Co-Dalneva pills 5 mg + 2.5 mg + 8 mg №30

Tradename: Ko-Dalneva^®

International non-proprietary or grouping name: amlodipine + Indapamide + Perindopril

Dosage Form: pills

Active ingredient

Active ingredients:

Amlodipine besylate (amlodipine besylate) 6.935 mg, equivalent to Amlodipine 5 mg, Indapamide 0.625 mg,

Perindopril erbumin B substance-granules 10,206 mg,

contains perindopril erbumine 2 mg

Excipients: microcrystalline cellulose 90.244 mg, pregelatinized starch 21,000 mg, sodium carboxymethyl starch 8.400 mg, sodium bicarbonate 0.760 mg, colloidal silicon dioxide 0.430 mg, Magnesium stearate 1.400 mg

1 pill 5 mg + 1.25 mg + 4 mg contains:

Active ingredients:

Amlodipine besylate (amlodipine besylate) 6.935 mg, equivalent to amlodipine 5 mg, indapamide 1.250 mg,

Perindopril erbumin B substance-granules 20.412 mg,

contains perindopril erbumine 4 mg

Excipients: microcrystalline cellulose 79.413 mg, pregelatinized starch 21,000 mg, sodium carboxymethyl starch 8.400 mg, sodium hydrocarbonate 0.760 mg, colloidal silicon dioxide 0.430 mg, magnesium stearate 1.400 mg

1 pill 10 mg + 1.25 mg + 4 mg contains:

Active ingredients:

Amlodipine besylate (Amlodipine besylate) 13,870 mg,

equivalent to amlodipine 10 mg,

Indapamide 1,250 mg,

Perindopril erbumin B substance-granules 20.412 mg,

contains perindopril erbumine 4 mg

Excipients: microcrystalline cellulose 180.488 mg, pregelatinized starch 42.000 mg, sodium carboxymethyl starch 16.800 mg, sodium bicarbonate 1.520 mg, colloidal silicon dioxide 0.860 mg, magnesium stearate 2.800 mg

1 pill 5 mg + 2.5 mg + 8 mg contains:

Active ingredients:

Amlodipine besylate (amlodipine besylate) 6.935 mg, equivalent to amlodipine 5 mg, indapamide 2.500 mg,

Perindopril erbumin B substance-granules 40,824 mg,

contains perindopril erbumine 8 mg

Excipients: microcrystalline cellulose 165.761 mg, pregelatinized starch 42.000 mg, sodium carboxymethyl starch 16.800 mg, sodium bicarbonate 1.520 mg, colloidal silicon dioxide 0.860 mg, magnesium stearate 2.800 mg.

1 pill 10 mg + 2.5 mg + 8 mg contains:

Active ingredients:

Amlodipine besylate (Amlodipine besylate) 13,870 mg,

equivalent to amlodipine 10 mg,

Indapamide 2,500 mg,

Perindopril erbumin B substance-granules 40,824 mg,

contains perindopril erbumine 8 mg

Excipients: microcrystalline cellulose 158.826 mg, pregelatinized starch 42.000 mg, sodium carboxymethyl starch 16.800 mg, sodium bicarbonate 1.520 mg, silicon dioxide colloidal 0.860 mg, magnesium stearate 2.800 mg.

Description

Tablets 5 mg + 0.625 mg + 2 mg:

Oval, biconvex pills with a risk on one side, white or almost white.

Tablets 5 mg + 1.25 mg + 4 mg:

Round, slightly biconvex pills with a facet, white or almost white.

Tablets 5 mg + 2.5 mg + 8 mg:

Round, biconvex pills with a facet, white or almost white.

Tablets 10 mg + 1.25 mg + 4 mg:

Oval, biconvex pills with a risk on one side, white or almost white.

Tablets 10 mg + 2.5 mg + 8 mg:

Round, biconvex pills with a facet and a risk on one side, white or almost white.

Pharmacotherapeutic group: antihypertensive combination agent

Pharmacological properties

Ko-Dalneva^® - a combination preparation containing perindopril erbumin (an angiotensin-converting enzyme inhibitor (ACE)), indapamide (thiazide-like diuretic) and amlodipine besylate (blocker of “slow” Calcium channels (BMCC)).

Ko-Dalneva^® combines the properties of each of the active ingredients that have a potentiating effect.

Pharmacodynamics

Perindopril

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

As a result, perindopril provides the following effects:

• reduces the secretion of aldosterone;
• increases plasma renin activity by the principle of "negative" feedback;
• with prolonged use reduces the total peripheral vascular resistance (OPS) - afterload of the heart, which is mainly due to the effect on muscle and renal vessels. The reduction of OPSS is not accompanied by a delay of sodium and water and does not cause reflex tachycardia;

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

• decrease in filling pressure in the left and right ventricles of the heart;
• a decrease in fsr;
• increase in cardiac output and cardiac index;
• increased peripheral blood flow in the muscles.

In addition, an improvement in exercise results with exercise was noted.

The action of perindopril is carried out through an active metabolite - perindoprilat. Other metabolites have no 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 a maximum after 4-6 hours after a single ingestion and persists for 24 hours.

Antihypertensive effect after 24 hours after a single ingestion is about 87-100% of the maximum antihypertensive effect.

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

The therapeutic effect occurs less than 1 month from the start of therapy and is not accompanied by tachyphylaxis. Termination of therapy does not cause a "cancellation" syndrome.

Simultaneous use with thiazide diuretic increases the severity of the antihypertensive effect and reduces the risk of hypokalemia in the presence of diuretics.

Indapamide

Indapamide is a sulfonamide derivative. Pharmacologically similar to thiazide diuretics. Indapamide inhibits the reabsorption of sodium ions in the cortical segment of the loop of Henle, which leads to an increase in kidney excretion of sodium and chlorine ions, and to a lesser extent potassium and magnesium ions, thereby increasing diuresis and lowering blood pressure.

In monotherapy mode, the antihypertensive effect persists for 24 hours and manifests itself when the drug is used in doses that have minimal diuretic effect. The antihypertensive effect of indapamide is associated with an improvement in the elastic properties of large arteries, a decrease in CRPS. With indapamide, LVH is reduced. Indapamide does not affect the concentration of lipids in the blood plasma (triglycerides, total cholesterol, low-density and high-density lipoproteins), or indicators of carbohydrate metabolism (including in patients with diabetes mellitus (DM)).

Amlodipine

Amlodipine - 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 the direct relaxing effect on the smooth muscle cells of the vascular wall. The mechanism of antianginal action of amlodipine is not fully understood; it is presumably associated with the following effects:

• causes the expansion of peripheral arterioles, reducing the OPS - afterload, which leads to a decrease in myocardial oxygen demand;
• causes expansion of the coronary arteries and arterioles in both intact and ischemic sites of the myocardium, which increases the oxygen supply to the myocardium, including in patients with Prinzmetal angina pectoris.

In patients with hypertension, taking amlodipine once a day provides a clinically significant reduction in blood pressure (in the "lying" and "standing" position) for 24 hours. The antihypertensive effect develops slowly, and therefore, the development of acute arterial hypotension is uncharacteristic. In patients with angina, taking amlodipine 1 time per day increases exercise tolerance, the time before the onset of an attack of stenocardia and the "ischemic" depression of the ST segment, reduces the frequency of strokes and the need for Nitroglycerin (short-acting form). Amlodipine does not affect the lipid profile and does not cause changes in the hypolipidemic parameters of blood plasma. The drug can be used in patients with bronchial asthma (BA), diabetes and gout.

With long-term use of the combination of perindopril / amlodipine in patients aged 40 to 79 years with arterial hypertension and at least 3 of the additional risk factors (LVH, diabetes mellitus type 2, atherosclerosis of the peripheral arteries, a previous stroke or transient ischemic attack, male gender, age 55 years and older, microalbuminuria or proteinuria, smoking, total cholesterol / cholesterol high density lipoprotein ≥ 6,early development of coronary heart disease in next of kin) significantly reduced the incidence of complications such as coronary revascularization, fatal and nonfatal stroke, exacerbation of angina, development of diabetes, renal dysfunction and peripheral arterial disease, as well as general coronary and cardiovascular events, cardiovascular mortality compared with Atenolol / bendroflumethiazide.

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" position), regardless of the patient's age. Antihypertensive effect persists for 24 hours. The therapeutic effect occurs less than 1 month from the start of therapy and is not accompanied by tachyphylaxis. Termination of therapy does not cause a "cancellation" 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 erbumin) / indapamide resulted in a significantly more pronounced decrease in LVH than Enalapril monotherapy. The most significant effect on LVH is achieved with perindopril terbutylamine (perindopril erbumine) 8 mg / indapamide

2.5 mg.

Pharmacokinetics

Perindopril

Absorption, biotransformation

When taken inside, perindopril is rapidly absorbed.Maximum concentration (C_max) in blood plasma is achieved within 1 hour after ingestion.

Perindopril is a prodrug, i.e. it does not possess pharmacological activity. About 27% of the dose of perindopril, taken orally, enters the bloodstream in the form of an active metabolite - perindoprilat. In addition to the active metabolite, perindoprilat, 5 more metabolites are formed that do not possess pharmacological activity. C_max Perindoprilat in blood plasma is achieved in 3-4 hours after ingestion. Eating slows down the conversion of perindopril to perindoprilat, thereby affecting bioavailability. Therefore, perindopril should be taken 1 time per day, in the morning, before meals.

There is a linear dependence of the concentration of perindopril in plasma from the dose taken inside.

Distribution

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

Removal

Elimination half-life (t_1/2) perindopril from blood plasma is 1 hour. Perindoprilat is eliminated from the body by the kidneys. Final t_1/2 free fraction is about 17 hours, the equilibrium state is reached within 4 days. Removal of perindoprilat is delayed in elderly patients, as well as in patients with cardiac and renal failure. Dose adjustment in patients with renal insufficiency is based on the degree of renal dysfunction (creatinine clearance (CK)). The dialysis clearance of perindoprilat is 70 ml / min.

The pharmacokinetics of perindopril changes in patients with cirrhosis of the liver: the hepatic clearance is reduced by 2 times. However, the amount of perindoprilat formed does not decrease, therefore dose adjustment is not required (see the sections “Directions for use and dosage” and “Special instructions”).

Indapamide

Suction

Indapamide is rapidly and completely absorbed from the gastrointestinal tract (GIT). C_max in blood plasma is achieved approximately 1 hour after taking the drug inside. The degree of binding to plasma proteins is 79%.

Biotransformation, elimination

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

The pharmacokinetics of indapamide does not change in patients with renal insufficiency.

Amlodipine

Suction

After oral administration, amlodipine is slowly absorbed from the gastrointestinal tract. Eating does not affect the bioavailability of amlodipine. C_max amlodipine in blood plasma is achieved 6-12 hours after ingestion. Absolute bioavailability is about 64-80%. Vd is approximately 21 L / kg. In research in vitro The degree of binding of amlodipine to plasma proteins was about 97.5%.

Biotransformation / elimination

Final t_1/2 from blood plasma is about 35-50 hours, which allows taking amlodipine 1 time per day. Amlodipine is metabolized in the liver with the formation of inactive metabolites, while 10% of the amlodipine dose ingested is excreted unchanged, about 60% of the kidneys are excreted as metabolites.Amlodipine is not excreted through hemodialysis.

Time to reach C_max Amlodipine does not differ in patients of older and younger age. In elderly patients, there is a decrease in the clearance of amlodipine, which leads to an increase in the area under the concentration-time curve (AUC) and T_1/2. Dose adjustment in elderly patients is not required, but it is necessary to increase the dose of amlodipine with caution. Increased AUC and T_1/2 in patients with CHF corresponds to the estimated value for this age group.

In patients with impaired renal function, changes in the concentration of amlodipine in the blood plasma do not correlate with the degree of renal failure. Possible slight elongation T_1/2

In patients with impaired liver function data on the use of amlodipine are limited, there is a decrease in the clearance of amlodipine, which leads to an increase in T_1/2 and AUC by about 40-60%.

Indications for use

• Arterial hypertension (if necessary, combination therapy with perindopril / indapamide and amlodipine).

Contraindications

• Hypersensitivity to amlodipine and other dihydropyridine derivatives, indapamide and other sulfonamide derivatives, perindopril and other ACE inhibitors, as well as to the excipients that make up the drug.
• Angioedema (angioedema) in history, associated with taking ACE inhibitors
• Hereditary / idiopathic angioedema.
• Bilateral renal artery stenosis, single kidney artery stenosis.
• Severe arterial hypotension (systolic blood pressure less than 90 mm Hg. Art.)
• Shock, including cardiogenic shock
• Unstable angina (with the exception of Prinzmetal stenocardia).
• Obstruction of the output tract of the left ventricle (for example, clinically significant aortic stenosis).
• Hemodynamically unstable heart failure after acute myocardial infarction.
• Renal failure (creatinine clearance (CC) less than 60 ml / min).
• Severe hepatic impairment, including hepatic encephalopathy.
• Hypokalemia.
• Simultaneous use with drugs that can cause polymorphic ventricular arrhythmia type "pirouette" (see the section "Interaction with other drugs").
• Simultaneous use with potassium-sparing diuretics, potassium and lithium preparations, in patients with an increased content of potassium in the blood plasma.
• The simultaneous use of drugs that extend the QT interval.

• Simultaneous use with aliskiren in patients with diabetes.

• Pregnancy and breastfeeding period (see section “Pregnancy and breastfeeding period”).
• Age up to 18 years (efficacy and safety have not been established).

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

With care (see also sections "Special Instructions" and "Interaction with Other Medicines"):

mild and moderate hepatic insufficiency, systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma), therapy with immunosuppressants, Allopurinol , procainamide (risk of developing neutropenia and agranulocytosis), bone marrow hematopoietic suppression, reduced circulating blood (receiving diuretics, salt-restricted diet, vomiting, diarrhea, hemodialysis), coronary heart disease, atherosclerosis, cerebrovascular diseases, renovascular hypertension, diabetes, CHF (IV function ny class NYHA classification), hyperuricemia (especially in combination with urate gout and nephrolithiasis), the simultaneous use of dantrolene, estramustine, surgery / anesthesia general, lability AD hemodialysis using vysokoprotochnyh membranes (e.g., AN69^®), Before the procedure apheresis low density lipoproteins (LDL) using the dextran sulfate simultaneous desensitizing therapy allergens (e.g., poison Hymenoptera), condition after kidney transplantation, aortic stenosis, mitral stenosis, hypertrophic obstructive cardiomyopathy (GOKMP) use in elderly patients age and Negroid patients.

Use during pregnancy and during breastfeeding

Pregnancy

The drug Co-Dalneva ^® contraindicated in pregnancy (see section "Contraindications").

When planning a pregnancy or when it occurs while taking the drug

Ko-Dalneva^® Stop taking immediately and prescribe an alternative antihypertensive therapy with a proven safety profile.

The available data on the teratogenicity of ACE inhibitors in the first trimester of pregnancy are not convincing, but this risk cannot be completely excluded. In the II and III trimesters of pregnancy, the effect of ACE inhibitors on the fetus can lead to impaired development (reduced kidney function, oligohydramnios, delayed ossification of the skull bones) and the development of complications in the newborn (renal failure, arterial hypotension, hyperkalemia). If the ACE inhibitor was used in the II or III trimester of pregnancy, an ultrasound examination of the kidneys and bones of the fetal skull is recommended. Newborns whose mothers received ACE inhibitors during pregnancy need careful medical observation, as there is a risk of arterial hypotension.

Prolonged use of thiazide diuretics in the third trimester of pregnancy can cause maternal hypovolemia and a decrease in uteroplacental blood flow, which

leads to placental ischemia and delayed fetal development. In rare cases

during diuretic administration, hypoglycemia and thrombocytopenia develop in newborns shortly before birth.

The safety of using amlodipine during pregnancy has not been established.The limited data available on the use of amlodipine and other BMCC during pregnancy indicate the absence of a negative effect on the fetus. In animal studies, signs of reproductive toxicity were observed with the use of high doses of amlodipine. In some patients treated with BMCC, a reversible decrease in sperm motility was observed. Clinical data regarding the potential effect of amlodipine on reproductive function is insufficient.

Breastfeeding period

The drug Co-Dalneva^® contraindicated in breastfeeding. If necessary, use of the drug Co-Dalneva^® during lactation, breastfeeding should be discontinued.

It is not known whether perindopril is excreted in breast milk.

Indapamide is excreted in breast milk. Acceptance of thiazide diuretics causes a decrease or suppression of lactation in the mother; in a newborn, it is possible that hypersensitivity to sulfonamide derivatives, hypokalemia and “nuclear” jaundice may develop.

There is no data on the excretion of amlodipine with breast milk. However, it is known that other BCCA derivatives of dihydropyridine are excreted in breast milk.

Dosage and administration

Inside, on 1 pill once a day, preferably in the morning, before meals.

The dose of the drug Co-Dalneva^® is selected after a previously conducted titration of doses of individual components of the drug.

The maximum daily dose of the drug Co-Dalneva^® makes 8 mg of perindopril +

2.5 mg indapamide + 10 mg amlodipine.

Elderly patients and patients with impaired renal function

The elimination of perindoprilat in elderly patients and patients with renal insufficiency is slow. Therefore, in such patients it is necessary to regularly monitor the concentration of creatinine and the content of potassium in the blood plasma.

The drug Co-Dalneva^® can be used in patients with QC equal and greater than

60 ml / min.

The drug Co-Dalneva^® contraindicated for use in patients with QA less than 60 ml / min (see section "Contraindications"). Such patients are recommended individual selection of doses of perindopril, amlodipine, indapamide. Amlodipine, used in equivalent doses, is equally well tolerated by patients of both elderly and younger age. No dosing regimen is required in elderly patients, but the dose should be increased with caution, which is associated with age-related changes and prolongation of T_1/2.

Changes in the concentration of amlodipine in the blood plasma do not correlate with the severity of renal failure.

Patients with impaired liver function

The drug Co-Dalneva^® contraindicated in patients with severe hepatic insufficiency.

Caution must be exercised when using the drug in patients with mild and moderate liver dysfunction.

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

very often ≥ 1/10

often from ≥ 1/100 to <1/10

infrequently from ≥ 1/1000 to <1/100

rarely from ≥ 1/10000 to <1/1000

very rarely <1/10000

frequency unknown cannot be estimated based on available data.