Consilar-D24, capsules 1.25mg+5 mg 30 pcs

Pharmacotherapeutic group

Hypertensive combined (diuretic + angiotensin-converting enzyme inhibitor (ACE inhibitor)).

ATX code

C09BA05

Pharmacological properties

Pharmacodynamics

Combined hypotensive drug containing the diuretic from the group of sulfonamide derivatives – indapamide and angiotensin-converting enzyme (ACE) inhibitor – ramipril. The pharmacological effect of the combination is due to the combination of individual properties of each of the components, which in turn reinforce each other’s action. The drug has antihypertensive, diuretic and vasodilatory actions.

Controlar-D24 has expressed dose-dependent antihypertensive effect both on systolic and diastolic blood pressure (BP). Antihypertensive effect does not depend on the age and body position of the patient. It does not affect lipid and carbohydrate metabolism, including in patients with diabetes.

The antihypertensive effect lasts for 24 hours.

A steady lowering of BP is achieved within 1 month of using CONSILAR-D24 without increasing of heart rate (HR). Discontinuation of treatment does not lead to development of “withdrawal” syndrome.

Indapamide

Indapamide belongs to derivatives of sulfonamide with an indole ring and has pharmacological properties similar to thiazide diuretics, which inhibit reabsorption of sodium ions in the cortical segment of the nephron loop. At the same time, renal excretion of sodium ions, chlorine and, to a lesser extent, potassium and magnesium ions increases, which is accompanied by increased diuresis and antihypertensive effect.

Indapamide reduces arterial smooth muscle tone and has a vasodilator effect, decreases total peripheral vascular resistance (TPR). These effects are mediated by the decrease of vascular wall reactivity to noradrenaline and angiotensin II; increase of prostaglandin E2 synthesis with vasodilator activity; inhibition of calcium current in vascular smooth muscle cells.

Indapamide promotes reduction of left ventricular hypertrophy.

Indapamide in monotherapy in doses that do not cause a pronounced diuretic effect has a 24-hour antihypertensive effect. Antihypertensive activity of indapamide is associated with improvement of elastic properties of large arteries, reduction of arteriolar and total peripheral vascular resistance.

The thiazide and thiazide-like diuretics reach a plateau of therapeutic effect at a certain dose, while the incidence of side effects continues to increase with further increase of the drug dose. Therefore, do not increase the dose of the drug if the therapeutic effect is not achieved at the recommended dose.

In short-, medium-, and long-term studies involving patients with arterial hypertension, it has been shown that indapamide:

– has no effect on lipid metabolism, including triglyceride, cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) concentrations;

– has no effect on carbohydrate metabolism, including in patients with diabetes.

Ramipril

The active metabolite of ramipril formed by liver enzymes, ramiprilate, is a long-acting ACE inhibitor (synonyms: kininase II, dipeptidylcarboxydipeptidase I), which is a peptidyl dipeptidase. ACE in blood plasma and tissues catalyzes the conversion of angiotensin I into angiotensin II, which has a vasoconstrictor effect, and the breakdown of bradykinin, which has a vasodilator effect. Therefore, oral administration of ramipril reduces angiotensin II formation and bradykinin accumulation, which leads to vasodilation and BP reduction. Increase of activity
of kallikrein-kinin system in blood and tissues causes cardioprotective and endoprotective effects of ramipril due to the activation of prostaglandin system and, correspondingly, increase of synthesis of prostaglandins that stimulate nitric oxide formation in endotheliocytes.

Angiotensin II stimulates production of aldosterone, so taking ramipril results in decreased secretion of aldosterone and increased plasma potassium ions.

When the concentration of angiotensin II in blood decreases, its negative feedback inhibitory effect on renin secretion is eliminated, resulting in increased plasma renin activity.

It is assumed that the development of some adverse reactions (in particular, dry cough) is also associated with increased bradykinin activity.

In patients with arterial hypertension administration of ramipril leads to a decrease in BP in lying and standing position without a compensatory increase in HR. Ramipril significantly reduces PPS with little or no change in renal blood flow and glomerular filtration rate. Antihypertensive effect begins to appear 1-2 hours after oral administration of a single dose of ramipril, reaching its greatest value after 3-6 hours, and lasts for 24 hours. When administered as a course, the antihypertensive effect may gradually increase, stabilizing usually by 3-4 weeks of regular ramipril administration and then persisting for a long time. Sudden discontinuation of ramipril does not lead to a rapid and significant increase in BP (no “withdrawal” syndrome).

In patients with arterial hypertension ramipril slows the development and progression of myocardial and vascular wall hypertrophy.

In patients with chronic heart failure, ramipril decreases PEEP (decreases afterload on the heart), increases venous capacitance and decreases left ventricular filling pressure, which consequently leads to a decrease in cardiac preload. In these patients, ramipril administration has increased cardiac output, ejection fraction and improved exercise tolerance.

In diabetic and nondiabetic nephropathy, taking ramipril slows the rate of progression of renal failure and time to end-stage renal failure and thus reduces the need for hemodialysis or renal transplantation. In the initial stages of diabetic or nondiabetic nephropathy, ramipril reduces the incidence of albuminuria.

In patients at high risk of cardiovascular disease Due to vascular lesions (diagnosed coronary heart disease (CHD), a history of peripheral arterial obliterative disease, a history of stroke) or diabetes with at least one additional risk factor (microalbuminuria, arterial hypertension, increased concentration of total cholesterol, decreased concentration of HDL cholesterol, smoking) the addition of ramipril to standard therapy significantly reduces the incidence of myocardial infarction, stroke and mortality from cardiovascular causes. In addition, ramipril reduces overall mortality as well as the need for revascularization procedures, and slows the onset or progression of chronic heart failure.

In patients with heart failure with clinical manifestations that developed during the first days of acute myocardial infarction (days 2-9), use of ramipril initiated from day 3 to day 10 of acute myocardial infarction reduced mortality (by 27%), risk of sudden death (by 30%), risk of progression of heart failure to severe (NYHA functional class III-IV)/resistant to therapy (by 23%), and likelihood of subsequent hospitalization due to development of heart failure (by 26%).

In the general patient population as well as in patients with diabetes mellitus (both hypertensive and normal AD, ramipril significantly reduces the risk of nephropathy and microalbuminuria.

Pharmacokinetics

The combined use of indapamide and ramipril has no effect on their pharmacokinetic parameters compared with taking these drugs in monotherapy.

Indapamide

absorption

The bioavailability of indapamide is 93%.

Released indapamide is quickly and completely absorbed in the gastrointestinal tract. Simultaneous intake of food slightly increases the time of absorption of indapamide without affecting the completeness of absorption. Maximum plasma concentration is reached 1-2 hours after a single oral dose of 2.5 mg. In repeated doses, the fluctuations in plasma concentrations of indapamide between doses are smoothed out. There is individual variability in indapamide absorption rates.

Distribution

About 75% of indapamide is bound to plasma proteins and due to its high affinity for elastin is concentrated in the smooth muscle of the vascular walls. It also binds to erythrocyte carboxyhydrazone without inhibiting the activity of this enzyme.

When taking the drug regularly, the equilibrium concentration of indapamide in plasma is increased (compared to a single dose). Equilibrium concentration is reached after 7 days of indapamide administration. No cumulation is observed when indapamide is taken repeatedly.

Metabolism

Indapamide is metabolized in the liver.

Elimation

The elimination half-life (T_1/2) is 14 to 24 h (18 h on average). It is excreted as inactive metabolites, mainly by the kidneys (60-80% of the dose taken) and through the intestine (22%). No more than 5% of indapamide is excreted unchanged by the kidneys.

Pharmacokinetics in special groups of patients

In patients with renal insufficiency pharmacokinetic parameters of indapamide do not change significantly.

Ramipril

absorption

. After oral administration, ramipril is rapidly absorbed from the gastrointestinal tract
(50-60%). Concomitant ingestion slows its absorption, but does not affect the completeness of absorption.

Distribution

The bioavailability of ramipril after oral administration ranges from 15% (for 2.5 mg dose) to 28% (for 5 mg dose). The bioavailability of the active metabolite, ramiprilate, after oral administration of 2.5 mg and 5 mg of ramipril is approximately 45% (compared to its bioavailability after intravenous administration at the same doses). After oral administration of ramipril, maximum plasma concentrations of ramipril and ramiprilate are reached after 1 and 2-4 hours, respectively.

Metabolism

. Ramipril undergoes extensive presystemic metabolism/activation (mainly in the liver by hydrolysis), which produces its only active metabolite, ramiprilate, which has approximately 6 times the activity of ramipril with respect to ACE inhibition. In addition, ramipril metabolism produces diketopiperazine, which has no pharmacological activity and then undergoes conjugation with glucuronic acid; ramiprilat is also glucuronized and metabolized to diketopiperazine acid.

Elimation

The decrease in plasma concentration of ramiprilat occurs in several phases: A distribution and excretion phase with a half-life (T_1/2) of ramiprilat of approximately 3 h, followed by an intermediate phase with T_1/2 of ramiprilat, which is approximately 15 h, and an end phase with very low plasma concentration of ramiprilat and T_1/2 ramiprilat, which is approximately 4-5 days. This end phase is due to the slow release of ramiprilat from its strong binding to ACE receptors. Despite the prolonged terminal phase when ramipril is administered orally at a single daily dose of 2.5 mg or more, the equilibrium plasma concentration of ramiprilat is reached after approximately 4 days of treatment. When the drug is administered in courses, the “effective” T_1/2 depending on the dose is
13-17 h.

After oral administration of radioactive isotope-labeled ramipril (10 mg), 39% of radioactivity is excreted through the intestine and about 60% by the kidneys. After intravenous administration of ramipril, 50-60% of the dose is detected in the urine as ramipril and its metabolites. After intravenous administration of ramiprilat about 70% of the dose is detected in the urine as ramiprilat and its metabolites, in other words, when ramipril and ramiprilat are administered intravenously, a significant part of the dose is excreted through the intestine with the bile, bypassing the kidneys (50% and 30%, respectively). After oral administration of 5 mg of ramipril in patients with bile duct drainage, almost equal amounts of ramipril and its metabolites are excreted by the kidneys and through the intestine during the first 24 h after administration.

About 80-90% of metabolites in urine and bile have been identified as ramipril and ramiprilate metabolites. Ramipril glucuronide and ramipril diketopiperazine account for approximately 10-20% of the total, and the urinary content of unmetabolized ramipril is approximately 2%.

In animal studies, ramipril has been shown to be excreted in maternal milk.

Pharmacokinetics in special patient groups

The pharmacokinetics of ramipril and ramiprilate are not significantly different in healthy elderly volunteers (65-76 years) than in young healthy volunteers.

In impaired renal function with creatinine clearance (CK) less than 60 mL/min, excretion of ramipril and its metabolites is delayed in proportion to the decrease in creatinine clearance (CK). This leads to an increase in plasma concentration of ramiprilat, which decreases more slowly than in patients with normal renal function.

When ramipril is taken at high doses (10 mg), impaired liver function leads to slower presystemic metabolism of ramipril to active ramiprilate and slower excretion of ramiprilate.

In patients with chronic heart failure, a 1.5-1.8-fold increase in plasma concentrations of ramiprilat and area under the pharmacokinetic curve “concentration-time” (AUC) was observed after two weeks of treatment with ramipril at a daily dose of 5 mg.

In healthy volunteers and in patients with arterial hypertension after two weeks of treatment with ramipril at a daily dose of 5 mg, there is no clinically significant accumulation of ramipril and ramiprilat.

Indications

Arterial hypertension of mild and moderate severity.

Pharmacological effect

Pharmacotherapeutic group

Combination antihypertensive drug (diuretic + angiotensin-converting enzyme inhibitor (ACE inhibitor)).

ATX code

C09BA05

Pharmacological properties

Pharmacodynamics

A combined antihypertensive drug containing a diuretic from the group of sulfonamide derivatives – indapamide and an angiotensin-converting enzyme (ACE) inhibitor – ramipril. The pharmacological effect of the combination is due to the combination of the individual properties of each of the components, which, in turn, enhance the effect of each other. The drug has antihypertensive, diuretic and vasodilating effects.

CONSILAR-D24 has a pronounced dose-dependent antihypertensive effect on both systolic and diastolic blood pressure (BP). The antihypertensive effect does not depend on the age and body position of the patient. Does not affect the metabolism of lipids and carbohydrates, including in patients with diabetes.

The antihypertensive effect lasts for 24 hours.

A stable reduction in blood pressure is achieved within 1 month with the use of the drug CONSILAR-D24 without an increase in heart rate (HR). Stopping treatment does not lead to the development of withdrawal syndrome.

Indapamide

Indapamide is a sulfonamide derivative with an indole ring and is similar in pharmacological properties to thiazide diuretics, which inhibit the reabsorption of sodium ions in the cortical segment of the nephron loop. At the same time, the kidneys excrete sodium and chloride ions and, to a lesser extent, potassium and magnesium ions, which is accompanied by an increase in diuresis and an antihypertensive effect.

Indapamide reduces the tone of the smooth muscles of the arteries and has a vasodilating effect, reduces total peripheral vascular resistance (TPVR). These effects are mediated by a decrease in the reactivity of the vascular wall to norepinephrine and angiotensin II; increased synthesis of prostaglandin E2, which has vasodilatory activity; inhibition of calcium flow in vascular smooth muscle cells.

Indapamide helps reduce left ventricular hypertrophy.

Indapamide in monotherapy in doses that do not cause a pronounced diuretic effect has a 24-hour antihypertensive effect. The antihypertensive activity of indapamide is associated with an improvement in the elastic properties of large arteries, a decrease in arteriolar and total peripheral vascular resistance.

Thiazide and thiazide-like diuretics at a certain dose reach a plateau of therapeutic effect, while the frequency of side effects continues to increase with further increases in the dose of the drug. Therefore, you should not increase the dose of the drug if a therapeutic effect is not achieved when using the recommended dose.

In short-term, intermediate-term and long-term studies in patients with hypertension, indapamide has been shown to:

– does not affect lipid metabolism parameters, including the concentration of triglycerides, cholesterol, low-density lipoproteins (LDL) and high-density lipoproteins (HDL);

– does not affect carbohydrate metabolism, including in patients with diabetes.

Ramipril

Formed under the influence of liver enzymes, the active metabolite of ramipril – ramiprilat – is a long-acting ACE inhibitor (synonyms: kininase II, dipeptidylcarboxydipeptidase I), which is a peptidyl dipeptidase. ACE in blood plasma and tissues catalyzes the conversion of angiotensin I to angiotensin II, which has a vasoconstrictor effect, and the breakdown of bradykinin, which has a vasodilator effect. Therefore, when ramipril is taken orally, the formation of angiotensin II decreases and bradykinin accumulates, which leads to vasodilation and a decrease in blood pressure. Increasing activity
The kallikrein-kinin system in the blood and tissues determines the cardioprotective and endothelial-protective effects of ramipril due to the activation of the prostaglandin system and, accordingly, an increase in the synthesis of prostaglandins that stimulate the formation of nitric oxide in endothelial cells.

Angiotensin II stimulates the production of aldosterone, so taking ramipril leads to a decrease in the secretion of aldosterone and an increase in the content of potassium ions in the blood plasma.

By reducing the concentration of angiotensin II in the blood, its inhibitory effect on renin secretion by negative feedback is eliminated, which leads to an increase in plasma renin activity.

It is assumed that the development of some undesirable reactions (in particular, dry cough) is also associated with an increase in bradykinin activity.

In patients with arterial hypertension, taking ramipril leads to a decrease in blood pressure in the “lying” and “standing” positions without a compensatory increase in heart rate. Ramipril significantly reduces peripheral vascular resistance, causing virtually no changes in renal blood flow and glomerular filtration rate. The antihypertensive effect begins to appear 1-2 hours after oral administration of a single dose of ramipril, reaching its greatest value after 3-6 hours, and persists for 24 hours. During a course of treatment, the antihypertensive effect can gradually increase, usually stabilizing by 3-4 weeks of regular use of ramipril, and then persist for a long time. Sudden cessation of taking ramipril does not lead to a rapid and significant increase in blood pressure (no withdrawal syndrome).

In patients with arterial hypertension, ramipril slows down the development and progression of myocardial and vascular wall hypertrophy.

In patients with chronic heart failure, ramipril reduces peripheral vascular resistance (reduces afterload on the heart), increases the capacity of the venous bed and reduces the filling pressure of the left ventricle, which, accordingly, leads to a decrease in preload on the heart. In these patients, when taking ramipril, there is an increase in cardiac output, ejection fraction and improved exercise tolerance.

In diabetic and non-diabetic nephropathy, taking ramipril slows down the rate of progression of renal failure and the time of onset of end-stage renal failure and, thereby, reduces the need for hemodialysis or kidney transplantation. In the initial stages of diabetic or non-diabetic nephropathy, ramipril reduces the incidence of albuminuria.

In patients with a high risk of developing cardiovascular diseases due to vascular lesions (diagnosed coronary heart disease (CHD), history of peripheral arterial occlusive disease, history of stroke) or diabetes mellitus with at least one additional risk factor (microalbuminuria, arterial hypertension, increased concentration of total cholesterol, decreased concentration of HDL cholesterol, smoking), the addition of ramipril to standard therapy significantly reduces the incidence of heart attack myocardium, stroke and mortality from cardiovascular causes. In addition, ramipril reduces overall mortality rates, as well as the need for revascularization procedures, and slows down the onset or progression of chronic heart failure.

In patients with heart failure with clinical manifestations that developed in the first days of acute myocardial infarction (days 2-9), the use of ramipril, started from the 3rd to the 10th day of acute myocardial infarction, reduced mortality (by 27%), the risk of sudden death (by 30%), the risk of progression to severe heart failure (III-IV functional class according to the NYHA classification)/resistant to therapy (by 23%), the likelihood of subsequent hospitalization due to the development of heart failure (by 26%).

In the general population of patients, as well as in patients with diabetes (both with arterial hypertension and normal blood pressure), ramipril significantly reduces the risk of developing nephropathy and microalbuminuria.

Pharmacokinetics

The combined use of indapamide and ramipril does not affect their pharmacokinetic parameters compared to taking these drugs in monotherapy.

Indapamide

Suction

Bioavailability of indapamide is 93%.

The released indapamide is quickly and completely absorbed in the gastrointestinal tract. Simultaneous food intake slightly increases the absorption time of indapamide, without affecting the completeness of absorption. The maximum concentration in blood plasma is achieved 1-2 hours after oral administration of a single dose of 2.5 mg. With repeated doses, fluctuations in the concentration of indapamide in the blood plasma during the interval between doses of the drug are smoothed out. There is individual variability in the absorption of indapamide.

Distribution

About 75% of indapamide binds to blood plasma proteins and, due to the presence of high affinity for elastin, is concentrated in the smooth muscles of the vascular walls. It also binds to erythrocyte carboxyhydrase without inhibiting the activity of this enzyme.

With regular use of the drug, the equilibrium concentration of indapamide in the blood plasma increases (compared to a single dose). Equilibrium concentration is achieved after 7 days of taking indapamide. When indapamide is taken repeatedly, its accumulation is not observed.

Metabolism

Indapamide is metabolized in the liver.

Removal

The half-life (T1/2) ranges from 14 to 24 hours (average 18 hours). It is excreted in the form of inactive metabolites, mainly by the kidneys (60-80% of the dose taken) and through the intestines (22%). No more than 5% of indapamide is excreted unchanged from the body by the kidneys.

Pharmacokinetics in special groups of patients

In patients with renal failure, the pharmacokinetic parameters of indapamide do not change significantly.

Ramipril

Suction

After oral administration, ramipril is rapidly absorbed from the gastrointestinal tract
(50-60%). Simultaneous food intake slows down its absorption, but does not affect the completeness of absorption.

Distribution

The bioavailability of ramipril after oral administration ranges from 15% (for a dose of 2.5 mg) to 28% (for a dose of 5 mg). The bioavailability of the active metabolite, ramiprilat, after oral administration of 2.5 mg and 5 mg of ramipril is approximately 45% (compared to its bioavailability after intravenous administration in the same doses). After taking ramipril orally, maximum plasma concentrations of ramipril and ramiprilat are reached after 1 and 2-4 hours, respectively.

Metabolism

Ramipril undergoes extensive first-pass metabolism/activation (mainly in the liver by hydrolysis), resulting in the formation of its only active metabolite, ramiprilat, whose ACE inhibitory activity is approximately 6 times greater than that of ramipril. In addition, as a result of the metabolism of ramipril, diketopiperazine, which does not have pharmacological activity, is formed, which is then conjugated with glucuronic acid; ramiprilat is also glucuronidated and metabolized to diketopiperazine acid.

Removal

The decrease in plasma concentration of ramiprilat occurs in several stages: a distribution and elimination phase with a half-life (T1/2) of ramiprilat of approximately 3 hours, then an intermediate phase with a T1/2 of ramiprilat of approximately 15 hours, and a final phase with a very low plasma concentration of ramiprilat and a T1/2 of ramiprilat of approximately 4–5 days. This final phase is due to the slow release of ramiprilat from its strong binding to ACE receptors. Despite the long final phase with a single oral dose of ramipril during the day at a dose of 2.5 mg or more, the equilibrium plasma concentration of ramiprilat is achieved after approximately 4 days of treatment. With a course prescription of the drug, the “effective” T1/2, depending on the dose, is
13–17 h.

After oral administration of radiolabeled ramipril (10 mg), 39% of the radioactivity is excreted through the intestines and about 60% by the kidneys. After intravenous administration of ramipril, 50–60% of the dose is found in the urine in the form of ramipril and its metabolites. After intravenous administration of ramiprilat, about 70% of the dose is found in the urine in the form of ramiprilat and its metabolites, in other words, with intravenous administration of ramipril and ramiprilat, a significant part of the dose is excreted through the intestines with bile, bypassing the kidneys (50% and 30%, respectively). After oral administration of 5 mg of ramipril in patients with bile duct drainage, almost equal amounts of ramipril and its metabolites are excreted by the kidneys and intestines during the first 24 hours after administration.

Approximately 80–90% of the metabolites in urine and bile were identified as ramiprilat and ramiprilat metabolites. Ramipril glucuronide and ramipril diketopiperazine account for approximately 10–20% of the total amount, and the level of unmetabolized ramipril in urine is approximately 2%.

In animal studies, ramipril has been shown to be excreted into human milk.

Pharmacokinetics in special groups of patients

In healthy elderly volunteers (65-76 years), the pharmacokinetics of ramipril and ramiprilat do not differ significantly from those in young healthy volunteers.

If renal function is impaired with creatinine clearance (CC) less than 60 ml/min, the elimination of ramipril and its metabolites slows down in proportion to the decrease in creatinine clearance (CC). This leads to an increase in plasma concentrations of ramiprilat, which decreases more slowly than in patients with normal renal function.

When taking ramipril in high doses (10 mg), impaired liver function leads to a slower first-pass metabolism of ramipril to active ramiprilat and a slower elimination of ramiprilat.

In patients with chronic heart failure, after two weeks of treatment with ramipril at a daily dose of 5 mg, there is a 1.5-1.8-fold increase in plasma concentrations of ramiprilat and the area under the concentration-time pharmacokinetic curve (AUC).

In healthy volunteers and patients with arterial hypertension, after two weeks of treatment with ramipril at a daily dose of 5 mg, no clinically significant accumulation of ramipril and ramiprilat is observed.

Special instructions

Before starting treatment, it is necessary to eliminate hyponatremia and hypovolemia.

Patients with previous diuretic therapy

If possible, it is necessary to discontinue diuretics 2-3 days (depending on the duration of action of the diuretics) before starting treatment with CONSILAR-D24 or at least reduce the dose of diuretics taken. Treatment of such patients should begin with taking 1 capsule with a dosage of 0.625 mg + 2.5 mg 1 time per day in the morning. After taking the first dose and after increasing the dose of CONSILAR-D24, patients should be under medical supervision for at least 8 hours to avoid an uncontrolled hypotensive reaction. Coronary heart disease and cerebrovascular insufficiency

The risk of arterial hypotension exists in all patients, however, in patients with coronary artery disease and cerebrovascular insufficiency, special caution should be exercised when treated with CONSILAR-D24. Treatment should begin with a daily dose of 0.625 mg + 2.5 mg (initial dose).

Renal dysfunction

Therapy with CONSILAR-D24 is contraindicated in patients with severe renal failure (creatinine clearance less than 30 ml/min). In some patients with arterial hypertension without previous renal impairment, symptoms of acute renal failure may appear during therapy with CONSILAR-D24. In this case, treatment with CONSILAR-D24 should be discontinued. In the future, you can resume combination therapy using low doses of CONSILAR-D24, or use indapamide and ramipril in monotherapy. Such patients require regular monitoring of potassium levels and creatinine concentrations in the blood plasma every 2 weeks after the start of therapy and every subsequent 2 months of therapy with CONSILAR-D24.

Acute renal failure most often develops in patients with severe chronic heart failure or underlying renal impairment, including bilateral renal artery stenosis or arterial stenosis of a single functioning kidney. Taking CONSILAR-D24 is contraindicated in patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney.

Arterial hypotension and water-electrolyte imbalance

Before starting treatment with CONSILAR-D24, it is necessary to eliminate hyponatremia and hypovolemia. Hyponatremia is associated with a risk of a sudden decrease in blood pressure (especially in patients with bilateral renal artery stenosis or arterial stenosis of a single functioning kidney). Therefore, during dynamic monitoring of patients, attention should be paid to possible symptoms of dehydration and decreased electrolyte levels in the blood plasma, for example, after prolonged diarrhea or vomiting. Such patients require regular monitoring of blood plasma electrolyte levels. With a pronounced decrease in blood pressure, intravenous administration of 0.9% sodium chloride solution may be required.

Transient arterial hypotension is not a contraindication for continued therapy. After restoration of blood volume and blood pressure, you can resume therapy with CONSILAR-D24, using low doses of the drug, or use indapamide and ramipril in monotherapy.

Potassium content

The combined use of indapamide and ramipril may lead to the development of hypokalemia, especially in patients with diabetes mellitus or renal failure. While taking CONSILAR-D24, it is necessary to regularly monitor the potassium content in the blood plasma. In patients with hypokalemia, the use of CONSILAR-D24 is contraindicated.

Excipients

It should be taken into account that the excipients of the drug CONSILAR-D24 include lactose monohydrate. The use of CONSILAR-D24 is contraindicated in patients with lactose intolerance, lactase deficiency, and glucose-galactose malabsorption.

Indapamide

Liver dysfunction

When using thiazide and thiazide-like diuretics in patients with impaired liver function, hepatic encephalopathy may develop, especially in the case of water and electrolyte imbalance, which can progress to hepatic coma. In this case, you should immediately stop taking CONSILAR-D24.

Visual disorders

When using thiazide and thiazide-like diuretics, there is a risk of developing acute myopia/secondary angle-closure glaucoma. If symptoms of these complications appear, emergency medical attention is required.

Photosensitivity

Cases of photosensitivity reactions have been reported while taking thiazide and thiazide-like diuretics. If photosensitivity reactions develop while taking CONSILAR-D24, treatment should be discontinued. If it is necessary to continue therapy with CONSILAR-D24, it is recommended to protect exposed skin from direct exposure to sunlight and artificial ultraviolet rays type A.

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 diuretic drugs can cause hyponatremia, sometimes leading to extremely serious consequences. Regular monitoring of sodium levels is necessary, since initially a decrease in sodium levels in the blood plasma may not be accompanied by the appearance of pathological symptoms. The most careful monitoring of sodium levels is indicated in patients with cirrhosis and elderly patients. Hyponatremia in combination with hypovolemia can cause dehydration and orthostatic hypotension.

A concomitant decrease in the concentration of chloride ions in the blood plasma can lead to secondary compensatory metabolic alkalosis: the frequency of development 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 (plasma potassium levels below 3.4 mmol/l) in the following patient categories: elderly patients, debilitated patients or those receiving concomitant drug therapy with other antiarrhythmic drugs and drugs that can prolong the QT interval, patients with cirrhosis, peripheral edema or ascites, coronary artery disease, heart failure. Hypokalemia in such patients increases the toxic effect of cardiac glycosides and increases the risk of developing arrhythmias.

In addition, patients with an increased QT interval on the ECG are at increased risk, and it does not matter whether this increase is caused by congenital causes or the effect of drugs.

Hypokalemia, like bradycardia, is a condition that contributes to the development of severe arrhythmias and, especially, pirouette-type arrhythmias, which can be fatal. In all the cases described above, it is necessary to regularly monitor the potassium content in the blood plasma more often than usual. The first measurement of potassium content in the blood plasma should be carried out within the first week from the start of therapy with CONSILAR-D24.

If hypokalemia is detected, appropriate treatment should be prescribed.

Calcium content in blood plasma

Thiazide and thiazide-like diuretics reduce the excretion of calcium by the kidneys, leading to a slight and temporary increase in calcium levels in the blood plasma. Severe hypercalcemia may be a consequence of latent hyperparathyroidism.

You should stop taking CONSILAR-D24 before testing the function of the parathyroid glands.

Plasma glucose concentration

It is necessary to monitor plasma glucose concentrations in patients with diabetes mellitus, especially in the presence of hypokalemia.

Uric acid

Patients with hyperuricemia may have an increased risk of developing gout attacks.

Diuretics and kidney function

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

It should be taken into account that at the beginning of treatment, patients may experience a decrease in glomerular filtration rate due to hypovolemia, which, in turn, is caused by the loss of fluid and sodium ions while taking diuretic drugs. As a result, the concentration of urea and creatinine in the blood plasma may increase. If renal function is not impaired, such temporary functional renal failure, as a rule, passes without consequences, however, with existing renal failure, the patient’s condition may worsen.

Athletes

Indapamide may give a positive result during doping control.

Ramipril

Neutropenia/agranulocytosis

In patients taking ACE inhibitors, cases of neutropenia/agranulocytosis may develop. The risk of developing neutropenia is dose-dependent and depends on the drug taken and the presence of concomitant diseases. In patients with normal renal function in the absence of other complications, neutropenia rarely develops and resolves spontaneously after discontinuation of ACE inhibitors. Particular caution must be observed at the beginning of treatment and in patients with systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma), as well as during therapy with immunosuppressants, allopurinol or procainamide, especially with existing renal impairment. Such patients may develop a severe infection that does not respond to intensive antibiotic therapy. It is recommended to periodically monitor the number of leukocytes in the blood. The patient should be warned that if any signs of an infectious disease appear (sore throat, fever), consult a doctor immediately. If neutropenia is detected (the number of neutrophils is less than 2000/μl), discontinuation of treatment with ACE inhibitors is required.

Angioedema (Quincke’s edema)

In rare cases, during therapy with ACE inhibitors, angioedema of the face, extremities, lips, tongue, uvula, pharynx and/or larynx may develop. If these symptoms appear, you should immediately stop taking CONSILAR-D24. The patient’s condition should be monitored until signs of edema disappear completely. If the swelling affects only the face and lips, its manifestations usually go away without special treatment, however, antihistamines can be used to more quickly relieve symptoms.

Angioedema, accompanied by swelling of the tongue, pharynx and/or larynx, can lead to airway obstruction and death. In this case, epinephrine (adrenaline) should be immediately administered subcutaneously at a dose of 1:1000 (0.3 to 0.5 ml) or 0.1 mg intravenously, and/or ensure airway patency, followed by the use of glucocorticosteroids (IV, IM or orally).

Intravenous administration of antihistamines (H1- and H2-histamine receptor antagonists) is also recommended, and in case of insufficiency of enzyme inactivators
C1-esterase, you can consider the need to administer C1-esterase enzyme inhibitors in addition to epinephrine (adrenaline). The patient should be hospitalized and monitored until symptoms are completely relieved, but not less than 24 hours. In the future, such patients should not be treated with ACE inhibitors. Patients with a history of angioedema not associated with taking ACE inhibitors may have an increased risk of developing angioedema when taking drugs of this group. When used simultaneously with other drugs that can cause the development of angioedema, the risk of angioedema increases.

In rare cases, intestinal angioedema develops during therapy with ACE inhibitors. In this case, patients experience abdominal pain, as an isolated symptom or in combination with nausea and vomiting, in some cases without previous angioedema of the face and at a normal level
C-1-esterase. The diagnosis is made using computed tomography of the abdominal cavity, ultrasound, or at the time of surgery. Symptoms disappear after stopping ACE inhibitors. In patients with abdominal pain receiving ACE inhibitors, the possibility of developing intestinal angioedema must be taken into account when making a differential diagnosis.

Anaphylactic and anaphylactoid reactions during desensitization

There are isolated reports of the development of prolonged life-threatening anaphylactic and anaphylactoid reactions (for example, decreased blood pressure, shortness of breath, vomiting, allergic skin reactions) in patients receiving ACE inhibitors during desensitizing therapy with hymenopteran insect venom (bees, wasps). During treatment with ACE inhibitors, hypersensitivity reactions to insect venom (such as bees, wasps) develop faster and are more severe. ACE inhibitors are contraindicated for use in patients receiving desensitizing therapy with venom from hymenoptera insects, such as bees and wasps. The development of anaphylactic and anaphylactoid reactions can be avoided by temporarily discontinuing the ACE inhibitor at least 24 hours before the start of the desensitization procedure.

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. Therefore, this method should not be used in patients receiving ACE inhibitors. To prevent an anaphylactoid reaction, ACE inhibitor therapy should be discontinued before each LDL apheresis procedure using dextran sulfate.

Anaphylactoid reactions during hemodialysis or plasma filtration using certain high-flow membranes

In patients receiving ACE inhibitors, anaphylactoid reactions, sometimes up to the development of shock, were observed during hemodialysis using high-flow membranes. Therefore, it is necessary to use a different type of membrane or use an antihypertensive drug of a different pharmacotherapeutic group.

Cough

During therapy with an ACE inhibitor, it is possible to develop a dry, unproductive, prolonged, persistent cough, which disappears after discontinuation of drugs in this group. If a patient develops a dry cough, one should be aware of the possible connection of this symptom with taking an ACE inhibitor. If the doctor believes that ACE inhibitor therapy is necessary for the patient, taking CONSILAR-D24 can be continued.

Risk of hypotension and/or renal failure

In some pathological conditions, significant activation of the RAAS may be observed, especially with severe hypovolemia and a decrease in plasma electrolytes (due to a salt-free diet or long-term use of diuretics), in patients with initially low blood pressure, with bilateral renal artery stenosis or with stenosis of the artery of a single kidney, chronic heart failure or cirrhosis of the liver with edema and ascites. The use of an ACE inhibitor causes blockade of the RAAS and therefore may be accompanied by a sharp decrease in blood pressure and/or an increase in creatinine concentration, azotemia in the blood plasma, oliguria, indicating the development of acute renal failure. These phenomena are more often observed when taking the first dose of ramipril or during the first two weeks of therapy. Sometimes these conditions develop acutely and during other periods of therapy. In such cases, when resuming therapy, it is recommended to use CONSILAR-D24 at a lower dose and then gradually increase the dose. Caution should be exercised when treating elderly patients, as they may be particularly sensitive to ACE inhibitors; monitoring of renal function is recommended during the initial phase of treatment. In patients for whom a decrease in blood pressure may pose a certain risk (for example, in patients with atherosclerotic narrowing of the coronary or cerebral arteries), treatment should begin under strict medical supervision. Caution should be exercised during physical activity and/or hot weather due to the risk of increased sweating and dehydration with the development of arterial hypotension due to a decrease in circulating blood volume and a decrease in sodium levels in the blood. A transient excessive decrease in blood pressure is not a contraindication for continuing treatment after stabilization of blood pressure. In case of repeated development of a pronounced decrease in blood pressure, the dose should be reduced or the drug discontinued.

In case of heart failure, especially in the acute stage of myocardial infarction, treatment with CONSILAR-D24 should only be started in a hospital setting.

The simultaneous use of CONSILAR-D24 with drugs containing aliskiren or with ARA II, leading to double blockade of the RAAS, is not recommended due to the risk of an excessive decrease in blood pressure, the development of hyperkalemia and deterioration of renal function compared to monotherapy. The simultaneous use of CONSILAR-D24 and drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or moderate to severe renal failure
(GFR less than 60 ml/min/1.73 m2 body surface area) and is not recommended in other patients. Concomitant use of APA II is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Diabetes mellitus

When using the drug CONSILAR-D24 in patients with diabetes mellitus receiving oral hypoglycemic agents or insulin, during the first month of therapy it is necessary to regularly monitor the concentration of glucose in the blood.

Renovascular hypertension

The use of ACE inhibitors has a beneficial effect in patients with renovascular hypertension, both awaiting surgery and when surgery is not possible. Treatment with CONSILAR-D24 should begin with a low dose of the drug in a hospital setting, monitoring renal function and potassium levels in the blood plasma. Some patients may develop functional renal failure, which quickly disappears when the drug is discontinued.

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 an antihypertensive effect. It is recommended to stop taking ACE inhibitors 48 hours before surgery, warning the anesthesiologist about the use of ACE inhibitors.

Anemia

Anemia may develop in patients who have undergone a kidney transplant or in patients undergoing hemodialysis. In this case, the decrease in hemoglobin concentration is greater, the higher its initial concentration was. This effect,
does not appear to be dose-dependent, but may be related to the mechanism of action of ACE inhibitors. A slight decrease in hemoglobin concentration occurs during the first 6 months of treatment, then the hemoglobin concentration remains stable and is completely restored after discontinuation of the drug. In such patients, treatment can be continued, but a complete blood count should be performed regularly.

Aortic stenosis/Mitral stenosis/Hypertrophic obstructive cardiomyopathy

ACE inhibitors are contraindicated in patients with left ventricular outflow tract obstruction and aortic and/or mitral stenosis and HOCM.

Liver failure

In patients with impaired liver function, the response to treatment with CONSILAR-D24 may be enhanced or weakened. In addition, in patients with severe liver cirrhosis with edema and/or ascites, significant activation of the RAAS is possible, so special care should be taken when treating these patients. In rare cases, while taking ACE inhibitors, cholestatic jaundice occurs, with the progression of which the rapid development of fulminant liver necrosis, sometimes with fatal outcome, is possible. If jaundice appears or a significant increase in the activity of liver transaminases while taking ACE inhibitors, the patient should stop taking CONSILAR-D24.

Hyperkalemia

During treatment with ACE inhibitors, hyperkalemia may develop. Risk factors for hyperkalemia are renal failure, old age, diabetes mellitus, some concomitant conditions (decrease in blood volume, acute heart failure in the stage of decompensation, metabolic acidosis), simultaneous use of potassium-sparing diuretics (such as spironolactone, eplerenone, triamterene, amiloride), as well as potassium preparations or potassium-containing substitutes for table salt and the use of other drugs that increase plasma potassium levels (for example, heparin). Hyperkalemia can cause serious heart rhythm problems, sometimes fatal. The simultaneous use of the above drugs is contraindicated.

Other risk groups

In patients with chronic heart failure (functional class IV according to the NYHA classification) and patients with type 1 diabetes mellitus (risk of spontaneous increase in potassium levels), treatment should begin with low doses of CONSILAR-D24 and be carried out under constant medical supervision.

In patients with arterial hypertension and coronary artery disease,
beta blockers: ACE inhibitors should be used together with
beta-blockers.

Elderly patients

In elderly patients, before starting to take CONSILAR-D24, it is necessary to evaluate renal function and potassium levels in the blood plasma. In order to prevent the development of arterial hypotension, sequential adjustment of the initial dose of the drug is carried out in accordance with blood pressure indicators, especially with a decrease in blood volume.

Ethnic differences

ACE inhibitors have a less pronounced antihypertensive effect in patients of the Black race compared to representatives of other races. CONSILAR-D24 should be prescribed with caution to patients of the Black race due to a higher risk of developing angioedema.

Patients after kidney transplantation

There is insufficient experience with the use of CONSILAR-D24 in patients who have recently undergone kidney transplantation.

Monitoring laboratory parameters before and during treatment with the drug
CONSILAR-D24 (up to 1 time per month in the first 3-6 months of treatment)

Monitoring kidney function (determining serum creatinine concentrations)

When treating with ACE inhibitors, in the first weeks of treatment and subsequently, it is recommended to monitor renal function. Particularly careful monitoring is required in patients with acute and chronic heart failure, impaired renal function, after kidney transplantation, patients with renovascular diseases, including patients with hemodynamically significant unilateral renal artery stenosis in the presence of two kidneys (in such patients, even a slight increase in serum creatinine concentration may be an indicator of decreased renal function).

Electrolyte control

Regular monitoring of potassium and sodium levels in the blood serum is recommended. Particularly careful monitoring of potassium levels in the blood serum is required for patients with impaired renal function, significant disturbances in water and electrolyte balance, and chronic heart failure.

Monitoring of hematological parameters (hemoglobin, number of leukocytes, erythrocytes, platelets, leukocyte formula)

It is recommended to monitor the complete blood count to identify possible leukopenia. More regular monitoring is recommended at the beginning of treatment and in patients with impaired renal function, as well as in patients with connective tissue diseases or in patients simultaneously receiving other drugs that can change the peripheral blood picture. Monitoring the number of leukocytes is necessary for the early detection of leukopenia, which is especially important in patients with an increased risk of its development, as well as at the first signs of infection. If neutropenia (neutrophil count less than 2000/μl) is detected, treatment with ACE inhibitors must be discontinued. If symptoms caused by leukopenia are detected (for example, fever, enlarged lymph nodes, tonsillitis), urgent monitoring of the peripheral blood picture is necessary. If signs of bleeding appear (tiny petechiae, red-brown rashes on the skin and mucous membranes), monitoring the number of platelets in the peripheral blood is also necessary.

Determination of the activity of “liver” enzymes, the concentration of bilirubin in the blood

If jaundice or a significant increase in the activity of liver enzymes appears, treatment with CONSILAR-D24 should be stopped and medical supervision of the patient should be provided.

Impact on the ability to drive vehicles and machinery

During treatment with CONSILAR-D24, it is necessary to refrain from engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions, including driving, since while taking CONSILAR-D24, dizziness and a decrease in the speed of psychomotor reactions and attention may occur, especially after taking the first dose.

Active ingredient

Indapamide, Ramipril

Composition

Dosage 1.25 mg + 5 mg

active ingredients: indapamide – 1.250 mg; ramipril – 5,000 mg;

excipients: lactose monohydrate – 140.750 mg; colloidal silicon dioxide – 1,500 mg; calcium stearate – 1,500 mg;

hard gelatin capsules: titanium dioxide – 2.0%, gelatin – up to 100%.

Pregnancy

Use during pregnancy

The use of CONSILAR-D24 is contraindicated during pregnancy. Before starting treatment, you should make sure there is no pregnancy. If you are planning pregnancy or if it occurs during treatment, you must immediately stop taking CONSILAR-D24 and prescribe another therapy with an established safety profile for use during pregnancy.

Indapamide

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.

Ramipril

ACE inhibitors are able to penetrate the placental barrier. When using ACE inhibitors during pregnancy, there is a risk of impaired development of the fetal kidneys, decreased blood pressure of the fetus and newborn, impaired renal function, hyperkalemia, hypoplasia of the skull bones, oligohydramnios, contracture of the limbs, deformation of the skull, pulmonary hypoplasia.

If exposure to ACE inhibitors occurred in the second trimester of pregnancy or later, ultrasound examination of the fetus is recommended to monitor renal function and the condition of the skull bones.

It is recommended to closely monitor neonates exposed in utero to ACE inhibitors for hypotension, oliguria, and hyperkalemia. With oliguria, it is necessary to maintain blood pressure and renal perfusion by replenishing blood volume and using vasoconstrictors. Neonates are at risk of oliguria and neurological disorders, possibly due to decreased renal and cerebral blood flow due to the decrease in blood pressure caused by ACE inhibitors (received by pregnant and lactating women).

Use during breastfeeding

The use of CONSILAR-D24 is contraindicated during breastfeeding. If treatment with CONSILAR-D24 is necessary, breastfeeding should be discontinued.

Indapamide

There is insufficient data on the penetration of indapamide or its metabolites into breast milk. Taking thiazide diuretics causes a decrease in the amount of breast milk or suppression of lactation. In this case, the newborn may develop increased sensitivity to sulfonamide derivatives and hypokalemia. Therefore, a risk to the newborn/infant cannot be excluded.

Ramipril

In animal studies, ramipril has been shown to be excreted in the milk of lactating animals.

Contraindications

hypersensitivity to indapamide, ramipril, other ACE inhibitors, sulfonamide derivatives and excipients included in the drug;
history of angioedema (hereditary or idiopathic, and also associated with previous therapy with ACE inhibitors);
hemodynamically significant stenosis of the renal arteries (bilateral or unilateral, in the case of a solitary kidney);
arterial hypotension (systolic blood pressure less than 90 mm Hg) or conditions with unstable hemodynamic parameters;
simultaneous use with angiotensin II receptor antagonists in patients with diabetic nephropathy;
simultaneous use with neutral endopeptidase inhibitors (for example, with drugs containing sacubitril) due to the high risk of developing angioedema;
simultaneous use with combination therapy sacubitril/valsartan (high risk of developing angioedema), see sections “Interaction with other drugs”, “Special instructions”.
hemodynamically significant stenosis of the aortic or mitral valve, or hypertrophic obstructive cardiomyopathy (HOCM);
primary hyperaldosteronism;
severe renal failure (GFR less than 20 ml/min-1.73 m2 body surface area) (insufficient clinical experience);
hemodialysis (experience of clinical use is insufficient);
nephropathy, which is treated with glucocorticosteroids, non-steroidal anti-inflammatory drugs, immunomodulators and/or other cytotoxic drugs (experience of clinical use is insufficient, see section “Interaction with other drugs”);
chronic heart failure in the stage of decompensation (experience of clinical use is insufficient);
hemodialysis or hemofiltration using certain membranes with a negatively charged surface, such as high-flow polyacrylonitrile membranes (risk of severe anaphylactoid reactions) (see sections “Interaction with other drugs”, “Special instructions”);
apheresis of LDL using dextran sulfate (risk of developing severe anaphylactoid reactions) (see sections “Interaction with other drugs”, “Special instructions”);
carrying out desensitizing therapy for hypersensitivity reactions to the poisons of hymenoptera insects, such as bees, wasps (see section “Special instructions”);
simultaneous use with aliskiren and 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);
acute stage of myocardial infarction in patients with diseases such as:
severe chronic heart failure (functional class IV according to the NYHA classification);
unstable angina;
life-threatening ventricular arrhythmias;
“pulmonary” heart;
hepatic encephalopathy or severe liver dysfunction;
hypokalemia;
galactose intolerance, lactase deficiency, glucose-galactose malabsorption;
pregnancy, breastfeeding period;
age under 18 years (efficacy and safety have not been established).

With caution

simultaneous use with drugs containing aliskiren or angiotensin II receptor antagonists (with double blockade
renin-angiotensin-aldosterone system (RAAS) there is an increased risk of a sharp decrease in blood pressure, the development of hyperkalemia and deterioration of renal function compared with monotherapy) (see section “Special instructions”);
conditions in which an excessive decrease in blood pressure is especially dangerous (with atherosclerotic lesions of the coronary and cerebral arteries);
conditions accompanied by increased activity of the RAAS, in which, with ACE inhibition, there is a risk of a sharp decrease in blood pressure with deterioration of renal function;
severe arterial hypertension, especially malignant arterial hypertension;
chronic heart failure, especially severe, or for which other medications with antihypertensive effects are being taken;
hemodynamically significant unilateral renal artery stenosis (in the presence of both kidneys) – in such patients, even a slight increase in serum creatinine concentration may be a manifestation of unilateral deterioration in renal function;
previous use of diuretics;
disturbances in water and electrolyte balance as a result of insufficient intake of liquid and table salt, diarrhea, vomiting, profuse sweating;
liver function disorders (experience of clinical use is insufficient: it is possible to either enhance or weaken the effects of the drug);
in patients with liver cirrhosis with ascites and edema, significant activation of the RAAS is possible, see above “Conditions accompanied by increased activity of the RAAS”));
diabetes mellitus (risk of developing hyperkalemia);
impaired renal function (GFR more than 20 ml/min/1.73 m2 body surface area) (risk of developing hyperkalemia and leukopenia);
condition after kidney transplantation;
systemic connective tissue diseases (systemic lupus erythematosus, systemic scleroderma);
inhibition of bone marrow hematopoiesis;
concomitant therapy with myelotoxic drugs, immunosuppressants that can cause changes in the peripheral blood picture (possible inhibition of bone marrow hematopoiesis, development of neutropenia or agranulocytosis) (see section “Interaction with other drugs);
hyperkalemia;
use during major surgical interventions or during general anesthesia (see section “Special instructions”);
hyperuricemia and gout;
hyperparathyroidism;
increase in QT interval on ECG;
use in patients receiving concomitant therapy with drugs that may prolong the QT interval; use with drugs that can cause polymorphic ventricular tachycardia of the “pirouette” type; lithium preparations; medications that can cause hypokalemia; cardiac glycosides (see section “Interaction with other drugs”);
use in malnourished patients;
old age (risk of increased antihypertensive effect);
in patients of the Negroid race (see section “Special instructions”).

Side Effects

Classification of the incidence of side effects according to the recommendations of the World Health Organization (WHO):

very often ³ 1/10;

often from ³ 1/100 to < 1/10;

infrequently from ³ 1/1000 to < 1/100;

rarely from ³ 1/10000 to < 1/1000;

very rarely <1/10000, including isolated reports;

frequency unknown – based on available data, it is not possible to determine the frequency of occurrence.

Cardiac disorders:

uncommon – myocardial ischemia, including the development of an attack of angina or myocardial infarction, tachycardia, arrhythmia, palpitations, peripheral edema;

very rarely – arrhythmia;

frequency unknown – polymorphic ventricular tachycardia of the “pirouette” type (potentially fatal).

Vascular disorders:

often – excessive decrease in blood pressure, orthostatic hypotension, syncope;

infrequently – “flushes” of blood to the skin of the face;

rarely – the occurrence or intensification of circulatory disorders against the background of stenotic vascular lesions, vasculitis;

frequency unknown – Raynaud’s syndrome.

Nervous system disorders:

often – headache, dizziness (feeling of “lightness” in the head);

uncommon – vertigo, paresthesia, ageusia (loss of taste sensitivity), dysgeusia (impaired taste sensitivity);

rarely – tremor, imbalance, increased fatigue;

frequency unknown – cerebral ischemia, including ischemic stroke and transient cerebrovascular accident, impaired psychomotor reactions, burning sensation, parosmia (impaired odor perception), fainting.

Visual disorders:

uncommon – visual disturbances, including blurred images;

rarely – conjunctivitis;

frequency unknown – myopia, blurred vision, choroidal effusion.

Disorders of the hearing organ and labyrinth:

rarely – hearing impairment, tinnitus.

Mental disorders:

uncommon – depressed mood, anxiety, nervousness, restlessness, sleep disturbances, including drowsiness;

rarely – confusion;

frequency unknown – impaired attention.

Disorders of the respiratory system, chest and mediastinal organs:

often – “dry” cough (worsening at night and when lying down), bronchitis, sinusitis, shortness of breath;

uncommon – bronchospasm, including worsening of bronchial asthma, nasal congestion.

Gastrointestinal disorders:

often – inflammatory reactions in the stomach and intestines, digestive disorders, discomfort in the abdominal area, dyspepsia, diarrhea, nausea, vomiting;

uncommon – fatal pancreatitis (cases of fatal pancreatitis when taking ACE inhibitors were extremely rare), increased activity of pancreatic enzymes in the blood plasma, angioedema of the small intestine, pain in the upper abdomen, including those associated with gastritis, constipation, dry oral mucosa;

rarely – glossitis;

very rarely – pancreatitis;

frequency unknown – aphthous stomatitis (inflammatory reactions of the oral mucosa).

Disorders of the liver and biliary tract:

infrequently – increased activity of liver enzymes and the concentration of conjugated bilirubin in the blood plasma;

rarely – cholestatic jaundice, hepatocellular lesions;

very rarely – liver dysfunction;

frequency unknown – acute liver failure, cholestatic or cytolytic hepatitis (extremely fatal), the possibility of developing hepatic encephalopathy in case of liver failure.

Renal and urinary tract disorders:

infrequently – impaired renal function, including the development of acute renal failure, an increase in the amount of urine excreted, an increase in pre-existing proteinuria, an increase in the concentration of urea and creatinine in the blood plasma;

very rarely – renal failure;

Disorders of the reproductive system and mammary glands:

uncommon – erectile dysfunction with transient impotence, decreased libido;

frequency unknown – gynecomastia.

Blood and lymphatic system disorders:

uncommon – eosinophilia;

rarely – leukopenia, including neutropenia and agranulocytosis, erythrocytopenia, decreased hemoglobin concentration, thrombocytopenia;

very rarely – aplastic anemia, hemolytic anemia;

frequency unknown – suppression of bone marrow hematopoiesis, pancytopenia.

Skin and subcutaneous tissue disorders:

often – skin rash, in particular macular-papular rash, hypersensitivity reactions;

uncommon – angioedema, including fatal ones (swelling of the larynx can cause airway obstruction leading to death), itching, hyperhidrosis (increased sweating), purpura;

rarely – exfoliative dermatitis, urticaria, onycholysis;

very rarely – photosensitivity reactions, angioedema, urticaria, toxic epidermal necrolysis, Stevens-Johnson syndrome;

frequency unknown – erythema multiforme, pemphigus, worsening psoriasis, psoriasis-like dermatitis, pemphigoid or lichenoid (lichenoid) exanthema or enanthema, alopecia, possible exacerbation of existing acute systemic lupus erythematosus, photosensitivity reactions.

Muscle, skeletal and connective tissue disorders:

often – muscle cramps, myalgia;

infrequently – arthralgia.

Endocrine disorders:

frequency unknown – syndrome of inappropriate secretion of antidiuretic hormone.

Metabolic and nutritional disorders:

often – hyperkalemia;

infrequently – anorexia, loss of appetite;

very rarely – hypercalcemia;

frequency unknown – decrease in potassium concentration and development of hypokalemia, especially significant for patients at risk, decrease in sodium content in the blood.

Immune system disorders:

frequency unknown – anaphylactic or anaphylactoid reactions (with ACE inhibition, the severity of anaphylactic or anaphylactoid reactions to the venoms of hymenoptera insects, such as bees, wasps increases), increased titer of antinuclear antibodies.

General disorders and reactions at the injection site:

often – chest pain, feeling tired;

uncommon – increased body temperature;

rarely – asthenia (weakness).

Laboratory and instrumental data:

Frequency unknown: prolongation of the QT interval on the ECG, increased concentrations of glucose in the blood, increased concentrations of uric acid in the blood, increased activity of liver enzymes.

Interaction

CONSILAR-D24

Concomitant use is contraindicated

With the simultaneous use of lithium preparations and ACE inhibitors, a reversible increase in the concentration of lithium in the blood plasma and an increase in the cardio- and neurotoxic effects of lithium are possible. Additional use of thiazide diuretics may further increase lithium concentrations due to decreased excretion and increase the risk of toxic reactions. The simultaneous use of CONSILAR-D24 with lithium preparations is contraindicated.

Concomitant use with potassium preparations, potassium-sparing diuretics (amiloride, spironolactone, eplerenone, triamterene), and other drugs that can increase the content of potassium in the blood plasma (including trimethoprim, tacrolimus, cyclosporine, heparin) increases the risk of developing hyperkalemia (especially in patients with diabetes mellitus and patients with renal failure).

Special caution is required during concomitant use

Baclofen potentiates the antihypertensive effect of indapamide and ramipril (monitoring of blood pressure, renal function and, if necessary, dose adjustment of CONSILAR-D24 is required).

Concomitant use with non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 inhibitors and non-selective NSAIDs, for example, acetylsalicylic acid in doses that have an anti-inflammatory effect (more than 3 g per day), reduces the antihypertensive effect of indapamide and ramipril; increases the risk of renal dysfunction, including the development of acute renal failure; increases potassium levels in the blood plasma in patients with pre-existing renal impairment. This combination is recommended to be used with caution, especially in elderly patients. Patients need to compensate for their blood volume, as well as monitor their kidney function before and after starting treatment with CONSILAR-D24.

Caution is required during simultaneous use

Tricyclic antidepressants and antipsychotics (neuroleptics) enhance the antihypertensive effect and increase the risk of developing orthostatic hypotension (additive effect).

Glucocorticosteroids and tetracosactide reduce the antihypertensive effect (fluid retention).

When used simultaneously with other antihypertensive drugs, the antihypertensive effect of CONSILAR-D24 may be enhanced.

Indapamide

Combinations not recommended for use

– Lithium preparations:

With the simultaneous use of indapamide and lithium preparations, as well as when following a salt-free diet, an increase in the concentration of lithium in the blood plasma may be observed due to a decrease in its excretion, accompanied by the appearance of signs of overdose. If necessary, diuretics can be used in combination with lithium preparations, and the concentration of lithium in the blood plasma should be carefully monitored and the dose of the drug should be adjusted accordingly.

Combinations requiring precautions

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

antiarrhythmic drugs: class IA (quinidine, hydroquinidine, disopyramide, procainamide) and class IC (flecainide);
class III antiarthymic drugs (amiodarone, sotalol, dofetilide, ibutilide, bretylium tosylate, dronedarone);
neuroleptics: phenothiazines (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine, fluphenazole), benzamides (amisulpride, sulpiride, sultopride, tiapride), butyrophenones (droperidol, haloperidol), pimozide, sertindole;
antidepressants: tricyclic antidepressants, selective serotonin reuptake inhibitors (citalopram, escitalopram);
antibacterial agents: fluoroquinolones (levofloxacin, moxifloxacin, sparfloxacin, ciprofloxacin), macrolides (erythromycin for intravenous administration, azithromycin, clarithromycin, roxithromycin, spiramycin), co-trimoxazole;
antifungal agents of a number of azoles (voriconazole, itraconazole, ketoconazole, fluconazole);
antimalarials (quinine, chloroquine, mefloquine, halofantrine, lumefantrine);
antianginal agents (ranolazine, bepridil);
antitumor drugs and immunomodulators (vandetanib, arsenic trioxide, oxaliplatin, tacrolimus, anagrelide);
antiemetics (ondansetron);
drugs that affect gastrointestinal motility (cisapride, domperidone);
antihistamines (astemizole, terfenadine, mizolastine);
others: pentamidine, diphemanil, vincamine for intravenous administration, vasopressin, terlipressin, ketanserin, probucol, propofol, sevoflurane, terodiline, cilostazol.

Increased risk of ventricular arrhythmias, especially polymorphic ventricular tachycardia of the “pirouette” type (risk factor – hypokalemia).

Before prescribing combination therapy with CONSILAR-D24 and the above drugs, a study should be conducted to identify hypokalemia and, if necessary, correction should be made. It is necessary to monitor the patient’s clinical condition, monitor the content of blood plasma electrolytes, and ECG indicators.

In patients with hypokalemia, it is necessary to use drugs that do not cause polymorphic ventricular tachycardia of the “pirouette” type.

– Non-steroidal anti-inflammatory drugs (when administered systemically), including selective COX-2 inhibitors, high doses of acetylsalicylic acid
(≥ 3 g/day):

The antihypertensive effect of indapamide may be reduced. Dehydrated patients are at risk of developing acute renal failure due to decreased glomerular filtration rate. Patients need to compensate for fluid loss and renal function should be carefully monitored at the beginning of treatment.

– Angiotensin-converting enzyme (ACE) inhibitors

Prescribing ACE inhibitors to patients with an initially reduced concentration of sodium ions in the blood is accompanied by a risk of sudden arterial hypotension and/or acute renal failure (in particular, patients with renal artery stenosis).

Patients with arterial hypertension and possibly reduced concentration of sodium ions in the blood plasma due to previous use of diuretics should:

– 3 days before starting treatment with an ACE inhibitor, stop taking diuretics; in the future, if necessary, the use of non-potassium-sparing diuretics can be resumed;

– or start ACE inhibitor therapy with low doses, followed by a gradual increase in dose if necessary.

In all cases, in the first weeks of taking ACE inhibitors in patients, it is necessary to monitor renal function (plasma creatinine concentration).

– Other drugs that can cause hypokalemia: amphotericin B (iv), gluco- and mineralocorticosteroids (for systemic use), tetracosactide, laxatives that stimulate intestinal motility:

Increased risk of hypokalemia (additive effect). Constant monitoring of the content of potassium ions in the blood plasma is necessary, and, if necessary, its correction. Particular attention should be paid to patients concomitantly receiving cardiac glycosides. It is recommended to use laxatives that do not stimulate intestinal motility.

– Baclofen:

There is an increase in the antihypertensive effect. Patients need to compensate for fluid loss and carefully monitor renal function at the beginning of treatment.

– Cardiac glycosides:

Hypokalemia enhances the toxic effect of cardiac glycosides. With the simultaneous use of indapamide and cardiac glycosides, the content of potassium ions in the blood plasma, ECG parameters should be monitored, and, if necessary, therapy should be adjusted.

Combinations requiring special attention

– Allopurinol:

Concomitant use with indapamide may increase the risk of hypersensitivity reactions during treatment with allopurinol.

Combinations that require attention

– Potassium-sparing diuretics (amiloride, spironolactone, triamterene):

Combination therapy with indapamide and potassium-sparing diuretics is advisable in some patients, but the possibility of developing hypokalemia or hyperkalemia cannot be excluded (especially in patients with renal failure or in patients with diabetes mellitus).

It is necessary to monitor the content of potassium ions in the blood plasma, ECG parameters and, if necessary, adjust therapy.

– Metformin:

Functional renal failure, which can occur while taking diuretics, especially loop diuretics, increases the risk of developing metformin-induced lactic acidosis.

Metformin should not be used if the creatinine concentration exceeds 15 mg/L (135 µmol/L) in men and 12 mg/L (110 µmol/L) in women.

– Iodinated contrast agents:

In case of dehydration while taking diuretics, the risk of developing acute renal failure increases, especially when using high doses of iodine-containing contrast agents.

Before using iodinated contrast agents, patients need to compensate for fluid loss.

– Tricyclic antidepressants, antipsychotics:

Drugs in these classes enhance the antihypertensive effect of indapamide and increase the risk of orthostatic hypotension (additive effect).

– Calcium (salts):

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

– Cyclosporine, tacrolimus:

It is possible to increase the concentration of creatinine in the blood plasma without changing the concentration of circulating cyclosporine, even in the absence of loss of water and sodium ions.

– Corticosteroid drugs, tetracosactide (for systemic use):

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

Ramipril

Contraindicated combinations

Neutral endopeptidase inhibitors: An increased risk of angioedema has been reported with concomitant use of ACE inhibitors and racecadotril (an enkephalinase 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.

With combination therapy sacubitril/valsartan

The combined use of ACE inhibitors and a combination of ARB II and the neutral endopeptidase inhibitor (syn.: NEP, neprilysin) – sacubitril / valsartan – is contraindicated due to the risk of developing angioedema. Treatment with CONSILAR-D24 should not be started until sacubitril and valsartan have been eliminated from the body. In case of switching from therapy with CONSILAR-D24 to combination therapy with sacubitril/valsartan, therapy with this combination of drugs should not be started until ramipril is eliminated from the body.

The use of certain high-flux membranes with a negatively charged surface (eg, polyacrylonitrile membranes) during hemodialysis or hemofiltration and the use of dextran sulfate during LDL apheresis increases the risk of severe anaphylactic reactions. If the patient requires these procedures, then other types of membranes should be used (in the case of plasmapheresis and hemofiltration) or the patient should be switched to taking antihypertensive drugs of other groups.

Concomitant use of ramipril with drugs containing aliskiren
Contraindicated in patients with diabetes mellitus and/or with moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m2 body surface area) and not recommended in other patients.

Concomitant use of ramipril with angiotensin II receptor antagonists is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Combinations not recommended

With potassium salts, potassium-sparing diuretics (for example, amiloride, triamterene, spironolactone, eplerenone [spironolactone derivative]), other drugs that can increase the level of potassium in the blood serum (including ARA II, tacrolimus, cyclosporine; trimethoprim, sulfamethoxazole, included in co-trimoxazole [combination antibacterial agent containing sulfamethoxazole and trimethoprim]).

An increase in the potassium content in the blood serum is possible, sometimes significantly (with simultaneous use, careful monitoring of the potassium content in the blood serum is required).

Combinations to use with caution

When used simultaneously with hypoglycemic agents, for example, insulins, hypoglycemic agents for oral administration (sulfonylurea derivatives), due to a decrease in insulin resistance under the influence of ramipril, the hypoglycemic effect of these drugs may be enhanced, up to the development of hypoglycemia. Particularly careful monitoring of blood glucose concentrations is recommended when initiating the combined use of hypoglycemic agents with ACE inhibitors.

In patients taking ACE inhibitors and dipeptidyl peptidase type IV (DPP-IV) inhibitors (gliptins), for example, sitagliptin, saxagliptin, vildagliptin, linagliptin, an increased incidence of angioedema was observed.

With the simultaneous use of ACE inhibitors and mTOR inhibitors (mammalian Target of Rapamycin – the target of rapamycin in mammalian cells), for example, temsirolimus, sirolimus, everolimus, an increase in the incidence of angioedema was observed.

When used simultaneously with vasopressor sympathomimetics (epinephrine, isoproterenol, dobutamine, dopamine), a decrease in the antihypertensive effect of ramipril is observed; regular blood pressure monitoring is required.

With antihypertensive drugs (for example, diuretics) and other drugs that lower blood pressure (nitrates, tricyclic antidepressants, general and local anesthesia, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin), a potentiation of the antihypertensive effect is observed. When combined with diuretics, serum sodium levels should be regularly monitored.

When used simultaneously with sleeping pills, narcotic and analgesic drugs, the antihypertensive effect may be enhanced.
When used simultaneously with allopurinol, procainamide, cytostatics, immunosuppressants, corticosteroids (glucocorticosteroids and mineralocorticosteroids) and other drugs that can affect hematological parameters, the risk of developing hematological reactions increases.

With lithium salts: increased serum concentration of lithium and increased cardio- and neurotoxic effects of lithium. Therefore, the lithium content in the blood serum should be monitored.

Concomitant use of ACE inhibitors with estramustine may lead to an increased risk of developing angioedema.

Combinations to Consider

With non-steroidal anti-inflammatory drugs (indomethacin, acetylsalicylic acid): the effect of ramipril may be weakened, the risk of renal dysfunction may be increased and the potassium level in the blood serum may increase.

With heparin: an increase in serum potassium levels is possible.

With sodium chloride: weakening of the antihypertensive effect of ramipril.

When used simultaneously with ethanol, increased symptoms of vasodilation are observed. Ramipril may increase the adverse effects of ethanol on the body.

When used simultaneously with estrogens, a weakening of the antihypertensive effect of ramipril (fluid retention) is observed.

Desensitization therapy for hypersensitivity to insect venoms: ACE inhibitors increase the likelihood of developing severe anaphylactic or anaphylactoid reactions to insect venoms. It is assumed that this effect may also occur with the use of other allergens.

With parenteral gold preparations (sodium aurothiomalate): When ACE inhibitors were used concomitantly with parenteral gold preparations (sodium aurothiomalate), the following reactions were reported: flushing of the scalp, nausea, vomiting and hypotension.

With tissue plasminogen activators: Observational studies have shown an increased incidence of angioedema in patients taking ACE inhibitors after the use of alteplase for thrombolytic therapy of ischemic stroke.

Overdose

Symptoms

Marked decrease in blood pressure, shock, bradycardia, nausea, vomiting, convulsions, dizziness, drowsiness, confusion, stupor, water and electrolyte imbalance (hyponatremia, hypokalemia), polyuria or oliguria up to anuria (due to hypovolemia), acute renal failure.

Treatment

In mild cases of overdose – gastric lavage, taking adsorbents (activated carbon), sodium sulfate (preferably within 30 minutes) followed by restoration of water-electrolyte balance. The function of vital organs should be monitored.

In more severe cases, additional measures are taken to stabilize blood pressure: intravenous administration of 0.9% sodium chloride solution, plasma expanders, installation of a temporary artificial pacemaker for bradycardia resistant to drug therapy. With a pronounced decrease in blood pressure, the administration of alpha-adrenergic agonists (norepinephrine, dopamine) can be added to therapy to replenish blood volume and restore water-electrolyte balance. In case of bradycardia, it is recommended to prescribe atropine or install a temporary artificial pacemaker. It is necessary to carefully monitor blood pressure, renal function and electrolyte levels in the blood plasma.

There is no experience with the use of forced diuresis, changes in urine pH, hemofiltration or hemodialysis. Hemodialysis is indicated in cases of renal failure.

Storage conditions

Store in a place protected from light at a temperature not exceeding 25 °C.

Shelf life

2 years.

Manufacturer

Vertex, Russia