Co-Dalneva Tablets 5 mg + 0.625 mg + 2 mg N30
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Active ingredients
Amlodipine + Indapamide + Perindopril
Release form
Pills
Composition
Amlodipine besylate 6,935 mg, which corresponds to the content of amlodipine 5 mgindapamid 0.625 mgperindoprila erbumine b substance-granules * 10,206 mg, which corresponds to the content of perindopril erbumine 2 mgvspomogatelnye substances: microcrystalline cellulose - 90,244 mg Starch pregelatinized - 21 mg sodium carboxymethyl starch - 8.4 mg sodium bicarbonate - 0.76 mg, colloidal silicon dioxide - 0.43 mg, magnesium stearate - 1.4 mg. * excipients of the granule substance: microcrystalline cellulose 7.9 mg, calcium chloride hexahydrate 0.6 mg.
Pharmacological effect
Dalnev - a combined antihypertensive drug. Perindopril Perindopril is an ACE inhibitor. ACE or kininase II is an exopeptidase that converts angiotensin I into a vasoconstrictor, angiotensin II, and also ACE destroys bradykinin, which has a vasodilator, to an inactive hectapeptide. Suppression of the activity of ACE leads to a decrease in angiotensin II, an increase in the activity of renin in the blood plasma and a decrease in the secretion of aldosterone. Since ACE also destroys bradykinin, ACE suppression also leads to an increase in the activity of the kallikrein-kinin system. Perindopril acts through its active metabolite, perindoprilat. Other metabolites have no inhibitory effect on ACE in vitro. Perindopril has a therapeutic effect on any degree of arterial hypertension, reducing systolic and diastolic blood pressure in the supine and standing position. It reduces the congestion, resulting in increased peripheral blood flow without changes in heart rate. Renal blood flow usually increases, while GFR does not change. The antihypertensive effect reaches its maximum after 4-6 hours after a single dose of perindopril inside and lasts for 24 hours. The hypotensive effect after 24 hours after a single dose is about 87-100% ie the maximum antihypertensive effekta.Snizhenie AD develops rapidly. The therapeutic effect occurs less than 1 month from the start of therapy and is not accompanied by tachycardia. The termination of therapy does not lead to the development of withdrawal syndrome. Perindopril has a vasodilating effect, helps to restore the elasticity of large arteries and the structure of the vascular wall of small arteries,and also reduces left ventricular hypertrophy. Amlodipine Derivative of dihydropyridine is a blocker of slow calcium channels, has antianginal and hypotensive action. It blocks calcium channels, reduces the transmembrane transition of calcium ions into the cell (to a greater extent in vascular smooth muscle cells than in cardiomyocytes). The antianginal effect is due to the expansion of coronary and peripheral arteries and arterioles: in angina pectoris reduces the severity of myocardial ischemia; expanding peripheral arterioles, reduces OPSS, reduces myocardial afterload, reduces myocardial oxygen demand, expanding coronary arteries and arterioles in unchanged and ischemic areas of myocardium, increases oxygen supply to the myocardium (especially with vasospastic angina); prevents spasm of the coronary arteries (including caused by smoking). In patients with stable angina, a single daily dose increases exercise tolerance, increases the time before the onset of an attack of angina pectoris and ischemic depression of the ST segment on the ECG, reduces the frequency of strokes and the consumption of nitroglycerin and other nitrates. It has a long dose-dependent hypotensive effect. The hypotensive effect is due to the direct vasodilating effect on vascular smooth muscle. In hypertension, a single dose provides a clinically significant reduction in blood pressure for 24 hours (in the position of the patient lying and standing). Orthostatic hypotension with the appointment of amlodipine is quite rare. It does not cause a decrease in the left ventricular ejection fraction. Decreases the degree of left ventricular myocardial hypertrophy. Does not affect the contractility and conductivity of the myocardium, does not cause a reflex increase in heart rate, inhibits platelet aggregation, increases GFR, has a weak natriuretic effect. In diabetic nephropathy does not increase the severity of microalbuminuria. It does not have any adverse effect on the metabolism and plasma lipid concentration 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 monodrugs. Perindopril Absorption After ingestion, perindopril is rapidly absorbed and reaches Cmax in the blood plasma within 1 hour. in the morning, before eating. There is a linear dependence of the concentration of perindopril in blood plasma on the magnitude of its dose. Distribution Binding of perindoprilat to plasma proteins to The level (mainly with ACE) is 20%, and depends on its concentration. Vd of free perindoprilat is about 0.2 l / kg. Metabolism Perindopril does not possess pharmacological activity, it is a prodrug. Approximately 27% of the total amount of perindopril ingested enters the bloodstream as an active metabolite, perindoprilat. In addition to perindoprilat, 5 more metabolites are formed that do not possess pharmacological activity. Cmax of perindoprilat in the blood plasma is reached 3-4 h after ingestion. Excretion of T1 / 2 of perindopril from the blood plasma is approximately 1 h. Perindoprilat is eliminated by the kidneys, T1 / 2 of the unbound fraction is approximately 17 h, therefore Css is reached within 4 days after ingestion. Pharmacokinetics in special clinical situations. Perindoprilat withdrawal is delayed in elderly patients and in patients with cardiac and renal failure, therefore, monitoring of these patients should include regular monitoring of con the concentration of creatinine and potassium in the blood plasma. The dialysis clearance of perindoprilat is 70 ml / min. Perindopril's pharmacokinetics is changed in patients with cirrhosis: hepatic clearance decreases by 2 times, but the amount of perindoprilat is not reduced, therefore dose adjustment is not required. ingestion in therapeutic doses. Cmax in plasma is reached in 6-12 hours. Absolute bioavailability is 64-80%. Food intake 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 elimination Amlodipine is metabolized in the liver to form inactive metabolites.The final T1 / 2 from blood plasma is 35-50 h, 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 situations. The time to reach Cmax in plasma is the same for patients elderly and young. There is a tendency to reduce the clearance of amlodipine in elderly patients, which is accompanied by an increase in AUC. The recommended dosing regimen for elderly patients is the same as for younger patients, although the dose should be increased with caution. T1 / 2 amlodipine is prolonged in patients with impaired liver function.
Indications
Arterial hypertension and / or coronary heart disease: stable exertional angina in patients who require perindopril and amlodipine.
Contraindications
Perindopril-hypersensitivity to perindopril or other ACE inhibitors; angioedema (Quincke edema) in history (including while taking other ACE inhibitors); hereditary / idiopathic angioedema; age up to 18 years (efficacy and safety not established). to amlodipine or other dihydropyridine derivatives, severe arterial hypotension (SAD less than 90 mmHg), shock, including cardiogenic, obstruction of the left ventricular output tract (including severe stenosis aorta); unstable stenocardia (with the exception of Prinzmetal's stenocardia); hemodynamically unstable heart failure after acute myocardial infarction; age up to 18 years (efficacy and safety not established). Far increased sensitivity to adjuvants included in the preparation; renal failure (Cl creatinine less 60 ml / min); age up to 18 years (efficacy and safety have not been established). With caution: liver failure; chronic heart failure; aortic and / or mitral stenosis; hypertrophic obstructive cardiomyopathy (GOKMP); elderly age; bilateral stenosis of the renal arteries; arterial stenosis of the only functioning kidney; renal failure (Cl creatinine less than 60 ml / min); Systemic diseases of the connective tissue (includingsystemic lupus erythematosus, scleroderma), therapy with immunosuppressants, allopurinol, procainamide (risk of developing neutropenia, agranulocytosis), reduced bcc (diuretic intake, diet with restricted salt, vomiting, diarrhea), atherosclerosis, cerebrovascular diseases, I am using, and I am not using i’s already in a line mode, I am not using i'm, I am not using i'm and I am not using i's idle mode and is not using i'm already using i'm already using i'm i'm not affected by rosacea; dantrolene, estramustine, potassium-saving diuretics, potassium preparations, potassium-containing food salt substitutes and lithium preparations, hyperkalemia; surgery / general anesthesia; Negroid patients; hemodialysis using high-flow polyacrylonitrile membranes - the risk of anaphylactoid reactions; before the procedure of LDL apheresis using dextran sulfate, simultaneous desensitization therapy with allergens (eg hymenoptera), the state after kidney transplantation (no clinical data).
Precautionary measures
During treatment, psoriasis may worsen. During pheochromocytoma, propranolol can only be used after taking an alpha blocker. After a long course of treatment, propranolol should be discontinued gradually, under the supervision of a physician. during anesthesia, you must stop taking propranolol or find a remedy for anesthesia with minimal negative inotropic effects. The impact on the ability to drive vehicles and control mechanisms of patients whose activities require increased attention, the question of the use of propranolol on an outpatient basis should be addressed only after evaluating the individual response of the patient.
Dosage and administration
Inside, one tablet 1 time per day, preferably in the morning before a meal. The dose of the Dalnev drug is selected after previously titrated doses of individual components of the drug - perindopril and amlodipine - in patients with arterial hypertension and stable angina. If necessary, the dose of the Dalnev drug can be changed based on individual selection of doses of 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 + n rindopril 8 mg) .The max daily dose - 10 mg + Amlodipine perindopril 8 mg.Narushenie renal function. The drug Dalnev can be used in patients with Cl creatinine more than 60 ml / min.The drug Far contraindicated for use in patients with Cl creatinine less than 60 ml / min. These patients are recommended individual selection of doses of perindopril and amlodipine. Changes in the concentration of amlodipine in the blood plasma do not correlate with the severity of renal failure. Hepatic failure. Care must be taken when using the drug Dalnev in patients with liver failure, because there are no recommendations for the dosage of the drug in such patients. Elderly patients. When using the drug Dalnev in elderly patients, dose adjustment is not required. Children and adolescents. Dalnev's drug should not be prescribed to children and adolescents under 18 years of age. because there are no data on the efficacy and safety of perindopril and amlodipine in these groups of patients both in monotherapy and as part of combination therapy.
Side effects
Classification of the incidence of side effects WHO: very often - ≥1 / 10; often from ≥1 / 100 to less than 1/10; infrequently - from ≥1 / 1000 to less than 1/100; rarely from ≥1 / 10000 to less than 1/1000; very rarely - less than 1 / 10,000; frequency unknown - cannot be estimated based on available data.
Overdose
Symptoms: The most likely symptoms in overdose are marked reduction in blood pressure with possible development of reflex tachycardia and excessive peripheral vasodilation (the risk of severe and persistent hypotension, including the development of shock and death). Sometimes a pronounced decrease in blood pressure is accompanied by nausea, vomiting, seizures, dizziness, drowsiness, confusion, oliguria, which can turn into anuria (as a result of hypovolemia). Water-electrolyte imbalance (hyponatremia, hypokalemia) can also be observed. Treatment: emergency measures are aimed at removing the drug from the gastrointestinal tract: washing the stomach and / or taking activated carbon and then restoring the water-electrolyte balance. With a marked decrease in blood pressure, a patient should be placed with an elevated position of the lower extremities, if necessary, correction of hypovolemia (for example, IV infusion of 0.9% sodium chloride solution). Perindopril, the active metabolite of perindopril, is removed by dialysis.Amlodipine binds strongly to plasma proteins, therefore dialysis is ineffective. Indapamide is not removed by hemodialysis.
Interaction with other drugs
Amlodipine Simultaneous use is not recommended Dantrolen (in / in the introduction). In laboratory animals, there were cases of ventricular fibrillation with a fatal outcome and collapse during the use of verapamil and iv injection of dantrolene, accompanied by hyperkalemia. Due to the risk of developing hyperkalemia, it is recommended to avoid the simultaneous use of BPC (amlodipine) and dantrolen in patients prone to malignant hyperthermia, as well as in the treatment of malignant hyperthermia. Simultaneous use requiring special attention isoenzyme inducers of CYP3A4. Data regarding the effect of CYP3A4 isoenzyme inducers on amlodipine are not available. The simultaneous use of CYP3A4 isoenzyme inducers (rifampicin, Hypericum perforatum preparations) can lead to a decrease in the concentration of amlodipine in the blood plasma. Care should be taken when taking amlodipine with inducers of the CYP3A4 isoenzyme. Inhibitors of the CYP3A4 isoenzyme. Simultaneous use of amlodipine with potent or mild inhibitors of the CYP3A4 isoenzyme (protease inhibitors, antifungals of the azole group, macrolides, such as erythromycin or clarithromycin, verapamil or diltiazem) can lead to a significant increase in the concentration of amlodipine. The 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. Simultaneous use requiring attentionAmlodipine enhances the antihypertensive effect of drugs for antihypertensive therapy. Other combinations of drugs. In clinical trials of drug interactions, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin, warfarin, or cyclosporine. Simultaneous intake of amlodipine and the use of grapefruit or grapefruit juice is not recommended due to the possible increase in the availability of amlodipine in some patients, which may lead to increased antihypertensive effects. Indapamide is a simultaneous use requiring special attention.Given the risk of hypokalemia, care should be taken when using indapamide with drugs that can cause polymorphic ventricular tachycardia of the “pirouette” type, such as antiarrhythmic drugs (quinidine, hydroquinidine, disopyramide, amiodarone, dofetilide, ibutilide, bifilianum, tisylate, iputilid, bifilidae, ipilitam, tampylate, iputilide, tampylate, bifilidine, iputilid, tsilidin, bifilidine, iputilid, tsilidinom, iputilid, bifilidine, dizopyramide, amidarone, dofetilide, ibutilid, antiarrhythmic drugs). chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoroperazine), benzamides (amisulride, sulpiride, sultopride, tiaprid), butyrophenones (droperidol, haloperidol), other ileleptics (pimozide), other drugs such as bepridil, cisapride, diphemethyl methyl sulfate, erythromycin IV, halofantrine, mizolastine, moxifloxacin, pentamidine, sparfloxacin, vincamine IV, methadone, astemizol, terfadine. It is necessary to avoid simultaneous use with the above preparations, with the development of hypokalemia carry out its correction, monitor the ECG (QT interval). Preparations that can cause hypokalemia. Simultaneous intake with amphotericin B in / in, systemic GCS and mineralocorticosteroids, tetracosactids, laxatives that stimulate gastrointestinal motility, increases the risk of hypokalemia (additive effect). It is necessary to control the content of potassium in the blood plasma, if necessary - correction of hypokalemia. Particular care should be taken when used simultaneously with cardiac glycosides. Laxatives that do not stimulate GI motility should be used. Cardiac glycosides. Hypokalemia enhances the toxic effect of cardiac glycosides. With simultaneous use should be monitored the content of potassium in the blood plasma and ECG indicators and, if necessary, decide whether to continue therapy. Simultaneous use requiring attention Methformin. Functional renal failure, which may occur in the presence of diuretics, especially loopback, while the use of metformin increases the risk of developing lactic acidosis. Metformin should not be used if Cl of creatinine in the blood 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 developing 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 may develop hypercalcemia due to a decrease in calcium excretion by the kidneys. Cyclosporine. It is possible to increase Cl creatinine in the blood plasma without changing the concentration of cyclosporine, even with normal water and sodium. Perindopril. Simultaneous use is not recommended Aliskiren. The simultaneous use of perindopril with aliskiren is contraindicated in patients with diabetes or with moderate and severe renal dysfunction (creatinine Cl less than 60 ml / min). Kaliisberegaushie diuretics, potassium preparations and potassium-containing salt substitutes. During therapy with ACE inhibitors, the content of potassium in the blood plasma, as a rule, remains within the normal range, but hyperkalemia may develop. Simultaneous intake of potassium-sparing diuretics (spironolactone, triamterene, amiloride, eplerenone), potassium preparations, and potassium-containing substitutes for edible salt can lead to a significant increase in the content of potassium in the blood plasma. If necessary, the simultaneous use of an ACE inhibitor with the above drugs (in the case of hypokalemia), care should be taken to regularly monitor the content of potassium in the blood plasma and ECG parameters. Estramustin. The simultaneous use of ACE inhibitors is accompanied with estramustine risk of angioedema oteka.Odnovremennoe application requiring special vnimaniyaDvoynaya blockade of the RAAS in patients with atherosclerosis, heart failure or diabetes accompanied by end-organ damage associated with higher incidence of arterial hypotension, syncope, hyperkalemia, and dysfunction kidneys (including the development of acute renal failure) in comparison with the use of the drug of one of these groups. Double blockade of the RAAS is possible only in some cases under the careful control 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 ASK at a dose that has anti-inflammatory effect, COX-2 inhibitors and non-selective NSAIDs) can lead to a decrease in antihypertensive effect, as well as to the deterioration of kidney function, including the development of acute renal failure, and an increase in plasma potassium blood, especially in patients with reduced kidney function. Caution must be exercised when using this combination, especially in elderly patients.Patients need to compensate for fluid loss and conduct regular monitoring of kidney function, both at the beginning of treatment and during treatment. Hypoglycemic agents (sulfonylurea derivatives and insulin) ACE inhibitors can enhance the hypoglycemic effect of insulin and sulfonylurea derivatives in patients with diabetes mellitus. The development of hypoglycemia is observed very rarely (probably due to an increase in glucose tolerance and a decrease in the need for insulin). Simultaneous use requiring attention Diuretics (thiazide and loop). In patients receiving diuretics, especially with excessive removal of fluid and / or electrolytes, at the beginning of therapy with an ACE inhibitor, a significant decrease in blood pressure may be observed. The risk of 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. Simultaneous 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 increased antihypertensive effect. Gold preparations. When using ACE inhibitors, incl. perindopril, in patients receiving IV gold medication (sodium aurothiomalate), a symptom complex was described, including facial flushing, nausea, vomiting, arterial hypotension. Sympathomimetics. They may weaken the antihypertensive effect of ACE inhibitors. Glyptin (linagliptin, saxagliptin, sitagliptin, vitagliptin). Simultaneous use with ACE inhibitors may increase the risk of developing angioedema due to the suppression of dipeptidyl peptidase IV (DPP-IV) activity by glyptin. Ko-Dalneva® Simultaneous use is not recommended. Lithium preparations. With the simultaneous use of ACE inhibitors with lithium preparations, a reversible increase in plasma concentration of lithium may occur with the development of intoxication. Simultaneous use with thiazide diuretics may 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 indicated therapy, regular monitoring of the concentration of lithium in the blood plasma is necessary. Simultaneous use requiring particular attention to baclofen. Perhaps increased antihypertensive action. Blood pressure and kidney function should be monitored, if necessary, dose adjustment of antihypertensive drugs should be carried out. Simultaneous use requiring attention. Antihypertensive drugs (for example, beta-blockers) and vasodilators. With simultaneous use with antihypertensive drugs may enhance the antihypertensive effect. Caution should be exercised when used with nitroglycerin, other nitrates or other vasodilators, since this may further decrease blood pressure. Corticosteroids (mineral and glucocorticosteroids), tetracosactide. Reduced antihypertensive effect (fluid and sodium retention due to corticosteroids). Alpha-adrenergic blockers (prazosin, alfuzosin, doxazosin, tamsulozin, terazosin). Increased antihypertensive effect and increased risk of orthostatic hypotension. Amifostine. It is possible to enhance the antihypertensive effect of amlodipine. Tricyclic antidepressants / neuroleptics / agents for general anesthesia. Increased antihypertensive effect and increased risk of orthostatic hypotension (additive effect).