Baby food "Humana": composition, instructions, reviews. Indications for the appointment of Prestansa, pharmacodynamics, pharmacokinetics, instructions for use Pre instructions for use

INN: Perindopril

Manufacturer: Krka, dd, Novo Mesto

Anatomical-therapeutic-chemical classification: Perindopril

Registration number in the RK: No. RK-LS-5 No. 014922

Registration period: 16.01.2015 - 16.01.2020

Instructions

Tradename

Prenessa®

International non-proprietary name

Perindopril

Dosage form

Tablets 2 mg, 4 mg, 8 mg

Composition

One tablet contains

active substance -perindopril erbumine 2 mg, 4 mg or 8 mg,

excipients: calcium chloride hexahydrate, lactose monohydrate, crospovidone, microcrystalline cellulose, colloidal anhydrous silicon dioxide, magnesium stearate

Description

Round tablets, white or nearly white, slightly biconvex, beveled (for a dosage of 2 mg).

Oval tablets of white or almost white color, slightly biconvex, with a score on one side and a bevel (for a dosage of 4 mg).

Round tablets of white or almost white color, slightly biconvex, with a score on one side and a chamfer (for a dosage of 8 mg).

Pharmacotherapeutic group

Drugs affecting the renin-angiotensin system. Angiotensin-converting enzyme (ACE) inhibitors. Perindopril

ATX code C09AA04

Pharmacological properties

Pharmacokinetics

After oral administration, perindopril is rapidly absorbed, and the maximum concentration in the blood plasma is reached within 1 hour. Bioavailability ranges from 65 to 70%.

About 20% of taken perindopril is converted to perindoprilat, an active metabolite. In addition to the active metabolite, 5 more inactive metabolites of the drug were identified. The half-life (T1 / 2) of perindopril is 1 hour. The maximum concentration (Cmax) of perindoprilat in the blood plasma is reached within 3 to 4 hours.

Simultaneous food intake slows down the conversion of perindopril to perindoprilat, and, therefore, bioavailability decreases, therefore, perindopril should be taken orally, once a day, before breakfast.

The volume of distribution is approximately 0.2 L / kg for unbound perindoprilat. Protein binding is negligible (binding of perindoprilat to angiotensin converting enzymes is less than 30%), but it depends on the concentration.

Perindoprilat is excreted in the urine and T1 / 2 of the unbound fraction is approximately 3 to 5 hours. The disintegration of perindoprilat associated with ACE leads to an increase in effective T1 / 2 up to 25 hours. With repeated administration of the drug, stabilization of pharmacokinetic parameters is achieved within 4 days. After repeated administration, no accumulation of perindopril occurred.

In elderly patients and in patients with cardiac or renal failure excretion of perindoprilat decreases. In case of impaired renal function, it is recommended to change the dose depending on the severity

violations (level of creatinine clearance).

Perindoprilat is eliminated from the circulation by dialysis, its clearance is 70 ml / min.

With cirrhosis of the liver, the kinetics of perindopril changes, while the hepatic clearance of the initial molecule is reduced by 2 times, however, the amount of perindoprilat formed does not change, and therefore, in this disease, the dose of the drug can not be changed.

Pharmacodynamics

Prenessa® is an angiotensin converting enzyme (ACE) inhibitor. The converting enzyme, kinase, is an oxopeptidase that promotes the conversion of angiotensin I to angiotensin II and destroys the vasodilator bradykinin to an inactive hectapeptide. ACE inhibition leads to a decrease in the formation of angiotensin II in plasma, which is accompanied by an increase in renin activity in blood plasma (due to inhibition of negative feedback) and a decrease in aldosterone secretion. Since ACE inactivates bradykinin, suppression of ACE is accompanied by an increase in the activity of both the circulating and tissue kallikrein-kinin systems (the prostaglandin system is activated). Perhaps this particular

mechanism promotes action aCE inhibitorwhich lowers blood pressure and partially contributes to the appearance of some side effects (for example, cough).

Perindopril acts through its active metabolite, perindoprilat.

Arterial hypertension

Prenessa® is effective at any stage of arterial hypertension: mild, moderate, severe; with a decrease in systolic and diastolic blood pressure (in the "lying" and "standing" position). Prenessa® reduces the total peripheral vascular resistance, which leads to a systemic decrease in blood pressure. In this case, peripheral blood flow is accelerated, but the heart rate (HR) does not increase.

Renal blood flow increases, but the glomerular filtration rate does not change. After taking single dose, the maximum antihypertensive effect is achieved after 4 to 6 hours and lasts at least 24 hours; the residual effect is 87-100% of the maximum effect. The drop in blood pressure occurs quickly. In patients with a good response to treatment, normalization is achieved within a month and persists without the occurrence of tachyphylaxis. Interruption of treatment is not accompanied by a withdrawal syndrome.

Perindopril reduces left ventricular hypertrophy.

Perindopril has a vasodilating effect, improves the elasticity of large arteries and reduces the medium / lumen ratio of small arteries. Additional therapy with thiazide diuretics enhances the effect. The combination of an ACE inhibitor and thiazide diuretics also reduces the risk of hypokalemia while taking diuretics.

Heart failure

Prenessa® reduces the work of the heart by reducing pre- and afterload.

In patients with heart failure, Prenessa® reduces filling pressure in the right and left ventricles, reduces total peripheral vascular resistance , increases cardiac index and cardiac output.

Patients with history of cerebrovascular disease

In patients with a history of cerebrovascular diseases (stroke or transient ischemic episodes in the last 5 years), Prenessa® helps to reduce the risk of recurrent stroke (both ischemic and hemorrhagic) by 28%. It was also found that perindopril, in general, reduces the risk of developing: fatal or disabling strokes (by 33%), cardiovascular complications such as death, nonfatal myocardial infarction and nonfatal stroke (by 26%), dementia, associated with stroke (34%), severe cognitive impairment (45%), major coronary events, including nonfatal myocardial infarction and mortality from ischemic disease hearts (by 26%).

These therapeutic benefits have been observed in both patients with arterial hypertensionand in patients with normal blood pressureregardless of age, gender, presence or absence of diabetes and type of stroke. It was found that active therapy for 5 years avoids the development of one stroke in 23 patients and one significant cardiovascular complication in 18 patients.

Patients with stable coronary artery disease:

In patients with signs of coronary artery disease without clinical signs heart failure who received perindopril at a dose of 8 mg 1 time per day, in addition to conventional therapy (including platelet inhibitors, lipid-lowering drugs and beta-blockers), there was a significant absolute decrease in the primary endpoint by 1.9% (a decrease in the relative risk of development by 20 %, 95% CI - p<0,001), у пациентов с инфарктом миокарда и / или реваскуляризацией в анамнезе, абсолютное снижение на 2.2%, (снижение относительного риска на 22.4% (95% ДИ - р <0,001) по сравнению с плацебо.

Indications for use

Arterial hypertension:

Hypertension treatment

Heart failure:

Treating symptomatic heart failure

Stable coronary artery disease:

Reducing the risk of cardiovascular complications in patients with a history of myocardial infarction and / or revascularization.

Prevention recurrent stroke (as part of complex therapy with indapamide) in patients withhistory of cerebrovascular disease, stroke or transient cerebralischemic attack

Method of administration and dosage

Prenessa® tablets should be taken before meals, once a day, in the morning.

The dose is selected individually for each patient, depending on the patient's condition and blood pressure level.

Arterial hypertension

Prenessa® can be used alone or in combination with other antihypertensive drugs.

Patients with an activated renin-angiotensin-aldosterone system (in particular, with renovascular hypertension, with a decrease in the volume of intercellular fluid and / or salt, with heart failure or severe hypertension) may experience an excessive decrease in blood pressure after the first dose. For such patients, the recommended starting dose of Prenessa® is 2 mg and the initiation of treatment should be carried out under medical supervision.

After 1 month of treatment, the dose can be increased to 8 mg per day.

At the beginning of treatment with Prenessa®, especially in patients receiving diuretics, symptomatic arterial hypotension may develop, therefore, the drug should be prescribed with caution to such patients, since they may experience a decrease in the volume of intercellular fluid and / or salt; if possible, you should stop taking diuretics 2-3 days before starting therapy with perindopril.

In hypertensive patients who cannot be discontinued with diuretics, treatment with perindopril should be started with a dose of 2 mg. Renal function and plasma potassium levels should be monitored. Subsequent doses of perindopril should be adjusted depending on the patient's blood pressure response. If necessary, diuretic therapy can be resumed.

Treatment of elderly patients should be started with a dose of 2 mg, which can be gradually increased to 4 mg, and if necessary, after a month, up to 8 mg, depending on renal function (see table below).

Symptomatic heart failure

Perindopril, combined with non-potassium-sparing diuretics and / or digoxin and / or a beta-blocker, is recommended for use under close medical supervision with a recommended starting dose of 2 mg taken in the morning. With good tolerance, the dose can be increased by 2 mg at intervals of at least 2 weeks to 4 mg once a day.

Dose adjustments should be based on the clinical response of each patient. In severe heart failure and in patients at increased risk (patients with impaired renal function and a tendency to electrolyte disturbances, patients receiving concomitant treatment with diuretics and / or vasodilating drugs), treatment should be started under close supervision.

Patients with an increased risk of developing symptomatic hypotension (patients with salt deficiency, with or without hyponatremia, patients with hypovolemia, or patients receiving vigorous diuretic therapy), before starting treatment with perindopril, should correct these conditions, if possible, before starting treatment with perindopril. Both before and during treatment with perindopril, blood pressure, renal function and plasma potassium should be carefully monitored.

:

Perindopril should be administered at a dose of 4 mg once a day for

two weeks, then increase to 8 mg once a day, depending on renal function, and provided that the 4 mg dose is well tolerated by the patient.

Elderly patients should be prescribed the drug at a dose of 2 mg once a day for the first week, then 4 mg once a day the next week before increasing the dose to 8 mg once a day, depending on renal function (see table below) ... The dose should be increased only if the previous lower doses of the drug are well tolerated.

Prevention recurrent stroke

The initial dose of perindopril in patients with a history of cerebrovascular disease is 2 mg per day. After two weeks, the dose should be increased to 4 mg per day and applied for another two weeks before indapamide is prescribed. Treatment can be started at any time, from two weeks to several years after the first stroke.

Dose adjustment with renal failure

Dosage in patients with renal impairment should be based on creatinine clearance as indicated in the table below:

Table: Dose adjustment for renal failure.

* Dialysis clearance of perindopril is 70 ml / min.

For patients on hemodialysis, the dose should be given after the dialysis procedure.

Dose adjustment with liver failure

When administered to patients with impaired liver function, dose adjustment is not required.

Application in pediatrics

The efficacy and safety of the drug in children has not been established, therefore, the use of the drug in children is not recommended.

Side effects

Often (from 1/100 to<1/10)

Headache, dizziness, vertigo and paresthesia

Visual impairment

Noise in ears

Hypotension and effects associated with hypotension

Cough, shortness of breath

Nausea, vomiting, abdominal pain, dysgeusia, dyspepsia, diarrhea, constipation

Rash, itching

Muscle cramps

Asthenia

Infrequently (from 1 / 1,000 to<1/100)

Sleep disturbances or mood swings

Bronchospasm

Dry mouth

Angioneurotic edema of the face, limbs, lips, mucous membranes, tongue,

Renal failure

Impotence

Sweating

Rarely (from 1 / 10,000 do <1/1,000)

- decreased hemoglobin and hematocrit, thrombocytopenia,

leukopenia / neutropenia, agranulocytosis, or pancytopenia

Very rarely (<1/10,000), в единичных случаях (cannot be estimated based on available data)

- confusion

Arrhythmia, angina pectoris, myocardial infarction, and stroke, possibly secondary

in relation to excessive hypotension in high-risk patients

Eosinophilic pneumonia, rhinitis

Pancreatitis

Hepatitis (cytolytic or cholestatic)

Erythema multiforme

Acute renal failure

Hemolytic anemia (in patients with congenital G-6PDH deficiency)

Research:

Increases in blood urea and creatinine levels in blood plasma, as well as hyperkalemia, reversible after discontinuation of the drug, may occur, especially in patients with renal failure, severe heart failure, and renovascular hypertension. Increases in liver enzymes and plasma bilirubin have been reported on rare occasions.

Contraindications

hypersensitivity to perindopril and other constituents of the drug or any other ACE inhibitor

history of angioneurotic edema during therapy with ACE inhibitors

hereditary or idiopathic angioedema

pregnancy and lactation

Drug interactions

Patients taking diuretics, and especially patients with fluid and / or salt deficiencymay experience an excessive decrease in blood pressure after starting therapy with an ACE inhibitor. The antihypertensive effect can be reduced by stopping diuretics, increasing salt and fluid intake before starting therapy with low and progressive doses of perindopril.

Although plasma potassium levels usually remain within the normal range, hyperkalemia may occur in some patients treated with perindopril. Application toali-sparing diuretics (spironolactone, triamterene or amiloride), potassiumadditives or potassium-containingsubstitutes salt can lead to a significant increase in the level of potassium in the blood plasma. Therefore, the combination of perindopril with the aforementioned drugs is not recommended, but if simultaneous use is necessary due to hypokalemia, they must be used with caution, and with frequent monitoring of the level of potassium in the blood plasma.

With simultaneous use lithium and ACE inhibitors, reversible increases in plasma lithium concentrations and toxicity have been reported. Concomitant use with thiazide diuretics may increase the risk of lithium toxicity and lead to an even greater increase in the risk of lithium toxicity when used with ACE inhibitors. The simultaneous use of perindopril with lithium is not recommended, but if combined treatment is necessary, close monitoring of the lithium level in the blood plasma should be carried out

Papplication nonsteroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid in a dose 3 g / daymay reduce the antihypertensive effect of ACE inhibitors. In addition, NSAIDs and ACE inhibitors have an additive effect on increasing plasma potassium levels, which can lead to impaired renal function. These effects are usually reversible. In rare cases, acute renal failure may occur, especially in patients with impaired renal function (elderly patients or patients with hypovolemia).

The simultaneous use of antihypertensive drugs and vasodilators may increase the hypotensive effect of perindopril. Concomitant use with nitroglycerin, other nitrates or other vasodilators may further lower blood pressure.

The simultaneous use of ACE inhibitors and antidiabetic drugs (insulin, oral hypoglycemic drugs), can cause an increased hypoglycemic effect with the risk of hypoglycemia. This phenomenon is more often observed during the first weeks of combination treatment and in patients with renal insufficiency.

Perindopril can be used in combination with acetylsalicylic acid (when used as a thrombolytic agent), thrombolytics and beta-blockers and / or nitrates.

Simultaneous application certain anesthetics, tricyclic antidepressants, and antipsychotics with ACE inhibitors may further lower blood pressure.

Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.

special instructions

Stable coronary artery disease

In case of an episode of unstable angina pectoris during the first month of therapy with perindopril, a careful analysis of the benefit / risk ratio should be carried out before continuing treatment.

Hypotension ACE inhibitors can lower blood pressure. Symptomatic hypotension rarely develops in patients with uncomplicated hypertension, and develops in patients with reduced circulating blood volume, due to diuretic therapy, with a strict salt-free diet, hemodialysis, with vomiting and diarrhea, and in patients with severe renin-dependent arterial hypertension ... Symptomatic arterial hypotension occurs in patients with symptomatic heart failure, both in the presence of concomitant renal failure and in its absence. This is most often seen in patients with more severe heart failure receiving high-dose loop diuretics, hyponatremia, or renal impairment. In patients with an increased risk of developing symptomatic arterial hypotension, treatment should be initiated and the dose adjusted under close medical supervision.

A similar approach is also used in patients with ischemic heart disease or with cerebrovascular diseases, in whom severe arterial hypotension can lead to the development of myocardial infarction or cerebrovascular complications.

If arterial hypotension develops, the patient should be transferred to the supine position and, if necessary, intravenous saline should be administered. A transient hypotensive reaction is not a contraindication to taking subsequent doses, which can usually be taken without complications if blood pressure rises after an increase in blood volume.

In the case of patients with congestive heart failure, with normal or low blood pressure, taking perindopril can lead to an even greater decrease in systemic blood pressure. This effect can be expected and is not a reason for stopping treatment. If hypotension becomes chronic, it may be necessary to reduce the dose or stop taking perindopril.

Aortic and mitral valve stenosis, hypertrophic cardiomyopathy

As with other ACE inhibitors, perindopril should be used with caution in patients with mitral valve stenosis or obstruction of the left ventricular outflow tract (eg, aortic stenosis or hypertrophic cardiomyopathy).

Impaired kidney function

In cases of impaired renal function (creatinine clearance<60 мл / мин), начальную дозу периндоприла следует скорректировать в зависимости от клиренса креатинина, а также в зависимости от реакции пациента на лечение. Постоянный контроль уровня калия в плазме крови и креатинина являются частью нормальной медицинской практики для этих пациентов.

In patients with symptomatic heart failure, hypotension resulting from treatment with ACE inhibitors may further worsen renal impairment. In this situation, acute renal failure has been reported to be usually reversible.

In some patients with bilateral renal artery stenosis or stenosis of an artery of a single functioning kidney treated with ACE inhibitors, increases in blood urea and plasma creatinine levels have been observed, which are usually reversible after discontinuation of therapy. This can be especially the case in patients with renal insufficiency. With renovascular arterial hypertension, there is an increased risk of severe arterial hypotension and renal failure. Treatment of such patients begins under close medical supervision with the appointment of the drug in small doses and further adequate selection of the dose. Since diuretic treatment may be a contributing factor to the above, during the first few weeks of perindopril therapy, diuretic treatment should be discontinued and renal function monitored.

Havein some hypertensive patients with invisible signs of pre-existing renal vascular disease, increases in blood urea and plasma creatinine levels have appeared, usually insignificant and transient, especially when perindopril is taken concomitantly with diuretics. This is more likely to occur in patients with chronic renal failure. In this case, a dose reduction and / or discontinuation of diuretics and / or perindopril may be required.

Patients on hemodialysis

The occurrence of anaphylactoid reactions has been reported among patients on hemodialysis using high-flow membranes and simultaneously taking ACE inhibitors. In these patients, consideration should be given to using a different type of membrane for dialysis or another antihypertensive agent.

Kidney transplant

There are no data on the use of perindopril in patients who have recently undergone kidney transplantation.

Hypersensitivity / angioedema

Among patients taking ACE inhibitors, including perindopril, the development of angioedema of the face, limbs, lips, mucous membranes, tongue, glottis and / or larynx has been reported rarely. This can happen at any time during treatment. In such cases, treatment with perindopril should be discontinued and appropriate measures taken to ensure complete disappearance of symptoms in the patient. Angioedema of the face and lips usually does not require treatment, and antihistamines may be used to relieve the patient's symptoms.

Angioneurotic edema in the larynx region can be fatal. If swelling of the tongue, glottis or larynx threatens the development of airway obstruction, it is necessary to carry out emergency therapy as soon as possible, which includes the introduction of an adrenaline solution, and to take measures to ensure airway patency. The patient should be under close medical supervision until the symptoms disappear completely and sustainably.

Patients with a history of Quincke's edema, not associated with therapy with ACE inhibitors, may be at increased risk of angioedema if taking ACE inhibitors.

Anaphylactoid reactions during apheresis ​​ low density lipoprotein (LDL)

In patients receiving ACE inhibitors during apheresis of low density lipoprotein (LDL) with dextran sulfate, in rare cases, life-threatening anaphylactoid reactions are possible. The development of these reactions can be avoided by temporarily canceling the ACE inhibitor before each apheresis procedure.

Anaphylactoid reactions at desensitization

Patients who received ACE inhibitors during a course of desensitization (for example, hymenoptera venom) experienced anaphylactoid reactions. The development of these reactions in these same patients could have been avoided by temporarily discontinuing the ACE inhibitor, however, they appear after inadvertent re-administration of the drug.

Liver failure

During therapy with ACE inhibitors, in rare cases, a syndrome may develop that begins with cholestatic jaundice and then progresses to fulminant liver necrosis and (sometimes) with a fatal outcome. The mechanism for the development of this syndrome is unclear. If jaundice or an increase in liver enzyme levels occurs while taking an ACE inhibitor, the drug taken should be discontinued immediately, and the patient should be under close medical supervision.

Neutropenia/ agranulocytosis /thrombocytopenia / anemia

In patients taking ACE inhibitors, cases of neutropenia / agranulocytosis, thrombocytopenia and anemia have been noted. In patients with normal renal function in the absence of other complications, neutropenia is rare.

Perindopril should be used very carefully in patients with collagens of vascular diseases, patients receiving immunosuppressive therapy, allopurinol or procainamide, as well as with a combination of these factors, especially with existing renal dysfunction. Some of these patients may develop severe infections that do not respond to intensive antibiotic therapy. When prescribing perindopril to such patients, it is recommended to periodically monitor the number of leukocytes in the blood and the patient should be warned that in case of any signs of infection, it is necessary to immediately consult a doctor. There have been reports of sporadic cases of hemolytic anemia in patients with congenital G6-PD deficiency.

Racial differences

The use of angiotensin-converting enzyme inhibitors in dark-skinned patients results in a higher level of angioedema than in other patients.

Like other angiotensin-converting enzyme inhibitors, perindopril is less effective in lowering blood pressure in dark-skinned people than in others, possibly due to more

high prevalence of low-renin status among black populations with hypertension.

CoughDuring treatment with ACE inhibitors, a persistent, unproductive cough may occur, which disappears after stopping therapy. ACE inhibitor cough should be considered as part of the differential cough diagnosis.

Operation / anesthesia

In patients undergoing major surgery, or during general anesthesia with antihypertensive drugs, perindopril can block the formation of angiotensin II, secondary to compensatory renin release. Treatment should be stopped one day before surgery. If the doctor suspects hypotension due to this mechanism, treatment may be aimed at increasing the volume of circulating blood.

HyperkalemiaIn some patients, plasma potassium levels may rise during treatment with ACE inhibitors, including perindopril. Patients with renal insufficiency, uncontrolled diabetes mellitus are at increased risk of developing hyperkalemia; patients who are simultaneously taking potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes; or patients taking other drugs that can cause hyperkalemia (such as heparin). If it is advisable to use enalapril at the same time with any of the above agents, it is recommended to regularly monitor the level of potassium in the blood plasma.

Patients with diabetes mellitus

In patients with diabetes mellitus receiving oral antidiabetic drugs or insulin, glycemic control of blood sugar must be carefully monitored during the first month of treatment with ACE inhibitors.

Information on excipients

Prenessa® tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption syndrome should not take this drug.

Use in pediatrics

The efficacy and safety of using the drug in children has not been established, and therefore the administration of the drug to children is not recommended.

Influence on the ability to drive vehicles and potentially dangerous mechanisms

Care should be taken when driving vehicles and working with potentially dangerous mechanisms due to the possible development of dizziness.

Overdose

Symptoms: acute hypotension, bradycardia, dizziness, anxiety, cough, electrolyte disturbances, renal failure, shock state.

Treatment: giving a horizontal position, intravenous administration of saline, gastric lavage with adsorbents and sodium sulfate within 30 minutes after taking the drug, infusion of angiotensin II and / or catecholamines. In the event of an overdose, the patient should be monitored closely, preferably in an intensive care unit. The content of electrolytes and creatinine in the patient's serum should be constantly monitored. If necessary, cardiac stimulation. Perindopril can be removed from the systemic circulation by hemodialysis (avoid the use of high-flow polyacrylonitrile membranes).

Release form and packaging

Combined antihypertensive drug (ACE inhibitor + slow calcium channel blocker)

Active ingredients

Release form, composition and packaging

Pills white, oblong, biconvex, engraved "5/5" on one side and the company logo - another.

Excipients: microcrystalline cellulose - 26 mg, lactose monohydrate - 65.233 mg, magnesium stearate - 0.52 mg, colloidal anhydrous silicon dioxide - 0.312 mg.

Hospital packaging:

Pills white, square, biconvex, engraved "5/10" on one side and company logo - another.

Excipients: microcrystalline cellulose - 52 mg, lactose monohydrate - 135.466 mg, magnesium stearate - 1.04 mg, colloidal anhydrous silicon dioxide - 0.624 mg.

29 pcs. - polypropylene bottles with a dispenser and a stopper containing a moisture-absorbing gel (1) - cardboard packs with first opening control.
30 pcs. - polypropylene bottles with a dispenser and a stopper containing a moisture-absorbing gel (1) - cardboard packs with first opening control.

Hospital packaging:
30 pcs. - polypropylene bottles with a dispenser and a stopper containing a moisture-absorbing gel (3) - cardboard packs with first opening control.

Pills white, triangular, biconvex, engraved "10/5" on one side and company logo - another.

Excipients: microcrystalline cellulose - 52 mg, lactose monohydrate - 137.401 mg, magnesium stearate - 1.04 mg, colloidal anhydrous silicon dioxide - 0.624 mg.

29 pcs. - polypropylene bottles with a dispenser and a stopper containing a moisture-absorbing gel (1) - cardboard packs with first opening control.
30 pcs. - polypropylene bottles with a dispenser and a stopper containing a moisture-absorbing gel (1) - cardboard packs with first opening control.

Hospital packaging:
30 pcs. - polypropylene bottles with a dispenser and a stopper containing a moisture-absorbing gel (3) - cardboard packs with first opening control.

Pills white, round, biconvex, engraved "10/10" on one side and company logo - another.

Excipients: microcrystalline cellulose - 52 mg, lactose monohydrate - 130.466 mg, magnesium stearate - 1.04 mg, colloidal anhydrous silicon dioxide - 0.624 mg.

29 pcs. - polypropylene bottles with a dispenser and a stopper containing a moisture-absorbing gel (1) - cardboard packs with first opening control.
30 pcs. - polypropylene bottles with a dispenser and a stopper containing a moisture-absorbing gel (1) - cardboard packs with first opening control.

Hospital packaging:
30 pcs. - polypropylene bottles with a dispenser and a stopper containing a moisture-absorbing gel (3) - cardboard packs with first opening control.

pharmachologic effect

Pharmacodynamics

Perindopril

Perindopril is an inhibitor of the enzyme that converts angiotensin I to angiotensin II (ACE inhibitor). ACE, or kininase II, is an exopeptidase that performs both the conversion of angiotensin I into the vasoconstrictor substance angiotensin II and the breakdown of bradykinin, which has a vasodilating effect, to an inactive heptapeptide.

Since ACE inactivates bradykinin, suppression of ACE is accompanied by an increase in the activity of both the circulating and tissue kallikrein-kinin systems, while the prostaglandin system is also activated.

Perindopril has a therapeutic effect due to its active metabolite, perindoprilat. Other metabolites do not inhibit ACE in vitro.

Arterial hypertension

Perindopril is a drug for the treatment of arterial hypertension of any severity. Against the background of its use, there is a decrease in both systolic and diastolic blood pressure in the supine and standing positions. Perindopril reduces the OPSS, which leads to a decrease in blood pressure and an improvement in peripheral blood flow without changing heart rate.

As a rule, taking perindopril increases renal blood flow, while the glomerular filtration rate does not change.

The antihypertensive effect of the drug reaches a maximum 4-6 hours after a single oral administration and lasts for 24 hours.

The antihypertensive effect 24 hours after a single oral administration is about 87-100% of the maximum antihypertensive effect. A decrease in blood pressure is achieved quickly enough.

The therapeutic effect occurs less than 1 month after the start of therapy and is not accompanied by tachyphylaxis. Termination of treatment does not cause a "rebound" effect. Perindopril has a vasodilating effect, helps to restore the elasticity of large arteries and the structure of the vascular wall of small arteries, and also reduces left ventricular hypertrophy.

Stable ischemic heart disease

The efficacy of perindopril in patients (12,218 patients over 18 years of age) with stable coronary artery disease without clinical symptoms of chronic heart failure was studied in a 4-year study. 90% of the study participants had previous acute myocardial infarction and / or revascularization procedure.

The majority of patients received, in addition to the study drug, standard therapy, including antiplatelet agents, lipid-lowering drugs, etc. A combined endpoint of cardiovascular mortality, nonfatal myocardial infarction, and / or cardiac arrest with successful resuscitation was chosen as the main efficacy criterion.

Therapy with perindopril tert-butylamine at a dose of 8 mg 1 time / day (equivalent to 10 mg of perindopril arginine) led to a significant decrease in the absolute risk in relation to the combined endpoint by 1.9%; in patients who had previously undergone myocardial infarction and / or the revascularization procedure, the decrease in the absolute risk was 2.2% compared to placebo group.

Double blockade of RAAS

There are data from clinical trials of combination therapy with an ACE inhibitor and an angiotensin II receptor antagonist (ARA II).

A clinical study was conducted with the participation of patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus, accompanied by confirmed target organ damage, as well as studies involving patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies did not reveal a significant positive effect of combination therapy on the occurrence of renal and / or cardiovascular events and on mortality rates, while the risk of developing hyperkalemia, acute renal failure and / or arterial hypotension increased compared with monotherapy.

Taking into account the similar intragroup pharmacodynamic properties of ACE inhibitors and ARA II, these results can be expected for the interaction of any other drugs, representatives of the classes of ACE inhibitors and ARA II.

Therefore, the use of ACE inhibitors in combination with angiotensin II receptor antagonists in patients with diabetic nephropathy is contraindicated.

There is evidence from a clinical study examining the positive effect of adding aliskiren to standard therapy with an ACE inhibitor or ARA II in patients with type 2 diabetes and chronic kidney disease or cardiovascular disease, or with a combination of these diseases. The study was terminated early due to the increased risk of adverse outcomes. Cardiovascular death and stroke were more frequent in the aliskiren group than in the placebo group; also adverse events and serious adverse events of special interest (hyperkalemia, arterial hypotension and renal dysfunction) were recorded more often in the aliskiren group than in the placebo group.

Amlodipine

Amlodipine is a slow calcium channel blocker, a dihydropyridine derivative. Amlodipine inhibits the transmembrane transition of calcium ions into cardiomyocytes and smooth muscle cells of the vascular wall.

The antihypertensive effect of amlodipine is due to a direct relaxing effect on the smooth muscle cells of the vascular wall. The detailed mechanism by which amlodipine exerts its antianginal action is not fully understood, but amlodipine is known to reduce total ischemic stress through two actions:

Causes expansion of peripheral arterioles, decreasing OPSS (afterload). Since the heart rate does not change, the myocardial oxygen demand decreases;

It causes expansion of coronary arteries and arterioles in both ischemic and intact areas. Their dilation increases the flow of oxygen to the myocardium in patients with vasospastic angina (Prinzmetal's angina, or variant angina).

In patients with arterial hypertension, taking amlodipine 1 time / day provides a clinically significant decrease in blood pressure in the standing and lying position for 24 hours. The antihypertensive effect develops slowly, and therefore the development of acute arterial hypotension is uncharacteristic.

In patients with angina pectoris, taking amlodipine 1 time / day increases the total time of physical activity, increases the time until the onset of an angina attack and before the appearance of ST segment depression by 1 mm, and also reduces the frequency of angina attacks and sublingual consumption.

Amlodipine does not have adverse metabolic effects and does not affect plasma lipid concentration. The drug can be used in patients with concomitant bronchial asthma, diabetes mellitus and gout.

The results of the efficacy assessment indicate that the use of amlodipine is characterized by a smaller number of hospitalizations for angina pectoris and revascularization procedures in patients with coronary artery disease.

Heart failure

The results of hemodynamic studies, as well as the results of clinical studies involving patients with chronic heart failure of FC II-IV according to the NYHA classification, have demonstrated that amlodipine does not lead to clinical deterioration, based on data on exercise tolerance, left ventricular ejection fraction and clinical symptoms.

In patients with chronic heart failure of FC III-IV according to the NYHA classification, while taking digoxin, diuretics and ACE inhibitors, it was shown that taking amlodipine does not lead to an increased risk of mortality or mortality and morbidity associated with heart failure.

The results of long-term studies in patients with chronic heart failure of III and IV FC according to the NYHA classification without clinical symptoms of coronary artery disease or objective data indicating the presence of coronary artery disease, while taking stable doses of ACE inhibitors, cardiac glycosides and diuretics, showed that taking amlodipine does not affect mortality rate from cardiovascular diseases. In this patient population, the use of amlodipine was accompanied by an increase in the number of reports of the development of pulmonary edema.

Prevention of myocardial infarction

The efficacy and safety of the use of amlodipine at a dose of 2.5-10 mg / day, the ACE inhibitor lisinopril at a dose of 10-40 mg / day and the thiazide diuretic chlorthalidone at a dose of 12.5-25 mg / day as a first-line drug was studied in patients with mild or moderate severity. Hypertension and at least one of the additional risk factors for coronary complications, such as myocardial infarction or stroke, suffered more than 6 months before enrollment in the study, or other confirmed cardiovascular disease of atherosclerotic genesis; diabetes; HDL cholesterol concentration less than 35 mg / dL; left ventricular hypertrophy by ECG or echocardiography; smoking.

The main criterion for evaluating the effectiveness is a combined indicator of the incidence of deaths from coronary heart disease and the incidence of nonfatal myocardial infarction. There were no significant differences between the groups of amlodipine and chlorthalidone in terms of the main assessment criterion. The incidence of heart failure in the amlodipine group was significantly higher than in the chlorthalidone group - 10.2% and 7.7%, respectively, the overall mortality rate in the amlodipine and chlorthalidone group did not differ significantly.

Perindopril and amlodipine

Efficacy with long-term use of amlodipine in combination with perindopril and atenolol in combination with bendroflumethiazide in patients aged 40 to 79 years with hypertension and at least 3 of the additional risk factors, such as left ventricular hypertrophy on ECG or echocardiography; type 2 diabetes mellitus; peripheral arterial atherosclerosis; a previous stroke or transient ischemic attack; male gender; age 55 and older; microalbuminuria or proteinuria; smoking; total cholesterol / HDL cholesterol ≥ 6; early development of coronary artery disease in close relatives, was studied in the ASCOT-BPLA study.

The main criterion for evaluating the effectiveness is a combined indicator of the incidence of nonfatal myocardial infarction (including painless) and lethal outcomes of coronary heart disease.

The incidence of complications, provided for by the main assessment criterion, in the amlodipine / perindopril group was 10% lower than in the atenolol / bendroflumethiazide group, but this difference was not statistically significant. In the amlodipine / perindopril group, there was a significant decrease in the incidence of complications provided for by the additional criteria for effectiveness (except for fatal and nonfatal heart failure).

Pharmacokinetics

The amount of absorption of perindopril and amlodipine when using the drug Prestans does not differ significantly from that when using monopreparations.

Perindopril

Suction

When taken orally, perindopril is rapidly absorbed, C max in blood plasma is reached within 1 hour. T 1/2 of perindopril from blood plasma is 1 hour.

Perindopril has no pharmacological activity. Approximately 27% of the total amount of perindopril taken orally enters the bloodstream as the active metabolite of perindoprilat. In addition to perindoprilat, 5 more metabolites are formed that do not have pharmacological activity. C max of perindoprilat in blood plasma is achieved 3-4 hours after oral administration. Food intake slows down the conversion of perindopril to perindoprilat, thus affecting bioavailability. Therefore, the drug should be taken 1 time / day, in the morning, before meals.

Distribution

There is a linear dependence of the concentration of perindopril in blood plasma from its dose. The V d of free perindoprilat is approximately 0.2 l / kg. The connection of perindoprilat with blood plasma proteins, mainly with ACE, is about 20% and is dose-dependent.

Withdrawal

Perindoprilat is excreted by the kidneys. The final T 1/2 of the free fraction is about 17 hours, so the equilibrium state is reached within 4 days.

Excretion of perindoprilat is slowed down in old age, as well as in patients with heart and renal failure (see section "Dosage regimen"). Therefore, in these groups of patients, it is necessary to regularly monitor the concentration of creatinine and potassium in the blood plasma.

The dialysis clearance of perindoprilat is 70 ml / min.

The pharmacokinetics of perindopril is impaired in patients with liver cirrhosis: its hepatic clearance is halved. However, the amount of perindoprilat formed does not decrease, which does not require dose adjustment (see section "Dosing regimen" and "Special instructions").

Amlodipine

Suction

After oral administration, amlodipine is slowly absorbed from the gastrointestinal tract. Food intake does not affect the bioavailability of amlodipine. C max of amlodipine in blood plasma is achieved 6-12 hours after taking the drug inside. The absolute bioavailability is about 64-80%.

Distribution

V d - about 21 l / kg. In vitro studies have shown that about 97.5% of circulating amlodipine is associated with blood plasma proteins.

Metabolism and excretion

The final T 1/2 of amlodipine from blood plasma is 35-50 hours, which allows you to take the drug 1 time / day. Amlodipine is metabolized in the liver with the formation of inactive metabolites, while 10% of the dose taken is excreted unchanged and 60% - by the kidneys as metabolites. Amlodipine is not eliminated from the body through dialysis.

The time from taking the drug to reaching the C max of amlodipine does not differ in elderly and younger patients. In elderly patients, there is a slowdown in the clearance of amlodipine, which leads to an increase in AUC.

The increase in AUC and T 1/2 in patients with CHF corresponds to the expected value for this age group.

In patients with impaired renal function, changes in the concentration of amlodipine in blood plasma do not correlate with the degree of renal failure. A slight increase in T 1/2 is possible.

Data on the use of amlodipine in patients with hepatic impairment are limited. In patients with hepatic insufficiency, a decrease in the clearance of amlodipine is observed, which leads to an increase in T 1/2 and AUC by approximately 40-60%.

Indications

- arterial hypertension and / or ischemic heart disease: stable exertional angina in patients who require therapy with perindopril and amlodipine.

Contraindications

Perindopril

- hypersensitivity to perindopril or other ACE inhibitors;

- a history of angioedema (Quincke's edema) (including while taking other ACE inhibitors);

- hereditary / idiopathic angioedema;

- simultaneous use with aliskiren and drugs containing aliskiren in patients with diabetes mellitus and / or moderate to severe renal impairment (GFR<60 мл/мин/1.73 м 2 площади поверхности тела) (см. разделы "Лекарственное взаимодействие" и "Фармакологическое действие", подраздел "Фармакодинамика");

- simultaneous use with angiotensin II receptor antagonists (APA II) in patients with diabetic nephropathy (see section "Special instructions");

- pregnancy (see section "Pregnancy and lactation");

Amlodipine

- hypersensitivity to amlodipine and other dihydropyridine derivatives;

- severe arterial hypotension (systolic blood pressure less than 90 mm Hg);

- shock (including cardiogenic);

- obstruction of the left ventricular outflow tract (for example, clinically significant aortic stenosis);

- hemodynamically unstable heart failure after acute myocardial infarction;

- age up to 18 years (efficacy and safety have not been established).

Prestans

- hypersensitivity to excipients that make up the drug;

- renal failure (CC less than 60 ml / min);

- age up to 18 years (efficacy and safety have not been established);

- hereditary galactose intolerance, lactase deficiency and glucose-galactose malabsorption.

All of the above contraindications for perindopril and amlodipine also apply to the combined drug Prestans.

Carefully

Renal artery stenosis (including bilateral), the only functioning kidney, liver failure, renal failure, systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma), therapy with immunosuppressants, allopurinol, procainamide (risk of neutropenia, agranulocytosis), reduced BCC (taking diuretics, salt-free diet, vomiting, diarrhea), atherosclerosis, cerebrovascular diseases, renovascular hypertension, diabetes mellitus, chronic heart failure, concomitant use of dantrolene, estramustine, potassium-sparing drugs, dietary diuretics, dietary diuretics lithium, hyperkalemia, surgery / general anesthesia, advanced age, hemodialysis with high-flow membranes (e.g. AN69), desensitizing therapy, LDL apheresis, aortic stenosis / mitral stenosis / hypertrophic obstructive cardiomyopathy, use in patients not hroid race, chronic heart failure of non-ischemic etiology III-IV FC according to NYHA classification.

Dosage

The drug is administered orally, 1 tab. 1 time / day, preferably in the morning before meals. The dose of the drug Prestans is selected after previously titrated doses of individual components of the drug: perindopril and amlodipine in patients with arterial hypertension and / or ischemic heart disease.

In case of therapeutic necessity, the dose of the drug Prestans can be changed or an individual selection of doses of individual components can be performed in advance:

5 mg perindopril + 5 mg amlodipine or
5 mg perindopril + 10 mg amlodipine or
10 mg perindopril + 5 mg amlodipine or
10 mg perindopril + 10 mg amlodipine.

Special patient groups

Elderly patients and patients with renal insufficiency (see sections "Pharmacokinetics" and "Special instructions")

Withdrawal of perindoprilat from elderly patients and patients with renal insufficiency slowed down. Therefore, in such patients, it is necessary to regularly monitor the concentration of creatinine and potassium in the blood plasma. The drug Prestans can be prescribed patients with CC ≥ 60 ml / min... Prestans is contraindicated to patients with CC< 60 мл/мин (see section "Contraindications"). For such patients, individual selection of doses of perindopril and amlodipine is recommended. Amlodipine, used in equivalent doses, is equally well tolerated by patients, both elderly and younger patients. There is no need to change the dosage regimen in elderly patients, however, increasing the dose should be carried out with caution, which is associated with age-related changes and an increase in T 1/2. The change in the concentration of amlodipine in blood plasma does not correlate with the severity of renal failure. Amlodipine is not eliminated from the body through dialysis.

Patients with hepatic impairment (see sections "Dosing regimen" and "Special instructions").

For patients with mild to moderate hepatic impairment dose selection should be done with caution. It is recommended to start taking the drug with low doses (see sections "Dosage regimen" and "Special instructions"). Finding the optimal initial and maintenance dose for patients with liver failure should be carried out individually, using preparations of amlodipine and perindopril in monotherapy. Pharmacokinetics of amlodipine in patients with severe hepatic impairment has not been studied... For these patients, taking amlodipine should be started at the lowest dose and increased gradually.

The drug Prestans should not be prescribed children and adolescents under 18

Side effects

The frequency of adverse reactions that were observed during monotherapy with perindopril and amlodipine is given in the form of the following gradation: very often (≥1 / 10); often (≥1 / 100,<1/10); нечасто (≥1/1000, <1/100); редко (≥1/10 000, <1/1000); очень редко (<1/10 000), включая отдельные сообщения; неуточненной частоты (частота не может быть подсчитана по доступным данным).

From the hematopoietic and lymphatic system: very rarely - leukopenia, neutropenia, agranulocytosis, pancytopenia, thrombocytopenia, hemolytic anemia in patients with congenital glucose-6-phosphate dehydrogenase deficiency, decreased hemoglobin and hematocrit.

From the immune system: infrequently - allergic reactions.

From the side of metabolism: very rarely - hyperglycemia; unspecified frequency - hypoglycemia.

From the side of the central nervous system:often - drowsiness (especially at the beginning of treatment), dizziness (especially at the beginning of treatment), headache, paresthesia, vertigo; infrequently - insomnia, mood lability (including anxiety), sleep disturbances, tremors, hypesthesia, depression, fainting; rarely - confusion of consciousness; very rarely - peripheral neuropathy, hypertonicity.

On the part of the organ of vision:often - visual impairment (including diplopia).

On the part of the organ of hearing:often - tinnitus.

On the part of the cardiovascular system:often - a feeling of palpitations, flushes of blood to the skin of the face, a pronounced decrease in blood pressure; very rarely - angina pectoris, myocardial infarction, possibly due to an excessive decrease in blood pressure in high-risk patients (see the section "Special instructions"), arrhythmias (including bradycardia, ventricular tachycardia and atrial fibrillation), stroke, possibly due to excessive decrease in blood pressure in high-risk patients (see section "Special instructions"), vasculitis.

From the respiratory system: often - shortness of breath, cough; infrequently - rhinitis, bronchospasm; very rarely - eosinophilic pneumonia.

From the digestive system:often - abdominal pain, nausea, vomiting, dyspepsia, diarrhea, constipation; infrequently - a change in the rhythm of defecation, dryness of the oral mucosa; very rarely - pancreatitis, gingival hyperplasia, gastritis.

From the liver and biliary tract: very rarely - hepatitis, jaundice, increased activity of liver enzymes (most often - in combination with cholestasis), cytolytic or cholestatic hepatitis (see the section "Special instructions").

On the part of the skin and subcutaneous fat: often - itching, rash, exanthema; infrequently - angioedema of the face, limbs, lips, mucous membranes, tongue, vocal folds and / or larynx (see section "Special instructions"), alopecia, hemorrhagic rash, skin discoloration, increased sweating, urticaria; very rarely - Quincke's edema, erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, photosensitivity.

From the musculoskeletal system and connective tissue:often - muscle spasms, swelling of the legs; infrequently - arthralgia, myalgia, back pain.

From the kidneys and urinary tract:infrequently - violation of urination, nocturia, frequent urination, impaired renal function; very rarely - acute renal failure.

On the part of the reproductive system and mammary glands: infrequently - impotence, gynecomastia.

General disorders and symptoms: often - edema, asthenia, increased fatigue; infrequently - chest pain, malaise, pain.

Laboratory indicators: infrequently - an increase in body weight, a decrease in body weight; rarely - an increase in the concentration of bilirubin; unspecified frequency - increased concentration of urea and creatinine in serum, hyperkalemia (see section "Special instructions").

Additional data on amlodipine:isolated cases of extrapyramidal syndrome have been reported.

Overdose

There is no information on drug overdose in humans.

Amlodipine

Information on amlodipine overdose is limited.

Symptoms: excessive peripheral vasodilation leading to reflex tachycardia, pronounced and persistent decrease in blood pressure, incl. with the development of shock and death.

Treatment: a pronounced decrease in blood pressure caused by an overdose of amlodipine requires active measures aimed at maintaining the function of the cardiovascular system, including monitoring the performance of the heart and lungs, elevated position of the limbs, control of BCC and diuresis. To restore vascular tone and blood pressure, it may be useful to use a vasoconstrictor drug, if there are no contraindications to its use, to eliminate the consequences of calcium channel blockade - intravenous administration. In some cases, gastric lavage may be effective. Taking activated charcoal during the first 2 hours after taking amlodipine at a dose of 10 mg leads to a delay in the absorption of the drug. Because amlodipine actively binds to blood plasma proteins, hemodialysis is ineffective.

Perindopril

Data on overdose of perindopril in humans are limited.

Symptoms: with an overdose of ACE inhibitors, there may be a marked decrease in blood pressure, shock, disturbances in water and electrolyte balance, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, cough.

Treatment: i / v infusion of 0.9% solution. With a significant decrease in blood pressure, the patient should be transferred to a supine position with raised legs. If necessary, you can enter a solution of catecholamines IV. Dialysis can remove perindopril from the systemic circulation (see section "Special instructions"). With the development of therapy-resistant bradycardia, an artificial pacemaker may be required. It is necessary to constantly monitor the indicators of the basic vital functions of the body, the concentration of creatinine and electrolytes in the blood serum.

Drug interactions

Perindopril

Clinical research data show that double blockade of the RAAS as a result of the simultaneous administration of ACE inhibitors, ARA II or aliskiren leads to an increase in the incidence of such adverse events as arterial hypotension, hyperkalemia and renal dysfunction (including acute renal failure), compared with situations when only one drug that affects the RAAS is used (see sections "Contraindications", "Special instructions" and "Pharmacological action").

Medicines that cause hyperkalemia

Combination of ACE inhibitors with drugs containing trimethoprim, incl. a fixed combination of trimethoprim and sulfamethoxazole increases the risk of hyperkalemia.

Simultaneous use is contraindicated

Aliskiren and medicines containing aliskiren... The simultaneous use of ACE inhibitors with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and / or moderate or severe renal impairment (GFR less than 60 ml / min / 1.73 m2 body surface area) and is not recommended in other patients. (see section "Contraindications").

Potassium-sparing diuretics, potassium supplements and potassium-containing table salt substitutes: Despite the fact that the serum potassium content remains within the normal range, hyperkalemia may be observed in some patients when using perindopril. Potassium-sparing diuretics (for example, spironolactone, eplerenone (a derivative of spironolactone), triamterene, amiloride), potassium supplements and potassium-containing table salt substitutes can lead to a significant increase in serum potassium. In this connection, the simultaneous use of an ACE inhibitor and the above funds is not recommended (see the section "Special instructions"). If simultaneous use is necessary (in the case of confirmed hypokalemia), caution should be exercised and regular monitoring of plasma potassium and ECG parameters should be carried out.

Lithium preparations: with the simultaneous use of lithium preparations and ACE inhibitors, a reversible increase in the content of lithium in the blood plasma and associated toxic effects may occur. The simultaneous use of perindopril and lithium preparations is not recommended. If such therapy is necessary, regular monitoring of the lithium content in the blood plasma is necessary (see the "Special instructions" section).

Estramustine: the simultaneous use of estramustine with ACE inhibitors is accompanied by an increased risk of developing angioedema.

Racecadotril. It is known that ACE inhibitors (for example, perindopril) can cause the development of angioedema. The risk of its development may be increased when used together with racecadotril (an enkephalinase inhibitor used to treat acute diarrhea).

MTOR inhibitors (mammalian Target of Rapamycin - the target of rapamycin in mammalian cells) (eg sirolimus, everolimus, temsirolimus). Patients concurrently receiving therapy with mTOR inhibitors may increase the risk of developing angioedema (see section "Special instructions").

NSAIDs, including high doses (≥ 3 g / day): the simultaneous use of ACE inhibitors with NSAIDs (acetylsalicylic acid in a dose that has an anti-inflammatory effect, COX-2 inhibitors and non-selective NSAIDs) can lead to a decrease in the antihypertensive effect of ACE inhibitors. The simultaneous use of ACE inhibitors and NSAIDs can lead to a deterioration in renal function, including the development of acute renal failure, and an increase in serum potassium, especially in patients with reduced renal function. Care should be taken when prescribing this combination, especially in elderly patients. In patients, it is necessary to compensate for fluid loss and carefully monitor renal function both at the beginning of treatment and during treatment.

Hypoglycemic agents (insulin, sulfonylurea derivatives): ACE inhibitors can enhance the hypoglycemic effect of insulin and sulfonylurea derivatives in patients with diabetes mellitus. The development of hypoglycemia is very rare (probably due to an increase in glucose tolerance and a decrease in insulin requirements).

Diuretics (thiazide and "loop"): in patients receiving diuretics, especially with excessive excretion of fluid and / or electrolytes, at the beginning of therapy with an ACE inhibitor, a significant decrease in blood pressure may be observed, the risk of which can be reduced by discontinuing the diuretic, introducing an increased amount of fluid and / or sodium chloride, and prescribing perindopril at a low dose with a further gradual increase.

Sympathomimeticsmay weaken the antihypertensive effect of ACE inhibitors.

Gold preparations: when using ACE inhibitors, incl. perindopril, in patients receiving iv gold preparations (sodium aurothiomalate), a symptom complex was described, including flushing of the skin of the face, nausea, vomiting, arterial hypotension.

Concomitant use with ACE inhibitors allopurinol, immunosuppressants, corticosteroids (if used systemically) and procainamide may be accompanied by an increased risk of leukopenia, especially in patients with pre-existing renal impairment.

General anesthesia products: the simultaneous use of ACE inhibitors and general anesthetics can lead to a hypotensive effect.

Dantrolene (i / v introduction): in laboratory animals, there were cases of ventricular fibrillation with a lethal outcome and collapse during the use of verapamil and iv administration of dantrolene, accompanied by hyperkalemia. Due to the risk of developing hyperkalemia, concomitant use of slow calcium channel blockers, incl. amlodipine, in patients prone to malignant hyperthermia, as well as in the treatment of malignant hyperthermia.

Combinations of drugs requiring special attention

CYP3A4 isoenzyme inducers: there are no data regarding the effect of inducers of the isoenzyme CYP3A4 on amlodipine. Concomitant use of inducers of the isoenzyme CYP3A4 (for example, rifampicin, St. John's wort preparations) can lead to a decrease in the plasma concentration of amlodipine. Care should be taken with the simultaneous use of amlodipine and inducers of microsomal oxidation.

CYP3A4 isoenzyme inhibitors: concomitant use of amlodipine and powerful or moderate inhibitors of the isoenzyme CYP3A4 (protease inhibitors, antifungals of the azole group, macrolides, for example, erythromycin or clarithromycin, verapamil or diltiazem) can lead to a significant increase in the concentration of amlodipine. Clinical manifestations of these pharmacokinetic abnormalities may be more pronounced in elderly patients, and therefore may require monitoring of the clinical condition and dose adjustment.

Drug combinations requiring attention

Amlodipine enhances the antihypertensive effect of drugs with antihypertensive action.

Other drug combinations

In clinical studies of drug interactions, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin, warfarin or cyclosporin.

The simultaneous use of amlodipine and the use of grapefruit or grapefruit juice is not recommended, due to the possible increase in the bioavailability of amlodipine in some patients, which, in turn, may lead to an increase in the effects of lowering blood pressure.

Prestans

Combinations of drugs requiring special attention

Baclofen: it is possible to increase the antihypertensive effect. Blood pressure and renal function should be monitored, if necessary, dose adjustment of amlodipine is required.

A combination of drugs requiring attention

Antihypertensives (eg, beta-blockers) and vasodilators may enhance the antihypertensive effect of perindopril and amlodipine. Caution should be exercised when administered concomitantly with nitroglycerin, other nitrates, or other vasodilators, since this may further reduce blood pressure.

Corticosteroids (mineral and glucocorticosteroids), tetracosactide reduce the antihypertensive effect (retention of fluid and sodium ions as a result of the action of corticosteroids).

Alpha blockers (prazosin, alfuzosin, doxazosin, tamsulosin, terazosin)

Amifostine may enhance the antihypertensive effect of amlodipine.

Tricyclic antidepressants, antipsychotics, general anesthetics increase the antihypertensive effect and increase the risk of orthostatic hypotension.

special instructions

Special instructions related to perindopril and amlodipine apply to Prestans.

Perindopril

Hypersensitivity / angioedema

When taking ACE inhibitors, incl. and perindopril, in rare cases the development of angioedema of the face, extremities, lips, mucous membranes, tongue, vocal folds and / or larynx can be observed (see the section "Side effects"). This can happen at any time during therapy. When symptoms appear, the drug should be discontinued immediately, and the patient should be observed until the signs of edema disappear completely. If the swelling only affects the face and lips, it usually resolves on its own, although antihistamines can be used to treat symptoms.

Angioneurotic edema, accompanied by laryngeal edema, can be fatal. Swelling of the tongue, vocal cords, or larynx can lead to airway obstruction. When these symptoms appear, epinephrine (adrenaline) should be administered subcutaneously and / or an airway should be maintained. The patient should be under medical supervision until the symptoms disappear completely and permanently.

In patients with a history of Quincke's edema, not associated with the use of ACE inhibitors, the risk of its development may be increased when taking drugs of this group (see section "Contraindications").

In rare cases, angioedema of the intestine develops during therapy with ACE inhibitors. At the same time, patients have abdominal pain as an isolated symptom or in combination with nausea or vomiting, in some cases, without previous angioedema of the face and at a normal level of C1-esterase. Diagnosis is by abdominal computed tomography, ultrasound, or surgery. Symptoms disappear after stopping ACE inhibitors. Therefore, in patients with abdominal pain receiving ACE inhibitors, when carrying out differential diagnostics, it is necessary to take into account the possibility of developing angioedema of the intestine (see the "Side Effects" section).

Concomitant use with mTOR inhibitors (eg, sirolimus, everolimus, temsirolimus)

Patients receiving mTOR inhibitor therapy (eg, sirolimus, everolimus, temsirolimus) may be at increased risk of angioedema (eg, swelling of the airways or tongue with or without respiratory failure) (see Drug Interactions).

Anaphylactoid reactions during LDL apheresis

In rare cases, patients receiving ACE inhibitors may develop life-threatening anaphylactoid reactions during LDL apheresis with dextran sulfate. To prevent anaphylactoid reaction, you should temporarily discontinue therapy with an ACE inhibitor before each apheresis procedure.

Anaphylactoid reactions during desensitization

There are isolated reports of the development of anaphylactoid reactions in patients receiving ACE inhibitors during desensitizing therapy (for example, hymenoptera venom). In the same patients, the anaphylactoid reaction could be avoided by temporarily canceling the ACE inhibitors, and with accidental administration of the drug, the anaphylactoid reaction occurred again.

Neutropenia, agranulocytosis, thrombocytopenia, anemia

While taking ACE inhibitors, neutropenia / agranulocytosis, thrombocytopenia, and anemia may occur. In patients with normal renal function and in the absence of other aggravating factors, neutropenia rarely develops. Perindopril should be used with extreme caution in patients with systemic connective tissue diseases, while taking immunosuppressants, allopurinol or procainamide, especially in patients with impaired renal function.

Some patients developed severe infections, in some cases resistant to intensive antibiotic therapy. When prescribing perindopril, such patients are advised to periodically monitor the number of leukocytes in the blood. Patients should inform their doctor about any sign of infectious disease (eg, sore throat, fever).

Double blockade of RAAS

There is evidence that the combined use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren increases the risk of arterial hypotension, hyperkalemia and renal dysfunction (including acute renal failure). Thus, the double blockade of the RAAS by the combined use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren is not recommended (see sections "Drug Interactions" and "Pharmacological Effects"). If dual blockade therapy is deemed absolutely necessary, it should only be carried out under strict medical supervision and with regular monitoring of renal function, blood electrolytes and blood pressure.

The use of ACE inhibitors in combination with angiotensin II receptor antagonists is contraindicated in patients with diabetic nephropathy and is not recommended in other patients (see section "Contraindications").

Arterial hypotension

ACE inhibitors can cause a sharp drop in blood pressure. Symptomatic hypotension rarely develops in patients without concomitant diseases. The risk of an excessive decrease in blood pressure is increased in patients with reduced BCC, which can be observed during therapy with diuretics, with a strict salt-free diet, hemodialysis, diarrhea and vomiting, as well as in patients with severe hypertension with high renin activity (see sections "Medicinal interaction "and" Side effect "). In patients with an increased risk of developing symptomatic arterial hypotension, it is necessary to carefully monitor blood pressure, renal function and serum potassium during therapy with Prestans.

A similar approach is used in patients with angina pectoris and cerebrovascular diseases, in whom severe arterial hypotension can lead to myocardial infarction or cerebrovascular accident.

In the event of arterial hypotension, the patient should be transferred to the supine position with raised legs. If necessary, the BCC should be replenished with intravenous administration of 0.9% sodium chloride solution. Transient arterial hypotension is not an obstacle to further administration of the drug. After the restoration of the BCC and blood pressure, treatment can be continued.

Mitral stenosis, aortic stenosis, hypertrophic obstructive cardiomyopathy

Perindopril, like other ACE inhibitors, should be used with caution in patients with obstruction of the left ventricular outflow tract (aortic stenosis, hypertrophic obstructive cardiomyopathy), as well as in patients with mitral stenosis. Amlodipine is contraindicated in patients with left ventricular outflow tract obstruction.

Impaired renal function

Patients with renal insufficiency (CC less than 60 ml / min) are recommended to individually select doses of perindopril and amlodipine (see section "Dosage regimen"). Such patients need regular monitoring of serum potassium and creatinine levels (see the "Side Effects" section).

In patients with bilateral renal artery stenosis or stenosis of an artery of a solitary kidney during therapy with ACE inhibitors, it is possible to increase the content of urea and creatinine in the blood serum, which usually disappears when therapy is discontinued. More often this effect is observed in patients with renal insufficiency. The additional presence of renovascular hypertension is associated with an increased risk of severe arterial hypotension and renal failure in these patients.

In some patients with arterial hypertension without signs of renal vascular damage, an increase in the concentration of urea and creatinine in the blood serum is possible, especially with the simultaneous administration of perindopril with a diuretic, usually insignificant and transient. More often this effect is observed in patients with previous renal impairment.

Liver failure

In rare cases, cholestatic jaundice occurs while taking ACE inhibitors. With the progression of this syndrome, fulminant necrosis of the liver develops, sometimes with a fatal outcome. The mechanism for the development of this syndrome is unclear. If jaundice or significant increase in the activity of liver enzymes occurs while taking ACE inhibitors, you should stop taking the drug (see the "Side Effects" section) and consult a doctor.

Ethnic differences

In patients of the Negroid race, angioedema develops more often than in representatives of other races, while taking ACE inhibitors.

Perindopril, like other ACE inhibitors, may have a less pronounced antihypertensive effect in black patients than in other races. Perhaps this difference is due to the fact that in patients with arterial hypertension of the Negroid race, low renin activity is more often observed.

Cough

During therapy with an ACE inhibitor, a dry cough may occur. The cough persists for a long time while taking drugs of this group and disappears after they are canceled. This should be taken into account when conducting a differential diagnosis of cough.

Surgery / general anesthesia

In patients who are planning to undergo major surgeries or the use of anesthetic agents that cause arterial hypotension, the use of perindopril can block the formation of angiotensin II against the background of compensatory renin release. Treatment should be discontinued one day before surgery. With the development of arterial hypotension according to the specified mechanism, blood pressure should be maintained by replenishing the BCC.

Hyperkalemia

Hyperkalemia can develop during treatment with ACE inhibitors, incl. and perindopril. Risk factors for hyperkalemia are renal failure, impaired renal function, age over 70, diabetes mellitus, certain concomitant conditions (dehydration, acute decompensation of chronic heart failure, metabolic acidosis), concomitant use of potassium-sparing diuretics (such as spironolactone and its derivative eplerenone, triamterene, amiloride), as well as preparations of potassium or potassium-containing substitutes for table salt, as well as the use of other drugs that increase the level of potassium in the blood plasma (for example, heparin). The use of potassium preparations, potassium-sparing diuretics, potassium-containing substitutes for table salt can lead to a significant increase in the level of potassium in the blood, especially in patients with reduced kidney function.

Hyperkalemia can lead to serious, sometimes fatal, heart rhythm disturbances. If it is necessary to take perindopril and the above drugs at the same time, treatment should be carried out with caution against the background of regular monitoring of the serum potassium content (see the section "Drug Interactions").

Patients with diabetes mellitus

When prescribing the drug to patients with diabetes mellitus receiving oral hypoglycemic agents or insulin, during the first month of therapy, it is necessary to carefully monitor the concentration of glucose in the blood (see the section "Drug Interactions").

Amlodipine

The efficacy and safety of the use of amlodipine in hypertensive crisis has not been established.

Heart failure

Patients with heart failure should be treated with caution. When using amlodipine in patients with chronic heart failure of FC III and IV according to the NYHA classification, the development of pulmonary edema is possible. Slow calcium channel blockers, including amlodipine, should be used with caution in patients with chronic heart failure, due to the possible increase in the risk of developing adverse events from the cardiovascular system and mortality.

Liver failure

In patients with impaired liver function, T 1/2 and AUC of amlodipine increases. Dosing recommendations have not been established. Reception of amlodipine should be started with the lowest doses and precautions should be taken, both at the beginning of treatment and when increasing the dose. In patients with severe hepatic impairment, the dose should be increased gradually, ensuring careful monitoring of the clinical condition.

Elderly patients

In elderly patients, the dose should be increased with caution (see sections "Dosage regimen" and "Pharmacokinetics").

Renal failure

Patients with renal impairment can take amlodipine in standard doses. Changes in plasma concentrations of amlodipine do not correlate with the degree of renal failure. Amlodipine is not eliminated from the body through dialysis.

Prestans

Special instructions regarding amlodipine and perindopril also apply to the drug Prestans.

Excipients

Due to the presence of lactose in the composition of the drug, Prestan should not be prescribed to patients with hereditary lactose intolerance, lactase deficiency and glucose-galactose malabsorption.

Influence on the ability to drive vehicles and mechanisms

Although while taking the drug Prestans, no negative effect on the ability to drive vehicles or other complex mechanisms was observed, however, due to a possible excessive decrease in blood pressure, the development of dizziness, drowsiness and other adverse reactions, caution should be exercised in these situations, especially at the beginning of treatment and when the dose is increased.

Pregnancy and lactation

The drug is contraindicated in pregnancy.

Pregnancy

Perindopril

The use of ACE inhibitors is not recommended for use in the first trimester of pregnancy (see section "Special instructions"). The use of ACE inhibitors is contraindicated in the II and III trimesters of pregnancy (see the sections "Contraindications" and "Special instructions").

At the moment, there is no irrefutable epidemiological data on the teratogenic risk when taking ACE inhibitors in the first trimester of pregnancy. However, a slight increase in the risk of fetal developmental disorders cannot be ruled out. When planning pregnancy, the drug should be discontinued and other antihypertensive drugs approved for use during pregnancy should be prescribed. When pregnancy occurs, you should immediately stop therapy with ACE inhibitors and, if necessary, prescribe another therapy.

It is known that the effect of ACE inhibitors on the fetus in the II and III trimesters of pregnancy can lead to a violation of its development (decreased renal function, oligohydramnios, slowed ossification of the skull bones) and the development of complications in the newborn (renal failure, arterial hypotension, hyperkalemia).

If the patient received ACE inhibitors in the II and III trimesters of pregnancy, it is recommended to conduct an ultrasound scan to assess the condition of the skull and kidney function of the fetus / child.

Newborns whose mothers received ACE inhibitors during pregnancy should be under close medical supervision because of the risk of developing arterial hypotension (see sections "Contraindications" and "Special instructions").

Amlodipine

The safety of using amlodipine during pregnancy has not been established.

In experimental studies on animals, the fetotoxic and embryotoxic effects of the drug were established when used in high doses. Use during pregnancy is possible only if there is no safer alternative and when the disease carries a greater risk to the mother and fetus.

Breastfeeding period

Perindopril

Due to the lack of information regarding the use of perindopril during breastfeeding, perindopril is not recommended, it is preferable to adhere to alternative treatment during breastfeeding with a more studied safety profile, especially when feeding newborns or premature babies. There are no data on the excretion of perindopril in breast milk.

Amlodipine

There are no data on the excretion of amlodipine in breast milk. The decision to continue / discontinue therapy or breastfeeding should be made taking into account the benefits of breastfeeding for the baby and the benefits of taking amlodipine for the mother.

Impact on fertility

Perindopril

There was no evidence of the effect of perindopril on reproductive function or fertility.

Amlodipine

In some patients who received slow calcium channel blockers, biochemical changes in the sperm head were found. However, there is currently no sufficient clinical data regarding the potential effect of amlodipine on fertility. In a study in rats, undesirable effects on fertility were found in males.

Childhood use

Prestans should not be prescribed children and adolescents under 18 due to the lack of data on the efficacy and safety of perindopril and amlodipine in these groups of patients, both as monotherapy and as combination therapy.

With impaired renal function

Withdrawal of perindoprilat from patients with renal failure slowed down. Therefore, in such patients, it is necessary to regularly monitor the concentration of creatinine and potassium in the blood plasma. Prestans can be assigned patients with QC ≥ 60 ml / min... Prestans is contraindicated patients with QC< 60 мл/мин ... For such patients, individual selection of doses of perindopril and amlodipine is recommended. The change in the concentration of amlodipine in blood plasma does not correlate with the severity of renal failure.

For violations of liver function

Care should be taken when prescribing Prestans patients with hepatic impairment due to the lack of recommendations for dosing the drug in such patients.

Instructions for use

An instruction is attached to the Co-Preness preparation, which should be familiarized with. Ignoring the recommendations can lead to unpleasant consequences.

Indications

A doctor may prescribe this drug for essential hypertension.

1 tablet must be taken orally 1 time / day. It is best to drink tablets in the morning before meals.

Treatment with Co-Prenessa in the elderly begins with an initial dosage of 2 mg (1 tab) 1 time / day. Plasma creatinine should be adjusted according to gender, age, and weight of the patient.

Therapy can be started only if the kidney condition is normal.

If the patient has been diagnosed with mild renal failure, then dosage adjustment is not required. However, in the future, it is necessary to monitor the content of creatinine and potassium 1 week after the start of therapy, and then after 2-4 months.

If the patient has been diagnosed with liver failure, then no adjustment of treatment is required.

Release form and composition

Co-Prenessa medicinal product is available in the form:

1. 2 mg tablets;
2. with a dosage of 4 mg;
3. with a dose of 8 mg.

One tablet contains perindopril, indapamide, as well as calcium chloride hexahydrate, crospovidone, lactose, magnesium stearate, microcrystalline cellulose, monohydrate, sodium bicarbonate.

The drug is available in 30, 60, and 90 tablets.

Interaction with other drugs

Co-Presidency Reception with:

Side effects

Co-Prenessa drug can cause a number of undesirable effects. To neither include:

1. Decrease in blood pressure, angina pectoris, leukopenia, agranulocytosis, anemia, thrombocytopenia, myocardial infarction, hypotension, neutropenia.
2. Headache, sleep disturbances, convulsions, dizziness, tinnitus, emotional agitation, depression (can be severe), and visual impairment.
3. Cough (dry), rhinitis, shortness of breath, pneumonia.
4. Constipation, nausea, dysgevesia, cholestasis, diarrhea, hepatitis, digestive disorders, pancreatitis, encephalopathy.
5. Lupus erythematosus, photosensitivity, necrolysis, skin rash, anaphylactic shock, Steves-Johnson syndrome.
6. General weakness, erectral dysfunction.

People who are professionally involved in sports should take into account that the drug can give a positive reaction to doping control.

Contraindications

The drug has a number of contraindications, which include:

1. Anuria.
2. Azotemia.
3. Allergy to the components that make up the drug.
4. Hyperkalemia.
5. Stenosis of the arteries of one or two kidneys.

If the patient has been diagnosed with acute liver failure, then taking the medication is contraindicated.

Pregnancy and lactation

You should stop taking this medication during pregnancy. This is due to the fact that the remedy can have a negative effect on the fetus.

If it is not possible to refuse taking the medicine, then the doctor must choose a safe analogue.

While breastfeeding the baby, it is also necessary to stop taking Co-Prenessa.

If it is not possible to refuse the admission, then the baby should be transferred to artificial nutrition.

Storage

If all conditions are met, the shelf life of Co-Prenessa is no more than 2 years. After the expiration date has passed, the medicine must be disposed of.

Price

The exact price of Co-Prenessa medicine must be checked at the city pharmacies. The instructions show the approximate cost.

The price is based on the dosage and the number of tablets.

1. In Moscow, you will have to pay 300 rubles for 30 tablets in a dosage of 2 mg.
2. For the drug Co-Prenessa (30 tablets) at a dosage of 4 mg, on average, you will have to pay 400 rubles.
3. The medicine (30 tablets) in a dosage of 8 mg costs 490 rubles on average.

Ukraine:

1. In Kiev pharmacies for 30 tablets of the drug Co-Prenessa in a dosage of 2 mg you will have to pay UAH 106.04.
2. For 30 tablets of the drug in a dosage of 4 mg, you will have to pay 144, 25 UAH.
3. The drug (30 tablets) 8 mg costs on average 160, 89 UAH.