Indapril

General characteristics. Structure:

Active ingredients: 0,625 mg of an indapamid, 2 mg of a perindopril of tretbutilaminovy salt (that corresponds to a pe-rindopril – 1,669 mg).

The combined antihypertensive with diuretic.

Pharmacological properties:

Pharmacodynamics. The combined drug containing perindoprit (APF inhibitor) and индапамид (diuretic from group of sulfonamide). Pharmacological effect of drug is caused by a combination of separate properties of each of components which combination strengthens action of each other. Drug has hypotensive effect.

Indapril has the expressed dozozavisimy hypotensive effect on systolic and diastolic the ABP in a prone position and standing, not depending on age and position of a body of the patient. Effect of drug continues 24 h. The lasting clinical effect occurs less than in 1 month from the beginning of therapy and is not followed by tachycardia. The termination of treatment is not followed by development of a withdrawal.

Indapril reduces degree of a hypertrophy of a left ventricle, improves elasticity of arteries, reduces OPSS, does not influence metabolism of lipids (the general cholesterol, LPVP, LPNP, triglycerides) and does not influence metabolism of carbohydrates (including at patients with a diabetes mellitus).

Perindopril treats group of APF inhibitors, renders a hypotensive, vasodilating, cardioprotective, natriuretic effect. Inactivates APF in plasma, an endothelium of a vascular wall, perhaps, in cells of renal balls and tubules, tissue of lungs, hearts, adrenal glands and a brain. Lowers angiotensin II level in blood and fabrics, reduces products and release of Aldosteronum from adrenal glands, suppresses noradrenaline liberation from the terminations of sympathetic nerve fibrils and formation of endothelin in a wall of vessels, increases concentration of bradikinin, vazodilatatorny prostaglandins. Increases activity of kallikrein-kinin system, stabilizes the level of atrial natriuretic peptide.

Decrease in formation of angiotensin II is followed by increase in activity of a renin of a blood plasma.

Reduces OPSS, the ABP (without development of tachycardia), the filling pressure of the left and right ventricles. The arterial and venous vazodilatation is followed by easing post-and preloads of a myocardium, moderate decrease in ChSS, increase in cordial emission. Improves regional (coronary, cerebral, renal, muscular) blood circulation, reduces the need of a myocardium for oxygen at an ischemic heart disease. Inhibiting fabric a system renin-angiotenzinovye, renders cardioprotective (reduces a hypertrophy of a left ventricle) and angioprotektivny action (warns a hyperplasia and proliferation of smooth muscle cells of vessels, induces involution of a hypertrophy of a vascular wall, recovers elasticity of large vessels and function of an endothelium, including ability to release nitrogen oxide, the endothelial running-down factor).

Slows down development of tolerance to nitrates and strengthens their vazodilatiruyushchy action.

At patients with chronic heart failure statistically authentically reduces expressiveness of clinical symptoms and increases tolerance to an exercise stress. Does not cause fluctuations of the ABP after the first reception and during long therapy.

Indapamid on pharmacological properties is close to thiazide diuretics (breaks a reabsorption of ions of sodium in a cortical segment of a Henle's loop). Increases removal with urine Na+, Cl-and to a lesser extent K+ and Mg2+. Having ability to selectively block "slow" calcium channels, increases elasticity of walls of arteries and reduces OPSS. Promotes reduction of a hypertrophy of LZh of heart. Reduces sensitivity of a vascular wall to noradrenaline and angiotensin II, stimulates synthesis of PgE2 prostaglandin and PgI2 prostacyclin, reduces products of free and stable oxygen radicals. Hypotensive action is shown in the doses which almost are not causing diuretic effect.

Pharmacokinetics. Pharmacokinetic parameters of a perindopril and indapamid at a combination do not change in comparison with their separate use.

Perindopril at intake is quickly absorbed from a GIT. In the course of metabolism perindoprit it biotransformirutsya with formation of an active metabolite – a perindoprilata (about 20%) and 5 inactive connections. Bioavailability makes 65-95%, decreases by 35% at a concomitant use of food. Cmax is reached in 1 h (a perindoprilat – in 3-4 h) and goes down by the end of days to 33-44%. Communication with proteins of plasma is insignificant, makes less than 30% and depends on concentration of drug. The volume of distribution of a free perindorilat – 0,2 l/kg.

Perindoprilat is excreted by kidneys. T1/2 of free fraction of a metabolite makes 3-5 h. Slowly dissociates from communication with APF owing to what "effective" T1/2 makes 25-30 h. Equilibrium concentration at repeated use of a perindopril are reached in 4 days.
At elderly patients, and also at patients with renal and heart failure removal of a perindopril is slowed down (correction of the mode of dosing is necessary). The dialysis clearance of a perindopril makes 70 ml/min.
At patients with cirrhosis the hepatic clearance of a perindopril decreases twice, at the same time total quantity of the formed perindoprilat does not change and correction of the mode of dosing is not required.
Indapamid is quickly and completely soaked up from a GIT; bioavailability - high. Meal slows down absorption speed a little, but does not influence final amount of the soaked-up drug. TCmax is 1-2 h after oral administration. At repeated methods of fluctuation of concentration of drug in plasma in an interval between receptions of 2 doses decrease. Css is established in 7 days of regular reception. Communication with proteins of plasma - 71-79%. Contacts also elastin of unstriated muscles of a vascular wall. Has the high volume of distribution, passes through gistogematichesky barriers (including placental). It is metabolized in a liver. T1/2 is 14-24 h (on average 19 h). Kidneys remove 60-70% in the form of metabolites (in not changed look about 5-7% are removed), through intestines - 20-23%. At patients with a renal failure the pharmacokinetics does not change. Does not kumulirut.

Indications to use:

Treatment of arterial hypertension. Indapril's capsules are shown to those patients at whom arterial pressure is not controlled properly at use only of a perindopril.

Route of administration and doses:

Inside, it is preferable in the morning, before meal, on 1 capsule of drug Indapril of 1 time a day. It is recommended to titrate previously separately doses of an indapamid and a perindopril.

Purpose of drug Indapril is possible instead of monotherapy by separate components of drug at their insufficient efficiency.

The maintenance dose is selected individually, depending on portability of drug, therapeutic effect and a condition of the patient.

Patients of advanced age. Before administration of drug it is necessary to estimate function of kidneys and potassium concentration in a blood plasma. At purpose of drug it is necessary to consider extent of decrease in the ABP, especially in case of dehydration and loss of electrolytes.

Renal failure. Drug is contraindicated to patients with a heavy renal failure (KK less than 30 ml/min.). For patients with moderately expressed renal failure (KK of 30-60 ml/min.) it is recommended to begin therapy with necessary doses of the drugs (in the form of monotherapy) which are a part of drug Indapril.

Some patients with AG without the previous obvious renal failure against the background of therapy can have laboratory symptoms of a renal failure. In this case treatment should be stopped. Further it is possible to renew a combination therapy, using lower doses perindoprit also an indapamid, or to use drugs in the monotherapy mode.

The renal failure arises at patients with heavy chronic heart failure or initially an impaired renal function more often, including, at a stenosis of one or two renal arteries.

To patients with KK equal or exceeding 60 ml/min., dose adjustment is not required. Against the background of therapy control of level of creatinine and potassium in a blood plasma is necessary.

Liver failure. Drug is contraindicated to patients with a heavy liver failure.

At moderately expressed liver failure of dose adjustment it is not required.

Children and teenagers. Indapril should not appoint children and teenagers up to 18 years due to the lack of data on efficiency and safety at patients of this age group.

Features of use:

Perindopril, индапамид. Drug use Indapril is not followed by essential decrease in frequency of side effects (see the section "Side effect"). At the beginning of therapy by two hypotensive drugs which the patient did not receive earlier it is impossible to exclude the increased risk of an idiosyncrasy. Careful observation of the patient allows to minimize this risk.

Lithium drugs. Perindoprit simultaneous use of a combination and the indapamida with drugs of lithium is not recommended.

Renal failure. Therapy is contraindicated to patients with the expressed renal failure (KK less than 30 ml/min.). Some patients with AG without the previous obvious renal failure against the background of therapy can have laboratory symptoms of a functional renal failure. In this case treatment should be stopped. Further it is possible to renew a combination therapy, using low doses of drugs, or to use drugs in the monotherapy mode.

Regular control of level of potassium and creatinine in serum - in 2 weeks after the beginning of therapy and further each 2 months is necessary for such patients. The renal failure arises at patients with heavy chronic heart failure or an initial renal failure more often, including, at a stenosis of one or two renal arteries.

As a rule, reception of a perindopril and indapamid is not recommended to patients with a bilateral stenosis of renal arteries or a stenosis of the only functioning kidney.

Arterial hypotension and disturbance of water and electrolytic balance. The hyponatremia is connected with risk of sudden development of arterial hypotension (especially at patients with a stenosis of one or two renal arteries). Therefore at dynamic observation of patients it is necessary to pay attention to possible symptoms of dehydration and decrease in level of electrolytes in a blood plasma, for example, after diarrhea or vomiting. Regular control of level of electrolytes of a blood plasma is necessary for such patients.

At the expressed arterial hypotension intravenous administration of 0,9% of solution of sodium of chloride can be required.

Tranzitorny arterial hypotension is not a contraindication for therapy continuation. After recovery of volume of the circulating blood and the ABP it is possible to resume therapy, using drugs in the monotherapy mode.

Potassium level. The combined use of a perindopril and indapamid does not prevent development of a hypopotassemia, especially at patients with a diabetes mellitus or a renal failure. As well as in case of the combined use of hypotensive drugs and diuretic regular control of level of potassium in a blood plasma is necessary.

Excipients. It is necessary to consider that monohydrate is a part of excipients of drug lactoses. It is not necessary to appoint Indapril to patients with hereditary intolerance of a galactose, a lactose intolerance and glyukozo-galaktozny malabsorption.

Perindopril. Neurosinging/agranulocytosis. The risk of development of a neutropenia against the background of reception of APF inhibitors has dozozavisimy character and depends on the accepted medicine and existence of associated diseases. The neutropenia seldom arises at patients without associated diseases, however, the risk increases at patients with a renal failure, especially against the background of general diseases of connecting fabric (including, a system lupus erythematosus, a scleroderma).

After cancellation of APF inhibitors clinical signs of a neutropenia pass independently.

With extra care it is necessary to apply perindoprit at patients with diffusion diseases of connecting fabric, against the background of reception of immunosuppressive drugs, Allopyrinolum or procaineamide and at their combined use, especially at patients with an initial renal failure. Some patients had crushing infectious defeats, in some cases steady against an intensive antibioticotherapia. At purpose of a perindopril such patients are recommended to control periodically quantity of leukocytes in blood. Patients have to report to the doctor about any symptoms of infectious diseases (for example, quinsy, fever).

The increased sensitivity / a Quincke's disease (Quincke's edema). At reception of APF inhibitors including the perindoprila, in rare instances can be observed development of a Quincke's disease of the person, extremities, lips, language, a glottis and/or throat. At emergence of symptoms reception of a perindopril has to be immediately stopped, and the patient has to be observed until symptoms of hypostasis do not disappear completely. If hypostasis affects only a face and lips, then its manifestations usually take place independently though for treatment of its symptoms antihistaminic drugs can be used.

The Quincke's disease which is followed by throat hypostasis can lead to a lethal outcome. The paraglossa, a glottis or a throat can lead to obstruction of respiratory tracts. At emergence of such symptoms it is necessary to enter immediately subcutaneously Epinephrinum (adrenaline) in cultivation 1:1000 (0,3 or 0,5 ml) and/or to provide passability of respiratory tracts.

At patients in whose anamnesis the Quincke's edema which is not connected with reception of APF inhibitors was noted the risk of its development at administration of drugs of this group can be increased (see the section "Contraindications").

In rare instances against the background of therapy by APF inhibitors the Quincke's disease of intestines develops. At the same time at patients the abdominal pain as the isolated symptom or in combination with nausea and vomiting, in certain cases without the previous Quincke's disease of the person is noted and at the normal S-1 level of esterase. The diagnosis is established by means of a computer tomography of belly area, ultrasonography or at the time of surgical intervention. Symptoms disappear after the termination of reception of APF inhibitors. At the patients with pain in a stomach receiving APF inhibitors when carrying out the differential diagnosis it is necessary to consider a possibility of development of a Quincke's disease of intestines.

Anaphylactoid reactions when performing desensitization. There are separate messages on development of long, life-threatening anaphylactoid reactions in the patients receiving APF inhibitors during the desensibilizing therapy by poison of hymenopterous insects (a bee, a wasp).

APF inhibitors need to be applied with care at the patients, inclined to allergic reactions, undergoing procedures of desensitization. It is necessary to avoid purpose of APF inhibitor to the patients receiving an immunotherapy poison of hymenopterous insects. Nevertheless, anaphylactoid reaction can be avoided by temporary cancellation of APF inhibitors not less, than in 24 hours prior to the procedure.

Anaphylactoid reactions when carrying out an aferez of LPNP. In rare instances at the patients receiving APF inhibitors when carrying out an aferez of lipoproteins of the low density (LPNP) with use of sulfate of a dextran life-threatening anaphylactoid reactions can develop. For prevention of anaphylactoid reaction it is necessary to stop temporarily therapy by APF inhibitor before each procedure of an aferez.

Hemodialysis. At the patients receiving APF inhibitors when carrying out a hemodialysis with use of high-flowing membranes (for example, AN69®) noted anaphylactoid reactions. Therefore it is desirable to use a membrane of other type or to use hypotensive drug of other pharmakoterapevtichesky group.

Kaliysberegayushchy diuretics and drugs of potassium. As a rule, combined use of a perindopril and kaliysberegayushchy diuretics, and also drugs of potassium and potassium of the containing substitutes of edible salt is not recommended (see the section "Interaction with other medicines).

Cough. Against the background of therapy dry cough can arise APF inhibitor. Cough it is long remains against the background of administration of drugs of this group and disappears after their cancellation. At emergence in the patient of dry cough it is necessary to remember possible communication of this symptom with APF inhibitor reception. If the attending physician considers that therapy by APF inhibitor is necessary for the patient, administration of drug can be continued.

Children and teenagers. Indapril should not appoint children and teenagers aged up to 18 years due to the lack of data on efficiency and safety of use of a perindopril in the form of monotherapy or as a part of a combination therapy at patients of this age group.

Risk of arterial hypotension and/or renal failure (at patients with chronic heart failure, disturbance of water and electrolytic balance, etc.).

At some morbid conditions considerable activation of the renin-angiotensin-Aldosteronum system can be noted, especially at the expressed hypovolemia and decrease in level of electrolytes of a blood plasma (against the background of an electrolyte-deficient diet or long reception of diuretics), at patients with initially low ABP, a stenosis of one or two renal arteries, chronic heart failure or cirrhosis with existence of hypostases and ascites.

Use of APF inhibitor causes blockade of this system and therefore decrease in the ABP and/or in a blood plasma, testimonial of development of a functional renal failure can be followed by increase in level of creatinine sharp. These phenomena are more often observed at reception of the first dose of drug or within the first two weeks of therapy. Sometimes these states develop sharply and in other terms of therapy. In such cases when resuming therapy it is recommended to use drug in lower dose and to gradually increase a dose.

Patients of advanced age. Before administration of drug it is necessary to estimate functional activity of kidneys and potassium concentration in a blood plasma. At the beginning of therapy the dose of drug is selected, considering extent of decrease in the ABP, especially in case of dehydration and loss of electrolytes. Similar measures allow to avoid sharp decrease in the ABP.

Atherosclerosis. The risk of arterial hypotension exists at all patients, however, extra care should be observed, using drug at patients with coronary heart disease and insufficiency of cerebral circulation. At such patients treatment should be begun with low doses.

Patients with renovascular hypertensia. Method of treatment of renovascular hypertensia is revascularization. Nevertheless, use of APF inhibitors has favorable effect at patients as expecting an operative measure, and in that case when such operation cannot be performed.

At patients with the diagnosed or estimated renal artery stenosis treatment should be begun with lower doses of a perindopril and an indapamid. At some patients the functional renal failure which disappears at drug withdrawal can develop.

Other risk groups. At persons with chronic heart failure (the IV functional class on NYHA classification) and patients with an insulin-dependent diabetes mellitus (danger of spontaneous increase in potassium concentration) treatment has to begin with lower doses of a perindopril and an indapamid and under constant medical control. Patients with arterial hypertension and coronary heart disease should not stop reception of beta adrenoblockers: APF inhibitors have to be used together with beta adrenoblockers.

Patients with a diabetes mellitus. At purpose of drug patients with the diabetes mellitus receiving hypoglycemic means for intake or insulin within the first month of therapy need to control carefully glucose level in blood.

Ethnic distinctions. Perindopril, as well as other APF inhibitors, obviously, has less expressed hypotensive effect at patients of negroid race in comparison with representatives of other races. Perhaps, this distinction is caused by the fact that at patients with arterial hypertension of negroid race low activity of a renin is more often noted.

Surgical intervention / General anesthesia. Use of APF inhibitors for the patients who are exposed to surgical intervention using the general anesthesia can lead to the expressed decrease in the ABP, especially when using the means for the general anesthesia having hypotensive effect. It is recommended to stop reception of APF inhibitors of long action, including perindoprit, in 12 hours prior to surgical intervention.

Aortal stenosis / Mitral stenosis / Hypertrophic cardiomyopathy. APF inhibitors have to be appointed with care the patient with obstruction of outlet opening of a left ventricle.

Liver failure. In rare instances against the background of reception of APF inhibitors there is cholestatic jaundice. When progressing this syndrome the fulminantny necrosis of a liver, sometimes with a lethal outcome develops. The mechanism of development of this syndrome is not clear. At emergence of jaundice against the background of reception of APF inhibitors the patient should see a doctor. At substantial increase of activity of "hepatic" enzymes against the background of reception of APF inhibitors it is necessary to stop administration of drug.

Anemia. Anemia can develop at patients after transplantation of a kidney or at the patients who are on a hemodialysis. At the same time decrease in concentration of hemoglobin of subjects is more, than its initial indicator was higher: This effect, apparently, is not dozozavisimy, but can be connected with the mechanism of effect of APF inhibitors.

Hyperpotassemia. The hyperpotassemia can develop in treatment time APF inhibitors including perindoprily. Risk factors of a hyperpotassemia are the renal failure, a renal failure, advanced age, a diabetes mellitus some the accompanying states (dehydration, an acute decompensation of heart failure, a metabolic acidosis) a concomitant use of kaliysberegayushchy diuretics (such as Spironolactonum, эплеренон, Triamterenum, amiloride), and also drugs of potassium or kaliysoderzhashchy substitutes of edible salt, and also use of other drugs promoting increase in level of potassium in a blood plasma (for example, heparin). Use of drugs of potassium, kaliysberegayushchy diuretics, kaliysberegayushchy substitutes of edible salt can lead to substantial increase of level of potassium in blood, especially at patients with reduced function of kidneys. The hyperpotassemia can bring to serious, sometimes to fatal disturbances of a cordial rhythm. If the combined reception of the drugs stated above is necessary, treatment has to be carried out with care, against the background of regular control of content of potassium in blood serum.

Indapamid. At purpose of thiazide and tiazidopodobny diuretics the patient with abnormal liver functions development of hepatic encephalopathy is possible. In this case reception of diuretics should be stopped immediately.

Photosensitivity. Against the background of reception of thiazide and tiazidopodobny diuretics it was reported about cases of development of reactions of photosensitivity (see the section "Side effect"). In case of development of reactions of photosensitivity against the background of administration of drug it is necessary to stop treatment. In case of need therapy continuations diuretics recommend to protect integuments from influence of sunshine and artificial UV rays.

Water and electrolytic balance. The maintenance of ions of sodium in a blood plasma. Prior to treatment it is necessary to define the maintenance of ions of sodium in a blood plasma. Against the background of administration of drug it is necessary to control this indicator regularly. All diuretic drugs are capable to cause a hyponatremia which sometimes leads to serious complications. The hyponatremia at the initial stage can not be followed by clinical symptoms therefore regular laboratory control is necessary. More frequent control of maintenance of ions of sodium is shown to patients with cirrhosis and to elderly people.

The maintenance of potassium ions in a blood plasma. Therapy by thiazide and tiazidopodobny diuretics is connected with risk of development of a hypopotassemia. It is necessary to avoid a hypopotassemia (less than 3,4 mmol/l) at the following categories of patients from group of high risk: patients of advanced age, the exhausted patients or receiving the combined medicamentous therapy, patients with cirrhosis, peripheral hypostases or ascites, coronary heart disease, heart failure. The hypopotassemia at these patients strengthens toxic effect of cardiac glycosides and increases risk of development of arrhythmias.

Patients with the increased QT interval also treat group of the increased risk, at the same time does not matter: this increase is caused by the inborn reasons or effect of medicines.

The hypopotassemia, as well as bradycardia, promotes development of heavy disturbances of a cordial rhythm, especially arrhythmia like "pirouette" which can be fatal. In all the cases described above more regular control of maintenance of potassium ions in a blood plasma is necessary. The first measurement of concentration of potassium ions needs to be taken within the first week from the beginning of therapy.

At identification of a hypopotassemia the corresponding treatment has to be appointed.

The maintenance of calcium ions in a blood plasma. Thiazide and tiazidopodobny diuretics reduce removal of calcium ions with kidneys, leading to slight and temporary increase of concentration of calcium in a blood plasma. The expressed hypercalcemia can be a consequence of earlier not diagnosed hyperparathyreosis. Before a research of function of epithelial bodies it is necessary to cancel reception of diuretic drugs.

Content of glucose in a blood plasma. It is necessary to control glucose level in blood at patients with a diabetes mellitus, especially in the presence of a hypopotassemia.

Uric acid. At patients with the increased level of uric acid in a blood plasma against the background of therapy the frequency of emergence of attacks of gout can increase.

Diuretic means and function of kidneys. Thiazide and tiazidopodobny diuretics are effective fully only at patients from normal or insignificantly an impaired renal function (content of creatinine in a blood plasma at adult persons lower than 25 mg/mol or 220 µmol/l). At patients of advanced age the clearance of creatinine is calculated taking into account age, body weight and a floor. In an initiation of treatment by diuretics at patients because of a hypovolemia and a hyponatremia temporary reduction in the rate of glomerular filtering and increase in concentration of urea and creatinine in a blood plasma can be observed. This tranzitorny functional renal failure is not dangerous to patients with not changed function of kidneys, however at patients with a renal failure its expressiveness can amplify.

Athletes. Indapamid can give positive reaction when carrying out a drug test.

Pregnancy and period of breastfeeding. Pregnancy. Indapril is contraindicated at pregnancy. Indapril it is not necessary to apply in the I trimester of pregnancy. When planning pregnancy or at its emergence against the background of administration of drug it is necessary to stop immediately administration of drug and to appoint other hypotensive therapy. The corresponding controlled researches of APF inhibitors at pregnant women were not conducted. The available limited data on influence of drug in the first trimester of pregnancy demonstrates that drug did not lead to the malformations connected with a fetotoksichnost.

It is known that long impact of APF inhibitors on a fruit in II and III trimesters of pregnancy can lead to disturbance of its development (to depression of function of kidneys, an oligogidramnion, delay of ossification of bones of a skull) and to development of complications in the newborn (such as renal failure, arterial hypotension, hyperpotassemia).

Prolonged use of thiazide diuretics in the III trimester of pregnancy can cause a hypovolemia in mother and decrease in an uteroplacental blood-groove that leads to fetoplacental ischemia and an arrest of development of a fruit. In rare instances against the background of reception of diuretics shortly before childbirth at newborns the hypoglycemia and thrombocytopenia develops.

If the patient received Indapril during II or III trimesters of pregnancy, it is recommended to conduct ultrasonic examination of a fruit for assessment of a condition of bones of a skull and function of kidneys.

Breastfeeding period. Indapril is contraindicated during breastfeeding.

It is unknown whether gets perindoprit in breast milk. Indapamid gets into breast milk. Reception of thiazide diuretics causes reduction of amount of breast milk or suppression of a lactation. At the child at the same time hypersensitivity to derivatives of sulfonamides, a hypopotassemia and "nuclear" jaundice can develop.

As use of a perindopril and indapamid in the period of a lactation can cause heavy complications in the baby, it is necessary to estimate the importance of therapy for mother and to make the decision on the termination of breastfeeding or on the termination of reception of these drugs.

Effect of the substances which are a part of drug Indapril does not lead to disturbance of psychomotor reactions. However at some patients in response to decrease in the ABP various individual reactions, especially at the beginning of therapy can develop and at addition to the carried-out therapy of other antihypertensives. In this case ability to drive the car or other mechanisms can be reduced.       

Side effects:

Perindopril has an inhibiting effect on the renin-angiotensin-Aldosteronum system and reduces potassium loss by kidneys against the background of reception of an indapamid. At 2% of patients against the background of drug use Indapril develops a hypopotassemia (potassium level less than 3,4 mmol/l).

Frequency of side reactions which can arise during therapy is specified in a type of the following gradation: very often (> 1/10); often (> 1/100, <1/10); infrequently (> 1/1000, <1/100); seldom (> 1/10000, <1/1000); very seldom (<1/10000); not specified frequency (frequency cannot be counted according to available data), including separate messages.

From the alimentary system. Often: dryness in a mouth, nausea, vomiting, an abdominal pain, pain in epigastriums, disturbance of flavoring perception, a loss of appetite, dyspepsia, a lock, diarrhea. Seldom: Quincke's disease of intestines, cholestatic jaundice. Very seldom: pancreatitis. At patients with a liver failure development of hepatic encephalopathy is possible.

From respiratory system. Often: against the background of use of APF inhibitors there can be dry cough, is long remaining during administration of drugs of this group and disappearing after their cancellation. Asthma. Infrequently: bronchospasm. Very seldom: eosinophilic pneumonia, rhinitis.

From cardiovascular system. Infrequently: the expressed decrease in the ABP, including, orthostatic hypotension. Very seldom: disturbances of a cordial rhythm, including, bradycardia, ventricular tachycardia, a ciliary arrhythmia, and also stenocardia and a myocardial infarction, perhaps, owing to excess decrease in the ABP at patients of group of high risk (see the section "Special Instructions").

From integuments and a hypodermic fatty tissue. Often: rash, skin rash, itch, makulopapulezny rash. Infrequently: Quincke's disease of the person, lips, extremities, mucous membranes, glottis and/or throat; a small tortoiseshell (see the section "Special Instructions"); hypersensitivity reactions, generally skin, at the patients predisposed to asthmatic and allergic reactions; hemorrhagic vasculitis. At patients with an acute form of the disseminated lupus erythematosus the aggravation of a course of a disease is possible. Very seldom: multiformny erythema, toxic epidermal necrolysis, Stephens-Johnson's syndrome. Cases of reactions of photosensitivity are noted (see the section "Special Instructions").

From the central nervous system. Often: paresthesias, headache, dizziness, adynamy. Infrequently: sleep disorder, lability of mood. Very seldom: confusion of consciousness.

From a musculoskeletal system and connecting fabric. Often: spasms of muscles. From circulatory and lymphatic system. Very seldom: thrombocytopenia, leukopenia/neutropenia, agranulocytosis, aplastic anemia, hemolitic anemia. In certain clinical situations (patients after transplantation of a kidney, patients on a hemodialysis) APF inhibitors can cause anemia (see the section "Special Instructions").

From an organ of sight. Often: visual disturbance. From an acoustic organ. Often: sonitus.

From an urinary system. Infrequently: renal failure. Very seldom: acute renal failure.

From reproductive system. Infrequently: impotence. General frustration and symptoms. Often: adynamy. Infrequently: perspiration.

Laboratory indicators. A hypopotassemia, especially significant for the patients belonging to risk group (see the section "Special Instructions").

The hyponatremia and hypovolemia leading to dehydration and orthostatic hypotension. Increase in level of uric acid and glucose in blood during administration of drug.

Small increase in creatinine in urine and in a blood plasma, passing after therapy cancellation, is more often at patients with a renal artery stenosis, at treatment of arterial hypertension diuretics and in case of a renal failure. The hyperpotassemia, is more often tranzitorny. Seldom: hypercalcemia.

Interaction with other medicines:

Perindopril, индапамид. Undesirable combination of medicines:
- Lithium drugs: at simultaneous use of drugs of lithium and APF inhibitors there can be a reversible increase in concentration of lithium in a blood plasma and the toxic effects connected with it. Additional purpose of thiazide diuretics can promote further increase in concentration of lithium and increase risk of manifestations of toxicity. Perindoprit simultaneous use of a combination and the indapamida with drugs of lithium is not recommended. In case of performing such therapy regular control of lithium in a blood plasma is necessary.

The combination of means requiring special attention:
- Baclofenum: strengthening of hypotensive action is possible. It is necessary to control the ABP and function of kidneys, if necessary dose adjustment of hypotensive drugs is required.
- Non-steroidal anti-inflammatory drugs (NPVP), including high doses of acetylsalicylic acid (more than 3 g/days): purpose of NPVP can lead to decrease in diuretic, natriuretic and hypotensive effects. At considerable loss of liquid, and also at elderly patients the acute renal failure can develop (owing to reduction in the rate of glomerular filtering). Patients need to offset loss of liquid and in an initiation of treatment carefully to control function of kidneys.
The combination of means requiring attention.
- Tricyclic antidepressants, antipsychotic means (neuroleptics): drugs of these classes strengthen anti-hypertensive effect and increase risk of orthostatic hypotension (the additive effect).
- Glucocorticosteroids, тетракозактид: decrease in hypotensive action (a delay of liquid and ions of sodium as a result of action of glucocorticosteroids).
- Other antihypertensives: strengthening of hypotensive effect is possible.

Perindopril. Undesirable combination of medicines:
- Kaliysberegayushchy diuretics (amiloride, Spironolactonum, Triamterenum both as monotherapy, and in a combination) and potassium drugs: APF inhibitors reduce the potassium loss by kidneys caused by diuretic. Kaliysberegayushchy diuretics (for example, Spironolactonum, Triamterenum, amiloride), can lead drugs of potassium and kaliysoderzhashchy substitutes of edible salt to essential increase in potassium concentration in blood serum up to a lethal outcome. If combined use of APF inhibitors and the drugs stated above is necessary (in case of the confirmed hypopotassemia), it is necessary to be careful and carry out regular control of potassium concentration in a blood plasma and the ECG parameters.

The combination of means requiring special attention:
- Hypoglycemic means (insulin, sulphonylurea derivatives): the effects provided below were described for captopril and enalapril. APF inhibitors can strengthen hypoglycemic effect of insulin and derivatives of sulphonylurea at patients with a diabetes mellitus. Development of a hypoglycemia is observed very seldom (due to increase in tolerance to glucose and decrease in need for insulin).

The combination of means requiring attention:
- Allopyrinolum, cytostatic and immunosuppressive means, glucocorticosteroids (at system use) and procaineamide:
- Simultaneous use with APF inhibitors can be followed by the increased risk of a leukopenia.
- Means for the general anesthesia: combined use of APF inhibitors and means for the general anesthesia can lead to strengthening of hypotensive effect.
- Diuretics (thiazide and loopback): use of diuretics in high doses can lead to a hypovolemia, and addition to therapy of a perindopril - to hypotension.
- Gold drugs: at purpose of APF inhibitors, including perindoprit to the patients receiving injection drugs of gold (ауротиомалат sodium), nitratopodobny reactions (a dermahemia of the person, nausea, vomiting, arterial hypotension) were noted.

Indapamid. The combination of means requiring special attention:
- The medicines capable to cause arrhythmia like "pirouette": because of risk of development of a hypopotassemia it is necessary to be careful at combined use of an indapamid with the drugs capable to cause arrhythmia like "pirouette", for example, antiarrhytmic drugs (quinidine, hydroquinidine, Disopyramidum, Amiodaronum, дофетилид, ибутилид, бретилиум, соталол); some neuroleptics (Chlorpromazinum, циамемазин, levomepromazinum, thioridazine, трифлуоперазин); benzamides (амисульприд, Sulpiridum, сультоприд, тиаприд); phenyl propyl ketones (Droperidolum, haloperidol); other neuroleptics (Pimozidum); other drugs, such, as: bepridit, цизаприд, difemanit methyl sulfate, erythromycin in/in, галофантрин, мизоластин, moxifloxacin, pentamidine, спарфлоксацин, Vincaminum in/in, methadone, астемизол, терфенадин. It is necessary to avoid development of a hypopotassemia and, if necessary, to carry out its correction; to control QT interval.
- The medicines capable to cause a hypopotassemia: Amphotericinum In (in/in), glyuko-and mineralokortikosteroida (at system appointment), тетракозактид, the purgatives stimulating motility of intestines: increase in risk of development of a hypopotassemia (additive effect). Control of level of potassium in a blood plasma, if necessary - its correction is necessary. Special attention should be paid to the patients who is at the same time receiving cardiac glycosides. It is necessary to use the purgatives which are not stimulating motility of intestines.
- Cardiac glycosides: the hypopotassemia strengthens toxic effect of cardiac glycosides. At simultaneous use of an indapamid and cardiac glycosides it is necessary to control potassium level in a blood plasma and indicators of an ECG and, if necessary, to adjust therapy.

The combination of means requiring attention:
- Metforminum: the functional renal failure which can arise against the background of reception of diuretics especially loopback, at co-administration of Metforminum increases risk of development of lactic acidosis. It is not necessary to use Metforminum if creatinine level in a blood plasma exceeds 15 mg/l (135 µmol/l) at men and women have 12 mg/l (110 µmol/l).
- Iodinated contrast agents: organism dehydration against the background of reception of diuretic drugs increases risk of development of a renal failure, especially when using high doses of iodinated contrast agents. Before use of iodinated contrast agents by the patient it is necessary to offset liquid loss.
- Calcium salts: at co-administration development of a hypercalcemia owing to decrease in excretion of calcium ions by kidneys is possible.
- Cyclosporine: increase in level of creatinine in a blood plasma without change of concentration of the circulating cyclosporine, even is possible at the normal content of liquid and ions of sodium.

Contraindications:

Perindopril:
- Hypersensitivity to a perindopril and other APF inhibitors. A Quincke's disease (Quincke's edema) in the anamnesis (including against the background of reception of other APF inhibitors).
- Hereditary / idiopathic Quincke's disease.
- Pregnancy.

Indapamid:
- Hypersensitivity to an indapamid and other sulfonamides.
- The expressed renal failure (the clearance of creatinine (CC) less than 30 ml/min.).
- The expressed liver failure (including with encephalopathy).
- Hypopotassemia.
- Simultaneous use with the antiarrhytmic means capable to cause arrhythmia like "pirouette" (see the section "Interaction with Other Medicines").
- The breastfeeding period (see the section "Pregnancy and the period of breastfeeding).

Indapril:
- Hypersensitivity to the excipients which are a part of drug.
- Joint administration of drug with kaliysberegayushchy diuretics, drugs of potassium and lithium, and at patients with the increased content of potassium in a blood plasma.
- Existence of a lactose intolerance, galactosemia or syndrome of glyukozo-galaktozny malabsorption.
- A concomitant use of the drugs extending QT interval.
- Due to the lack of sufficient clinical experience Indapril it is not necessary to apply at the patients who are on a hemodialysis.
- Patients with not treated chronic heart failure in a decompensation stage.
- Age up to 18 years (efficiency and safety are not established).

With care: general diseases of connecting fabric (including, a system lupus erythematosus, a scleroderma), therapy by immunodepressants (risk of development of a neutropenia, agranulocytosis), oppression of a marrowy hemopoiesis, reduced volume of the circulating blood (reception of diuretics, an electrolyte-deficient diet, vomiting, diarrhea), stenocardia, cerebrovascular diseases, renovascular hypertensia, a diabetes mellitus, chronic heart failure (the IV functional class on NYHA classification), the hyperuricemia (which is especially followed by gout and an uratny nephrolithiasis), lability of the ABP, advanced age; carrying out a hemodialysis with use of highly flowing membranes (for example, АN69®) or desensitization, before the procedure of an aferez of lipoproteins of the low density (LPNP); a state after transplantation of kidneys; stenosis of the aortal valve / hypertrophic cardiomyopathy.

Storage conditions:

To store far from children at the room temperature. A period of validity - 2 years.

Issue conditions:

According to the recipe

Packaging:

On 10 capsules in blister strip packagings, on 3 strip packagings in a cardboard box.