Co-Dalneva, tablets 5 mg+2, 5 mg+8 mg 90 pcs

Co-Dalneva^® is a combination drug containing perindoprilairbumin (angiotensin-converting enzyme (ACE) inhibitor), indapamide (thiazide-like diuretic) and amlodipine (slow calcium channel blocker (CCB).

The drug Co-Dalneva^® combines the properties of each of the active ingredients while having potentiating effects.

Pharmacodynamics

Amlodipine

Amlodipine is a BMCC, a dihydropyridine derivative. Amlodipine inhibits transmembrane transition of calcium ions in 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 mechanism of antianginal action of amlodipine is not fully understood, presumably it is related to the following effects:

• causes dilation of peripheral arterioles, reducing total peripheral vascular resistance (PPR)-postload, which leads to a reduction in myocardial oxygen demand;

causes dilation of coronary arteries and arterioles in both intact and ischemic areas of the myocardium, which increases oxygen supply to the myocardium, including in patients with Prinzmetal angina.

In patients with arterial hypertension (AH), administration of amlodipine once daily provides clinically significant reduction of blood pressure (BP) (in lying and standing position) for 24 hours. Antihypertensive effect develops slowly, so the development of acute arterial hypotension is uncommon.

In patients with stenocardia once daily administration of amlodipine increases exercise tolerance, time to angina attack and to “coronary” ST-segment depression, decreases angina attacks frequency and necessity of taking nitroglycerin (short-acting forms). Amlodipine has no effect on lipid profile parameters and does not cause changes in blood plasma hypolipidemic parameters. The drug may be used in patients with bronchial asthma (BA), diabetes mellitus (DM) and gout.

Indapamide

Indapamide is a sulfonamide derivative. In terms of pharmacological properties, it is close to thiazide diuretics. Indapamide inhibits reabsorption of sodium ions in the cortical segment of the loop of Genle, which leads to increased renal excretion of sodium and chlorine ions and, to a lesser extent, potassium and magnesium ions, thereby increasing diuresis and reducing BP.

In monotherapy the antihypertensive effect is maintained for 24 hours and is seen when the drug is used in doses that have minimal diuretic effect. Antihypertensive effect of indapamide is associated with improvement of elastic properties of large arteries, reduction of PPS. Against the background of taking indapamide, left ventricular hypertrophy (LVH) decreases.

Indapamide does not influence plasma concentration of lipids (triglycerides, total cholesterol, low-density and high-density lipoproteins), indices of carbohydrate metabolism (including in patients with diabetes).

Perindopril

Perindopril is an angiotensin-converting enzyme inhibitor. ACE, or kininase II, is an exopeptidase that converts angiotensin I into the vasoconstrictor, angiotensin II, and also degrades bradykinin, which has vasodilatory properties, into an inactive heptapeptide.

As a result, perindopril provides the following effects:

– reduces the secretion of aldosterone;

– increases the activity of blood renin-plasma by the principle of “negative” feedback;

– with long-term use it reduces the OPPS – post-load of the heart, which is mainly due to the action on the muscular and renal vessels. Reduction of OPPS is not accompanied with retention of sodium and water and does not cause reflex tachycardia.

The study of hemodynamic parameters in patients with chronic heart failure (CHF) revealed:

– decreased filling pressures in the left and right ventricles of the heart;

– decreased PPSS;

– increased cardiac output and cardiac index;

– increased peripheral blood flow in the muscles.

In addition, there was an improvement in the results of the exercise test.

The action of perindopril is through the active metabolite, perindoprilat. Other metabolites have no inhibitory effect on ACE under in-vitro conditions.

Perindopril is effective in the treatment of AH of any severity, reduces both systolic and diastolic BP in lying and standing position.

The antihypertensive effect peaks 4-6 hours after a single oral dose and lasts for 24 hours.

The antihypertensive effect 24 hours after a single oral dose is about 87-100% of the maximum antihypertensive effect.

Perindopril has antihypertensive effect in patients with both low and normal plasma renin activity.

Therapeutic effect occurs in less than 1 month from the beginning of therapy and is not accompanied by tachyphylaxis. Discontinuation of therapy does not cause “withdrawal” syndrome.

Perindoprilobin has vasodilator properties and promotes restoration of elasticity of large arteries, structure of vascular wall of small arteries, and also reduces VFD.

The concomitant use with thiazide diuretic increases the severity of antihypertensive effect and reduces the risk of hypokalemia with diuretic.

Perindopril/indapamide

The perindopril/indapamide combination has dose-dependent antihypertensive effects on both systolic and diastolic BP (standing and lying) regardless of patient age. Antihypertensive effect lasts for 24 hours. Therapeutic effect occurs in less than 1 month from the start of therapy and is not accompanied by tachyphylaxis. Discontinuation of therapy does not cause “withdrawal” syndrome.

In clinical studies, concomitant use of perindopril and indapamide increased the severity of antihypertensive effect compared to monotherapy with each drug. The perindoprilatetbutylamine (perindopril erbumin)/indapamide combination resulted in a significantly more pronounced reduction in VLDL than did enalapril monotherapy. The most significant effect on VFD was achieved with perindoprilatetbutylamine (perindopril erbumin) 8 mg/indapamide 2.5 mg.

Pharmacokinetics

Amlodipine

Intake, distribution

After oral administration, amlodipine is slowly absorbed from the gastrointestinal tract (GIT). Food intake has no effect on the bioavailability of amlodipine. Maximum concentration (C_max) of amlodipine in plasma is achieved 6-12 hours after oral administration. Absolute bioavailability is approximately 64-80%. The volume of distribution (Vd) is approximately 21 l/kg. In xin vitro studies the degree of binding of amlodipine to plasma proteins was about 97.5%.

Metabolism, excretion

The final half-life (T_1/2) from blood plasma is about 35-50 hours, which allows taking amlodipine once daily. Amlodipine is metabolized in the liver to form inactive metabolites, with 10% of the ingested dose of amlodipine excreted unchanged, about 60% – by the kidneys as metabolites. Amlodipine is not excreted from the body by hemodialysis.

The time to reach C_max amlodipine does not differ in elderly and younger patients. Amlodipine clearance is decreased in elderly patients, resulting in increased area under the concentration-time curve (AUC) and T_1/2. Dose adjustment in elderly patients is not required, but the dose of amlodipine should be increased with caution. The increase in AUC and T_1/2 in patients with CHF is as expected for this age group.

In patients with impaired renal function, changes in plasma amlodipine concentrations do not correlate with the degree of renal failure. There may be a slight prolongation of T_1/2.

In patients with impaired hepatic function, there are limited data on the use of amlodipine and a decrease in clearance of amlodipine, resulting in an increase in T_1/2 and AUC of approximately 40-60%.

Indapamide

Indapamide is rapidly and completely absorbed from the gastrointestinal tract. C_max in blood plasma is reached approximately 1 hour after oral administration. The degree of binding to plasma proteins is 79%.

Metabolism, excretion

T_1/2 is 14-24 hours (average 18 hours). Repeated administration of indapamide does not result in its cumulation. It is eliminated mainly by the kidneys (70% of the oral dose) and through the intestine (22%) in the form of inactive metabolites.

Pharmacokinetics of indapamide does not change in patients with renal insufficiency.

Perindopril

Intake, metabolism

Perindopril is rapidly absorbed when taken orally. C_max in plasma is reached 1 hour after oral administration.

Perindopril is a prodrug, which means it has no pharmacological activity. About 27% of the oral dose of perindopril enters the bloodstream as the active metabolite – perindoprilate. In addition to the active metabolite – perindoprilat, 5 other metabolites are formed that have no pharmacological activity. C_max perindoprilat in blood plasma is reached 3-4 hours after oral administration.

Eating slows the conversion of perindopril to perindoprilat, thus affecting bioavailability. Therefore, perindopril should be taken once daily, in the morning, before meals.

There is a linear dependence of plasma concentration of perindopril on the dose taken orally.

Distribution

The Vdc of free perindoprilat is approximately 0.2 L/kg. The degree of binding of perindoprilat to plasma proteins (mainly ACE) is about 20% and is dose-dependent.

T_1/2perindoprilat from blood plasma is 1 hour. Perindoprilat is eliminated from the body by the kidneys. The final T_1/2 free fraction is about 17 hours, the equilibrium state is reached within 4 days.

The excretion of perindoprilat is delayed in elderly patients as well as in patients with cardiac and renal insufficiency. Dose adjustment in patients with renal insufficiency is carried out taking into account the degree of renal impairment (creatinine clearance (CK)). Dialysis clearance of perindoprilat is 70 ml/min.

The pharmacokinetics of perindopril changes in patients with cirrhosis: hepatic clearance decreases by half. However, the amount of perindoprilat produced is not decreased, therefore no dose adjustment is required (see sections “Dosage and administration” and “Precautions”).

Indications

Arterial hypertension (if necessary, simultaneous therapy with amlodipine, indapamide and perindopril in doses used in monotherapy of the individual components).

Pharmacological effect

Co-Dalneva® is a combination drug containing perindoprilaerbumine (angiotensin-converting enzyme (ACE) inhibitor), indapamide (thiazide-like diuretic) and amlodipine (slow calcium channel blocker (SCBC)).

The drug Co-Dalneva® combines the properties of each of the active substances, which also have a potentiating effect.

Pharmacodynamics

Amlodipine

Amlodipine is a BMCC, 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 mechanism of the antianginal action of amlodipine is not fully understood; it is presumably associated with the following effects:

causes expansion of peripheral arterioles, reducing total peripheral vascular resistance (TPVR) – afterload, which leads to a decrease in myocardial oxygen demand;

causes dilation of the coronary arteries and arterioles in both intact and ischemic areas of the myocardium, which increases the supply of oxygen to the myocardium, including in patients with Prinzmetal’s angina.

In patients with arterial hypertension (AH), taking amlodipine once a day provides a clinically significant decrease in blood pressure (BP) (in the “lying” and “standing” positions) within 24 hours. The antihypertensive effect develops slowly, and therefore the development of acute arterial hypotension is uncharacteristic.

In patients with angina pectoris, taking amlodipine once a day increases exercise tolerance, the time before the development of an angina attack and until “ischemic” depression of the ST segment, reduces the frequency of angina attacks and the need for taking nitroglycerin (short-acting forms). Amlodipine has no effect on the lipid profile and does not cause changes in lipid-lowering parameters of blood plasma. The drug can be used in patients with bronchial asthma (BA), diabetes mellitus (DM) and gout.

Indapamide

Indapamide is a sulfonamide derivative. Its pharmacological properties are similar to thiazide diuretics. Indapamide inhibits the reabsorption of sodium ions in the cortical segment of the loop of Henle, which leads to increased excretion by the kidneys of sodium and chloride ions, and to a lesser extent, potassium and magnesium ions, thereby increasing diuresis and reducing blood pressure.

In monotherapy mode, the antihypertensive effect persists for 24 hours and manifests itself when the drug is used in doses that have a minimal diuretic effect. The antihypertensive effect of indapamide is associated with an improvement in the elastic properties of large arteries and a decrease in peripheral vascular resistance. When taking indapamide, left ventricular hypertrophy (LVH) decreases.

Indapamide does not affect the concentration of lipids in the blood plasma (triglycerides, total cholesterol, low- and high-density lipoproteins), or carbohydrate metabolism (including in patients with diabetes).

Perindopril

Perindopril is an angiotensin-converting enzyme inhibitor. ACE, or kininase II, is an exopeptidase that converts angiotensin I into the vasoconstrictor angiotensin II, and also destroys bradykinin, which has vasodilatory properties, into an inactive heptapeptide.

As a result, perindopril provides the following effects:

· reduces the secretion of aldosterone;

· increases the activity of blood reninaplasma according to the principle of “negative” feedback;

· with long-term use, it reduces the peripheral vascular resistance – the afterload of the heart, which is mainly due to the effect on the muscular and renal vessels. A decrease in peripheral vascular resistance is not accompanied by sodium and water retention and does not cause reflex tachycardia.

A study of hemodynamic parameters in patients with chronic heart failure (CHF) revealed:

· decrease in filling pressure in the left and right ventricles of the heart;

· decrease in OPSS;

Increased cardiac output and cardiac index;

Increased peripheral blood flow in muscles.

In addition, an improvement in the results of the exercise test was noted.

The action of perindopril is carried out through the active metabolite – perindoprilate. Other metabolites do not have an inhibitory effect on ACE in vitro.

Perindopril is effective in the treatment of hypertension of any severity, reduces both systolic and diastolic blood pressure in the “lying” and “standing” positions.

The antihypertensive effect reaches its maximum 4-6 hours after a single oral dose and persists for 24 hours.

The antihypertensive effect 24 hours after a single oral dose is about 87-100% of the maximum antihypertensive effect.

Perindopril has an antihypertensive effect in patients with both low and normal plasma renin activity.

The therapeutic effect occurs in less than 1 month from the start of therapy and is not accompanied by tachyphylaxis. Stopping therapy does not cause withdrawal syndrome.

Perindopril has vasodilating properties and helps restore the elasticity of large arteries, the structure of the vascular wall of small arteries, and also reduces LVH.

Concomitant use with a thiazide diuretic increases the severity of the antihypertensive effect and reduces the risk of developing hypokalemia while taking diuretics.

Perindopril/Indapamide

The combination of perindopril/indapamide has a dose-dependent antihypertensive effect on both systolic and diastolic blood pressure (in the “standing” and “lying” positions), regardless of the patient’s age. The antihypertensive effect lasts for 24 hours. The therapeutic effect occurs in less than 1 month from the start of therapy and is not accompanied by tachyphylaxis. Stopping therapy does not cause withdrawal syndrome.

In clinical studies, the simultaneous use of perindopril and indapamide increased the severity of the antihypertensive effect compared with monotherapy with each drug. The combination of perindoprilatertebutylamine (perindopril erbumine)/indapamide resulted in a significantly greater reduction in LVH than enalapril monotherapy. The most significant effect on LVH is achieved with the use of perindoprilatertebutylamine (perindopril erbumine) 8 mg/indapamide 2.5 mg.

Pharmacokinetics

Amlodipine

Suction, distribution

After oral administration, amlodipine is slowly absorbed from the gastrointestinal tract (GIT). Food intake does not affect the bioavailability of amlodipine. The maximum concentration (Cmax) of amlodipine in plasma is reached 6-12 hours after oral administration. Absolute bioavailability is about 64-80%. The volume of distribution (Vd) is approximately 21 l/kg. In an in vitro study, the degree of binding of amlodipine to plasma proteins was about 97.5%.

Metabolism, excretion

The final half-life (T1/2) from blood plasma is about 35-50 hours, which allows amlodipine to be taken once a day. Amlodipine is metabolized in the liver with the formation of inactive metabolites, while 10% of the amlodipine dose taken orally is excreted unchanged, about 60% is excreted by the kidneys in the form of metabolites. Amlodipine is not excreted from the body by hemodialysis.

The time to reach Cmax of amlodipine does not differ between elderly and younger patients. In elderly patients, there is a decrease in the clearance of amlodipine, which leads to an increase in the area under the concentration-time curve (AUC) and T1/2. No dose adjustment is required in elderly patients, but increasing the dose of amlodipine should be done with caution. The increase in AUC and T1/2 in patients with CHF corresponds to the expected value for this age group.

In patients with impaired renal function, changes in plasma concentrations of amlodipine do not correlate with the degree of renal failure. A slight prolongation of T1/2 is possible.

In patients with impaired liver function, data on the use of amlodipine are limited; a decrease in the clearance of amlodipine is observed, which leads to an increase in T1/2 and AUC by approximately 40-60%.

Indapamide

Suction, distribution

Indapamide is quickly and completely absorbed from the gastrointestinal tract. Cmax in blood plasma is reached approximately 1 hour after taking the drug orally. The degree of binding to blood plasma proteins is 79%.

Metabolism, excretion

T1/2 is 14-24 hours (average 18 hours). Repeated administration of indapamide does not lead to its accumulation. Eliminated mainly by the kidneys (70% of the dose taken orally) and through the intestines (22%) in the form of inactive metabolites.

The pharmacokinetics of indapamide do not change in patients with renal failure.

Perindopril

Absorption, metabolism

When taken orally, perindopril is rapidly absorbed. Cmax in blood plasma is achieved 1 hour after oral administration.

Perindopril is a prodrug, i.e. has no pharmacological activity. About 27% of a dose of perindopril taken orally enters the bloodstream in the form of an active metabolite, perindoprilate. In addition to the active metabolite, perindoprilate, 5 more metabolites are formed that do not have pharmacological activity. Cmax of perindoprilate in blood plasma is achieved 3-4 hours after oral administration.

Eating slows down the conversion of perindopril to perindoprilat, thereby affecting bioavailability. Therefore, perindopril should be taken once a day, in the morning, before meals.

There is a linear relationship between the concentration of perindopril in the blood plasma and the dose taken orally.

Distribution

The Vd of free perindoprilate is approximately 0.2 l/kg. The degree of binding of perindoprilate to plasma proteins (mainly ACE) is about 20% and is dose-dependent.

Removal

T1/2 of perindoprila from blood plasma is 1 hour. Perindoprilat is eliminated from the body by the kidneys. The final T1/2 of the free fraction is about 17 hours, the equilibrium state is reached within 4 days.

The elimination of perindoprilate is slowed down in elderly patients, as well as in patients with heart and renal failure. Dose adjustment in patients with renal failure is carried out taking into account the degree of renal dysfunction (creatinine clearance (CC)). The dialysis clearance of perindoprilate is 70 ml/min.

The pharmacokinetics of perindopril changes in patients with liver cirrhosis: hepatic clearance decreases by 2 times. However, the amount of perindoprilate formed does not decrease, so no dose adjustment is required (see sections “Dosage and Administration” and “Special Instructions”).

Special instructions

Liver failure of mild to moderate severity, renal failure of moderate severity (creatinine clearance 30-60 ml/min), systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma), bilateral renal artery stenosis, stenosis of the artery of a single kidney, therapy with immunosuppressants, allopurinol, procainamide (risk of developing neutropenia and agranulocytosis), simultaneous use with drugs that can cause polymorphic ventricular tachycardia of the “pirouette” type, simultaneous use with potassium-sparing diuretics, potassium and lithium preparations, simultaneous use of drugs that prolong the QT interval, hyperkalemia, inhibition of bone marrow hematopoiesis, reduced circulating blood volume (taking diuretics, a diet with limited salt, vomiting, diarrhea, hemodialysis), coronary heart disease (CHD), unstable angina (with the exception of Prinzmetal’s angina), atherosclerosis, cerebrovascular diseases, renovascular hypertension, diabetes mellitus, CHF (III-IV functional class according to the NYHA classification), acute myocardial infarction (within 1 month after myocardial infarction), sick sinus syndrome, fluid and electrolyte disturbances balance, use in patients with prolongation of the QT interval on the electrocardiogram (ECG), hyperuricemia (especially in combination with gout and urate nephrolithiasis), hyperparathyroidism, simultaneous use of dantrolene, estramustine, simultaneous use with inducers and/or inhibitors of the CYP3A4 isoenzyme, surgery/general anesthesia, blood pressure lability, hemodialysis using high-flux membranes (for example, AN69®), before the procedure of low-density lipoprotein (LDL) apheresis with dextran sulfate, simultaneous desensitization therapy with allergens (for example, hymenoptera venom), condition after kidney transplantation, aortic stenosis, mitral stenosis, hypertrophic obstructive cardiomyopathy (HOCM), congenital deficiency of glucose-6-phosphate dehydrogenase, use in elderly patients and in patients of the Negroid race.

Contraindicated in persons under 18 years of age (efficacy and safety have not been established).

Elderly patients and patients with impaired renal function

The drug Co-Dalneva® is contraindicated for use in patients with severe renal impairment (creatinine clearance less than 30 ml/min) (see section “Contraindications”). The drug Co-Dalneva® can be used in patients with moderate renal impairment (creatinine clearance 30-60 ml/min). For such patients, individual selection of doses of amlodipine, indapamide, and perindopril is recommended.

For patients with impaired renal function (creatinine clearance equal to 60 ml/min or more), no dose adjustment is required. Amlodipine, used in equivalent doses, is equally well tolerated by both elderly and younger patients. There is no need to change the dosage regimen in elderly patients, however, increasing the dose should be done with caution, which is associated with age-related changes and prolongation of T1/2. Changes in the concentration of amlodipine in blood plasma do not correlate with the severity of renal failure. Amlodipine is not dialysable.

The elimination of perindoprilate in elderly patients and patients with renal failure is slower. Therefore, in such patients it is necessary to regularly monitor the concentration of creatinine and potassium levels in the blood plasma.

Patients with liver dysfunction

Co-Dalneva® is contraindicated in patients with severe liver failure (see section “Contraindications”).

Caution should be exercised when using the drug in patients with mild to moderate liver dysfunction.

Ko-Dalneva®

Renal dysfunction

Co-Dalneva® is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 ml/min).

The drug Co-Dalneva® can be used in patients with moderate renal impairment (creatinine clearance 30-60 ml/min). For such patients, individual selection of doses of amlodipine, indapamide, and perindopril is recommended.

In some patients with hypertension without previous obvious renal impairment, laboratory signs of functional renal failure may appear during therapy. In this case, treatment with the drug should be stopped. In the future, combination therapy can be resumed using low doses of a combination of perindopril and indapamide, or these drugs can be used separately. Such patients require regular monitoring of potassium levels and creatinine concentrations in the blood serum 2 weeks after the start of therapy and every 2 months thereafter.

In patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney during therapy with ACE inhibitors, there may be an increase in the concentration of urea and creatinine in the blood serum, which usually resolves when therapy is discontinued.

The development of renal failure more often occurs in patients with severe CHF or underlying renal impairment, including renal artery stenosis.

Arterial hypotension and water-electrolyte imbalance

Patients with hyponatremia (especially with renal artery stenosis, including bilateral) are at risk of sudden development of arterial hypotension. Therefore, you should pay attention to possible symptoms of dehydration and decreased electrolyte levels in the blood plasma, for example, after diarrhea or vomiting. The use of ACE inhibitors causes blockade of the RAAS, and therefore may be accompanied by a sharp decrease in blood pressure and/or an increase in the concentration of creatinine in the blood plasma, which indicates the development of functional renal failure. These phenomena are more often observed when taking the first dose of the drug or during the first two weeks of therapy and sometimes develop acutely. Such patients require regular monitoring of blood plasma electrolyte levels. In case of severe arterial hypotension, intravenous administration of 0.9% sodium chloride solution may be required. Transient arterial hypotension is not a contraindication for continued therapy. After restoration of circulating blood volume (CBV) and blood pressure, treatment can be resumed using low doses of perindopril and indapamide, or used separately.

Elderly patients

Before starting to take Co-Dalneva®, it is necessary to evaluate the functional activity of the kidneys and the potassium content in the blood plasma. At the beginning of therapy, the dose of the drug is selected taking into account the degree of decrease in blood pressure, especially in the case of a decrease in blood volume and loss of electrolytes, which helps to avoid a sharp decrease in blood pressure.

Atherosclerosis

The risk of developing arterial hypotension exists in all patients, however, special caution should be observed in patients with coronary artery disease and cerebrovascular diseases. In such patients, treatment begins with low doses of the drug.

Children

The drug Co-Dalneva® is contraindicated for use in children under 18 years of age due to the lack of data on effectiveness and safety in this age group.

Amlodipine

During treatment with amlodipine, it is necessary to monitor body weight and sodium intake, and prescribe an appropriate diet. It is necessary to maintain dental hygiene and follow-up with a dentist (to prevent pain, bleeding and gum hyperplasia).

Patients with low body weight, patients of short stature and patients with severe liver dysfunction may require a lower dose.

CHF

In patients with CHF (functional class III and IV according to the NYHA classification), treatment is carried out with caution, due to the possibility of developing pulmonary edema. BMCCs, including amlodipine, should be used with caution in patients with CHF due to a possible increased risk of adverse events from the cardiovascular system and mortality.

Liver dysfunction

In patients with impaired liver function, T1/2 and AUC of camlodipine increase. Amlodipine should be started with the lowest doses and caution should be exercised both when starting therapy and when increasing the dose of amlodipine. In patients with severe hepatic impairment, the dose should be increased gradually and careful monitoring of the clinical condition is required.

Elderly patients

In elderly patients, T1/2 may increase and the clearance of samlodipine may decrease. No dosage adjustment is required, but careful monitoring of patients is necessary.

Indapamide

In the presence of liver dysfunction, taking thiazide and thiazide-like diuretics can lead to the development of hepatic encephalopathy. In this case, you should immediately stop taking the drug.

Photosensitivity

Cases of photosensitivity reactions have been reported while taking thiazide and thiazide-like diuretics. If a photosensitivity reaction develops, treatment should be discontinued. If it is necessary to continue diuretic therapy, it is recommended to protect the skin from exposure to sunlight or artificial ultraviolet rays.

Water and electrolyte balance

Sodium content in blood plasma

Before starting treatment, it is necessary to determine the sodium content in the blood plasma. While taking the drug, this indicator should be regularly monitored. All diuretics can cause hyponatremia, which sometimes leads to serious complications. At the initial stage of therapy, a decrease in sodium levels in the blood plasma may be asymptomatic, so regular laboratory monitoring is necessary. Elderly patients are advised to monitor plasma sodium levels more frequently.

Hyponatremia in combination with hypovolemia can cause dehydration and orthostatic hypotension.

A concomitant decrease in chlorine content in the blood plasma can lead to secondary compensatory metabolic alkalosis (the incidence and severity of this effect are insignificant).

Potassium content in blood plasma

Therapy with thiazide and thiazide-like diuretics is associated with a risk of hypokalemia. It is necessary to avoid hypokalemia (less than 3.4 mmol/l) in the following categories of patients from high-risk groups: elderly patients, malnourished patients, patients with liver cirrhosis, including edema and ascites, patients with coronary artery disease, CHF. In such patients, hypokalemia enhances the toxic effect of cardiac glycosides and increases the risk of developing arrhythmia.

Patients with a prolonged QT interval, either hereditary or drug-induced, are also at increased risk. Hypokalemia, like bradycardia, contributes to the development of severe cardiac arrhythmias, especially polymorphic ventricular tachycardia of the “pirouette” type, which can be fatal. In all the cases described above, regular monitoring of the potassium content in the blood plasma is necessary. It is necessary to determine the potassium content in the blood plasma during the first week after starting therapy. If hypokalemia is detected, appropriate therapy should be provided.

Calcium content in blood plasma

Thiazide and thiazide-like diuretics reduce the excretion of calcium by the kidneys, which may cause a slight temporary increase in plasma calcium. Severe hypercalcemia may be associated with previously undiagnosed hyperparathyroidism. In such cases, it is necessary to conduct a study of the function of the parathyroid glands, having first stopped taking diuretics.

Uric acid

In patients with elevated concentrations of uric acid in the blood plasma, the frequency of gout attacks may increase during therapy.

Renal dysfunction

Thiazide and thiazide-like diuretics are fully effective only in patients with normal or slightly impaired renal function (plasma creatinine concentration in adult patients below 25 mg/l or 220 µmol/l). In elderly patients, CC is calculated taking into account age, body weight and gender.

In patients with hypovolemia and hyponatremia at the beginning of diuretic therapy, a temporary decrease in GFR and an increase in the concentration of urea and creatinine in the blood plasma may be observed. This transient functional renal failure is not dangerous for patients with unchanged renal function, but its severity may increase in patients with renal failure.

In such patients, potassium levels and plasma creatinine concentrations should be regularly monitored.

Athletes

Indapamide may give a positive reaction during doping control.

Acute myopia and secondary acute angle-closure glaucoma

Sulfonamides and their derivatives can cause an idiosyncratic reaction, leading to the development of acute transient myopia and an acute attack of angle-closure glaucoma. If left untreated, an acute attack of angle-closure glaucoma can lead to permanent vision loss. First of all, it is necessary to stop taking the drug as quickly as possible. If intraocular pressure remains uncontrolled, emergency medication or surgery may be required. Risk factors for the development of an acute attack of angle-closure glaucoma are a history of allergic reactions to sulfonamide derivatives and penicillins.

Perindopril

Double blockade of the RAAS

There is evidence of an increased risk of arterial hypotension, hyperkalemia and renal dysfunction (including acute renal failure) with simultaneous use of ACE inhibitors and ARB II or aliskiren. Therefore, double blockade of the RAAS by combining an ACE inhibitor with ARA II or aliskiren is not recommended (see section “Interaction with other drugs”). If a double blockade is necessary, then this should be performed under the strict supervision of a specialist with regular monitoring of kidney function, potassium levels in the blood plasma and blood pressure.

Concomitant use of ACE inhibitors with aliskiren or drugs containing aliskiren is contraindicated in patients with diabetes 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.

Concomitant use of ACE inhibitors with ARB II is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Neutropenia/Agranulocytosis/Thrombocytopenia/Anemia

While taking ACE inhibitors, neutropenia/agranulocytosis, thrombocytopenia and anemia may occur. In patients with normal renal function in the absence of other risk factors, neutropenia rarely develops. After discontinuation of the ACE inhibitor, neutropenia and agranulocytosis resolve on their own. Perindopril should be used with extreme caution in patients with systemic connective tissue diseases during therapy with 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 using perindopril in such patients, it is recommended to periodically monitor the number of leukocytes in the blood plasma. If any symptoms of infectious diseases (for example, sore throat, fever) appear, patients should consult a doctor.

Hypersensitivity/angioedema

While taking ACE inhibitors, including perindopril, in rare cases, the development of angioedema of the face, extremities, lips, tongue, vocal folds and/or larynx may occur. If symptoms appear, you should immediately stop taking the drug and continue to monitor the patient until symptoms are completely relieved. As a rule, swelling of the face and lips does not require treatment, although antihistamines can be used to relieve symptoms.

Angioedema, accompanied by swelling of the larynx, can be fatal. Swelling of the tongue, vocal folds, or larynx can lead to airway obstruction. If such symptoms appear, you should immediately administer a subcutaneous solution of epinephrine (adrenaline) at a dilution of 1:1000 (0.3-0.5 ml) and/or ensure airway patency. Patients with a history of angioedema not associated with taking ACE inhibitors may have an increased risk of developing it when taking drugs of this group.

In rare cases, angioedema of the intestine develops during therapy with ACE inhibitors. In this case, patients complain of abdominal pain as an isolated symptom or in combination with nausea and vomiting, in some cases without previous angioedema of the face and with a normal level of C1-esterase. The diagnosis was made using computed tomography, ultrasound examination of the abdominal organs, or during surgery. Symptoms disappear after stopping ACE inhibitors. Therefore, in patients with complaints of abdominal pain taking ACE inhibitors, when carrying out differential diagnosis, it is necessary to take into account the possibility of developing angioedema of the intestine.

mTOR inhibitors

In patients concomitantly taking mTOR inhibitors (eg, sirolimus, everolimus, temsirolimus), therapy may be associated with an increased risk of angioedema (eg, swelling of the upper respiratory tract or tongue with or without respiratory distress).

Anaphylactoid reactions during desensitization

There are isolated reports of the development of anaphylactoid reactions in patients taking ACE inhibitors during desensitizing therapy (for example, hymenoptera venom: bees, wasps). The development of such reactions was avoided by temporarily discontinuing ACE inhibitors (at least 24 hours before desensitization); if an ACE inhibitor was accidentally taken, the anaphylactoid reaction occurred again.

Anaphylactoid reactions during LDL apheresis

In rare cases, life-threatening anaphylactoid reactions may occur in patients receiving ACE inhibitors during LDL apheresis using dextran sulfate. To prevent such reactions, ACE inhibitors should be temporarily discontinued before each apheresis procedure.

Hemodialysis

In rare cases, anaphylactoid reactions have developed in patients receiving ACE inhibitors during hemodialysis using high-flux membranes (for example, AN69®). Therefore, it is recommended to use a different type of membrane or use an antihypertensive drug of a different pharmacotherapeutic group.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism are usually refractory to antihypertensive drugs that act by inhibiting the RAAS. Therefore, the use of this drug is not recommended.

Cough

During therapy with ACE inhibitors, a dry cough may occur. The cough persists for a long time while taking drugs of this group and disappears after their discontinuation. If a patient develops a dry cough, one should remember the possibility of its occurrence in connection with taking an ACE inhibitor. If it is necessary to use drugs in this group, taking an ACE inhibitor can be continued.

Aortic and mitral stenosis, HOCM

ACE inhibitors should be used with caution in patients with left ventricular outflow tract obstruction and mitral stenosis.

diabetes mellitus

In patients with diabetes mellitus receiving oral hypoglycemic agents or insulin, regular monitoring of plasma glucose concentrations is necessary during the first month of treatment with an ACE inhibitor.

Surgery/general anesthesia

The use of ACE inhibitors in patients undergoing surgery under general anesthesia can lead to a significant decrease in blood pressure, especially when using general anesthetic agents that have antihypertensive effects. It is recommended to stop taking long-acting ACE inhibitors, including perindopril, 24 hours before surgery.

Ethnic differences

In patients of the Negroid race, angioedema develops more often than in representatives of other races while using ACE inhibitors. Perindopril, like other ACE inhibitors, apparently has a less pronounced antihypertensive effect in patients of the Black race compared to representatives of other races. Perhaps this difference is due to the fact that black patients with arterial hypertension more often have low plasma renin activity.

Liver failure

In rare cases, cholestatic jaundice occurs while taking ACE inhibitors. As this syndrome progresses, fulminant liver necrosis develops, sometimes with death. The mechanism of development of this syndrome is unclear. If there is a significant increase in the activity of liver enzymes or the appearance of jaundice while taking ACE inhibitors, you should stop taking the drug and continue to monitor the patient.

Hyperkalemia

The use of ACE inhibitors may cause hyperkalemia due to inhibition of aldosterone release, which is usually mild in patients with normal renal function. Risk factors for hyperkalemia are renal failure, old age (over 70 years), diabetes mellitus, some concomitant conditions (dehydration, acute decompensation of chronic heart failure, metabolic acidosis), simultaneous use of potassium-sparing diuretics (spironolactone, eplerenone, triamterene, amiloride), potassium supplements, potassium-containing substitutes for table salt, as well as other drugs that increase plasma potassium levels (for example, heparin, trimethoprim or co-trimoxazole (sulfamethoxazole + trimethoprim) and especially aldosterone antagonists or ARB II, ASA ≥ 3 g/day, COX-2 inhibitors and non-selective NSAIDs, immunosuppressants such as cyclosporine or tacrolimus (especially in patients with reduced function kidneys). Hyperkalemia can lead to serious, sometimes fatal, cardiac arrhythmias. Caution should be exercised when using ACE inhibitors and potassium-sparing diuretics and ARB II; renal function and serum potassium levels should be monitored.

Kidney transplant

There is no experience with the use of perindopril in patients with recent kidney transplantation.

Renovascular hypertension

The treatment method for renovascular hypertension is revascularization. However, the use of ACE inhibitors may be effective in patients with renovascular hypertension, both awaiting surgery and those who cannot undergo surgery.

In patients with bilateral renal artery stenosis or renal artery stenosis of a single functioning kidney, the risk of arterial hypotension and renal failure increases during therapy with ACE inhibitors. Taking diuretics may be an additional risk factor. Deterioration of renal function can be observed with even a slight change in plasma creatinine concentration, even in patients with unilateral renal artery stenosis.

In patients with diagnosed or suspected renal artery stenosis, treatment should begin with lower doses of Co-Dalneva®. Some patients may develop functional renal failure, which resolves after discontinuation of the drug.

Due to the possibility of weakness and dizziness while using the drug Co-Dalneva®, care must be taken when driving vehicles and working with other technical devices that require increased concentration and speed of psychomotor reactions.

Active ingredient

Amlodipine, Indapamide, Perindopril

Composition

For 1 tablet 5 mg + 2.5 mg + 8 mg

Active ingredients:

Amlodipine besylate (amlodipine besylate) 6.935 mg, equivalent to amlodipine 5.000 mg Indapamide 2.500 mg

Perindoprilaerbumine B, granular substance 40.824 mg

[Active ingredient of the granular substance: Perindoprilaerbumine 8,000 mg

Excipients of granular substance: microcrystalline cellulose, calcium chloride hexahydrate]

Excipients: microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, sodium bicarbonate, colloidal silicon dioxide, magnesium stearate.

Pregnancy

Pregnancy

Co-Dalneva® is contraindicated during pregnancy (see section “Contraindications”).

If you are planning pregnancy or if it occurs while taking Co-Dalneva®, you should immediately stop taking it and prescribe alternative antihypertensive therapy with a proven safety profile.

The safety of amlodipine during pregnancy has not been established. The limited available data on the use of amlodipine and other BMCCs during pregnancy indicate the absence of negative effects on the fetus. In animal experiments, signs of reproductive toxicity were observed when using high doses of amlodipine.

Some patients receiving BMCC therapy experienced a reversible decrease in sperm motility. There is insufficient clinical data regarding the potential effect of amlodipine on reproductive function.

There are no or limited data on the use of indapamide in pregnant women (less than 300 cases). Long-term use of thiazide diuretics in the third trimester of pregnancy can cause hypovolemia in the mother and a decrease in uteroplacental blood flow, which leads to fetoplacental ischemia and fetal growth retardation. In rare cases, while taking diuretics shortly before birth, newborns develop hypoglycemia and thrombocytopenia.

Animal studies have not revealed direct or indirect toxic effects on reproductive function.

As a precaution, it is recommended to avoid the use of indapamide during pregnancy.

The available data on the teratogenicity of ACE inhibitors in the first trimester of pregnancy are not convincing, but this risk cannot be completely excluded. In the second and third trimesters of pregnancy, the effect of ACE inhibitors on the fetus can lead to disruption of its development (decreased renal function, oligohydramnios, delayed ossification of the skull bones) and the development of complications in newborns (renal failure, arterial hypotension, hyperkalemia).

If an ACE inhibitor was used in the second or third trimester of pregnancy, it is recommended to conduct an ultrasound examination of the fetal kidneys and skull bones. Newborns whose mothers received ACE inhibitors during pregnancy require careful medical supervision, as there is a risk of developing arterial hypotension.

Breastfeeding period

Amlodipine is excreted in breast milk. The proportion of maternal dose received by the child was estimated at an interquartile range of 3% to 7%, with a maximum of 15%. The effect of amlodipine on infants is unknown. The decision to continue/discontinue breastfeeding or continue/discontinue amlodipine therapy should be made taking into account the benefits of breastfeeding for the child and the benefits of amlodipine for the mother.

At the moment, there is no reliable information about the excretion of indapamide or its metabolites in breast milk.

Taking thiazide diuretics causes a decrease or suppression of lactation in the mother; the newborn may develop hypersensitivity to sulfonamide derivatives, hypokalemia and nuclear jaundice.

Indapamide is contraindicated during breastfeeding.

It is unknown whether perindopril is excreted in breast milk.

Co-Dalneva® is contraindicated during breastfeeding. If it is necessary to use the drug Co-Dalneva® during lactation, breastfeeding should be discontinued.

Contraindications

Hypersensitivity to amlodipine and other dihydropyridine derivatives, indapamide and other sulfonamide derivatives, perindopril and other ACE inhibitors, as well as to the excipients included in the drug.
History of angioedema (Quincke’s edema) associated with taking ACE inhibitors.
Hereditary/idiopathic angioedema.
Severe arterial hypotension (systolic blood pressure less than 90 mm Hg).
Shock, including cardiogenic shock.
Left ventricular outflow tract obstruction (eg, clinically significant aortic stenosis).
Hemodynamically unstable heart failure after acute myocardial infarction.
Severe renal failure (creatinine clearance less than 30 ml/min).
Severe liver failure, including hepatic encephalopathy.
Refractory hypokalemia.
Concomitant use with aliskiren or drugs containing aliskiren in patients with diabetes mellitus and/or moderate or severe renal impairment (glomerular filtration rate (GFR) less than 60 ml/min/1.73 m2 body surface area).
Concomitant use with angiotensin II receptor antagonists (ARA II) in patients with diabetic nephropathy.
Concomitant use with neutral endopeptidase inhibitors (for example, with drugs containing sacubitril) due to the high risk of developing angioedema (see section “Interaction with other drugs”).
extracorporeal treatments using certain membranes with a negatively charged surface.
Severe bilateral renal artery stenosis or renal artery stenosis of a single functioning kidney.
Pregnancy and breastfeeding (see section “Use during pregnancy and breastfeeding”).
Age up to 18 years (efficacy and safety have not been established).

Given the lack of sufficient clinical experience, it should not be used in patients on hemodialysis, as well as in patients with untreated heart failure in the stage of decompensation.

Interaction

Amlodipine

Concomitant use is not recommended

Dantrolene (intravenous administration)

Cases of fatal ventricular fibrillation and collapse have been reported in laboratory animals with the use of verapamil and intravenous (IV) dantrolene, accompanied by hyperkalemia. Due to the risk of hyperkalemia, it is recommended to avoid the simultaneous use of BMCC (amlodipine) and dantrolene in patients susceptible to malignant hyperthermia, as well as in the treatment of malignant hyperthermia.

Concomitant use requiring special attention

Inducers of the CYP3A4 isoenzyme

With simultaneous use of inducers of the CYP3A4 isoenzyme, the concentration of amlodipine in the blood plasma may change. Therefore, it is necessary to monitor blood pressure and adjust the dose both during and after simultaneous use, especially with strong inducers of the CYP3A4 isoenzyme (for example, rifampicin, St. John’s wort preparations).

CYP3A4 isoenzyme inhibitors

The simultaneous use of amlodipine with strong or moderate inhibitors of the CYP3A4 isoenzyme (protease inhibitors, azole antifungals, macrolides, for example, erythromycin or clarithromycin, verapamil or diltiazem) can lead to a significant increase in the concentration of amlodipine, which increases the risk of arterial hypotension. Clinical manifestations of these pharmacokinetic abnormalities may be more pronounced in elderly patients. In this regard, monitoring of the clinical condition and dose adjustment may be required.

Mammalian mechanistic target of rapamycin (mTOR) inhibitors

mTOR inhibitors, such as xirolimus, temsirolimus and everolimus, are substrates of the CYP3A isoenzyme. Amlodipine is a weak inhibitor of the CYP3A isoenzyme. When used concomitantly with mTOR inhibitors, amlodipine may increase their exposure.

Clarithromycin

Clarithromycin is an inhibitor of the CYP3A4 isoenzyme. With simultaneous use of amlodipine and clarithromycin, the risk of developing arterial hypotension is increased. Close medical monitoring of patients receiving amlodipine concomitantly with clarithromycin is recommended.

Tacrolimus

When used concomitantly with amlodipine, there is a risk of increasing the concentration of tacrolimus in the blood plasma, but the pharmacokinetic mechanism of this interaction has not been fully studied. To prevent the toxic effect of tacrolimus when used concomitantly with amlodipine, the concentration of tacrolimus in the blood plasma should be monitored and the dose of tacrolimus should be adjusted if necessary.

Cyclosporine

Drug interaction studies have not been conducted with cyclosporine and amlodipine in healthy volunteers or other patient populations, except for renal transplant patients in whom variable trough concentrations (mean: 0%-40%) of cyclosporine were observed. With the simultaneous use of amlodipine in patients who have undergone kidney transplantation, the concentration of cyclosporine in the blood plasma should be monitored and, if necessary, its dose should be reduced.

Simvastatin

Simultaneous repeated use of amlodipine at a dose of 10 mg and with imvastatin at a dose of 80 mg increases the exposure of simvastatin by 77% compared with that of monotherapy with imvastatin. For patients receiving amlodipine, it is recommended to use simvastatin at a dose of no more than 20 mg/day.

Concomitant use requiring attention

Amlodipine enhances the antihypertensive effect of drugs for antihypertensive therapy.

Tasonermin

With simultaneous use, amlodipine may increase the systemic exposure of tasonermin in blood plasma. In such cases, regular monitoring of the concentration of tasonermin in the blood and dose adjustment if necessary is necessary.

Other drug combinations

Cimetidine

Cimetidine does not affect the pharmacokinetics of amlodipine.

Aluminum- or magnesium-containing antacids

A single dose of aluminum or magnesium-containing antacids does not have a significant effect on the pharmacokinetics of amlodipine.

Sildenafil

A single dose of 100 mg of sildenafil in patients with essential hypertension does not affect the pharmacokinetic parameters of amlodipine.

In clinical drug interaction studies, amlodipine had no effect on the pharmacokinetics of atorvastatin, digoxin, or warfarin.

Concomitant use of amlodipine and consumption of grapefruits or grapefruit juice is not recommended due to the possible increase in the bioavailability of amlodipine in some patients, which may lead to an enhanced antihypertensive effect.

Indapamide

Concomitant use requiring special attention

Drugs that can cause polymorphic ventricular tachycardia of the “pirouette” type

Considering the risk of developing hypokalemia, caution should be exercised when using indapamide simultaneously with drugs that can cause polymorphic ventricular tachycardia of the torsade de pointes type, for example, antiarrhythmic drugs (quinidine, hydroquinidine, disopyramide, amiodarone, dofetilide, ibutilide, bretylium atosylate, sotalol), some antipsychotics (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoroperazine), benzamides (amisulpride, sulpiride, sultopride, tiapride), butyrophenones (droperidol, haloperidol), other antipsychotics (pimozide), other drugs such as bepridil, cisapride, difemanyl methyl sulfate, erythromycin IV, halofantrine, mizolastine, moxifloxacin, pentamidine, sparfloxacin, vincamine IV, methadone, astemizole, terfenadine. If hypokalemia develops, simultaneous use with the above drugs should be avoided, its correction should be carried out, and ECG (QT interval) monitoring should be monitored.

Drugs that can cause hypokalemia

Concomitant use with intravenous amphotericin B, systemic glucocorticosteroids and mineralocorticosteroids, tetracosactide, laxatives that stimulate gastrointestinal motility increases the risk of hypokalemia (additive effect). It is necessary to monitor the potassium content in the blood plasma and, if necessary, correct hypokalemia. Particular caution should be observed when used simultaneously with cardiac glycosides. Laxatives that do not stimulate gastrointestinal motility should be used.

Cardiac glycosides

Hypokalemia enhances the toxic effect of cardiac glycosides. With simultaneous use, you should monitor the potassium content in the blood plasma and ECG indicators and, if necessary, decide on the advisability of continuing therapy.

Concomitant use requiring attention

Metformin

Functional renal failure, which can occur while taking diuretics, especially loop diuretics, with simultaneous use of metformin increases the risk of developing lactic acidosis. Metformin should not be used if plasma creatinine clearance exceeds 15 mg/l (135 µmol/l) in men and 12 mg/l (110 µmol/l) in women.

Iodinated contrast agents

Dehydration while taking diuretics increases the risk of developing acute renal failure, especially when high doses of iodinated contrast agents are administered. Before using iodinated contrast agents, it is necessary to compensate for hypovolemia.

Calcium salts

With simultaneous use, the development of hypercalcemia may occur due to a decrease in calcium excretion by the kidneys.

Cyclosporine

It is possible to increase QC in blood plasma without changing the concentration of cyclosporine, even with normal water and sodium content.

Perindopril

Data from clinical studies show that dual blockade of the RAAS as a result of concomitant use of ACE inhibitors, ARB II or aliskiren leads to an increased incidence of adverse events such as arterial hypotension, hyperkalemia and renal dysfunction (including acute renal failure), compared with situations where only one drug acting on the RAAS is used (see sections “Pharmacodynamics”, “Contraindications” and “Special Instructions”).

Drugs that cause hyperkalemia

Certain drugs or classes of drugs may increase the incidence of hyperkalemia: aliskiren, potassium salts, potassium-sparing diuretics, ACE inhibitors, ARB II, NSAIDs, heparin, immunosuppressants such as cyclosporine or tacrolimus, drugs containing trimethoprim.

Concomitant use with these drugs increases the risk of developing hyperkalemia.

Concomitant use is contraindicated

Aliskiren

Patients with diabetes mellitus or renal failure have an increased risk of hyperkalemia, worsening renal function, increased incidence of cardiovascular adverse events, and cardiovascular mortality.

The simultaneous use of ACE inhibitors with aliskiren or drugs containing aliskiren in patients with diabetes mellitus and/or moderate or severe renal impairment (GFR < 60 ml/min/1.73 m2 body surface area) is contraindicated (see section "Contraindications").

Neutral endopeptidase inhibitors

An increased risk of angioedema has been reported with concomitant use of ACE inhibitors and racecadotril (renkephalinase inhibitor).

When ACE inhibitors are used simultaneously with drugs containing sacubitril (neprilysin inhibitor), the risk of developing angioedema increases, and therefore the simultaneous use of these drugs is contraindicated. ACE inhibitors should be prescribed no earlier than 36 hours after discontinuation of drugs containing sacubitril. Prescription of drugs containing sacubitril is contraindicated in patients receiving ACE inhibitors, as well as within 36 hours after discontinuation of ACE inhibitors.

Extracorporeal therapy

Extracorporeal treatments that expose blood to negatively charged surfaces, such as hemodialysis using high-flux membranes (eg, polyacrylonitrile membranes) and LDL apheresis using dextran sulfate, may increase the risk of severe anaphylactoid reactions (see Contraindications). Therefore, it is advisable to use a different type of membrane or use an antihypertensive drug of a different pharmacotherapeutic group.

Concomitant use is not recommended

Aliskiren

In patients without diabetes mellitus or renal impairment, there may be an increased risk of hyperkalemia, worsening renal function, and increased incidence of cardiovascular morbidity and mortality.

Double blockade of the renin-angiotensin-aldosterone system in patients with atherosclerosis, CHF or diabetes accompanied by target organ damage is associated with a higher incidence of arterial hypotension, syncope, hyperkalemia and renal dysfunction (including the development of acute renal failure) compared with the use of a drug from one of the listed groups. Double blockade of the RAAS is possible only in selected cases under careful monitoring of renal function, potassium levels and blood pressure.

Concomitant use of ACE inhibitors with ARB II is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Estramustine

The simultaneous use of ACE inhibitors with estramustine is accompanied by a risk of developing angioedema.

Lithium

With the simultaneous use of lithium preparations and ACE inhibitors, a reversible increase in the content of lithium in the blood serum and associated toxic effects may be observed. The use of perindopril in combination with indapamide and lithium is not recommended, but if necessary, serum lithium levels should be carefully monitored.

The simultaneous use of thiazide diuretics may further increase the content of lithium in the blood plasma and increase the risk of its toxic effect while taking an ACE inhibitor.

The simultaneous use of a combination of perindopril and indapamide with lithium preparations is not recommended. If simultaneous use is necessary, it is necessary to carefully monitor the lithium content in the blood plasma.

Potassium-sparing diuretics, potassium preparations and potassium-containing table salt substitutes

During therapy with ACE inhibitors, the potassium content in the blood plasma, as a rule, remains within normal limits, but hyperkalemia may develop. The simultaneous use of potassium-sparing diuretics (triamterene, amiloride), potassium supplements and potassium-containing table salt substitutes can lead to a significant increase in potassium levels in the blood plasma. Caution should also be exercised when using perindopril concomitantly with other drugs that increase serum potassium levels, such as trimethoprim and co-trimoxazole (sulfamethoxazole + trimethoprim), since trimethoprim is known to act similarly to the potassium-sparing diuretic amiloride. If it is necessary to take an ACE inhibitor simultaneously with the above drugs (in case of hypokalemia), caution should be exercised and regular monitoring of potassium levels in the blood plasma and ECG parameters should be carried out.

mTOR inhibitors (eg, sirolimus, everolimus, temsirolimus)

In patients taking both an ACE inhibitor and an mTOR inhibitor, therapy may be associated with an increased risk of angioedema.

Concomitant use requiring special attention

Nonsteroidal anti-inflammatory drugs (NSAIDs), including high doses of acetylsalicylic acid (ASA) (more than 3 g/day)

Concomitant use of ACE inhibitors with NSAIDs (including ASA at a dose that has an anti-inflammatory effect, cyclooxygenase-2 (COX-2) inhibitors and non-selective NSAIDs) may lead to a decrease in the antihypertensive effect, as well as a deterioration in renal function, including the development of acute renal failure, and an increase in plasma potassium, especially in patients with reduced renal function. Caution should be exercised when using this combination, especially in elderly patients. Patients need to compensate for fluid loss and regularly monitor kidney function both at the beginning of treatment and during treatment.

Hypoglycemic agents (insulin, hypoglycemic agents for oral administration)

Epidemiological studies have shown that the simultaneous use of ACE inhibitors and hypoglycemic agents (insulin, oral hypoglycemic agents) can enhance the hypoglycemic effect of insulin and oral hypoglycemic agents, up to the development of hypoglycemia. This effect is most likely to be observed during the first weeks of concomitant therapy, as well as in patients with impaired renal function.

Potassium-sparing diuretics

In patients taking diuretics, especially those that remove fluid and/or salts, a significant decrease in blood pressure may be observed when initiating therapy with an ACE inhibitor. The risk of developing a hypotensive effect can be reduced by discontinuing the diuretic, replacing fluid or salt loss before starting perindopril therapy, as well as prescribing a low dose of perindopril with a gradual increase.

For arterial hypertension in patients with previous diuretic therapy, which could lead to excessive excretion of fluid and/or salts, diuretics should be discontinued before starting the use of ACE inhibitors (in this case, a potassium-sparing diuretic can be re-prescribed later) or treatment with an ACE inhibitor should be started at a low dose and gradually increased.

When using diuretics for the treatment of CHF, an ACE inhibitor should be prescribed in a very low dose, possibly after reducing the dose of a potassium-sparing diuretic used simultaneously.

In all cases, renal function (creatinine concentration) should be monitored in the first weeks of using an ACE inhibitor.

Potassium-sparing diuretics (eplerenone, spironolactone)

The use of eplerenone or spironolactone in doses from 12.5 mg to 50 mg per day and low doses of ACE inhibitors: when treating heart failure of functional class II-IV according to the NYHA classification with a left ventricular ejection fraction <40% in patients who have previously received ACE inhibitors and loop diuretics, there is a risk of developing hyperkalemia (with possible death), especially if the recommendations for this combination of drugs are not followed.

Before using this combination of drugs, you must ensure that there is no hyperkalemia or renal failure.

Regular monitoring of creatinine concentrations and potassium levels in the blood plasma is necessary weekly in the first month of therapy and monthly thereafter.

Concomitant use requiring attention

Allopurinol, cytostatic and immunosuppressive drugs, glucocorticosteroids (for systemic use) and procainamide

Concomitant use with ACE inhibitors may increase the risk of developing leukopenia.

Preparations for general anesthesia

The simultaneous use of ACE inhibitors and general anesthesia may lead to increased antihypertensive effect.

Gold preparations

When using ACE inhibitors, including perindopril, in patients receiving intravenous gold (sodium aurothiomalate), a symptom complex was described, including facial flushing, nausea, vomiting, and arterial hypotension.

Co-trimoxazole (sulfamethoxazole + trimethoprim)

Concomitant use with ACE inhibitors may increase the risk of developing hyperkalemia.

Gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin)

Concomitant use with ACE inhibitors may increase the risk of developing angioedema due to the inhibition of dipeptidyl peptidase IV (DPP-IV) activity by gliptin.

Sympathomimetics

Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.

Cyclosporine

Concomitant use with ACE inhibitors may increase the risk of developing hyperkalemia. It is recommended to monitor serum potassium levels.

Heparin

Concomitant use with ACE inhibitors may increase the risk of developing hyperkalemia. It is recommended to monitor serum potassium levels.

Tissue plasminogen activators

Observational studies have shown an increased incidence of angioedema in patients taking ACE inhibitors following the use of alteplase for thrombolytic therapy of ischemic stroke.

Ko-Dalneva®

Concomitant use requiring special attention

Baclofen

The antihypertensive effect may be enhanced. Blood pressure and renal function should be monitored and, if necessary, the dose of antihypertensive drugs should be adjusted.

Concomitant use requiring attention

Antihypertensives (eg, beta-blockers) and vasodilators

When used simultaneously with antihypertensive drugs, the antihypertensive effect may be enhanced. Caution should be exercised when used concomitantly with nitroglycerin, other nitrates or other vasodilators, since an additional decrease in blood pressure may occur.

Corticosteroids (mineral and glucocorticosteroids), tetracosactide (systemic action)

Decreased antihypertensive effect (fluid and sodium retention as a result of the action of corticosteroids).

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

Strengthening the antihypertensive effect and increasing the risk of developing orthostatic hypotension.

Amifostin

The antihypertensive effect of amlodipine may be enhanced.

Tricyclic antidepressants/neuroleptics/general anesthetics

Strengthening the antihypertensive effect and increasing the risk of developing orthostatic hypotension (additive effect).

Overdose

Symptoms

The most likely symptoms of overdose are a pronounced decrease in blood pressure with the possible development of reflex tachycardia and excessive peripheral vasodilation (risk of developing severe and persistent arterial hypotension, including the development of shock and death). Sometimes a pronounced decrease in blood pressure is accompanied by nausea, vomiting, convulsions, dizziness, drowsiness, confusion, oliguria, which can turn into anuria (as a result of hypovolemia). Disturbances in water and electrolyte balance (hyponatremia, hypokalemia) may also be observed.

Treatment

Emergency measures are aimed at removing the drug from the gastrointestinal tract: gastric lavage and/or taking activated charcoal, followed by restoration of water and electrolyte balance. If there is a pronounced decrease in blood pressure, the patient should be placed in an elevated position of the lower extremities, and, if necessary, correct hypovolemia (for example, intravenous infusion of 0.9% sodium chloride solution).

Perindoprilate, the active metabolite of perindopril, is removed by hemodialysis. Amlodipine binds closely to plasma proteins, so hemodialysis is ineffective.

Indapamide is not removed by hemodialysis.

Storage conditions

At a temperature not exceeding 25 ºС, in the original packaging.

Keep out of the reach of children.

Shelf life

2 years.

Do not use the drug after the expiration date.

Manufacturer

KRKA-RUS, Russia