Co-Dalneva Tablets, 30 pcs., 5+0.625 + 2 mg + mg + mg

Pharmacological groups

• Antihypertensive combination drug (slow calcium channel blocker + diuretic + angiotensin-converting enzyme inhibitor) [ACE inhibitors in combinations]
• Antihypertensive combination drug (slow calcium channel blocker + diuretic + angiotensin-converting enzyme inhibitor) [Diuretics in combinations]
• Antihypertensive combination drug (slow calcium channel blocker + diuretic + angiotensin-converting enzyme inhibitor) [Calcium channel blockers in combinations]

Compound

Description of the dosage form

Tablets 5 mg + 0.625 mg + 2 mg: oval, biconvex tablets with a score on one side, white or almost white.

Tablets 5 mg + 1.25 mg + 4 mg: round, slightly biconvex tablets with a bevel on both sides, white or almost white.

Tablets 5 mg + 2.5 mg + 8 mg: round, biconvex tablets with a bevel on both sides, white or almost white.

Tablets 10 mg + 1.25 mg + 4 mg: oval, biconvex tablets with a score on one side, white or almost white.

Tablets 10 mg + 2.5 mg + 8 mg: round, biconvex tablets with a bevel on both sides and a score on one side, white or almost white.

Pharmacodynamics

Co-Dalneva® is a combination drug containing perindopril erbumine (ACE inhibitor), indapamide (thiazide-like diuretic) and amlodipine (CCB).

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

Amlodipine

Amlodipine is a CCB, 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 dilation of peripheral arterioles, reducing peripheral vascular resistance - afterload on the heart, which leads to a decrease in myocardial oxygen demand;

- causes expansion of the coronary arteries and arterioles in both intact and ischemic areas of the myocardium, which increases the supply of oxygen to the myocardium, incl. in patients with Prinzmetal's angina.

In patients with hypertension, taking amlodipine once a day provides a clinically significant decrease in blood pressure (lying and standing) 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 does not affect 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 and gout.

With long-term use of the perindopril/amlodipine combination in patients aged 40 to 79 years with hypertension and the presence of at least 3 additional risk factors (LVH, type 2 diabetes, peripheral arterial atherosclerosis, previous stroke or transient ischemic attack, male gender, age 55 years and older, microalbuminuria or proteinuria, smoking, total cholesterol/HDL cholesterol ≥6, early development of coronary artery disease in immediate relatives) the incidence of complications such as coronary revascularization, fatal and non-fatal stroke, exacerbation of angina pectoris, development of diabetes, disorders renal function and peripheral arterial disease, as well as total coronary and cardiovascular events, cardiovascular mortality, compared with the use of the atenolol/bendroflumethiazide combination.

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, LVH decreases. Indapamide does not affect the concentration of lipids in the blood plasma (triglycerides, total cholesterol, HDL, LDL), or carbohydrate metabolism (including in patients with diabetes mellitus (DM).

Perindopril

Perindopril, an ACE inhibitor, 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 plasma renin according to the principle of negative feedback;

- with long-term use, it reduces the peripheral vascular resistance - afterload on 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 CHF revealed:

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

— decrease in OPSS;

- increase in cardiac output and cardiac index;

- increased peripheral blood flow in the 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 arterial hypertension (AH) of any severity, reducing both SBP and DBP in the supine and standing position.

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. Discontinuation of therapy does not cause withdrawal syndrome.

Perindopril has vasodilatory properties and helps restore the elasticity of large arteries, the structure of the vascular wall of small arteries, and also reduces left ventricular hypertrophy (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 SBP and DBP (standing and lying down), regardless of the patient's age. The antihypertensive effect persists for 24 hours. The 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, the simultaneous use of perindopril and indapamide increased the severity of the antihypertensive effect compared with monotherapy with each drug. The combination of perindopril tert-butylamine (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 perindopril tert-butylamine (perindopril erbumine) 8 mg/indapamide 2.5 mg.

Ko-Dalneva, 30 pcs., 5 mg+0.625 mg+2 mg, tablets

Amlodipine

Concomitant use is not recommended

Dantrolene (intravenous administration).

In laboratory animals, cases of ventricular fibrillation with death and collapse have been reported during the use of verapamil and intravenous administration of dantrolene, accompanied by hyperkalemia. Due to the risk of hyperkalemia, it is recommended to avoid the simultaneous use of a CCB (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.

There are no data regarding the effect of inducers of the CYP3A4 isoenzyme on amlodipine. The simultaneous use of inducers of the CYP3A4 isoenzyme (rifampicin, St. John's wort preparations) may lead to a decrease in the concentration of amlodipine in the blood plasma. Caution should be exercised when taking amlodipine simultaneously with inducers of the CYP3A4 isoenzyme.

Inhibitors of the CYP3A4 isoenzyme.

Concomitant use of amlodipine with strong or moderate inhibitors of the CYP3A4 isoenzyme (protease inhibitors, azole antifungals, macrolides, such as erythromycin or clarithromycin, verapamil or diltiazem) can lead to a significant increase in the concentration of amlodipine. Clinical manifestations of these pharmacokinetic abnormalities may be more pronounced in elderly patients, and therefore monitoring of the clinical condition and dose adjustment may be required.

Concomitant use requiring attention

Amlodipine enhances the antihypertensive effect of drugs for antihypertensive therapy.

Other drug combinations.

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

Given the risk of developing hypokalemia, caution should be exercised when using indapamide simultaneously with drugs that can cause polymorphic ventricular tachycardia of the “pirouette” type, for example, antiarrhythmic drugs (quinidine, hydroquinidine, disopyramide, amiodarone, dofetilide, ibutilide, bretylium tosylate, 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, difemanil methyl sulfate, erythromycin IV c, halofantrine, mizolastine, moxifloxacin, pentamidine, sparfloxacin, vincamine IV, methadone, astemizole, terfenadine. Simultaneous use with the above drugs should be avoided; if hypokalemia develops, correct it and monitor the ECG (QT interval).

Drugs that can cause hypokalemia.

Concomitant use with intravenous amphotericin B, systemic corticosteroids 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 Cl 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 Cl creatinine in blood plasma without changing the concentration of cyclosporine, even with normal water and sodium content.

Perindopril

Concomitant use is not recommended

Aliskiren.

Concomitant use of perindopril with aliskiren is contraindicated in patients with diabetes or moderate to severe renal impairment (creatinine clearance less than 60 ml/min).

Potassium-sparing diuretics, potassium supplements 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. Concomitant use of potassium-sparing diuretics (spironolactone, triamterene, amiloride, eplerenone), potassium supplements and potassium-containing table salt substitutes can lead to a significant increase in potassium levels in the blood plasma. 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.

Estramustine.

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

Concomitant use requiring special attention

Double blockade of the RAAS in patients with atherosclerosis, CHF or diabetes mellitus accompanied by target organ damage is associated with a higher incidence of arterial hypotension, fainting, hyperkalemia and renal dysfunction (including the development of acute renal failure) compared with the use of the drug one of the listed groups. Double blockade of the RAAS is possible only in selected cases under careful monitoring of renal function.

NSAIDs, including high doses of acetylsalicylic acid (ASA) (more than 3 g/day).

The simultaneous use of ACE inhibitors with NSAIDs (including ASA at a dose that has an anti-inflammatory effect, COX-2 inhibitors and non-selective NSAIDs) can lead to a decrease in the antihypertensive effect, as well as to a deterioration in renal function, including the development of acute renal failure, and an increase in plasma potassium levels blood, 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 (sulfonylureas and insulin)

ACE inhibitors may enhance the hypoglycemic effect of insulin and sulfonylureas in patients with diabetes mellitus. The development of hypoglycemia is very rare (probably due to increased glucose tolerance and decreased insulin requirements).

Concomitant use requiring attention

Diuretics (thiazide and loop).

In patients receiving diuretics, especially those with excessive fluid and/or electrolyte excretion, a significant decrease in blood pressure may be observed when initiating ACE inhibitor therapy. The risk of developing arterial hypotension can be reduced by discontinuing the diuretic, correcting hypovolemia and electrolyte balance, as well as prescribing perindopril in a low dose (2 mg/day), gradually increasing it.

Allopurinol, cytostatic and immunosuppressive drugs, GCS (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, incl. perindopril, in patients receiving intravenous gold (sodium aurothiomalate), a symptom complex was described, including facial flushing, nausea, vomiting, and arterial hypotension.

Sympathomimetics.

May weaken the antihypertensive effect of ACE inhibitors.

Gliptins (linagliptin, saxagliptin, sitagliptin, vitagliptin).

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.

Ko-Dalneva®

Concomitant use is not recommended

Lithium preparations.

With the simultaneous use of ACE inhibitors with lithium preparations, a reversible increase in the concentration of lithium in the blood plasma may occur with the development of intoxication. Concomitant use with thiazide diuretics may further increase lithium concentrations and increase the risk of intoxication. The simultaneous use of a combination of perindopril and indapamide with lithium preparations is not recommended. In the case of this therapy, regular monitoring of the concentration of lithium in the blood plasma is necessary.

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.

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.

Amifostine.

The antihypertensive effect of amlodipine may be enhanced.

Tricyclic antidepressants/neuroleptics/general anesthesia.

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

Pharmacokinetics

Amlodipine

Absorption, distribution. After oral administration, amlodipine is slowly absorbed from the gastrointestinal tract. Food intake does not affect the bioavailability of amlodipine. Cmax of amlodipine in blood plasma is achieved 6–12 hours after oral administration. Absolute bioavailability is about 64–80%. Vd is approximately 21 l/kg. In in vitro studies, the degree of binding of amlodipine to plasma proteins was about 97.5%.

Metabolism/excretion. The final T1/2 from blood plasma is about 35–50 hours, which makes it possible to take amlodipine 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 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

Absorption, distribution. Indapamide is quickly and completely absorbed from the gastrointestinal tract. Cmax in blood plasma is achieved 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 the 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.

Excretion. T1/2 of perindopril 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 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). 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 dose adjustment is not required (see “Dosage and Administration” and “Special Instructions”).

Co-Dalneva tablets 5 mg+0.625 mg+2 mg 30 pcs.

Co-Dalneva is a combination drug containing perindopril erbumine (angiotensin-converting enzyme (ACE) inhibitor), indapamide (thiazide-like diuretic) and amlodipine besylate (slow calcium channel blocker (SCBC)). Ko-Dalneva combines the properties of each of the active substances, which also have a potentiating effect. 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 plasma renin according to the principle of “negative” feedback; with long-term use, it reduces total peripheral vascular resistance (TPVR) - 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: a 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 the 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 arterial hypertension (AH) of any severity, reduces both systolic and diastolic blood pressure (BP) 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. Concomitant use with a thiazide diuretic increases the severity of the antihypertensive effect and reduces the risk of developing hypokalemia while taking diuretics. 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, 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 mellitus (DM)). 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 has not been fully studied, presumably it is associated with the following effects: causes dilation of peripheral arterioles, reducing peripheral vascular resistance - 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 hypertension, taking amlodipine once a day provides a clinically significant reduction in blood pressure (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 and gout. With long-term use of the perindopril/amlodipine combination in patients aged 40 to 79 years with arterial hypertension and at least 3 of the additional risk factors (LVH, type 2 diabetes mellitus, peripheral arterial atherosclerosis, previous stroke or transient ischemic attack, male gender, age 55 years and older, microalbuminuria or proteinuria, smoking, total cholesterol/high-density lipoprotein cholesterol ≥ 6, early development of coronary heart disease in close relatives) the incidence of complications such as coronary revascularization, fatal and non-fatal, was significantly reduced stroke, exacerbation of angina pectoris, development of diabetes mellitus, renal dysfunction and peripheral artery disease, as well as total coronary and cardiovascular events, cardiovascular mortality, compared with the use of the atenolol/bendroflumethiazide combination. 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 perindopril tertbutylamine (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 perindopril tertbutylamine (perindopril erbumine) 8 mg/indapamide 2.5 mg.

Contraindications

hypersensitivity to amlodipine and other dihydropyridine derivatives, indapamide and other sulfonamide derivatives, perindopril and other ACE inhibitors, as well as excipients included in the drug;

history of angioedema (Quincke's edema) associated with taking ACE inhibitors;

hereditary/idiopathic angioedema;

bilateral renal artery stenosis, stenosis of the artery of a single kidney;

severe arterial hypotension (SBP less than 90 mm Hg);

shock (including cardiogenic);

unstable angina (with the exception of Prinzmetal angina);

left ventricular outflow tract obstruction (eg, clinically significant aortic stenosis);

hemodynamically unstable heart failure after acute myocardial infarction;

renal failure (creatinine Cl less than 60 ml/min);

severe liver failure, incl. hepatic encephalopathy;

refractory hypokalemia;

simultaneous use with drugs that can cause polymorphic ventricular ari (see “Interaction”);

simultaneous use with potassium-sparing diuretics, potassium and lithium preparations, in patients with elevated potassium levels in the blood plasma;

simultaneous use of drugs that prolong the QT interval;

simultaneous use with aliskiren and aliskiren-containing drugs in patients with diabetes mellitus;

patients on hemodialysis, as well as patients with untreated heart failure in the stage of decompensation (there is no sufficient clinical experience);

pregnancy (see “Use during pregnancy and lactation”);

period of breastfeeding (see “Use during pregnancy and lactation”);

age under 18 years (efficacy and safety have not been established).

Co-Dalneva Tablets, 30 pcs., 5+0.625 + 2 mg + mg + mg

Pharmacological properties

Dalneva is a combined antihypertensive drug. Perindopril Perindopril is an ACE inhibitor. ACE or kininase II is an exopeptidase that converts angiotensin I into a vasoconstrictor substance - angiotensin II, in addition, ACE destroys bradykinin, which has a vasodilator effect, into an inactive hectapeptide. Suppression of ACE activity leads to a decrease in angiotensin II, an increase in renin activity in the blood plasma and a weakening of aldosterone secretion. Since ACE also destroys bradykinin, suppression of ACE also leads to increased activity of the kallikrein-kinin system. Perindopril acts through its active metabolite, perindoprilate. Other metabolites do not have an inhibitory effect on ACE in vitro. Perindopril has a therapeutic effect for any degree of arterial hypertension, reducing systolic and diastolic blood pressure in the supine and standing position. Reduces peripheral vascular resistance, resulting in increased peripheral blood flow without changes in heart rate. Renal blood flow usually increases, while GFR does not change. The hypotensive effect reaches its maximum 4-6 hours after a single oral dose of perindopril and persists for 24 hours. The hypotensive effect 24 hours after a single oral dose is about 87-100% of the maximum hypotensive effect. The decrease in blood pressure develops quickly. The therapeutic effect occurs in less than 1 month from the start of therapy and is not accompanied by tachycardia. Discontinuation of therapy does not lead to the development of withdrawal syndrome. Perindopril has a vasodilating effect, helps restore the elasticity of large arteries and the structure of the vascular wall of small arteries, and also reduces left ventricular hypertrophy. Amlodipine A dihydropyridine derivative is a slow calcium channel blocker that has antianginal and hypotensive effects. Blocks calcium channels, reduces the transmembrane transition of calcium ions into the cell (to a greater extent into vascular smooth muscle cells than into cardiomyocytes). The antianginal effect is due to the expansion of the coronary and peripheral arteries and arterioles: in case of angina pectoris, it reduces the severity of myocardial ischemia; expanding peripheral arterioles, reduces peripheral vascular resistance, reduces afterload on the myocardium, reduces myocardial oxygen demand, expanding coronary arteries and arterioles in unchanged and ischemic areas of the myocardium, increases the supply of oxygen to the myocardium (especially with vasospastic angina); prevents spasm of the coronary arteries (including those caused by smoking). In patients with stable angina, a single daily dose increases exercise tolerance, increases the time before the onset of an angina attack and ischemic depression of the ST segment on the ECG, reduces the frequency of angina attacks and the consumption of nitroglycerin and other nitrates. It has a long-term dose-dependent hypotensive effect. The hypotensive effect is due to a direct vasodilating effect on vascular smooth muscle. For arterial hypertension, a single dose provides a clinically significant reduction in blood pressure over 24 hours (with the patient lying and standing). Orthostatic hypotension when prescribing amlodipine is quite rare. Does not cause a decrease in left ventricular ejection fraction. Reduces the degree of left ventricular myocardial hypertrophy. It has no effect on myocardial contractility and conductivity, does not cause a reflex increase in heart rate, inhibits platelet aggregation, increases GFR, and has a weak natriuretic effect. In diabetic nephropathy, it does not increase the severity of microalbuminuria. It does not have any adverse effect on metabolism and plasma lipid concentrations and can be used in the treatment of patients with bronchial asthma, diabetes mellitus and gout. A significant decrease in blood pressure is observed after 6-10 hours, the duration of the effect is 24 hours.

Side effects

WHO classification of the incidence of side effects: very often - ≥1/10; often - from ≥1/100 to <1/10; uncommon - from ≥1/1000 to <1/100; rarely - from ≥1/10000 to <1/1000; very rarely - <1/10000; frequency unknown—cannot be estimated from available data.

* Most cases are associated with cholestasis.

Co-Dalneva® (Co-Dalneva®)

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).

Low body weight patients, short patients and patients with severe hepatic impairment 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 amlodipine 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 amlodipine clearance 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 potassium levels 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 calcium levels in the blood plasma. 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.

Choroidal effusion/acute myopia/acute secondary angle-closure glaucoma

Sulfonamides and their derivatives can cause an idiosyncratic reaction, leading to the development of choroidal effusion with visual field impairment, acute myopia and an acute attack of secondary closed-angle glaucoma. Symptoms include sudden loss of vision or pain in the eye; usually occur within hours or weeks after starting thiazide/thiazide-like diuretic therapy. If left untreated, acute secondary angle-closure glaucoma can lead to irreversible vision loss. If symptoms occur, the thiazide/thiazide-like diuretic should be discontinued as soon as possible. If intraocular pressure remains uncontrolled, emergency medical treatment or surgery may be required. Risk factors for the development of angle-closure glaucoma are a history of an allergic reaction to sulfonamide derivatives and/or 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, it should be performed under strict medical supervision with regular monitoring of renal function, plasma potassium levels and blood pressure. Concomitant use of ACE inhibitors with aliskiren or drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m2 body surface area) and is not recommended in other patients.

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 appear (for example, sore throat, fever), 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 be aware of 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

In patients with diabetes mellitus receiving oral hypoglycemic agents or insulin, regular monitoring of blood 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 in the blood plasma or the appearance of jaundice while taking ACE inhibitors, you should stop taking perindopril 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 CHF, metabolic acidosis), simultaneous use of potassium-sparing diuretics (spironolactone, eplerenone, triamterene, amiloride), potassium preparations, potassium-containing table salt substitutes, as well as other drugs that help increase potassium levels in the blood plasma (for example, heparin, trimethoprim or co-trimoxazole (sulfamethoxazole + trimethoprim) and especially aldosterone antagonists or ARA II, ASA ≥ 3 g / day, COX-inhibitors 2 and non-selective NSAIDs, immunosuppressants such as cyclosporine or tacrolimus (especially in patients with reduced renal function)). Hyperkalemia can lead to serious, sometimes fatal, heart rhythm disturbances. Caution should be exercised during the simultaneous use of ACE inhibitors and potassium-sparing diuretics and ARA II; renal function and serum potassium levels must 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 during therapy with ACE inhibitors, there may be an increase in serum urea and creatinine concentrations (usually resolving when therapy is discontinued), and the risk of developing arterial hypotension and renal failure also increases. 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.

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

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 blood volume 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, but 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.