sodium sulfate (the first 30 min. if it is possible). It is necessary to control carefully the ABP, function of kidneys and level of potassium in blood plasma. In hypotension, besides compensation of volume and electrolytes, it is possible to enter agonist α ₁ - adrenergic receptors (for example Norepinephrinum, a dopamine) and angiotensin II (Angiotensinamidum). The efficiency of dialysis in treatment of intoxication is not proved.

Storage conditions

In original packing for protection against effect of moisture, at a temperature not above 25 °C.