Нолипрел® And Bee forte

General characteristics. Structure:

Active agents: perindoprit arginine of 10 mg that corresponds to 6,79 mg of a perindopril and индапамид 2,5 mg.
Excipients: lactoses monohydrate, magnesium stearate, maltodextrin, silicon dioxide colloid anhydrous, sodium carboxymethylstarch (type A), Structure of a film cover: macrogoal 6000, magnesium stearate, titanium dioxide (E171), глицерол, gipromelloza.
DESCRIPTION
Round biconvex tablets of white color, film coated.

Pharmacological properties:

Pharmacodynamics. Нолипрел® And Bee forte – the combined drug containing a perindopril arginine and индапамид. Pharmacological properties of the drug Noliprel® A of Bee forte combine separate properties of each of components.
Action mechanism
Нолипрел® And Bee forte
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 Bee forte
Нолипрел® And Bee forte has dozozavisimy anti-hypertensive effect, both on diastolic, and on systolic the ABP as in a standing position, and "lying".
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 Bee-forteumenshayet 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, on 1 tablet of 1 times a day, it is preferable in the morning, before meal.
Patients of advanced age (see the section "Special Instructions")
At patients of advanced age the clearance of creatinine is calculated taking into account age, body weight and a floor. To patients of advanced age with normal function of kidneys appoint Noliprel® And Bee forte on 1 tablet of 1 times a day, at the same time it is necessary to control extent of decrease in the ABP.
Renal failure (see the section "Special Instructions")
Drug is contraindicated to patients with a moderate and heavy renal failure (KK less than 60 ml/min.).
Or exceeding 60 ml/min., against the background of therapy regular control of concentration of creatinine and potassium in a blood plasma is necessary for patients with KK equal.
Liver failure (see sections of "Contraindication", "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® And should not appoint Bee forte 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 Bee forte
Lithium drugs
Perindoprit simultaneous use of a combination and the indapamida with drugs of lithium is not recommended (see the section "Interaction with Other Medicines").
Renal failure
Therapy by the drug Noliprel® A of Bee forte is contraindicated to patients with a moderate and heavy renal failure (KK less than 60 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 by the drug Noliprel® A of Bee forte should be stopped. Further it is possible to renew a combination therapy, using low doses of a combination perindoprit also an indapamid, or to use drugs in the monotherapy mode.
Regular control of maintenance of potassium ions 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.
Нолипрел® And Bee forte it is not recommended to patients with a bilateral stenosis of renal arteries or a stenosis of an artery 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 renal artery stenosis, including, bilateral). Therefore at observation of patients it is necessary to pay attention to possible symptoms of dehydration and decrease in content of electrolytes in a blood plasma, for example, after diarrhea or vomiting. Regular control of content 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 OTsK and the ABP it is possible to resume therapy, using low doses of a combination perindoprit also an indapamid, or to use drugs in the monotherapy mode.
Content of potassium
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 use of other antihypertensives in a combination with diuretic, regular control of maintenance of potassium ions 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 Noliprel® forte to patients with hereditary intolerance of a galactose, a lactose intolerance and glyukozo-galaktozny malabsorption.
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 (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 general diseases of connecting fabric, against the background of reception of immunodepressive means, Allopyrinolum or procaineamide and at their combined use, especially at patients with an initial renal failure. Some patients had serious infectious diseases, 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 administration of drug of Noliprel® And Bee forte has to be immediately stopped, and the patient has to be observed until symptoms of hypostasis do not disappear completely. If hypostasis 17
affects only a face and lips, its manifestations usually take place independently though antihistamines can be applied to treatment of its symptoms.
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 normal activity of S-1 enzyme 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 with the burdened allergological anamnesis or tendency to allergic reactions undergoing procedures of desensitization. It is necessary to avoid APF inhibitor use 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 of desensitization.
Anaphylactoid reactions when carrying out an aferez of LPNP
In rare instances at the patients receiving APF inhibitors when carrying out an aferez of LPNP with use of a dextran of sulfate 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 apply an antihypertensive 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 kaliysoderzhashchy 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 doctor considers that therapy by APF inhibitor is necessary for the patient, administration of drug can be continued.
Children and teenagers
Нолипрел® And should not appoint Bee forte children and teenagers aged up to 18 years due to the lack of data on efficiency and safety of use of monodrugs or a combination therapy at patients of this age group.
Risk of arterial hypotension and/or renal failure (at patients with chronic heart failure, disturbances of water and electrolytic balance, etc.)
At some morbid conditions considerable activation of RAAS can be noted, especially at the expressed hypovolemia and decrease in content 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 renal artery stenosis (including, bilateral), chronic heart failure or cirrhosis with hypostases and ascites.
Use of APF inhibitors causes blockade of RAAS and therefore can be followed by sharp decrease in the ABP and/or increase in concentration 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. In such cases when resuming therapy it is recommended to use a combination of a perindopril and an indapamid in lower dose and then to gradually increase a dose.
Patients of advanced age
Before administration of drug of Noliprel® And Bee forte it is necessary to estimate functional activity of kidneys and the maintenance of potassium ions 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 decrease in OTsK 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 of a combination of a perindopril of arginine and an indapamid.
Patients with renovascular hypertensia
Method of treatment of renovascular hypertensia is revascularization. Nevertheless, use of APF inhibitors has favorable effect at 20
patients, as expecting surgical intervention, and in that case when carrying out surgical intervention cannot be carried out.
At patients with the diagnosed or estimated renal artery stenosis treatment should be begun with lower doses of a combination of a perindopril and an inadpamid. At some patients the functional renal failure which disappears at drug withdrawal of Noliprel® And Bee forte can develop.
Other risk groups
At patients with chronic heart failure (the IV funktsinoalny class on NYHA classification) and patients with a diabetes mellitus of 1 type (danger of spontaneous increase in maintenance of potassium ions) treatment has to begin with lower doses of a combination 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: the combination perindoprit and the indapamida has to be used together with beta adrenoblockers.
Patients with a diabetes mellitus
At purpose of the drug Noliprel® A of Bee forte regular control of concentration of glucose in a blood plasma is necessary for patients with the diabetes mellitus receiving hypoglycemic means for intake or insulin within the first month of therapy.
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 bring to expressed 21
to decrease in the ABP, especially when using the means for the general anesthesia having anti-hypertensive 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 and at a mitral stenosis.
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 of Noliprel® And Bee forte (see the section "Side effect").
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 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 chronic 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 means promoting increase 22
the maintenance of potassium ions in a blood plasma (for example, heparin) (especially at patients with reduced function of kidneys). The hyperpotassemia can bring to serious, sometimes to fatal disturbances of a heart rhythm. If the combined reception of the means stated above is necessary, treatment has to be carried out with care, against the background of regular control of maintenance of potassium ions in blood serum (see the section "Interaction with Other Medicines").
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 immediately administration of drug of Noliprel® And Bee forte.
Photosensitivity
Against the background of reception of thiazide and tiazidopodobny diuretics it was reported about photosensitivity reaction development cases (see the section "Side effect"). In case of development of reaction of photosensitivity against the background of administration of drug it is necessary to stop treatment. In need of therapy continuation diuretics recommend to protect integuments from influence of sunshine or artificial ultraviolet 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 means 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 of advanced age (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: patients of advanced age, the exhausted patients or receiving the combined medicamentous therapy, patients with cirrhosis, peripheral hypostases or ascites, coronary heart disease, chronic heart failure. The hypopotassemia at these patients strengthens toxic effect of cardiac glycosides and increases risk of development of arrhythmia.
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 heart rhythm, especially, to arrhythmia like "pirouette" which can be fatal. In all the cases described above regular control of maintenance of potassium ions in a blood plasma is necessary. The first measurement of maintenance 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 maintenance of calcium ions 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 means.
Concentration of glucose in a blood plasma
It is necessary to control concentration of glucose in blood at patients with a diabetes mellitus, especially in the presence of a hypopotassemia.
Uric acid
At patients with the increased concentration 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 (concentration of creatinine in a blood plasma at adult patients lower than 25 mg/l or 220 µmol/l). At patients of advanced age of KK calculate 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.
Influence on ability to drive the car or mechanical devices
Action of the means which are a part of the drug Noliprel® A of Bee forte 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 or at addition to the carried-out therapy of other antihypertensives. In this case ability to manage motor transport 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:

Нолипрел® And Bee forte
Undesirable combination of medicines
Lithium drugs
- at simultaneous use of drugs of lithium and APF inhibitors there can be a reversible increase in content of lithium in a blood plasma and the toxic effects connected with it. Additional use of thiazide diuretics can promote further increase in content 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 concentration of lithium in a blood plasma is necessary (see the section "Special Instructions").
The combination of drugs 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 antihypertensives 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 regularly 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 anti-hypertensive effect (a delay of liquid and ions of sodium as a result of action glyuko-corticosteroids).
- Other antihypertensives: strengthening of anti-hypertensive effect is possible.
Perindopril
Undesirable combination of medicines
Kaliysberegayushchy diuretics (amiloride, Spironolactonum, Triamterenum both as monotherapy, and in a combination) and potassium drugs: against the background of therapy by APF inhibitors, as a rule, the content of potassium in blood serum remains within norm, but the hyperpotassemia can sometimes develop. The concomitant use of kaliysberegayushchy diuretics (for example, Spironolactonum, Triamterenum, amiloride), drugs of potassium and kaliysoderzhashchy substitutes of edible salt can lead to essential increase in maintenance of potassium ions in blood serum up to a lethal outcome. If combined 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 maintenance of potassium ions in a blood plasma and the ECG parameters.
The combination of means 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 means requiring attention
- Allopyrinolum, cytostatic and immunodepressive means, glyukokortikosteroda (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 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 infusionally gold drugs (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 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 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 the digestive tract (DT): increase in risk of development of a hypopotassemia (additive effect). Control of maintenance of potassium ions 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 a GIT.
- 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 maintenance of potassium ions 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 at simultaneous use of Metforminum increases risk of development of lactic acidosis. It is not necessary to use 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 means: organism dehydration against the background of reception of diuretic means increases risk of development of an acute renal failure, especially when using high doses of iodinated contrast means. Before use of iodinated contrast means by the patient it is necessary to compensate the volume of the circulating blood.
- Calcium salts: at simultaneous use development of a hypercalcemia owing to decrease in removal of calcium ions by kidneys is possible.
- Cyclosporine: increase in concentration of creatinine in a blood plasma without change of content of the circulating cyclosporine, even is possible at the normal content of liquid 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® And forte 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 forte 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 forte 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 forte 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 forte 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, 10 mg + 2,5mg.
On 30 tablets in the bottle from polypropylene supplied with the doser and the stopper containing the moisture absorbing gel. On 1 bottle on 30 tablets with the instruction on a medical use in a pack cardboard.
When packaging (packaging) at the Russian enterprise LLC Serdiks:
On 30 tablets in the bottle from polypropylene supplied with the doser and the stopper containing the moisture absorbing gel. On 1 bottle on 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 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.