Ko-Dalnev tablets 5 + 2.5 + 8 mg 30 pcs. pack (amlodipine, indapamide, Perindopril)

Release form

Tablets

Packaging

30 pcs

The pharmacological effect of

Dalnev 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 vasodilating effect, to an inactive hectapeptide. Inhibition of ACE activity leads to a decrease in angiotensin II, increased plasma renin activity and decreased aldosterone secretion. Since ACE also destroys bradykinin, inhibition of ACE also leads to an increase in the activity of the kallikrein-kinin system.

Perindopril acts through its active metabolite, perindoprilat. Other metabolites do not inhibit ACE in vitro. Perindopril has a therapeutic effect with any degree of arterial hypertension, reducing systolic and diastolic blood pressure in the supine and standing position.

Reduces OPSS, resulting in increased peripheral blood flow without changes in heart rate.

Renal blood flow tends to increase, while GFR does not change.

The antihypertensive effect reaches its maximum 4-6 hours after a single oral administration of perindopril and persists for 24 hours. The antihypertensive effect 24 hours after a single oral administration is about 87-100% of the maximum antihypertensive effect.

A decrease in blood pressure is developing rapidly. The therapeutic effect occurs less than 1 month after the start of therapy and is not accompanied by tachycardia.

Discontinuation of therapy does not lead to 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 derivative of dihydropyridine - a blocker of slow calcium channels, has an antianginal and hypotensive effect. It blocks calcium channels, reduces the transmembrane transition of calcium ions into the cell (more to the smooth muscle cells of blood vessels than to cardiomyocytes).

The antianginal effect is due to the expansion of the coronary and peripheral arteries and arterioles: with angina pectoris it reduces the severity of myocardial ischemia by expanding peripheral arterioles, reduces OPSS, reduces myocardial afterload, decreases myocardial oxygen demand, expanding coronary arteries and arterioles in unchanged and ischemic areas of the myocardium, increases oxygen to the myocardium (especially with vasospastic angina pectoris) 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 until an attack of angina pectoris and ischemic depression of the ST segment on the ECG, reduces the frequency of angina attacks and the consumption of nitroglycerin and other nitrates.

Has a prolonged dose-dependent hypotensive effect. The antihypertensive effect is due to a direct vasodilating effect on the smooth muscles of blood vessels. With arterial hypertension, a single dose provides a clinically significant reduction in blood pressure over 24 hours (in the patient’s position, lying and standing). Orthostatic hypotension with the appointment of amlodipine is quite rare. Does not cause a decrease in the ejection fraction of the left ventricle.

Reduces the degree of left ventricular myocardial hypertrophy. It does not affect myocardial contractility and conductivity, does not cause a reflex increase in heart rate, inhibits platelet aggregation, increases GFR, and has a weak natriuretic effect. With diabetic nephropathy does not increase the severity of microalbuminuria. It does not have any adverse effect on the metabolism and concentration of blood plasma lipids 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.

Pharmacokinetics

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

Perindopril

Absorption

After oral administration, perindopril is rapidly absorbed and reaches Cmax in the blood plasma within 1 hour. Eating reduces the bioavailability of perindopril, so the drug should be taken 1 time / day, in the morning, before meals.

There is a linear dependence of the concentration of perindopril in blood plasma on the value of its dose.

Distribution of

The binding of perindoprilat to plasma proteins (mainly ACE) is 20%, and depends on its concentration. Vd of free perindoprilat is approximately 0.2 L / kg.

Metabolism

Perindopril does not have pharmacological activity, is a prodrug. Approximately 27% of the total amount of perindopril taken internally enters the bloodstream as an active metabolite - perindoprilat. In addition to perindoprilat, 5 more metabolites are formed that do not have pharmacological activity. Cmax of perindoprilat in blood plasma is achieved 3-4 hours after ingestion.

The excretion of

T1 / 2 of perindopril from blood plasma is approximately 1 hour.

Perindoprilat is excreted by the kidneys, T1 / 2 of the unbound fraction is approximately 17 hours, therefore, Css is achieved within 4 days after ingestion.

Pharmacokinetics in special clinical cases

Excretion of perindoprilat is slowed down in elderly patients and in patients with heart and kidney failure, therefore monitoring of such patients should include regular monitoring of plasma creatinine and potassium concentrations.

Dialysis clearance of perindoprilat is 70 ml / min.

The pharmacokinetics of perindopril is changed in patients with cirrhosis of the liver: hepatic clearance is reduced by 2 times, but the amount of perindoprilat is not reduced, therefore, dose adjustment is not required.

Amlodipine

Absorption

Amlodipine is well absorbed when taken orally in therapeutic doses. Cmax in plasma is reached after 6-12 hours. The absolute bioavailability is 64-80%. Eating does not affect the bioavailability of amlodipine.

The distribution of

Vd is approximately 21 l / kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine is associated with plasma proteins.

Metabolism and excretion

Amlodipine is metabolized in the liver to form inactive metabolites. The final T1 / 2 from blood plasma is 35-50 hours, which allows you to take the drug 1 time / day.

Approximately 60% of the dose taken is excreted by the kidneys, 10% - unchanged.

Pharmacokinetics in special clinical cases

The time to reach Cmax in blood plasma is the same in elderly and young patients. Amlodipine clearance tends to decrease in elderly patients, which is accompanied by an increase in AUC. The recommended dosage regimen for elderly patients is the same as for younger patients, although a dose increase should be carried out with caution.

T1 / 2 of amlodipine lengthens in patients with impaired liver function.

Contraindications

Perindopril

hypersensitivity to perindopril or other ACE inhibitors

angioedema (Quincke's edema) in history (including the use of other ACE inhibitors)

age and / or not installed).

Amlodipine

hypersensitivity to amlodipine or other derivatives of dihydropyridine

severe arterial hypotension (SBP less than 90 mm Hg), shock, including cardiogenic

obstruction of the exit tract of the left ventricle (including severe stenosis of the aorta) with the exception of Prinzmetal angina)

hemodynamically unstable heart failure after acute myocardial infarction

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

DalnevaВ®

hypersensitivity to excipients that are part of the

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

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

Caution: liver failure chronic heart failure aortic and / or mitral stenosis hypertrophic obstructive cardiomyopathy (GOKMP) old age bilateral renal artery stenosis artery stenosis of a single functioning kidney renal failure (creatinine Cl less than 60 ml / min) systemic diseases of the connective tissue (including systemic lupus erythematosus, scleroderma), therapy with immunosuppressants, allopurinol, procainamide (risk of neutropenia, agranulocytosis), reduced BCC (taking diure Ikov, restricted diet salt, vomiting, diarrhea), atherosclerosis, cerebrovascular disease, renovascular hypertension, diabetes mellitus, the use of dantrolene, estramustine, potassium-sparing diuretics, potassium preparations, potassium-based salt substitutes food and drugs lithium hyperkalemia surgery / general anesthesia patients of the Negroid race hemodialysis using high-flow polyacrylonitrile membranes - the risk of anaphylactoid reactions before the LDL apheresis procedure with dextran sulfate, simultaneous desensitizing therapy with allergens (e.g., venomous membranes), .

Composition

1 tablet contains:

Active ingredients: amlodipine perilopril besilate erbumin A granule substance

Excipients: microcrystalline cellulose, starch pregelatinized, sodium carboxymethyl starch sodium carbamide, sodium magnesium carboxymethyl starch.

Dosage and administration

Inside, one tablet once a day, preferably in the morning before meals.

The dose of the drug DalnevВ® is selected after a previous titration of doses of the individual components of the drug - perindopril and amlodipine - in patients with arterial hypertension and stable angina pectoris.

If necessary, the dose of DalnevВ® can be changed based on individual selection of doses of the individual components: (amlodipine 5 mg + perindopril 4 mg) or (amlodipine 10 mg + perindopril 4 mg), or (amlodipine 5 mg + perindopril 8 mg), or (amlodipine 10 mg + perindopril 8 mg).

The maximum daily dose is amlodipine 10 mg + perindopril 8 mg.

Impaired renal function. DalnevВ® can be used in patients with Cl creatinine over 60 ml / min. The drug DalnevaВ® is contraindicated in patients with Cl creatinine less than 60 ml / min.

Such patients are advised to individually select the doses of perindopril and amlodipine. A change in the concentration of amlodipine in blood plasma does not correlate with the severity of renal failure.

Hepatic failure. Caution must be exercised when using the drug DalnevВ® in patients with liver failure, because there are no recommendations on the doses of the drug in such patients.

Elderly patients. When using the drug DalnevВ® in elderly patients, dose adjustment is not required.

Children and adolescents. DalnevВ® should not be prescribed to children and adolescents under 18 years of age. because there is no data on the efficacy and safety of perindopril and amlodipine in these patient groups both in monotherapy and in combination therapy.

Side effects

Classification of the frequency of development of side effects WHO: very often -? 1/10 often - from? 1/100 to <1/10 infrequently - from? 1/1000 to <1/100 rarely - from? 1/10000 up to <1/1000 is very rare - <1/10000 the frequency is unknown - cannot be estimated based on available data.

Classification of MedDRA Adverse Effects Frequency

Amlodipine Perindopril / Indapamide

Blood and lymphatic system Leukopenia / neutropenia Very rare Very rare

Agranulocytosis or pancytopenia - Very rarely

Very rarely - Very rarely srdlemp rarely

During treatment with ACE inhibitors in certain situations (after kidney transplantation, during dialysis) the development of anemia was observed - Very rarely

From the immune system Reactions hypersensitivity in patients anxiety) Infrequently Infrequently

Depression Infrequently -

Sleep disturbance - Infrequently

Confusion of consciousness Rarely Very rarely

From the nervous system Drowsiness (especially at the beginning of treatment) Often -

Dizziness (especially at the beginning of treatment) Often Often

Headache Infrequently -

Hypesthesia Infrequently -

Paresthesia Infrequently Often

Muscular hypertension Very rarely -

Peripheral neuropathy Very rare -

Vertigo - Often

Fainting Infrequently Frequency unknown

From the side impaired vision (including diplopia) Infrequently Often

On the part of the hearing organ and labyrinth disturbances Noise (ringing) in the ears Infrequently Often

On the part of the heart Sensation of heartbeat Often -

Angina pectoris - Very rarely

Myocardial infarction, possibly due to an excessive decrease in blood pressure in high-risk patients Very rarely Very rarely

Heart rhythm disturbances (including bradycardia, ventricular tachycardia and atrial fibrillation) Very rarely Very rarely

Polymorphic ventricular tachycardia of the pirouette type (possibly fatal) - Frequency unknown srdlp On the part of the vessels Sensation of flushing of the face skin Often -

Pronounced decrease in blood pressure (including orthostatic hypotension) Infrequently Infrequent

Vasculitis (including hemorrhagic vasculitis) Very rarely Infrequent

Co sides of the respiratory system constipation) Infrequently Often

Dryness of the oral mucosa Infrequently Often

Disorder of taste - Often

Pancreatitis Very rarely Very rarely

Gastritis Very rarely -

Decreased appetite - Often

Angioedema of the intestines Liver and gut Very rare -

Jaundice * Very rare Very rarely

Hepatic encephalopathy in patients with liver failure - Frequency unknown

Skin and subcutaneous tissue Urticaria Infrequently Infrequently

Eng Ioneurotic edema of the face, limbs, lips, mucous membrane of the tongue, vocal folds and / or larynx (see “Special instructions”) Very rarely Infrequent

Multiforme exudative erythema Very rarely Very rarely

Exanthema Infrequent -

Alopecia Infrequently -

Change skin color Infrequently -

Increased soreness Exfoliative dermatitis Very rare -

Stevens-Johnson syndrome Very rarely Very rarely

Photosensitivity Very rarely Frequency unknown

Maculopapular rash - Often

Toxic epidermal necrolysis - Very rarely

Possible worsening of the acute form of systemic lupus erythematosus - Infrequently

From the musculoskeletal system and connective tissue arthralgia, myalgia Infrequently -

Ankle swelling Often -

Muscle spasms Infrequently Often

Back pain Infrequently -

From the side of the kidneys and urinary tract Painful urination, nocturia, frequent urination Very often - No pain - Sard genitals and mammary glands Impotence Infrequently Infrequently

Gynecomastia Infrequently -

General disorders and disorders at the injection site Peripheral edema Often -

Increased fatigue Often -

Pain in Chest infrequently -

Asthenia Infrequently Often

Pain of various localization Infrequently -

General malaise Infrequently -

Laboratory and instrumental data Increased serum bilirubin concentration, liver enzyme activity (ALT *, AST *) Very rarely Frequency unknown

Increased QT interval on ECG - Frequency unknown

Increased creatinine concentration in urine and blood plasma after treatment withdrawal - Frequency unknown

Hypokalemia - Frequency unknown

Hyponatremia and hypovolemia leading to dehydration and orthostasis - orthostasis - Frequency unknown

Increased plasma uric acid and glucose concentrations - Frequency unknown

Hyperkalemia - Frequency unknown

Hypercalcemia - Rarely

* In most cases associated with cholestasis.

Drug Interactions

Amlodipine

Concomitant use is not recommended

Dantrolene (iv administration). In laboratory animals, cases of ventricular fibrillation with a fatal outcome and collapse were noted with the use of verapamil and iv administration of dantrolene, accompanied by hyperkalemia. Due to the risk of hyperkalemia, it is recommended to avoid the simultaneous use of BKK (amlodipine) and dantrolene in patients susceptible to malignant hyperthermia, as well as in the treatment of malignant hyperthermia.

Concomitant use requiring special attention

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

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

Concomitant use requiring attention

Amlodipine enhances the antihypertensive effect of antihypertensive drugs.

Other drug combinations. In clinical studies of drug interactions, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin, warfarin, or cyclosporine. The simultaneous administration of amlodipine and the use of grapefruit or grapefruit juice is not recommended due to the possible increase in the bioavailability of amlodipine in some patients, which can lead to an increase in the antihypertensive effect.

Indapamide

Concomitant use requiring special attention

Drugs that can cause polymorphic ventricular tachycardia of the pirouette type. Given the risk of hypokalemia, caution should be exercised while using indapamide with drugs that can cause polymorphic ventricular tachycardia of the pirouette type, such as antiarrhythmic drugs (quinidine, hydroquinidine, disopyramide, amiodarone, dofetilide, ibutilide, bretilia tosylate, sotalol), some antipsychotics (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoroorazine), benzamides (amisulpride, sulpiride, sultopride, tiapride), butyrophenones (droperidrolide, other drugs), other as bepridil, cisapride, diphenyl methyl sulfate, iv erythromycin, halofantrine, misolastine, moxifloxacin, pentamidine, sparfloxacin, iv vincamine, methadone, astemizole, terfenadine. Avoid simultaneous use with the above drugs, with the development of hypokalemia, carry out its correction, control the ECG (QT interval).

Drugs that can cause hypokalemia. Concomitant use with amphotericin I / O, systemic GCS and mineralocorticosteroids, tetracosactide, laxatives that stimulate gastrointestinal motility, increases the risk of hypokalemia (additive effect). It is necessary to control the potassium content in the blood plasma, if necessary, the correction of hypokalemia. Particular care should be taken while using 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, the potassium content in the blood plasma and ECG indices should be monitored and, if necessary, the question of the advisability of continuing therapy should be decided.

Concurrent use requiring attention

metformin. Functional renal failure, which can occur while taking diuretics, especially loopback, while using metformin, increases the risk of lactic acidosis. Metformin should not be used if Cl creatinine in plasma exceeds 15 mg / L (135 μmol / L) in men and 12 mg / L (110 μmol / L) in women.

Iodine-containing contrast agents. Dehydration of the body while taking diuretics increases the risk of acute renal failure, especially with the introduction of high doses of iodine-containing contrast agents. Before using iodine-containing contrast agents, it is necessary to compensate for hypovolemia.

Calcium salts. With simultaneous use, the development of hypercalcemia is possible due to a decrease in the excretion of calcium by the kidneys.

cyclosporine. An increase in Cl creatinine in blood plasma is possible without changing the concentration of cyclosporine, even with a normal content of water and sodium.

Perindopril

Concomitant use is not recommended

Aliskiren. The simultaneous use of perindopril with aliskiren is contraindicated in patients with diabetes or with moderate to severe impaired renal function (creatinine Cl less than 60 ml / min).

Potassium-sparing diuretics, potassium preparations and potassium-containing salt substitutes. During therapy with ACE inhibitors, the potassium content in blood plasma, as a rule, remains within the normal range, but hyperkalemia may develop. The simultaneous use of potassium-sparing diuretics (spironolactone, triamteren, amiloride, eplerenone), potassium preparations and potassium-containing substitutes for edible salt can lead to a significant increase in potassium in the blood plasma. If it is necessary to simultaneously take an ACE inhibitor with the above drugs (in case of hypokalemia), caution should be exercised and regular monitoring of the potassium content in blood plasma and ECG parameters should be carried out.

estramustine. The simultaneous use of ACE inhibitors with estramustine is associated with a risk of angioedema.

Concomitant use requiring special attention

Double blockade of RAAS in patients with atherosclerosis, CHF or diabetes mellitus accompanied by damage to target organs is associated with a higher incidence of arterial hypotension, syncope, hyperkalemia and impaired renal function (including the development of acute renal failure) in comparison with the use of the drug in one of these groups. Double blockade of RAAS is possible only in individual cases under close 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 in a dose that has an anti-inflammatory effect, COX-2 inhibitors and non-selective NSAIDs) can lead to a decrease in the antihypertensive effect, as well as to deterioration of renal function, including the development of acute renal failure, and an increase in potassium in the blood plasma, 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 (sulfonylurea derivatives and insulin)

ACE inhibitors may enhance the hypoglycemic effect of insulin and sulfonylurea derivatives in patients with diabetes mellitus. The development of hypoglycemia is very rare (probably by increasing glucose tolerance and lowering the need for insulin).

Concurrent use requiring attention

Diuretics (thiazide and loopback). In patients receiving diuretics, especially with excessive excretion of fluid and / or electrolytes, a significant decrease in blood pressure may be observed at the beginning of therapy with an ACE inhibitor. The risk of developing arterial hypotension can be reduced by canceling 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, corticosteroids (with 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 agents for general anesthesia can lead to an increase in the antihypertensive effect.

Gold preparations. When using ACE inhibitors, including perindopril, in patients receiving an / gold drug (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 suppression of the activity of dipeptidyl peptidase IV (DPP-IV) gliptin.

Co-Dalnev®

Concomitant use not recommended

Lithium preparations. With the simultaneous use of ACE inhibitors with lithium preparations, a reversible increase in the concentration of lithium in blood plasma with the development of intoxication may occur. The simultaneous use with thiazide diuretics can further increase the concentration of lithium 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 the specified therapy, regular monitoring of the concentration of lithium in the blood plasma is necessary.

Concomitant use requiring special attention

baclofen. Perhaps increased antihypertensive action. Blood pressure and kidney function should be monitored, and if necessary, dose adjustment of antihypertensive drugs should be carried out.

Concurrent use,

-requiring antihypertensives (e.g. beta-blockers) and vasodilators. With simultaneous use with antihypertensive drugs, an increase in the antihypertensive effect is possible. Caution should be exercised while using nitroglycerin, other nitrates, or other vasodilators, since an additional decrease in blood pressure is possible.

Corticosteroids (mineral and glucocorticosteroids), tetracosactide. Decreased antihypertensive effect (fluid and sodium retention due to corticosteroids).

Alpha-blockers (prazosin, alfuzosin, doxazosin, tamsulosin, terazosin). Increased antihypertensive effect and increased risk of orthostatic hypotension.

amifostine. Perhaps an increase in the antihypertensive effect of amlodipine.

Tricyclic antidepressants / antipsychotics / general anesthetics. Strengthening antihypertensive action and increasing the risk of developing orthostatic hypotension (additive effect).

Overdose

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

Treatment: emergency measures aimed at removing the drug from the gastrointestinal tract: gastric lavage and / or intake of activated charcoal, followed by restoration of water-electrolyte balance. With a pronounced decrease in blood pressure, a patient with an elevated position of the lower extremities should be laid, if necessary, correct hypovolemia (for example, iv infusion of 0.9% sodium chloride solution).

Perindoprilat, the active metabolite of perindopril, is removed by dialysis. Amlodipine firmly binds to plasma proteins, so dialysis is ineffective. Indapamide is not removed by hemodialysis.

Storage conditions

At a temperature not higher than 25 ° C, in the original packaging.

Keep out of the reach of children.

Term hodnosty

2 years

Active ingredient thy

Amlodipine, Indapamide, Perindopril

Dispatch conditions from pharmacies p14f66 srdl ек

Prescription

dosage form

tablet

KRKA dd AO new place, Slovenia



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