Pharmacological properties

Pharmacodynamics. to triplexes — the medicament containing three active hypotensive components which mechanism of action complements each other for control hell at patients with ag. perindoprit arginine — inhibitor apf, indapamid — sulfanamide diuretic, amlodipin — a blocker of slow calcium channels (bmkk), the representative of a class of dihydropyridines.

Pharmacological activity of the medicament Tripliksam is caused by properties of each of components separately. Besides, the combination perindopril/indapamid has additive, synergy effect of two antihypertensive components.

action Mechanism. Perindopril. Perindopril represents APF inhibitor. APF promotes transformation of angiotensin I in angiotensin II (vasopressor substance), in addition stimulates secretion of Aldosteronum with bark of adrenal glands and bradykinin disintegration (vazodilatatorny substance) to inactive heptapeptides. Owing to inhibition APF occurs: ↓ secretions of Aldosteronum, ↑ plasma activity of renin whereas Aldosteronum does not make negative impact; ↓ OPSS thanks to the prevailing impact on vessels of muscles and kidneys, at the same time the delay of water and salts or reflex tachycardia are not revealed, even in case of long therapy.

Perindopril lowers the arterial blood pressure also at patients with normal and low plasma concentration of renin.

Pharmacological action of a perindopril is caused by an active metabolite perindoprilaty. Other metabolites of a perindopril are inactive.

Perindopril reduces cardiac performance by vazodilatiruyushchy action on veins (perhaps, because of change of metabolism of prostaglandins) — preload of heart decreases; reduction of OPSS causes decrease in an afterload on heart.

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In the researches conducted with participation of patients with heart failure it was established that use of a perindopril gives to ↓ filling pressures of the left and right ventricles; ↓ OPSS; ↑ warm emission and to improvement of cardiac index; ↑ regional blood circulation in muscles.

Besides, indicators of tests with physical activity considerably improve.

Indapamid. Indapamid — the sulfanamide diuretic containing an indolovy ring, pharmacological related to thiazide diuretics. In a cortical segment of kidneys indapamid inhibits a sodium reabsorption. This effect increases excretion of sodium and chlorides with urine and, to a lesser extent, excretion of potassium and magnesium, thereby increasing a diuresis. This mechanism provides antihypertensive action.

Amlodipin. Amlodipin — BMKK (the antagonist of calcium) belonging to group of dihydropyridines and blocking transmembrane current of calcium ions in smooth muscle cells of a myocardium and vessels.

Pharmakodinamichesky effects. Perindopril/indapamid. The combination of a perindoprila/indapamid reduces systolic and diastolic arterial blood pressure at patients of any age from AG which are both in horizontal and in vertical position. Antihypertensive effect of medicament dozozavisimo. In clinical trials it was proved that co-administration of a perindopril and indapamid has the synergy antihypertensive effect which is result of separate effects of components of drug.

Perindopril. Perindopril effectively lowers the arterial blood pressure at easy, medium-weight, heavy AG. Decrease in systolic and diastolic arterial blood pressure is defined both in horizontal, and in vertical position of the patient. The maximum antihypertensive effect is observed in 4–6 h after use of a single dose and remains 1 days Perindopril has the high level of final inhibition of APF (≈80%) in 24 h after use.

At the patients who responded to therapy, normalization of the ABP happens within a month and remains without emergence of a tachyphylaxis.

Termination of therapy is not followed by effect of cancellation.

Perindopril has vazodilatiruyushchy properties, promotes recovery of elasticity of large arteries, correction of gistomorfometrichesky changes in resistance of arteries and reduction of a hypertrophy of a left ventricle.

because of addition of thiazide diuretic additional synergism in case of need develops.

Combination of APF inhibitor and thiazide diuretic reduces risk of a hypopotassemia which emergence is possible when assigning monotherapy by diuretic.

Indapamid. The hypotensive effect of monotherapy indapamidy is noted for 24 h. This effect is defined in doses at which diuretic properties are minimum.

Hypotensive effect of an indapamid is interconnected by

with improvement of elasticity of arteries and decrease in resistance of arterioles and OPSS.

Indapamid reduces a hypertrophy of a left ventricle.

in case of exceeding the recommended dose the expressiveness of therapeutic effect of thiazide and tiazidopodobny diuretics does not increase whereas the number of undesirable effects increases. If therapy is insufficiently effective, increase in a dose is not recommended.

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Besides, as it is shown during the short, average and long-term researches with participation of patients with AG, indapamid does not influence metabolism of lipids (TG, LPNP and LPVP), metabolism of carbohydrates even at patients with AG and diabetes.

Amlodipin. The mechanism of antihypertensive effect of an amlodipin is caused by the direct relaxing action on unstriated muscles of vessels. The exact mechanism thanks to which amlodipin reduces expressiveness of symptoms of stenocardia completely is not found out, at the same time it is known that medicament promotes decrease in the general ischemia of loading thanks to the following effects:

amlodipin expands with

• peripheral arterioles and, therefore, reduces OPSS (afterload); as ChSS does not change, decrease in load of heart reduces energy consumption of a myocardium and its oxygen requirement;
• amlodipin partially promotes dilatation of the main coronary arteries and arterioles both in not changed, and in ischemic zones of a myocardium; such dilatation increases intake of oxygen to a myocardium at patients with vasospastic stenocardia (Printsmetal's stenocardia or alternative stenocardia).

use of an amlodipin 1 r / provides to days with

At patients with AG clinically apparent decrease in the ABP during 24 h as in horizontal, and vertical position. Thanks to the slow beginning of action amlodipin does not cause acute hypotension.

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With purpose of an amlodipin did not connect negative metabolic manifestations or changes of plasma levels of lipids therefore its use for patients with OH, diabetes and gout is possible.

Clinical performance and safety. Perindopril/indapamid. ADVANCE — the international multicenter randomized study with bifaktorialny (2×2) design directed to definition of advantages of decrease in the ABP by the fixed combination of a perindoprila/indapamid in comparison with placebo against the background of the current standard therapy (double blind comparison (prospective randomized open study with definition by a blind method)) on influence on the main macro - and microvascular events at patients with diabetes of the II type. Primary final point consisted of the main macrovascular (a cardiovascular lethal outcome, a non-lethal myocardial infarction, a non-lethal stroke) and microvascular (new cases or deterioration in a nephropathy, a retinopathy) events.

11,140 patients with diabetes of the II type participated In a research. Among them at 83% of patients noted AG, 32 and 10% — micro and macrovascular diseases in the anamnesis respectively, 27% — a microalbuminuria. The accompanying therapy included medicaments for decrease in the ABP (75%), hypolipidemic medicaments (35%, generally statines — 28%), acetylsalicylic acid or other antithrombocytic medicaments (47%).

Therapy throughout 4.3 years a combination of a perindoprila/indapamid led

to reliable ↓ for 9% of relative risk of indicators of primary final point (95% of D (0.828; 0.996), r =0.041).

placebo, perindoprilom/indapamidy in comparison with group, were caused by

Advantage of therapy:

• reliable decrease in relative risk of the general mortality by 14% (95% of D (0.75; 0.98), r =0.025);
• reliable decrease in relative risk of cardiovascular mortality by 18% (95% of D (0.68; 0.98), r =0.027);
• reliable decrease in relative risk of all types of complications from kidneys for 21% (95% of D (0.74; 0.86), r0.001).

In subgroup of patients from AG accepting perindopril/indapamid noted reliable decrease in relative risk of the main macro - and microvascular complications for 9% (95% of D (0.82; 1.0), r =0.052) in comparison with group of placebo.

In subgroup of the patients accepting perindopril/indapamid in comparison with group of placebo, was also noted:

• reliable decrease in relative risk of the general mortality by 16% (95% of D (0.73; 0.97), r =0.019);
• reliable decrease in relative risk of cardiovascular mortality by 20% (95% of D (0.66; 0.97), r =0.023);

reliable decrease in relative risk of all types of complications from kidneys for 20% (95% of D (0.73; 0.87), r0.001).

Pharmacokinetics. Purpose of the fixed combination of a perindoprila/indapamida/amlodipin does not change their pharmacokinetic properties in comparison with use of separate components of the medicament Tripliksam as monotherapy.

Perindopril. After use of per os perindoprit quickly it is absorbed, the C _max is reached in 1 h T _½ perindoprit from blood plasma — 1 h Perindopril — pro-medicine. 27% of the accepted dose of a perindopril in the form of an active metabolite of the perindoprilat get to a blood stream. Besides the active perindoprilat, perindoprit forms 5 more inactive metabolites. The C _max perindoprilat in blood plasma — in 3–4 h

As meal reduces transformation of a perindopril in perindoprilat, therefore, also its bioavailability decreases, a perindopril arginine it is necessary to accept per os 1 r / days in the morning before food. There is a linear interrelation between a dose of a perindopril and its plasma concentration.

distribution Volume (V _d ) untied perindoprilat of ≈0.2 l/kg. Linking of the perindoprilat with proteins of blood plasma — 20%, generally with APF, also is dose-dependent. Perindoprilat is excreted with urine, final T _½ untied fraction of ≈17 h. Equilibrium state is reached in 4 days

Excretion of the perindoprilat decreases at elderly people and at patients with a heart or renal failure. With a renal failure it is necessary to choose a dose depending on degree of a renal failure (clearance of creatinine (CC)) for patients.

Dialysis clearance of the perindoprilat — 70 ml/min.

Pharmacokinetics of a perindopril changes at patients with cirrhosis: the hepatic clearance of the main molecule decreases twice. However the formed number of the perindoprilat does not decrease. Therefore, selection of a dose is not required to such patients (see USE and SPECIAL INSTRUCTIONS).

Indapamid. Indapamid is quickly and completely absorbed from a GIT. The C _max in blood plasma is reached in 1 h after use of per os. Linking with proteins of blood plasma — 79%. T _½ — 14–24 h (on average 18 h). Repeated reception does not cause cumulation.

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generally indapamid it is excreted with urine (70% of a dose) and a stake (22%) in the form of inactive metabolites. At patients with a renal failure the parameters of pharmacokinetics do not change.

Amlodipin. At use of per os in therapeutic doses amlodipin it is well absorbed and reaches the C _max in blood through 6–12 h after use. Absolute bioavailability — 64–80%. The volume of distribution is ≈21 l/kg. In the researches in vitro it was shown that ≈97.5% of the amlodipin circulating in blood contact proteins of blood plasma. Meal does not affect bioavailability of an amlodipin. T _½ an amlodipina from blood plasma of ≈35-50 h that allows to appoint medicament 1 r / days. Generally amlodipin it is metabolized in a liver with formation of inactive metabolites, 60% of metabolites are excreted with urine, and 10% — in not changed look.

Time of achievement of the C _max amlodipina in blood plasma at elderly people and young patients is identical. At patients of advanced age the tendency to decrease in clearance of an amlodipin is observed that leads to increase in AUC and T _½ . Increase in an indicator of AUC and T _½ at patients with stagnant heart failure corresponded to age features of the studied patients.

very limited amount of clinical data on purpose of an amlodipin to patients with an abnormal liver function Exists. At patients with a liver failure the clearance of an amlodipin decreases, it leads to increase in T _½ and AUC for ≈40–60%.

Indication

Terapiya ag at patients who need treatment perindoprily, indapamidy and amlodipiny in the doses which are available in the fixed combination.

Use

For use of per os.

for

1 tablet of the medicament Tripliksam a day once, it is desirable in the morning before food.

Use of the fixed combination is not provided by

for initial therapy.

If necessary a dose of the fixed combination Tripliksam can be changed

or individual selection of doses separately for each of components can be recommended.

Special groups of patients

Patients with a renal failure (see CONTRAINDICATIONS and SPECIAL INSTRUCTIONS). In a heavy renal failure (clearance of creatinine (CC) of 30 ml/min.) the therapy by medicament is contraindicated. To patients with a medium-weight renal failure (ml/min. KK=30-60) prescribing of the medicament Tripliksam in doses of 10 mg / 2.5 to mg / 5 mg and 10 mg / 2.5 to mg / 10 are contraindicated to mg. Routine medical observation has to include regular control of level of creatinine and potassium in blood.

Elderly person (see. Special INSTRUCTIONS). It is necessary to consider that excretion of the perindoprilat at elderly people decreases (see Pharmacokinetics). Prescribing of the medicament Tripliksam to elderly people is possible taking into account function of kidneys (see CONTRAINDICATIONS).

Patients with an abnormal liver function (see CONTRAINDICATIONS, SPECIAL INSTRUCTIONS and Pharmacokinetics). Therapy by the medicament Tripliksam is contraindicated to patients with a heavy abnormal liver function. Triplexes should appoint with care to patients with a slight and medium-weight abnormal liver function due to the lack of recommendations concerning dosing of an amlodipin.

Contraindication

• Use for the patients who are on a hemodialysis; use for patients with not treated dekompensirovanny heart failure; heavy renal failure (kk 30 ml/min.); a medium-weight renal failure (kk 60 ml/min.) at the medicament use to triplexes containing a combination of active ingredients in doses of 10 mg / 2.5 mg / 5 mg or 10 mg / 2.5 mg / 10 mg; hypersensitivity to the active ingredients, other sulfanamide medicaments derivative of dihydropyridine, any other inhibitor apf or to the excipients specified in the section "structure and form of release"; the pregnant women or women who are going to become pregnant (see use during pregnancy or feeding by a breast); the feeding period a breast (see. use during pregnancy or feeding by a breast); the Quincke's disease in the anamnesis connected with the previous treatment by inhibitor apf; congenital or idiopathic Quincke's disease; hepatic encephalopathy; heavy abnormal liver function; hypopotassemia; heavy arterial hypotension; shock, including cardiogenic; obstruction of an exit from a left ventricle (for example a stenosis of an aorta of heavy degree); heart failure with an unstable hemodynamics after an acute myocardial infarction; simultaneous use with the medicaments containing active ingredient aliskiren for patients with diabetes or a renal failure (glomerular filtration rate of 60 ml/min. / 1.73 sq.m) (see interactions).

Side effects

Most frequent side reactions noted at use of a perindopril, indapamid and amlodipin separately are dizziness, a headache, paresthesias, vertigo, drowsiness, a disorder of vision, a ring in ears, palpitation, inflows, arterial hypotension (and the related symptoms), cough, short wind, disturbances from a GIT (an abdominal pain, a constipation, diarrhea, disturbance of taste (dysgeusia), dyspepsia, nausea, vomiting), an itching, skin rash, makulopapulezny rash, myotonia, an asthenia, hypostasis of anklebones, hypostasis and fatigue.

during therapy perindoprily, indapamidy or amlodipiny the side reactions given below distributed on frequency according to the medical dictionary for regulatory activity of MedDRA as follows were defined by

: very often (≥1/10); often (from ≥1/100 to 1/10); infrequently (from 1/1000 to 1/100); seldom (from 1/10 000 to 1/1000); very seldom (1/10,000); frequency is unknown (it cannot be determined by the available information).

Infection and invasion. Rhinitis: perindoprit — very seldom; amlodipin — infrequently.

from blood and lymphatic system. Agranulocytosis: perindoprit and indapamid — it is very rare; aplastic anemia: indapamid — it is very rare; pancytopenia: perindoprit — very seldom; leukopenia: perindoprit, indapamid, amlodipin — it is very rare; neutropenia: perindoprit — very seldom; hemolytic anemia: perindoprit, indapamid — it is very rare; thrombocytopenia: perindoprit, indapamid, amlodipin — it is very rare; eosinophilia: perindoprit — nechasto*.

from the immune system. Reactions of hypersensitivity: amlodipin — it is very rare, indapamid — infrequently.

Disturbance of metabolism and metabolism. The hyperpotassemia disappearing after medicament withdrawal: perindoprit — infrequently *; hyperglycemia: amlodipin — it is very rare; hypercalcemia: indapamid — it is very rare; hypoglycemia: perindoprit — infrequently *; decrease in level of potassium with a hypopotassemia, in particular serious, at patients of high risk: indapamid — frequency is unknown; hyponatremia: perindoprit — infrequently *, indapamid — frequency is unknown.

from mentality. Confusion of consciousness: perindoprit — very seldom, amlodipin — it is rare; insomnia: amlodipin — infrequently; changes of mood (including alarm): amlodipin — infrequently, perindoprit — infrequently; depression: amlodipin — infrequently; sleep disorders: perindoprit — infrequently.

from nervous system. Dizziness: perindoprit and amlodipin — it is frequent; headache: perindoprit and amlodipin — it is frequent, indapamid — it is rare; paresthesia: perindoprit — often, indapamid — it is rare, amlodipin — infrequently; vertigo: perindoprit — often, indapamid — it is rare; confusion of consciousness: perindoprit — very seldom; hypertensia: amlodipin — it is very rare; peripheral neuropathy: amlodipin — it is very rare; hypesthesia: amlodipin — infrequently; disturbance of perception of taste (dysgeusia): perindoprit — often, amlodipin — infrequently; tremor: amlodipin — infrequently; syncope: perindoprit — infrequently *, indapamid — frequency is unknown, amlodipin — infrequently; drowsiness: perindoprit — infrequently *, amlodipin — it is frequent; extrapyramidal disorders (extrapyramidal syndrome): amlodipin — frequency is unknown; a stroke, it is possible owing to excessive decrease in the ABP at patients of group of high risk: perindoprit — very seldom.

from an organ of sight. Disorders of vision: perindoprit — often, indapamid — frequency is unknown, amlodipin — infrequently; doubling: amlodipin — infrequently; shortsightedness: indapamid — frequency is unknown; indistinct sight: indapamid — frequency is unknown.

from an organ of hearing and a labyrinth of an ear. A ring in ears: perindoprit — often, amlodipin — infrequently.

from heart. Stenocardia: perindoprit — very seldom; arrhythmia (including bradycardia, ventricular tachycardia and fibrillation of auricles): perindoprit, indapamid, amlodipin — it is very rare; the myocardial infarction can arise owing to excessive decrease in the ABP at patients of high risk: perindoprit and amlodipin — it is very rare; palpitation: perindoprit — infrequently *, amlodipin — it is frequent; Bouveret's ventricular disease like pirouette (torsade de pointes) which can be lethal: indapamid — frequency is unknown; tachycardia: perindoprit — nechasto*.

from the vascular system. Inflows: amlodipin — it is frequent; hypotension (and related symptoms): perindoprit — often, indapamid — it is very rare, amlodipin — infrequently; vasculitis: perindoprit — infrequently *, amlodipin — it is very rare.

from the respiratory system, bodies of a thorax and mediastinum. Cough: perindoprit — often, amlodipin — it is very rare; asthma: perindoprit — often, amlodipin — infrequently; bronchospasm: perindoprit — infrequently; eosinophilic pneumonia: perindoprit — very seldom.

from digestive system. Pain in abdominal area: perindoprit and amlodipin — it is frequent; constipation: perindoprit — often, indapamid — it is rare, amlodipin — infrequently; diarrhea: perindoprit — often, amlodipin — infrequently; dyspepsia: perindoprit — often, amlodipin — infrequently; nausea: perindoprit and amlodipin — it is frequent, indapamid — it is rare; vomiting: perindoprit — often, indapamid and amlodipin — infrequently; dryness in a mouth: perindoprit and amlodipin — infrequently, indapamid — it is rare; change of a rhythm of defecation: amlodipin — infrequently; hyperplasia of gums: amlodipin — it is very rare; pancreatitis: perindoprit, indapamid and amlodipin — it is very rare; gastritis: amlodipin — it is very rare.

from a gepatobiliarny system. Hepatitis: perindoprit and amlodipin — it is very rare, indapamid — frequency is unknown; jaundice: amlodipin — it is very rare; abnormal liver function: indapamid — it is very rare; in the presence of a liver failure the developing of hepatic encephalopathy is possible: indapamid — frequency is unknown.

from skin and hypodermic fabric. Quincke's edema: amlodipin — it is very rare; itching: perindoprit — often, amlodipin — infrequently; rash: perindoprit — often, amlodipin — infrequently; makulopapulezny rash: indapamid — it is frequent; small tortoiseshell: perindoprit — infrequently, indapamid and amlodipin — it is very rare; Quincke's disease: perindoprit — infrequently, indapamid and amlodipin — it is very rare; alopecia: amlodipin — infrequently; purpura: indapamid and amlodipin — infrequently; decolouration of skin: amlodipin — infrequently; hyperhidrosis: perindoprit and amlodipin — infrequently; dieback: amlodipin — infrequently; multiformny erythema: perindoprit and amlodipin — it is very rare; Stephens's syndrome — Johnson: indapamid and amlodipin — it is very rare; exfoliative dermatitis: amlodipin — it is very rare; toxic epidermal necrolysis: indapamid — it is very rare; photosensitization: perindoprit — infrequently *, indapamid — frequency is unknown, amlodipin — is very rare; strengthening of manifestation of the available system lupus erythematosus is possible: indapamid — frequency is unknown; pemphigoid: perindoprit — nechasto*.

from a skeletal and muscular system and connective tissue. Spasms in muscles: perindoprit — often, amlodipin — infrequently; hypostasis of anklebones: amlodipin — it is frequent; arthralgia: perindoprit — infrequently *, amlodipin — infrequently; myalgia: perindoprit — infrequently *, amlodipin — infrequently; dorsodynia: amlodipin — infrequently.

from kidneys and an urinary system. Urination disturbance, nocturia, frequent urination: amlodipin — infrequently; OPN: perindoprit — very seldom; renal failure: perindoprit — infrequently, indapamid — it is very rare.

from a reproductive system and mammary glands. Erectile dysfunction: perindoprit and amlodipin — infrequently; gynecomastia: amlodipin — infrequently.

General disorders. Asthenia: perindoprit — often, amlodipin — infrequently; increased fatigue: indapamid — it is rare, amlodipin — it is frequent; hypostases: amlodipin — it is frequent; thorax pain: perindoprit — infrequently *, amlodipin — infrequently; pain: amlodipin — infrequently; indisposition: perindoprit — infrequently *, amlodipin — infrequently; peripheral hypostases: perindoprit — infrequently *; hyperthermia: perindoprit — nechasto*.

Research. Increase/degrowth of a body: amlodipin — infrequently; increase in level of bilirubin in blood: perindoprit — seldom; increase in level of liver enzymes: perindoprit — seldom, indapamid — frequency is unknown, amlodipin — is very rare; increase in level of creatinine in blood: perindoprit — infrequently *; increase in level of urea in blood: perindoprit — infrequently *; decrease in level of hemoglobin and hematocrit: perindoprit — very seldom; lengthening of an interval of Q-T on the ECG: indapamid — frequency is unknown; increase in level of glucose of blood: indapamid — frequency is unknown; increase in level of uric acid in blood: indapamid — frequency is unknown.

Damage, poisoning and complication of reception. Falling: perindoprit — nechasto*.

* Frequency is calculated by

according to clinical trials for the side reactions defined on the basis of spontaneous messages.

Message about the suspected side reactions. It is important to report about the suspected side reactions after medicine registration. It will allow to continue monitoring of a ratio advantage/risk. Health workers are asked to report about the suspected side reactions through the national system of messages.

Special instructions

All cautions provided below for each component of medicament concern also fixed combination to triplexes.

Lities. Simultaneous use of lithium and a combination of a perindoprila/indapamid is not recommended (see INTERACTIONS).

Double blockade system renin-angiotensin-aldosteronovoy (SRAA). There are data that simultaneous use of APF inhibitors, blockers of receptors of angiotensin II (SCONCE) or an aliskiren increases risk of developing of arterial hypotension, a hyperpotassemia and depression of function of kidneys (including OPN). Therefore, carrying out double blockade of RAAS because of a concomitant use of APF, BRA inhibitors or an aliskiren is not recommended (see INTERACTIONS). In case of absolute necessity of performing therapy by double blockade of RAAS it should be carried out only under observation of the expert and at frequent careful monitoring of function of kidneys, level of electrolytes and the ABP. Patients with a diabetic nephropathy should not apply at the same time APF and SCONCE inhibitors.

Kaliysberegayushchy drugs, nutritional supplements containing potassium, or salt substitutes with potassium. Use of a combination of a perindopril and the kaliysberegayushchy means, additives or substitutes of salt containing potassium usually do not recommend (see INTERACTION).

neutropenia/agranulocytosis/thrombocytopenia/anemia. There are messages that at the patients accepting APF inhibitors cases of developing of a neutropenia/agranulocytosis, thrombocytopenia and anemia were noted. At patients with normal function of kidneys in the absence of other risk factors the neutropenia arises seldom. Perindopril it is necessary to apply extremely carefully at patients with collagenoses, during therapy by immunodepressants, Allopyrinolum or procaineamide or in case of a combination of these risk factors, especially in the presence of a renal failure. At some such patients the development of serious infectious diseases, sometimes resistant to intensive antibiotic treatment was noted. At use of a perindopril for such patients it is recommended to exercise periodic control of quantity of leukocytes in blood. Besides, patients should be informed on need to report to the doctor about any manifestations of an infectious disease (for example a sore throat, fervescence) (see INTERACTIONS, SIDE EFFECTS).

Hypersensitivity / Quincke's disease. There were messages that at use by patients of APF inhibitors, including perindoprit, rare episodes of a Quincke's disease of the face, extremities, lips, language, a glottis and/or throat were observed (see. Side EFFECTS). The specified episodes can occur at any moment of therapy. In this case urgent phase-out of medicament and medical observation of a condition of the patient before total disappearance of symptoms is necessary. At spread of hypostasis only in a face and lips the condition of the patient usually improved without therapy though use of antihistaminic medicaments was useful to reduction of expressiveness of symptoms. The Quincke's disease connected with a laryngeal edema can lead to a lethal outcome. At spread of hypostasis on language, a glottis or a throat which is capable to cause obstruction of airways the urgent emergency treatment which can include p / to administration of solution of epinephrine 1:1000 (0.3-0.5 ml) and/or measures for ensuring passability of airways is necessary. More often patients of negroid race who accepted APF inhibitors, in comparison with representatives of other races had messages about developing of a Quincke's disease. Patients with existence in the anamnesis of episodes of a Quincke's disease which was not connected with use of APF inhibitors treat group of the increased risk of developing a Quincke's disease during intake of APF inhibitors. The patients receiving therapy by APF inhibitors had messages about exceptional cases of an intestinal Quincke's disease. At these patients noted presence of abdominal pain (with nausea and vomiting or without); sometimes the intestinal Quincke's disease was not followed by manifestation of the previous Quincke's disease of the person and the level of C1 esterase inhibitor was normal. The Quincke's disease was diagnosed by means of such procedures as a computer tomography of abdominal area or ultrasonography, or during surgical intervention; after APF inhibitor cancellation the symptoms of a Quincke's disease disappeared. In case of developing of abdominal pain at the patients accepting APF inhibitors it is necessary to execute differential diagnostics for an exception of an intestinal Quincke's disease. At the patients who are at the same time receiving mTOR inhibitors (for example sirolimus, everolimus, temsirolimus), risk of developing a Quincke's disease is increased (in particular, hypostasis of airways or language, with dysfunction of breath or without) (see INTERACTIONS).

Anaphylactoid reactions during the desensibilizing therapy. The patients receiving therapy by APF inhibitors during the desensibilizing therapy by the medicaments containing apitoxin had messages about single episodes of long zhizneugrozhayushchy anaphylactoid reactions. It is necessary to apply with care APF inhibitors at patients with an allergy after performing desensitization and to avoid their inclusion in immunotherapy time the medicaments containing apitoxin. Nevertheless at patients who need use of both APF inhibitors, and the desensibilizing therapy such reactions can be avoided thanks to the temporary termination of intake of APF inhibitor not less than for 24 h prior to desensitization.

Anaphylactoid reactions during a LDL plasma exchange. At the patients accepting APF inhibitors during an aferez of LDL using a sulfate dextran it was seldom reported about emergence of zhizneugrozhayushchy anaphylactoid reactions. It is possible to avoid the specified reactions if temporarily to refrain from therapy by APF inhibitor before carrying out each aferez.

Patients who are on a hemodialysis. The patients accepting APF inhibitors during stay on a hemodialysis using high-flowing poly(acrylic membranes had messages about episodes of emergence of anaphylactoid reactions (for example AN 69). At such patients it is necessary to apply other type of dialysis membranes or to appoint other class of antihypertensive drugs.

Hepatic encephalopathy. With an abnormal liver function the use of thiazide and tiazidopodobny diuretics can cause hepatic encephalopathy in patients. In this case