Нолипрел® And

General characteristics. Structure:

Active agents of a perindopril of arginine - 2,5 mg that corresponds to 1,6975 mg of a perindopril and an indapamid of 0,625 mg.
Excipients: lactoses monohydrate of 74,455 mg, magnesium stearate of 0,45 mg, maltodextrin of 9 mg, silicon dioxide of colloid anhydrous 0,27 mg, sodium carboxymethylstarch (type A) of 2,7 mg.
The cover is film: a macrogoal of 6000 0,087 mg, premix for a film cover of white SEPIFILM 37781 RBC color (глицерол 4,5%, a gipromelloza of 74,8%, a macrogoal of 6000 1,8%, magnesium stearate of 4,5%, titanium dioxide (Е 171) 14,4%) 2,913 mg.
DESCRIPTION
Oblong tablets, film coated, white color, with risky on both parties.

Pharmacological properties:

Pharmacodynamics. Нолипрел® And – the combined drug containing a perindopril arginine and индапамид. Pharmacological properties of the drug Noliprel® A combine separate properties of each of components.
Action mechanism
Нолипрел® And
The combination perindoprit and the indapamida strengthens anti-hypertensive action of each of them.
Perindopril
Perindopril – inhibitor of the enzyme turning angiotensin I into angiotensin II (inhibitor of an angiotensin-converting enzyme (APF)). APF, or a kininaza of II, is ekzopeptidazy which carries out as transformation of angiotensin I into vasoconstrictive substance angiotensin II, and destruction of the bradikinin possessing vasodilating action to inactive heptapeptide. As a result perindoprit:
- reduces secretion of Aldosteronum;
- by the principle of negative feedback increases activity of a renin in a blood plasma;
- at prolonged use reduces the general peripheric vascular resistance (GPVR) that is caused, generally action by vessels in muscles and kidneys. These effects are not followed by a delay of ions of sodium and liquid or development of reflex tachycardia.
Perindopril normalizes work of a myocardium, reducing preloading and an afterload.
When studying indicators of a hemodynamics at patients with the chronic heart failure (CHF) it was revealed:
- pressure decrease of filling in the left and right ventricles of heart;
- decrease in OPSS;
- increase in cordial emission;
- increase in a muscular peripheral blood-groove.
Indapamid
Indapamid treats group of sulfonamides, on pharmacological properties is close to thiazide diuretics. Indapamid inhibits a reabsorption of ions of sodium in a cortical segment of a Henle's loop that leads to increase in removal by kidneys of ions of sodium, chlorine and to a lesser extent potassium ions and magnesium, strengthening thereby a diuresis, and reducing the arterial pressure (AP).
Anti-hypertensive action
Нолипрел® And
Нолипрел® And the ABP as in a standing position, and "lying" has dozozavisimy anti-hypertensive effect, both on diastolic, and on systolic.
Anti-hypertensive action remains during 24 h the Stabilnyyterapevtichesky effect develops less than in 1 month from the beginning of therapy and is not followed by tachycardia. The termination of treatment does not cause a syndrome of "cancellation".
Нолипрел® And reduces degree of a hypertrophy of a left ventricle (GTLZh), improves elasticity of arteries, reduces OPSS, does not influence metabolism of lipids (the general cholesterol, cholesterol of lipoproteins of high (LPVP) and lipoproteins of the low density (LPNP), triglycerides).
Influence of use of a combination of a perindopril and indapamid on GTLZh in comparison with enalapril is proved. At the patients with arterial hypertension and GTLZh receiving therapy of perindoprily erbuminy 2 mg (2,5 mg of a perindopril of arginine) / indapamidy 0,625 mg or enalapril in a dose of 10 mg are equivalent once a day, and at increase in a dose of a perindopril of an erbumin up to 8 mg (10 mg of a perindopril of arginine are equivalent) and an indapamida to 2,5 mg, or enalapril to 40 mg once a day, more significant decrease in the index of mass of a left ventricle (IMLV) in group perindopril/indapamid in comparison with group of enalapril is noted. At the same time the most significant influence on IMLZh is noted at use of a perindopril of an erbumin 8 mg / индапамида 2,5 mg. More expressed anti-hypertensive action against the background of a combination therapy perindoprily and indapamidy in comparison with enalapril is also noted. At patients with a diabetes mellitus 2 types (average values – age of 66 years, an index of the body weight of 28 kg/sq.m, glikozilirovanny hemoglobin (HbA1c) of 7,5%, the ABP of 145/81 mm hg) were studied influence of the fixed combination of a perindoprila/indapamid on the main micro and macrovascular complications in addition as to standard therapy of glycemic control, and the strategy of the intensive glycemic control (IGC) (target HbA1c <6,5%). At 83% of patients arterial hypertension, at 32% and 10% – macro - and microvascular complications, at 27% – a microalbuminuria was noted. Most of patients at the time of inclusion in a research received hypoglycemic therapy, 90% of patients – hypoglycemic means for intake (47% of patients – in monotherapy, 46% – therapy by two drugs, 7% – therapy by three drugs). 1% of patients received an insulin therapy, 9% – only a dietotherapy. Derivatives of sulphonylurea accepted 72% of patients, Metforminum – 61%. As the accompanying therapy of 75% of patients received antihypertensives, 35% of patients – hypolipidemic means (mainly, inhibitors of GMG-KOA-reduktazy (statines) – 28%), acetylsalicylic acid as antiagregantny means and other antiagregantny means (47%). After 6 weeks of the introduction period during which patients received therapy perindoprilom/indapamidy they were distributed in group of standard glycemic control or in the IGK group (Diabeton® of MV with an opportunity
increases in a dose up to the maximum 120 mg/days or addition of other hypoglycemic means).
In the IGK group (the average duration of observation of 4,8 years, average HbA1c 6,5%) in comparison with group of standard control (average HbA1c 7,3%) significant decrease by 10% of relative risk of the combined frequency macro - and microvascular complications is shown. Advantage was reached due to significant decrease in relative risk: the main microvascular complications for 14%, emergence and progressing of a nephropathy for 21%, microalbuminurias for 9%, macroalbuminurias for 30% and development of complications from kidneys for 11%. Advantages of hypotensive therapy did not depend on the advantages reached against the background of IGK.
Perindopril
Perindopril is effective in therapy of arterial hypertension of any severity.
Anti-hypertensive effect of drug reaches a maximum in 4-6 hours after a single dose inside and remains within 24 hours. In 24 hours after administration of drug the residual inhibition of APF is observed expressed (about 80%).
Perindopril has anti-hypertensive effect at patients, both with low, and with normal activity of a renin in a blood plasma. Co-administration of thiazide diuretics increases expressiveness of anti-hypertensive action. Besides, the combination of APF inhibitor and thiazide diuretic also leads to decrease in risk of a hypopotassemia against the background of reception of diuretics.
Indapamid
Anti-hypertensive action is shown at use of drug in the doses having the minimum diuretic effect. Anti-hypertensive action of an indapamid is connected with improvement of elastic properties of large arteries, reduction of OPSS.
Indapamid reduces GTLZh, does not influence concentration of lipids in a blood plasma: triglycerides, general cholesterol, LPNV, LPVP; carbohydrate metabolism (including at patients with the accompanying diabetes mellitus).

Pharmacokinetics. The combination perindoprit and the indapamida does not change their pharmacokinetic characteristics in comparison with separate reception of these drugs.
Perindopril
At intake perindoprit quickly it is soaked up. Bioavailability makes 65 - 70%.
About 20% of total quantity of the absorbed perindopril turn in периндоприлат – an active metabolite. Administration of drug during food is followed by reduction of metabolism of a perindopril in периндоприлат (this effect has no essential clinical value).
The maximum concentration of a perindoprilat in a blood plasma is reached in 3-4 hours after intake.
Communication with proteins of a blood plasma less than 30% also depends on concentration of a perindopril in blood.
Dissociation of the perindoprilat connected with APF is slowed down. Thereof the "effective" elimination half-life (T1/2) makes 25 hours. Repeated purpose of a perindopril does not lead to its cumulation, and T1/2 of a perindoprilat at repeated reception corresponds to the period of its activity, thus, the equilibrium state is reached in 4 days.
Perindoprilat is brought from an organism by kidneys. T1/2 of a metabolite makes 3-5 hours.
Removal of a perindoprilat is slowed down at advanced age, and also at patients with a heart and renal failure.
The dialysis clearance of a perindoprilat makes 70 ml/min. The pharmacokinetics of a perindopril is changed at patients with cirrhosis: its hepatic clearance decreases twice. Nevertheless, the quantity of the formed perindoprilat does not decrease so change of a dose of drug is not required.
Perindopril gets through a placenta. Indapamid
Indapamid is quickly and completely absorbed from digestive tract.
The maximum concentration of drug in a blood plasma is observed in 1 hour after intake.
Communication with proteins of a blood plasma – 79%.
T1/2 makes 14-24 hours (on average 19 hours). Repeated administration of drug does not lead to its cumulation in an organism. It is removed generally by kidneys (70% of the entered dose) and through intestines (22%) in the form of inactive metabolites.
The pharmacokinetics of drug does not change at patients with a renal failure.

Indications to use:

Essential hypertensia.
At patients with arterial hypertension and a diabetes mellitus 2 types for decrease in risk of development of microvascular complications (from kidneys) and rate of mortality from cardiovascular diseases.

Route of administration and doses:

Inside, it is preferable in the morning, before meal. Essential гипертензияПо to 1 tablet of the drug Noliprel® A of 1 times a day. Whenever possible administration of drug is begun with selection of doses of one-component drugs. In case of clinical need it is possible to consider the possibility of purpose of a combination therapy the drug Noliprel® A right after monotherapy. At patients with arterial hypertension and a diabetes mellitus 2 types for decrease in risk of development of microvascular complications (from kidneys) and rate of mortality from cardiovascular diseases. On 1 tablet Noliprel® A of 1 times a day. In 3 months of therapy, on condition of good tolerance, increase in a dose up to 2 tablets Noliprel® A of 1 times a day is possible (or on 1 tablet Noliprel® A forte 1 time a day). Patients of advanced age. It is necessary to appoint treatment drug after control of function of kidneys and the ABP.
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 Noliprel® A. Patsiyentam with KK equal or exceeding 60 ml/min., dose adjustment is not required. Against the background of therapy regular control of concentration of creatinine and potassium in a blood plasma is necessary. A liver failure (see sections of "Contraindication", "Special Instructions" and "Pharmacokinetics"). 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
Нолипрел® But should not appoint children and teenagers up to 18 years due to the lack of data on efficiency and safety of use of drug for patients of this age group.

Features of use:

Нолипрел® And
Use of the drug Noliprel® A of 2,5 mg + 0,625 mg, the indapamid containing a low dose and a perindopril of arginine, is not followed by essential decrease in frequency of side effects, except for a hypopotassemia, in comparison with perindoprily and indapamidy in the smallest doses allowed for use (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.
Dysfunction the pochekterapiya is contraindicated to patients with the expressed renal failure (KK less than 30 ml/min.). Some patients with arterial hypertension 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 blood 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 renal artery stenosis.
Arterial hypotension and disturbance of water and electrolytic balance. The hyponatremia is connected with risk of sudden development of arterial hypotension (especially patients with a stenosis have arteries of the only kidney and a bilateral stenosis of 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 low doses of drugs, or to use 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 to Noliprel® And patients with hereditary intolerance of a galactose, a lactose intolerance and glyukozo-galaktozny malabsorption.
Lithium drugs
Perindoprit simultaneous use of a combination and the indapamida with drugs of lithium is not recommended (see sections of "Contraindication" and "Interaction with Other Medicines").
Perindopril
Neutropenia/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 (in
that number, system lupus erythematosus, scleroderma). After cancellation of APF inhibitors signs of a neutropenia pass independently. For avoidance of development of similar reactions it is recommended to follow strictly recommended dose. At purpose of APF inhibitors this group of patients should correlate carefully a factor advantage/risk.
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 / Eli 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.
Anaphylactoid reactions when performing desensitization
There are separate messages on development of long, life-threatening anaphylactoid reactions in the patients receiving APF inhibitors during desensibilizirushchy 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 inhibitor 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 dextran sulfate use, at patients when carrying out a hemodialysis with use of high-flowing membranes life-threatening anaphylactoid reactions can develop. For prevention of anaphylactoid reaction follows temporarily
to stop therapy by APF inhibitor at least in 24 hours prior to the procedure of an aferez.
Cough
Nafone of therapy by APF inhibitor can arise dry cough. 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 iatrogenic character of this symptom. If the attending physician considers that therapy by APF inhibitor is necessary for the patient, administration of drug can be continued.
Children and teenagers
Should not appoint drug children and teenagers aged up to 18 years from-z 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 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, with a bilateral stenosis of renal arteries or with a stenosis of an artery of the only kidney, chronic heart failure or cirrhosis with hypostasis and ascites.
Use of APF inhibitor causes blockade of this system and therefore can be followed by sharp decrease in the ABP and/or increase in level of creatinine in a blood plasma, testimonial of development of a functional renal failure. 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 then 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 this category of patients as expecting an operative measure, and in that case when surgical intervention cannot be carried out. Treatment by the drug Noliprel® A of patients with the diagnosed or estimated bilateral stenosis of renal arteries or a stenosis of an artery of the only kidney should be begun with a low dose of drug in the conditions of a hospital, controlling function of kidneys and potassium concentration in a blood plasma. At some patients the functional renal failure which disappears at drug withdrawal can develop.
Other risk groups
At persons with heavy heart failure (the IV stage) and patients with an insulin-dependent diabetes mellitus (danger of spontaneous increase in potassium concentration) treatment has to begin with a low dose of drug and under constant medical control. Patients with arterial hypertension with coronary heart disease should not stop reception of beta adrenoblockers: APF inhibitors have to be used together with beta adrenoblockers.
Anemia
Anemia can develop at patients after transplantation of a kidney or at the persons which 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.
Insignificant decrease in concentration of hemoglobin happens within the first 6 months, then it remains stable and is completely recovered after drug withdrawal. At such patients treatment can be continued, however hematologic analyses have to be carried out regularly.
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, one day before surgery. It is necessary to warn the anesthesiologist that the patient accepts APF inhibitors.
Aortal stenosis / Hypertrophic cardiomyopathy
APF inhibitors have to be appointed with care the patient with obstruction of an output path 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 vomozhno bystry development of a necrosis of a liver, sometimes with a lethal outcome. The mechanism of development of this syndrome is not clear. At emergence of jaundice or substantial increase of activity of "hepatic" enzymes against the background of reception of APF inhibitors it is necessary to stop administration of drug and to see a doctor (see the section "Side effect").
Indapamid
In the presence of disturbances of functions of a liver reception of thiazide and tiazidopodobny diuretics can lead to development of hepatic encephalopathy. In this case it is necessary to stop administration of drug immediately.
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
the patient with cirrhosis and to elderly people (see the sections "Side Effect" and "Overdose").
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: elderly people, 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, to 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 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 body it is necessary to cancel reception of diuretic means.
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/l or 220 µmol/l).
In an initiation of treatment by diuretic 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 harmless for patients with not changed function of kidneys, however at patients with a renal failure its expressiveness can amplify.
Photosensitivity
Against the background of reception of thiazide and tiazidopodobny diuretics it was reported about a case of development of reactions of photosensitivity. In case of development of reactions of photosensitivity against the background of administration of drug it is necessary to stop treatment. In need of therapy continuation by diuretics, it is recommended to protect integuments from influence of sunshine or artificial ultraviolet rays.
Athletes
Indapamid can give positive reaction when carrying out a drug test.
Influence on ability to drive the car or mechanical devices.
Effect of the substances which are a part of the drug Noliprel® A does not lead to disturbance of psychomotor reactions. However at some people in response to decrease in the ABP various individual reactions, especially at the beginning of therapy can develop or at addition to the carried-out therapy of other hypotensive drugs. In this case ability to drive the car or other mechanisms can be reduced.

Side effects:

Perindopril has an inhibiting effect on the system "renin-angiotenzin-Aldosteronum" (RAAS) and reduces removal of potassium ions kidneys against the background of reception of an indapamid. At 4% of patients against the background of use of the drug Noliprel® A the hypopotassemia develops (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).
From circulatory and lymphatic system
Very seldom: thrombocytopenia, leukopenia/neutropenia, agranulocytosis, aplastic anemia, hemolitic anemia.
Anemia: in certain clinical situations (patients after transplantation of a kidney, the patients who are on a hemodialysis) APF inhibitors can cause anemia (see the section "Special Instructions").
From the central nervous system
Often: paresthesias, headache, dizziness, adynamy, вертиго.
Infrequently: sleep disorder, lability of mood.
Very seldom: confusion of consciousness.
Not specified frequency: syncope.
From an organ of sight
Often: vision disorder.
From an acoustic organ
Often: sonitus.
From outside warmly – vascular system
Often: the expressed decrease in the ABP, including, orthostatic hypotension.
Very seldom: disturbances of a heart 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").
Not specified frequency: arrhythmias like "pirouette" (perhaps, with a lethal outcome) (see the section "Interaction with Other Medicines").
From respiratory system, bodies of a thorax and a mediastinum
Chasto:na a background of use of APF inhibitors can arise 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 the alimentary system
Often: dryness of a mucous membrane of an oral cavity, nausea, vomiting, an abdominal pain, pain in epigastriums, disturbance of flavoring perception, a loss of appetite, dyspepsia, a lock, diarrhea.
Very seldom: Quincke's disease of intestines, cholestatic jaundice, pancreatitis
Not specified frequency: hepatic encephalopathy at patients with a liver failure (see sections of "Contraindication" and "Special Instructions"), hepatitis.
From integuments and a hypodermic fatty tissue
Often: skin rash, itch, makulopapulezny rash.
Infrequently: Quincke's disease of the person, lips, extremities, mucous membrane of language, voice folds and/or throats; a small tortoiseshell (see the section "Special Instructions"); hypersensitivity reactions at the patients predisposed to bronkhoobstruktivny and allergic reactions; purpura. At patients with an acute form of a system lupus erythematosus deterioration in a course of a disease is possible.
Very seldom: multiformny erythema, toxic epidermal necrolysis, Stephens-Johnson's syndrome.
Photosensitivity reaction cases are noted (see the section "Special Instructions").
From a musculoskeletal system and connecting fabric
Often: spasms of muscles.
From an urinary system
Infrequently: renal failure.
Very seldom: acute renal failure.
From reproductive system
Infrequently: impotence.
General frustration and symptoms
Often: adynamy.
Infrequently: the increased sweating. Laboratory indicators
- The hyperpotassemia, is more often passing.
- Slight increase of concentration of 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.
Seldom: hypercalcemia.
Not specified frequency:
− Increase in QT of an interval at an ECG (cf. the section "Special Instructions").
- Increase in concentration of uric acid and glucose in blood.
- Increase in activity of "hepatic" enzymes
- A hypopotassemia, especially significant for the patients belonging to risk group (see the section "Special Instructions").
- The hyponatremia and a hypovolemia leading to dehydration and orthostatic hypotension. The simultaneous hypochloraemia can lead to a metabolic alkalosis of compensatory character (the probability and weight of this effect is low).
The side effects noted during clinical trials
The side effects noted during the research ADVANCE will be coordinated with earlier established profile of safety of a combination of a perindopril and an indapamid. The serious undesirable phenomena were noted at some patients in the studied groups: hyperpotassemia (0,1%), acute renal failure (0,1%), arterial hypotension (0,1%) and cough (0,1%).
At three patients in group perindopril/indapamid the Quincke's disease was noted (against 2 in group of placebo).

Interaction with other medicines:

The combinations which are not recommended for use
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 need of performing such therapy it is necessary to control constantly the content of lithium in a blood plasma (see the section "Special Instructions").
Drugs, the combination to which requires special attention and care,
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 anti-hypertensive effects. At considerable loss of liquid the acute renal failure can develop (owing to reduction in the rate of glomerular filtering). Prior to treatment it is necessary to fill with drug loss of liquid and to regularly control function of kidneys in an initiation of treatment. The combination of drugs requiring attention Tricyclic antidepressants, antipsychotic means (neuroleptics): drugs of these classes strengthen anti-hypertensive effect and increase risk of orthostatic hypotension (the additive effect). Corticosteroids, тетракозактид: decrease in anti-hypertensive action (a delay of liquid and ions of sodium as a result of action of corticosteroids). Other antihypertensives: strengthening of anti-hypertensive effect is possible.
Perindopril
The combinations which are not recommended for use
Kaliysberegayushchy diuretics (amiloride, Spironolactonum, Triamterenum) 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 content of potassium in blood serum up to a lethal outcome. If simultaneous use of APF inhibitor 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 content of potassium in a blood plasma and the ECG parameters.
The combination of drugs requiring special attention
Hypoglycemic means for intake (sulphonylurea derivatives) and insulin: 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 drugs requiring attention
Allopyrinolum, cytostatic and immunosuppressive means, corticosteroids (at system use) and procaineamide: simultaneous use with APF inhibitors can be followed by the increased risk of a leukopenia.
Sredstvadlya of the general anesthesia: simultaneous use of APF inhibitors and means for the general anesthesia can lead to strengthening of anti-hypertensive effect.
Diuretics (thiazide and "loopback"): use of diuretics in high doses can lead to a hypovolemia, and addition to therapy of a perindopril – to arterial hypotension.
Gold drugs: at use of APF inhibitors, including, perindoprit to the patients receiving intravenously gold drug (ауротиомалат sodium), was
the symptom complex including is described: dermahemia of the person, nausea, vomiting, arterial hypotension.
Indapamid
The combination of drugs requiring special attention
The drugs capable to cause arrhythmia like "pirouette": because of risk of development of a hypopotassemia it is necessary to be careful at simultaneous use of an indapamid with the drugs capable to cause arrhythmia like "pirouette", for example, antiarrhytmic means (quinidine, hydroquinidine, Disopyramidum, Amiodaronum, дофетилид, ибутилид, a bretylium tosylate, 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 simultaneous use with above-mentioned drugs; risk of development of a hypopotassemia, if necessary to carry out its correction; to control QT interval.
The drugs 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 content of potassium in a blood plasma, if necessary – its correction is necessary. Special attention should be paid
to the patients who are at the same time receiving cardiac glycosides. It is necessary to apply 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 the content of potassium in a blood plasma and indicators of an ECG and, if necessary, to adjust therapy.
The combination of drugs 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 apply Metforminum if concentration of creatinine 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 an acute renal failure, especially at use of high doses of iodinated contrast agents. Before use of iodinated contrast agents patients need 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 concentration of creatinine in a blood plasma without change of concentration of cyclosporine in a blood plasma, even is possible at the normal content of water and ions of sodium.

Contraindications:

Hypersensitivity to a perindopril and other APF inhibitors, an indapamid, other sulfonamides, and also to other auxiliary components which are a part of drug, a Quincke's disease in the anamnesis (including against the background of reception of other APF inhibitors); hereditary/idiopathic Quincke's disease, hypopotassemia, the expressed renal failure (the clearance of creatinine (CC) less than 30 ml/min.), a stenosis of an artery of the only kidney, a bilateral stenosis of renal arteries, the expressed liver failure (including with encephalopathy), a concomitant use of the drugs extending QT interval, simultaneous use with the antiarrhytmic means capable to cause arrhythmia like "pirouette" (see the section "Interaction with Other Medicines"), pregnancy and the period of feeding by a breast. 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 is not recommended. Due to the lack of sufficient clinical experience of Noliprel® But it is not necessary to apply at the patients who are on a hemodialysis and also at patients with not treated dekompensirovanny heart failure.
With CARE (see also sections "Special Instructions" and "Interaction with Other Medicines"). 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, a hemodialysis), stenocardia, cerebrovascular diseases, renovascular hypertensia, a diabetes mellitus, chronic heart failure (the IV stages on NYHA classification), a hyperuricemia (especially followed by gout and an uratny nephrolithiasis), lability of the ABP, advanced age; carrying out a hemodialysis with use of high-flowing membranes or desensitization, before the procedure of an aferez of lipoproteins of the low density (LPNP); state after transplantation of kidneys; stenosis of the aortal valve / hypertrophic
cardiomyopathy; existence of a lactose intolerance, galactosemia or syndrome of glyukozo-galaktozny malabsorption; age up to 18 years (efficiency and safety are not established).
Pregnancy and period of feeding by a breast
Drug is contraindicated at pregnancy.
When planning pregnancy or at its approach against the background of administration of drug of Noliprel® And it is necessary to stop immediately administration of drug and to appoint other hypotensive therapy. It is not necessary to use the drug Noliprel® A in the I trimester of pregnancy. The corresponding controlled researches on use of APF inhibitors for pregnant women were not conducted. The available limited data on influence of APF inhibitors in the first trimester of pregnancy demonstrate that reception of APF inhibitors did not lead to the fruit malformations connected with a fetotoksichnost, but completely it is impossible to exclude fetotoksichesky influence of drug. Нолипрел® And it is contraindicated in II and the III trimester of pregnancy (see the section "Contraindications").
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 (depression of function of kidneys, олигогидрамнион, delay of ossification of bones of a skull) and to development of complications in the newborn (a renal failure, arterial hypotension, a 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 the drug Noliprel® A during II or III trimesters of pregnancy, it is recommended to conduct ultrasound examination of the newborn for assessment of a condition of a skull and function of kidneys. At newborns whose mothers received therapy by APF inhibitors arterial hypotension in this connection, newborns have to be under careful medical control can be observed.
Lactation period
Нолипрел® And it is contraindicated in the period of a lactation. It is unknown whether it is allocated perindoprit with breast milk. Indapamid is allocated with breast milk. Reception of thiazide diuretics causes reduction of amount of breast milk or suppression of a lactation. At the newborn at the same time hypersensitivity to sulfonamide derivatives, 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 administration of drug.

Overdose:

Symptoms
The most probable symptom of overdose – the expressed decrease in the ABP, sometimes in combination with nausea, vomiting, spasms, dizziness, drowsiness, confusion of consciousness and an oliguria which can pass into an anury (as a result of a hypovolemia). Also there can be electrolytic disturbances (a hyponatremia, a hypopotassemia).

Treatment of the Measure of acute management come down to removal of drug from an organism: to a gastric lavage and/or purpose of absorbent carbon with the subsequent recovery of water and electrolytic balance. At considerable decrease in the ABP it is necessary to transfer the patient to situation "lying" with the raised legs. If necessary to carry out correction of a hypovolemia (for example, intravenous infusion of 0,9% of solution of sodium of chloride). Perindoprilat, an active metabolite of a perindopril, can be removed from an organism by means of dialysis.

Storage conditions:

Special storage conditions are not required. PERIOD OF VALIDITY 3 years. NOT to APPLY AFTER the PERIOD OF VALIDITY SPECIFIED ON PACKAGING.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated, 2,5 mg + 0,625 mg.
On 14 or 30 tablets in the bottle from polypropylene supplied with the doser and the stopper containing the moisture absorbing gel.
On 1 bottle (on 14 and/or 30 tablets) or on 3 bottles (on 30 tablets) with the instruction on a medical use in a pack cardboard with control of the first opening.
When packaging (packaging)/production at the Russian enterprise LLC Serdiks:
On 14 or 30 tablets in the bottle from polypropylene supplied with the doser and the stopper containing the moisture absorbing gel.
On 1 bottle (on 14 and/or 30 tablets) with the instruction on a medical use in a pack cardboard with control of the first opening.
Packaging for hospitals: On 30 tablets in the bottle from polypropylene supplied with the doser and the stopper containing the moisture absorbing gel.
On 3 bottles on 30 tablets with instructions on a medical use in a pack cardboard with control of the first opening.
On 30 bottles on 30 tablets in the cardboard pallet for bottles with instructions on a medical use in a box cardboard with control of the first opening.