To - Perineva®

General characteristics. Structure:

Active ingredients:      
Perindoprila эрбумин To 
 полуфабрикат−гранулы 37,515 mg 75,03 mg 150,06 mg
[Active agent полуфабриката−гранул       
Perindoprila эрбумин 2 mg 4 mg 8 mg
Semi-finished product granules excipients: Calcii chloridum hexahydrate, lactoses monohydrate, кросповидон]
Indapamid of 0,625 mg 1,25 mg 2,5 mg
Excipients: cellulose microcrystallic, Natrii hydrocarbonas, silicon dioxide colloid, magnesium stearate.

Description:
Tablets of 0,625 mg + 2 mg: round, biconvex tablets of white or almost white color with a facet, on one party the short line is engraved.
Tablets of 1,25 mg + 4 mg: round, biconvex tablets of white or almost white color with risky on one party and with a facet.
Tablets of 2,5 mg + 8 mg: round, biconvex tablets of white or almost white color with risky on one party.

Pharmacological properties:

Ко-Перинева® - the combined drug containing inhibitor of an angiotensin-converting enzyme (APF) - perindoprit also tiazidopodobny diuretic - индапамид. Drug has anti-hypertensive, diuretic and vazodilatiruyushchy effect.
Ко-Перинева® has the expressed dozozavisimy anti-hypertensive effect which is not depending on age and position of a body of the patient and not followed by reflex tachycardia. Does not influence metabolism of lipids (the general cholesterol, lipoproteids of the low density (LPNP), lipoproteids of very low density (LPONP), lipoproteids of the high density (LPVP), triglycerides (TG) and carbohydrates), including at patients with a diabetes mellitus. Reduces risk of development of the hypopotassemia caused by monotherapy by diuretic.
The anti-hypertensive effect remains within 24 hours.
The stable lowering of arterial pressure (ABP) is reached within 1 month against the background of use of the drug Co-Perineva® without increase in the heart rate (HR). The termination of treatment does not lead to development of a syndrome of "cancellation".
Perindopril - APF inhibitor which mechanism of action is connected with oppression of activity of APF leading to reduction of formation of angiotensin II eliminates vasopressor effect of angiotensin II, reduces secretion of Aldosteronum. Use of a perindopril does not lead to a delay of sodium and liquid, does not cause reflex tachycardia at prolonged treatment. The anti-hypertensive effect of a perindopril develops at patients with low or normal activity of a renin of a blood plasma.
Perindopril acts by means of the main active metabolite - a perindoprilat. Other its metabolites are inactive.
Effect of the drug Co-Perineva® brings to:
 - to a phlebectasia (decrease in preload of heart), the metabolism of prostaglandins caused by change;
 - to reduction of the general peripheric vascular resistance (GPVR) (decrease in an afterload on heart).
At patients with heart failure perindoprit promotes:
 - to pressure decrease of filling of the left and right ventricles;
 - to increase in cordial emission and cardiac index;
 - to increase in a regional blood-groove in muscles.
Perindopril is effective at arterial hypertension of any severity: soft, moderate and heavy. The maximum anti-hypertensive effect develops in 4-6 hours after a single dose inside and remains within a day. The termination of therapy does not lead to development of a syndrome of "cancellation".
Has vasodilating properties and recovers elasticity of large arteries. Addition of tiazidopodobny diuretic strengthens anti-hypertensive (additive) effect of a perindopril.
Indapamid treats sulfonamide derivatives, is diuretic. Inhibits a sodium reabsorption in a cortical segment of renal tubules, increasing allocation by kidneys of sodium and chlorine, leading, thus, to strengthening of a diuresis. To a lesser extent raises excretion of potassium and magnesium. Having ability to selectively block "slow" calcium channels, индапамид increases elasticity of walls of arteries and reduces OPSS. Has hypotensive effect in the doses which do not have the expressed diuretic effect. Increase in a dose of an indapamid does not involve strengthening of anti-hypertensive effect, but increases risk of development of the undesirable phenomena.
Indapamid at patients with arterial hypertension does not exert impact on:
 - metabolism of lipids: TG, LPNP and LPVP,
 - metabolism of carbohydrates, even at patients with a diabetes mellitus and arterial hypertension.

Pharmacokinetics. The combined use of a perindopril and indapamid does not change them pharmacokinetic parameters in comparison with separate reception of these drugs. Perindopril after intake is quickly soaked up from the digestive tract (DT). Bioavailability makes 65-70%. Meal reduces transformation of a perindopril in периндоприлат. An elimination half-life (Т½) the perindoprila makes 1 hour of a blood plasma.
The maximum concentration in a blood plasma is reached in 3-4 hours after intake. As reception with food reduces transformation of a perindopril in периндоприлат and bioavailability of drug, perindoprit it is necessary to accept 1 time a day in the morning, before a breakfast. Accepting perindoprit once a day, equilibrium concentration is reached within 4 days.
In a liver is exposed to metabolism about formation of an active metabolite of a perindoprilat. In addition to an active metabolite of a perindoprilat, perindoprit forms 5 more inactive metabolites. Communication with proteins of a blood plasma of a perindoprilat of a dozozavisim also makes 20%. Perindoprilat easily passes through gistogematichesky barriers, excepting a blood-brain barrier, the insignificant quantity gets through a placenta and into breast milk. It is removed by kidneys, Т½ the perindoprilata makes about 17 hours. Does not kumulirut.
At elderly patients, at patients with renal and heart failure removal of a perindoprilat is slowed down.
At a renal failure it is recommended to reduce a dose of a perindopril depending on severity of a renal failure (clearance of creatinine (CC)).
The dialysis clearance of a perindoprilat makes 70 ml/min.
The kinetics of a perindopril is changed at patients with cirrhosis: the hepatic clearance is reduced half. Nevertheless, the quantity of the formed perindoprilat does not decrease that does not demand dose adjustment.
Indapamid
 It is quickly and almost completely soaked up in a GIT. Meal slows down absorption a little, but significantly does not influence quantity of the absorbed indapamid. The maximum concentration in a blood plasma is reached in 1 hour after intake of a single dose. Contacts proteins of a blood plasma for 79%. Т½ makes from 14 to 24 h (on average, 18 h). Does not kumulirut.
It is metabolized in a liver. It is removed by kidneys (70%) preferential in the form of metabolites (the fraction of not changed drug makes about 5%) and intestines with bile in the form of inactive metabolites (22%). At patients with a renal failure pharmacokinetic parameters of an indapamid significantly do not change.

Indications to use:

Arterial hypertension.

Route of administration and doses:

Inside, once a day, preferably in the morning till a breakfast, washing down with enough liquid.

Doses are given for a ratio indapamid/perindoprit.
Initial dose - on 1 tablet of the drug Co-Perineva® (0,625 mg / 2мг) 1 time a day.
If in 1 month of administration of drug it is not possible to achieve adequate control of the ABP, it is necessary to increase a dose of drug to 1 tablet of the drug Co-Perineva® (1,25 mg / 4мг) 1 time a day.
Elderly patients
 Initial dose-1 tablet on 0,625mg/2mg the drug Ко-Перинева® 1 of times a day.
Patients with a renal failure
 Dose adjustment is not required to patients with a renal failure (KK of 60 ml/min. and more).
For patients with KK of 30-60 ml/min. the maximum dose of the drug Co-Perineva® makes 0,625mg/2mg 1 times a day.
At the expressed renal failure (KK less than 30 ml/min.) therapy by the drug Co-Perineva® is contraindicated (see the section "Contraindications").
Patients with an abnormal liver function
 With moderate abnormal liver functions of correction of doses it is not required from patients.
Children and teenagers
 The drug Co-Perineva® should not be used to children and teenagers up to 18 years as efficiency and safety are not established.

Features of use:

Lithium drugs:
Simultaneous use of the drug Co-Perineva® with lithium drugs is not recommended.
Renal failure
 Therapy by the drug Co-Perinyova® is contraindicated to patients with the expressed renal failure (KK less than 30 ml/min.). Some patients with arterial hypertension without the previous renal failure against the background of therapy by the drug Co-Perineva® can have symptoms of an acute renal failure. In this case treatment by the drug Co-Perineva® should be stopped.
Further it is possible to renew a combination therapy, using low doses of the drug Co-Perineva®, or to use drugs perindoprit and индапамид in monotherapy.
Regular control of content of potassium and creatinine in blood serum after the beginning of therapy and each next 2 months of therapy by the drug Co-Perineva® is necessary every 2 week for such patients.
The acute renal failure develops at patients with heavy HSN or an initial renal failure more often, including, at a bilateral stenosis of renal arteries or a stenosis of an artery of the only functioning kidney.
Administration of drug of Co-Perineva® is not recommended to patients with a bilateral stenosis of renal arteries or a stenosis of an artery of the only functioning kidney.
Decrease in the ABP and disturbance of water and electrolytic balance
 The hyponatremia is connected with risk of sudden decrease in the ABP (especially patients with a bilateral stenosis of renal arteries or a stenosis have arteries of the only functioning kidney). Therefore at dynamic observation of patients it is necessary to pay attention to possible symptoms dehydration and decrease in content of electrolytes in a blood plasma, for example, after long diarrhea or vomiting. Regular control of electrolytes in a blood plasma is necessary for such patients.
At the expressed decrease in the ABP can be required in/in introduction of 0,9% of solution of sodium of chloride.
Passing arterial hypotension is not a contraindication for further continuation of therapy. After recovery of OTsK and the ABP it is possible to resume therapy by the drug Co-Perineva®, applying low doses of drug, or using drugs: perindoprit and индапамид in monotherapy,
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 the combined use of antihypertensives and diuretic regular control of content of potassium in a blood plasma is necessary.
Excipients
 It is necessary to consider that lactose monohydrate therefore drug is contraindicated to patients with a hereditary galactosemia, deficit of lactase, glyukozo-galaktozny malabsorption is a part of excipients of the drug Co-Perineva®. (see the section "Contraindications")

Perindopril
Neutropenia/agranulocytosis
 At the patients accepting APF inhibitors, chances of development of a neutropenia/agranulocytosis, thrombocytopenia and anemia. At patients with normal function of kidneys for lack of other complications the neutropenia develops seldom and passes independently after cancellation of APF inhibitors.
Perindopril it is necessary to apply carefully at patients with diseases of connecting fabric and at the same time receiving immunosuppressive therapy, Allopyrinolum or procaineamide, especially at the existing renal failures. At such patients the heavy infections which are not giving in to an intensive antibioticotherapia can develop. In case of purpose of a perindopril it is recommended to control periodically quantity of leukocytes in blood. The patient has to be warned that in case of any symptoms of an infectious disease (a pharyngalgia, temperature increase) it is necessary to see a doctor immediately.
The increased sensitivity / a Quincke's disease (Quincke's edema)
At reception of APF inhibitors, including perindoprit, development of a Quincke's disease of the person, lips, language, a uvula of the upper sky, and/or a throat in rare instances can be observed. At emergence of these symptoms administration of drug has to be immediately stopped, the patient has to be observed until symptoms of hypostasis do not disappear completely.
If the Quincke's disease affects only a face and lips, then its manifestations usually take place independently or for treatment of its symptoms antihistaminic drugs can be used. The Quincke's disease which is followed by a paraglossa or throats can lead to obstruction of respiratory tracts and by a lethal outcome.
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.
In rare instances against the background of therapy by APF inhibitors the Quincke's disease of intestines develops. At the same time at patients the abdominal pain as the isolated symptom or in combination with nausea and vomiting, in certain cases without the previous Quincke's disease of the Person is noted and at the normal S-1 level - esterases. The diagnosis is established by means of a computer tomography of an abdominal cavity, ultrasonography or at the time of surgical intervention.
Symptoms disappear after the termination of reception of APF inhibitors. At the patients with an abdominal pain 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 holding procedures of desensitization 
 There are separate messages on development of long, life-threatening anaphylactoid reactions in the patients receiving APF inhibitors during the desensibilizing therapy by poison of hymenopterous insects (a bee, a wasp).
APF inhibitors need to be applied with care at the patients inclined to allergic reactions undergoing procedures of desensitization. It is necessary to avoid purpose of APF inhibitor to the patients receiving an immunotherapy poison of hymenopterous insects. Nevertheless, development of anaphylactoid reactions can be avoided by temporary cancellation of APF inhibitor not less than in 24 hours prior to holding a 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 sulfate of a dextran life-threatening anaphylactoid reactions can develop. For prevention of anaphylactoid reaction it is necessary to stop therapy by APF inhibitor before each procedure of an aferez of LPNP with use of high-flowing membranes.
Hemodialysis
 At the patients receiving APF inhibitors when carrying out a hemodialysis with use of high-flowing membranes (for example, AN69®) noted anafilaktodny reactions. Therefore it is desirable to use a membrane of other type or to use hypotensive drug of other pharmakoterapevtichesky group (see the section "With Care").
Kaliysberegayushchy diuretics and drugs of potassium
 Combined use of a perindopril and kaliysberegayushchy diuretics, and also drugs of potassium and kaliysoderzhashchy substitutes of edible salt is not recommended.
Cough
 Against the background of therapy dry cough which disappears after cancellation of drugs of this group can arise APF inhibitor. At emergence 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 of Co-Perineva® can be continued.
Children and teenagers are younger than 18 years
 The drug Co-Perineva® is contraindicated to children and teenagers more young than 18 years due to the lack of data on efficiency and safety of use.
Risk of arterial hypotension and/or renal failure (at patients with HSN, disturbance of water and electrolytic balance, etc.)
At cirrhosis, by followed hypostases and ascites, arterial hypotension, HSN considerable activation the system renin-angiotensin-aldosteronovoy (SRAA) can be noted, especially at the expressed hypovolemia and decrease in content of electrolytes in a blood plasma (against the background of an electrolyte-deficient diet or long reception of diuretics).
Use of APF inhibitor causes blockade of RAAS, in this regard perhaps sharp decrease in the ABP and/or increase in concentration of creatinine in plasma — blood, testimonial of development of an acute renal failure that is more often observed at reception by a weld wignonette of a dose of the drug Co-Perineva® or within the first two weeks of therapy.
Patients of advanced age:
Before administration of drug of Co-Perineva® it is necessary to estimate function of kidneys and content of potassium in a blood plasma. The initial dose of the drug Co-Perineva® is selected depending on extent of decrease in the ABP, especially at reduction of OTsK and HSN (the IV functional class for NYHA classification). 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 at use of the drug Co-Perineva® for patients with coronary heart disease and insufficiency of cerebral circulation. At such patients treatment it is necessary to begin with a dose 0,625 mg / 2 with drug Co-Perineva® mg (an initial dose).
Patients with renovascular hypertensia
 Treatment by the drug Co-Perineva® of patients with the diagnosed or estimated renal artery stenosis should be begun in the conditions of a hospital with a drug dose To - Перинева® 0,625 mg / 2 with mg, controlling function of kidneys and content of potassium in a blood plasma. At some patients the acute renal failure which is reversible after drug withdrawal can develop.
Other risk groups
 At patients with HSN (the IV functional class on NYHA classification) and patients with a diabetes mellitus of 1 type (danger of spontaneous increase in content of potassium) treatment it is necessary to begin with an initial dose 0,625 mg / 2 with mg of the drug Co-Perineva® and under medical control.
Patients with a diabetes mellitus
 At purpose of the drug Co-Perineva® patients with the diabetes mellitus receiving hypoglycemic means for intake or insulin within the first month of therapy need to control regularly concentration of glucose in blood.
Ethnic features
 Perindopril (as well as other APF inhibitors), has less expressed hypotensive effect at patients of negroid race in comparison with representatives of other races.
Surgical interventions / 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 at use of the means for the general anesthesia having hypotensive effect.
It is recommended to stop reception of APF inhibitors, including perindoprit, in 12 hours prior to surgical intervention, having warned the anesthesiologist about use of APF inhibitors.
Aortal stenosis / Mitral stenosis / Hypertrophic subaortic stenosis
 APF inhibitors have to be applied with care at patients with obstruction of an output path of a left ventricle and at an aortal and/or mitral stenosis.
Liver failure
 In rare instances against the background of reception of APF inhibitors there is cholestatic jaundice, three progressing of which the fulminantny necrosis of a liver, sometimes with a lethal outcome develops. At emergence of jaundice or substantial increase of activity of "hepatic" transaminases against the background of reception of APF inhibitors administration of drug of Co-Perineva® should be stopped.
Anemia 
 Anemia can develop at patients after transplantation of a kidney or at the patients who are on a hemodialysis.
Hyperpotassemia
 Can develop in treatment time APF inhibitors including perindoprily.
Risk factors of a hyperpotassemia are the renal failure, advanced age, a diabetes mellitus some the accompanying states (decrease in OTsK, an acute heart failure in decompensation stages, 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 use of other drugs promoting increase in content of potassium in a blood plasma (for example, heparin). The hyperpotassemia can lead to serious violations of a cordial rhythm, sometimes with a lethal outcome. The combined use of the listed above drugs needs to be carried out with care.

Indapamid
Photosensitivity:
There are messages on cases of the increased photosensitivity against the background of reception of thiazide and tiazidopodobny diuretics. At development of reaction of photosensitivity against the background of administration of drug of Co-Perineva® treatment needs to be stopped. If there is a need to resume drug Co-Perineva® use, it is necessary to protect open sites of skin from direct influence of solar and artificial ultraviolet rays.
Water and electrolytic balance.
Content of sodium in a blood plasma
 Prior to treatment it is necessary to determine by the drug Co-Perineva® the content of sodium in a blood plasma and against the background of administration of drug to carry out regular control of electrolytes in a blood plasma. All diuretic means are capable to cause the hyponatremia leading to serious complications.
Content of potassium in a blood plasma
 Therapy by thiazide and tiazidopodobny diuretics is connected with risk of development of a hypopotassemia (less than 3,4 mmol/l) in the following patients: advanced age, the exhausted patients, patients with cirrhosis, patients with peripheral hypostases, ascites, coronary heart disease, HSN. The hypopotassemia at these patients strengthens toxic effect of cardiac glycosides and increases risk of development of arrhythmia.
Patients with the increased QT interval on an ECG treat group of the increased risk. The hypopotassemia, as well as bradycardia, promotes development of heavy disturbances of a cordial rhythm, Especially arrhythmia like "pirouette" which can be lethal. In all described cases regular control of content of potassium in a blood plasma is necessary. The first determination of content of potassium in a blood plasma needs to be carried out within the first week from the beginning of therapy by the drug Co-Perineva®.
Content of calcium in a blood plasma
 Thiazide and tiazidopodobny diuretics reduce calcium removal by kidneys, leading to slight and temporary increase of content of calcium in a blood plasma. The expressed hypercalcemia can be a consequence of the hidden hyperparathyreosis. Before a research of function of epithelial bodies it is necessary to cancel administration of drug of Co-Perineva®.
Concentration of glucose in a blood plasma
 It is necessary to control concentration of glucose at patients with a diabetes mellitus.
Uric acid
 At patients with the increased concentration of uric acid in a blood plasma against the background of therapy with the drug Co-Perineva® the frequency of an aggravation of a course of gout can increase.
Diuretic means and function of kidneys
 The hypovolemia as a result of decrease OTsK or a hyponatremia caused by reception of diuretics in an initiation of treatment the drug Co-Perineva® can lead to reduction in the rate of glomerular filtering and be followed by increase in concentration; creatinine and urea in a blood plasma.
Athletes:
Indapamid can give false positive reaction when carrying out a drug test.

Influence on ability to manage motor transport and other difficult mechanisms:
it is necessary to be careful at control of motor transport and other technical devices requiring special attention and speed of psychomotor reactions.

Side effects:

Classification of frequency of development of side effects of World Health Organization:
very often> 1/10
often from> 1/100 to <1/10
infrequently from> 1/1000 to <1/100
seldom from> 1/10000 to <1/1000
very seldom from <1/10000, including separate messages.
From system of a hemopoiesis and lymphatic system:
Very seldom hemorrhagic vasculitis, hemolitic anemia; at prolonged use in high doses - thrombocytopenia, a leukopenia/neutropenia, an agranulocytosis, aplastic anemia which was registered against the background of reception of APF inhibitors (the patients who are on a hemodialysis or on peritoneal dialysis).
From the central and peripheral nervous system:
Often: paresthesias, headache, dizziness, вертиго, adynamy.
Infrequently: lability of mood, a sleep disorder, the strengthened sweating.
Very seldom: confusion of consciousness.
From sense bodys:
Often: vision disorders, sonitus.
From cardiovascular system:
Often: the expressed decrease in the ABP, orthostatic hypotension.
Very seldom: arrhythmias, including bradycardia, ventricular tachycardia, an atrial flutter, stenocardia, a myocardial infarction or a stroke, perhaps secondary, owing to the expressed arterial hypotension at patients of group of high risk.
From respiratory system:
Often: dry, irritating, persistent character the cough passing after drug withdrawal, an asthma.
Infrequently: bronchospasm.
Very seldom: eosinophilic pneumonia, rhinitis.
From the alimentary system:
Often: a lock, dryness of a mucous membrane of an oral cavity, a loss of appetite, nausea, pain in epigastriums, an abdominal pain, taste changes, vomiting, dyspepsia, diarrhea.
Very seldom: pancreatitis, jaundice (cytolytic or cholestatic).
Frequency is not established: in case of a liver failure there is a probability of development of hepatic encephalopathy, intestinal hypostasis.
From integuments and a hypodermic fatty tissue:
Often: skin itch, makulopapulezny rashes.
Infrequently: Quincke's disease of the person, mucous membranes of an oral cavity, language, uvula of the upper sky, and/or throat, small tortoiseshell; reactions of individual hypersensitivity, generally dermatological, at patients with the burdened allergological anamnesis; purpura; possible aggravation of a current of the system lupus erythematosus (SLE).
Very seldom: multiformny erythema, toxic epidermal necrolysis, Stephens-Johnson's syndrome; isolated cases of reaction of photosensitivity.
From a musculoskeletal system:
Often: muscular spasms.
From an urinary system:
Infrequently: renal failure.
Very seldom: acute renal failure.
From reproductive system and chest glands:
Infrequently: impotence.
Laboratory indicators: hypopotassemia: a hyponatremia with the hypovolemia leading to decrease, the volume of the circulating blood (VCB) and orthostatic hypotension; increase in concentration of uric acid and glucose in blood serum; small increase in concentration of creatinine and urea in a blood plasma, reversible after the therapy termination which develops against the background of a stenosis of renal arteries or a stenosis of an artery of the only kidney, arterial hypertension against the background of therapy by diuretics, at a renal failure more often; passing increase in content of sodium in a blood plasma; hypochloraemia; proteinuria.
Seldom: hypercalcemia.

Interaction with other medicines:

Simultaneous use is not recommended:
Lithium drugs:
at simultaneous use of drugs of lithium and APF inhibitors cases of reversible increase in concentration of lithium in blood serum were registered.
The concomitant use of thiazide diuretics can promote increase in concentration of lithium and risk of its toxic action against the background of APF inhibitor reception.
Concomitant use of kaliysberegayushchy diuretics (such as Spironolactonum, эплеренон, Triamterenum, amiloride), drugs of potassium or kaliysoderzhashchy substitutes of edible salt, and also use of other drugs promoting increase in content of potassium in a blood plasma (for example, heparin).
The simultaneous use of drugs demanding extra care:
Baclofenum: potentiation of hypotensive effect. Control of the ABP, function of kidneys and if necessary dose adjustment of antihypertensives is necessary.
NPVP non-steroidal anti-inflammatory drugs):
Combination of APF inhibitors to NPVP (the TsOG non-selective inhibitors from the NPVP group, for example, acetylsalicylic acid in the doses having antiinflammatory effect; inhibitors of cyclooxygenase-2 (TsOG-2)):
• reduces hypotensive effect of APF inhibitors;
• increases risk of a renal failure, up to development of an acute renal failure
• increases the content of potassium in blood serum at patients with already existing renal failures.
Such combination is recommended to be applied with care, especially at patients of advanced age. Patients have to receive enough liquid, and also carry out control of function of kidneys before and after an initiation of treatment by the drug Co-Perineva®.
The simultaneous use demanding care:
Tricyclic antidepressants, antipsychotic means (neuroleptics):
- strengthen hypotensive effect and increase risk of development of orthostatic hypotension (the additive effect).
Glucocorticosteroids, тетракозактид:
- reduction of hypotensive effect (liquid delay).
Other antihypertensives: strengthening of hypotensive effect of the drug Co-Perineva® is possible.
Perindopril
Simultaneous use is not recommended:
Kaliysberegayushy diuretics (Spironolactonum, Triamterenum, amiloride, эплеренон) and potassium drugs:
- APF inhibitors reduce the potassium loss by kidneys caused by diuretic. At their combined use with APF inhibitors increase in content of potassium in blood serum up to a lethal outcome is possible. If combined use of APF inhibitor and the above-stated drugs 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 simultaneous use demanding extra care:
Hypoglycemic means for intake (sulphonylurea derivatives) and insulin:
- use of APF inhibitors can strengthen hypoglycemic effect of hypoglycemic means for intake and insulin at patients with a diabetes mellitus; at their combined use increase in tolerance to glucose is possible that can demand correction of doses of hypoglycemic means for intake and insulin.
The simultaneous use demanding care:
Allopyrinolum, cytostatic, immunodepressants, glucocorticosteroids (at system use) and procaineamide:
- the concomitant use of these drugs with APF inhibitors can increase risk of development of a leukopenia.
Means for the general anesthesia: APF inhibitors can strengthen hypotensive effect of some means for carrying out the general anesthesia.
Diuretics (thiazide and "loopback"):
- use of diuretics in high doses can lead to a hypovolemia (due to reduction of OTsK), and addition to therapy of a perindopril - to the expressed decrease in the ABP.
Gold drugs:
at purpose of APF inhibitors, including perindoprit, to the patients receiving gold drug (ауротиомалат sodium) in/in, nitratopodobny reactions (nausea, vomiting, the expressed decrease in the ABP, a dermahemia of the person) were noted.

Indapamid
The simultaneous use demanding extra care:
The drugs causing arrhythmia like "pirouette":
because of risk of a hypopotassemia, индапамид it is necessary to apply with care together with the medicines causing arrhythmia like "pirouette" such as: antiarrhytmic means (quinidine, hydroquinidine, Disopyramidum, Amiodaronum, дофетилид, ибутилид, бретилиум, соталол); some neuroleptics (Chlorpromazinum, циамемазин, levomepromazinum, thioridazine, трифлуоперазин), benzamides (амисульприд, сульприд, сультоприд, тиаприд), phenyl propyl ketones (Droperidolum, haloperidol), other neuroleptics (Pimozidum); other substances, such, as: bepridit, цизаприд, difemanit methyl sulfate, erythromycin at intravenous use, галофантрин, мизоластин, moxifloxacin, pentamidine, спарфлоксацин, Vincaminum at intravenous use, methadone, астемизол, терфенадин. It is necessary to control potassium concentration in order to avoid a hypopotassemia at which development it is necessary to carry out its correction, (to ontrolirovat QT interval on an ECG.
The medicines capable to cause a hypopotassemia:
Amphotericinum In at in introduction, glyuko-and mineralokortikoida (at system appointment), тетракозактид, the purgatives stimulating motility of intestines: increase in risk of development of a hypopotassemia (additive effect). Control of potassium concentration 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 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, indicators of an ECG and, if necessary, to adjust a dose of cardiac glycosides.
The simultaneous use demanding care:
Metforminum:
renal failure which can develop against the background of reception of diuretics. At simultaneous use with Metforminum the risk of development of lactic acidosis increases. 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 means:
decrease in OTsK against the background of reception of diuretics, increase in risk of development of an acute renal failure, especially at use of high doses of iodinated contrast means. Before use of iodinated contrast means it is necessary to compensate OTsK.
Calcium drugs:
at simultaneous use development of a hypercalcemia, owing to decrease in removal of calcium kidneys is possible.
Cyclosporine:
increases risk of development of renal failures (giperkreatininemiya).

Contraindications:

• hypersensitivity to active and to excipients of drug;
• a Quincke's disease in the anamnesis (a hereditary, idiopathic or Quincke's disease owing to reception of APF inhibitors (in the anamnesis));
• the expressed renal failure (KK less than 30 ml/min.);
• azotemia; anury;
• bilateral stenosis of renal arteries, stenosis of an artery of the only kidney;
• the chronic heart failure (CHF) in a decompensation stage;
• refractory hyperpotassemia;
• hereditary galactosemia, deficit of lactase, glyukozo-galaktozny malabsorption;
• age up to 18 years (efficiency and safety are not established);
• the expressed liver failure (including with encephalopathy);
• pregnancy, lactation period.
With care:
System 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 blood formation, decrease in the volume of the circulating blood (VCB) (reception of diuretics, an electrolyte-deficient diet, vomiting, diarrhea), stenocardia, cerebrovascular diseases, renovascular hypertensia, a diabetes mellitus, chronic heart failure (the IV functional class on NYHA classifications), the hyperuricemia (which is especially followed by gout and an uratny nephrolithiasis), lability of the ABP, advanced age, a hemodialysis with use of high-flowing poliakrilnitrilovy membranes - risk of development of anaphylactoid reactions; before the procedure of an aferez of lipoproteids of the low density (LPNP), simultaneous performing the desensibilizing therapy by allergens (for example, poison of Hymenoptera); state after transplantation of kidneys, a stenosis of the aortal and/or mitral valve, a hypertrophic subaortic stenosis, a hemodialysis, a concomitant use of the drugs extending QT interval.
Use at pregnancy and in the period of a lactation
 Administration of drug of Co-Perineva® is contraindicated at pregnancy. Use of drug can become the reason of fetoplacental ischemia with risk of delay of fetation.
It is not recommended to use drug during feeding by a breast (индапамид gets into breast milk). In need of drug Co-Perineva® use breastfeeding should be stopped.

Overdose:

Symptoms: the expressed decrease in the ABP, nausea, vomiting, muscular spasms, dizziness, drowsiness, confusion of consciousness, an oliguria up to an anury (owing to decrease in OTsK); disturbances of water and electrolytic balance are possible (low content of sodium and potassium in a blood plasma).
Treatment: a gastric lavage and/or purpose of absorbent carbon, recovery of water and electrolytic balance in the conditions of a hospital. At the expressed decrease in the ABP it is necessary to transfer the patient to situation "lying" on spin with raised head over heels; further it is necessary to hold the events directed to increase in OTsK (introduction of 0,9% of solution of sodium of chloride intravenously). Perindoprilat, an active metabolite of a perindopril, can be brought from an organism by means of dialysis.

Storage conditions:

At a temperature not above 30 °C, in original packaging. To store in the place, unavailable to children. Period of validity 2 years. Not to use drug after expiry date.

Issue conditions:

According to the recipe

Packaging:

Tablets of 0,625 mg + 2 mg, 1,25 mg + 4 mg, 2,5 mg + 8 mg.
On 10 tablets in a blister strip packaging.
On 3, 6 or 9 blister strip packagings together with the application instruction place in a pack from a cardboard.