Symptoms: the most likely symptoms of overdose are a marked decrease in blood pressure with the possible development of reflex tachycardia and excessive peripheral vasodilation (the risk of developing 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 turn into anuria (as a result of hypovolemia). There may also be violations of the water-electrolyte balance (hyponatremia, hypokalemia).
Treatment: emergency measures are aimed at removing the drug from the gastrointestinal tract: gastric lavage and / or taking activated charcoal, followed by restoring the water-electrolyte balance. With a pronounced decrease in blood pressure, the patient should be placed with an elevated position of the lower extremities, if necessary, to correct hypovolemia (for example, intravenous infusion of 0.9% sodium chloride solution).
Perindoprilat, the active metabolite of perindopril, is removed by dialysis. Amlodipine binds strongly to plasma proteins, so dialysis is ineffective. Indapamide is not removed by hemodialysis.
hypersensitivity to amlodipine and other dihydropyridine derivatives, indapamide and other sulfonamide derivatives, perindopril and other ACE inhibitors, as well as excipients that are part of the drug,
angioedema (Quincke's edema) in the anamnesis associated with the use of ACE inhibitors,
hereditary / idiopathic angioedema,
bilateral renal artery stenosis, stenosis of the artery to a solitary kidney,
severe arterial hypotension (sBP less than 90 mmHg),
shock (including cardiogenic),
unstable angina (with the exception of Prinzmetal angina),
obstruction of the output tract of the left ventricle (e.g., clinically significant aortic stenosis),
hemodynamically unstable heart failure after acute myocardial infarction,
renal insufficiency (Creatinine Cl less than 60 ml / min),
severe hepatic insufficiency, including hepatic encephalopathy,
refractory hypokalemia,
concomitant use with drugs that can cause polymorphic ventricular arrhythmia of the "pirouette" type (see " Interaction»),
concomitant use with potassium-sparing diuretics, potassium and lithium preparations, in patients with an increased content of potassium in the blood plasma,
simultaneous use of drugs that prolong the QT interval,
concomitant use with aliskiren and aliskiren-containing drugs in patients with diabetes mellitus,
patients undergoing hemodialysis, as well as patients with untreated heart failure in the decompensation stage (lack of sufficient clinical experience),
pregnancy (see " Use during pregnancy and lactation»),
the period of breastfeeding (see " Use during pregnancy and lactation»),
age under 18 (efficacy and safety not established).
Amlodipine
Simultaneous use is not recommended
Dantrolene (in / in the introduction). In laboratory animals, cases of ventricular fibrillation with a fatal outcome and collapse were noted against the background of the use of verapamil and intravenous administration of dantrolene, accompanied by hyperkalemia. Due to the risk of hyperkalemia, it is recommended to avoid concomitant use of BCC (amlodipine) and dantrolene in patients exposed to malignant hyperthermia, as well as in the treatment of malignant hyperthermia.
Simultaneous application that requires special attention
Inducers of the CYP3A4 isoenzyme. There are no data on the effect of inducers of the CYP3A4 isoenzyme on amlodipine. Simultaneous use of inducers of the CYP3A4 isoenzyme (rifampicin, preparations of St. John's wort) may lead to a decrease in the concentration of amlodipine in blood plasma. Caution should be exercised when concomitantly taking amlodipine with inducers of the CYP3A4 isoenzyme.
Inhibitors of the CYP3A4 isoenzyme. Concomitant use of amlodipine with potent or moderate inhibitors of the CYP3A4 isoenzyme (protease inhibitors, azole antifungal drugs, 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, it may be necessary to monitor the clinical condition and adjust the dose.
Simultaneous application that requires attention
Amlodipine increases the antihypertensive effect of drugs for antihypertensive therapy.
Other combinations of drugs. In clinical studies of drug interactions, amlodipine had no effect on the pharmacokinetics of atorvastatin, digoxin, warfarin, or cyclosporine. Concomitant 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 may lead to an increased antihypertensive effect.
Indapamide
Simultaneous application that requires special attention
Drugs that can cause polymorphic ventricular tachycardia of the "pirouette" type.. Simultaneous use with the above drugs should be avoided, with the development of hypokalemia, its correction should be carried out, and ECG (QT interval) should be monitored)
Drugs that can cause hypokalemia. Concomitant administration with amphotericin In / in, systemic corticosteroids and mineralocorticosteroids, tetracosactide, 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. Special care should be taken when used concomitantly with cardiac glycosides. Laxatives that do not stimulate the motility of the gastrointestinal tract should be used.
Cardiac glycosides. Hypokalemia increases the toxic effect of cardiac glycosides. With simultaneous use, the content of potassium in the blood plasma and ECG indicators should be monitored and, if necessary, decide whether to continue therapy.
Simultaneous application that requires attention
Metformin. Functional renal failure, which can occur against the background of taking diuretics, especially loop, with the simultaneous use of metformin increases the risk of lactic acidosis. Metformin should not be used if the Cl of creatinine in the blood plasma exceeds 15 mg/l (135 mmol/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 when high doses of iodine-containing contrast agents are administered. Before using iodine-containing contrast agents, it is necessary to compensate for hypovolemia.
Calcium salts. With simultaneous use, hypercalcemia may develop due to a decrease in the excretion of calcium by the kidneys.
Cyclosporine. It is possible to increase the Cl of creatinine in the blood plasma without changing the concentration of cyclosporine, even with normal water and sodium content.
Perindopril
Simultaneous use is not recommended
Aliskiren. Concomitant use of perindopril with aliskiren is contraindicated in patients with DM or with moderate to severe renal impairment (creatinine Cl less than 60 ml / min).
Potassium-sparing diuretics, potassium preparations and potassium-containing salt substitutes. Against the background of therapy with ACE inhibitors, the potassium content in the blood plasma, as a rule, remains within the normal range, but hyperkalemia may develop. Simultaneous administration of potassium-sparing diuretics (spironolactone, triamterene, amiloride, eplerenone), potassium preparations and potassium-containing salt substitutes can lead to a significant increase in the content of potassium in the blood plasma. If it is necessary to simultaneously take an ACE inhibitor with the above drugs (in the case of hypokalemia), caution should be exercised and regular monitoring of the potassium content in the blood plasma and ECG parameters should be carried out
Estramustin. Concomitant use of ACE inhibitors with estramustine is associated with the risk of angioedema.
Simultaneous application that requires special attention
Double blockade of RAAS in patients with atherosclerosis, CHF or diabetes mellitus, accompanied by damage to the target organs, is associated with a higher frequency 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 the RAAS is possible only in some cases under careful monitoring of renal function.
NSAIDs, including high doses of acetylsalicylic acid (ASA) (more than 3 g/day). Concomitant use of ACE inhibitors with NSAIDs (including anti-inflammatory ASA, COX-2 inhibitors, and non-selective NSAIDs) may 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 the content of 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 increase the hypoglycemic effect of insulin and sulfonylureas in patients with diabetes mellitus. The development of hypoglycemia is very rare (probably due to an increase in glucose tolerance and a decrease in the need for insulin).
Simultaneous application that requires attention
Diuretics (thiazide and loop). 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 discontinuing the diuretic, correcting hypovolemia and electrolyte balance, as well as prescribing perindopril at 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 general anesthesia agents may lead to an increased antihypertensive effect.
Preparations of gold. When using ACE inhibitors, including perindopril, in patients receiving an intravenous gold preparation (sodium aurothiomalate), a symptom complex was described, including facial skin hyperemia, nausea, vomiting, and hypotension.
The sympathomimetics. May weaken the antihypertensive effect of ACE inhibitors.
Gliptone (linagliptin, saxagliptin, sitagliptin, sitagliptin). Concomitant use with ACE inhibitors may increase the risk of angioedema due to the suppression of dipeptidyl peptidase IV (DPP-IV) activity by gliptin.
Ko Dulneva®
Simultaneous 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 contribute to an additional increase in the concentration of lithium and an increased risk of intoxication. Concomitant 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.
Simultaneous application that requires special attention
Baclofen. It is possible to increase the antihypertensive effect. It is necessary to monitor blood pressure and kidney function, if necessary, adjust the dose of antihypertensive drugs.
Simultaneous application that requires attention
Antihypertensive agents (e.g. beta-blockers) and vasodilators. When used simultaneously with antihypertensive drugs, the antihypertensive effect may increase. Caution should be exercised when used concomitantly with nitroglycerin, other nitrates or other vasodilators, as this may further reduce blood pressure.
Corticosteroids (mineral-and glucocorticosteroids), tetracosactide. Reduced antihypertensive effects (fluid retention and sodium retention as a result of corticosteroids).
Alpha-blockers (prazosin, alfuzosin, doxazosin, tamsulosin, terazosin). Increased antihypertensive effect and increased risk of orthostatic hypotension.
Amifostine. It is possible to increase the antihypertensive effect of amlodipine.
Tricyclic antidepressants/antipsychotics/general anaesthetics. Increased antihypertensive effect and increased risk of orthostatic hypotension (additive effect).
Amlodipine
Simultaneous use is not recommended
Dantrolene (in / in the introduction). In laboratory animals, cases of ventricular fibrillation with a fatal outcome and collapse were noted against the background of the use of verapamil and intravenous administration of dantrolene, accompanied by hyperkalemia. Due to the risk of hyperkalemia, it is recommended to avoid concomitant use of BCC (amlodipine) and dantrolene in patients exposed to malignant hyperthermia, as well as in the treatment of malignant hyperthermia.
Simultaneous application that requires special attention
Inducers of the CYP3A4 isoenzyme. There are no data on the effect of inducers of the CYP3A4 isoenzyme on amlodipine. Simultaneous use of inducers of the CYP3A4 isoenzyme (rifampicin, preparations of St. John's wort) may lead to a decrease in the concentration of amlodipine in blood plasma. Caution should be exercised when concomitantly taking amlodipine with inducers of the CYP3A4 isoenzyme.
Inhibitors of the CYP3A4 isoenzyme. Concomitant use of amlodipine with potent or moderate inhibitors of the CYP3A4 isoenzyme (protease inhibitors, azole antifungal drugs, 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, it may be necessary to monitor the clinical condition and adjust the dose.
Simultaneous application that requires attention
Amlodipine increases the antihypertensive effect of drugs for antihypertensive therapy.
Other combinations of drugs. In clinical studies of drug interactions, amlodipine had no effect on the pharmacokinetics of atorvastatin, digoxin, warfarin, or cyclosporine. Concomitant 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 may lead to an increased antihypertensive effect.
Indapamide
Simultaneous application that requires special attention
Drugs that can cause polymorphic ventricular tachycardia of the "pirouette" type.. Simultaneous use with the above drugs should be avoided, with the development of hypokalemia, its correction should be carried out, and ECG (QT interval) should be monitored)
Drugs that can cause hypokalemia. Concomitant administration with amphotericin In / in, systemic corticosteroids and mineralocorticosteroids, tetracosactide, 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. Special care should be taken when used concomitantly with cardiac glycosides. Laxatives that do not stimulate the motility of the gastrointestinal tract should be used.
Cardiac glycosides. Hypokalemia increases the toxic effect of cardiac glycosides. With simultaneous use, the content of potassium in the blood plasma and ECG indicators should be monitored and, if necessary, decide whether to continue therapy.
Simultaneous application that requires attention
Metformin. Functional renal failure, which can occur against the background of taking diuretics, especially loop, with the simultaneous use of metformin increases the risk of lactic acidosis. Metformin should not be used if the Cl of creatinine in the blood plasma exceeds 15 mg/l (135 mmol/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 when high doses of iodine-containing contrast agents are administered. Before using iodine-containing contrast agents, it is necessary to compensate for hypovolemia.
Calcium salts. With simultaneous use, hypercalcemia may develop due to a decrease in the excretion of calcium by the kidneys.
Cyclosporine. It is possible to increase the Cl of creatinine in the blood plasma without changing the concentration of cyclosporine, even with normal water and sodium content.
Perindopril
Simultaneous use is not recommended
Aliskiren. Concomitant use of perindopril with aliskiren is contraindicated in patients with DM or with moderate to severe renal impairment (creatinine Cl less than 60 ml / min).
Potassium-sparing diuretics, potassium preparations and potassium-containing salt substitutes. Against the background of therapy with ACE inhibitors, the potassium content in the blood plasma, as a rule, remains within the normal range, but hyperkalemia may develop. Simultaneous administration of potassium-sparing diuretics (spironolactone, triamterene, amiloride, eplerenone), potassium preparations and potassium-containing salt substitutes can lead to a significant increase in the content of potassium in the blood plasma. If it is necessary to simultaneously take an ACE inhibitor with the above drugs (in the case of hypokalemia), caution should be exercised and regular monitoring of the potassium content in the blood plasma and ECG parameters should be carried out
Estramustin. Concomitant use of ACE inhibitors with estramustine is associated with the risk of angioedema.
Simultaneous application that requires special attention
Double blockade of RAAS in patients with atherosclerosis, CHF or diabetes mellitus, accompanied by damage to the target organs, is associated with a higher frequency 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 the RAAS is possible only in some cases under careful monitoring of renal function.
NSAIDs, including high doses of acetylsalicylic acid (ASA) (more than 3 g/day). Concomitant use of ACE inhibitors with NSAIDs (including anti-inflammatory ASA, COX-2 inhibitors, and non-selective NSAIDs) may 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 the content of 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 increase the hypoglycemic effect of insulin and sulfonylureas in patients with diabetes mellitus. The development of hypoglycemia is very rare (probably due to an increase in glucose tolerance and a decrease in the need for insulin).
Simultaneous application that requires attention
Diuretics (thiazide and loop). 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 discontinuing the diuretic, correcting hypovolemia and electrolyte balance, as well as prescribing perindopril at 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 general anesthesia agents may lead to an increased antihypertensive effect.
Preparations of gold. When using ACE inhibitors, including perindopril, in patients receiving an intravenous gold preparation (sodium aurothiomalate), a symptom complex was described, including facial skin hyperemia, nausea, vomiting, and hypotension.
The sympathomimetics. May weaken the antihypertensive effect of ACE inhibitors.
Gliptone (linagliptin, saxagliptin, sitagliptin, sitagliptin). Concomitant use with ACE inhibitors may increase the risk of angioedema due to the suppression of dipeptidyl peptidase IV (DPP-IV) activity by gliptin.
Co-Amlessa®
Simultaneous 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 contribute to an additional increase in lithium concentration and an increased risk of intoxication. Concomitant 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.
Simultaneous application that requires special attention
Baclofen. It is possible to increase the antihypertensive effect. It is necessary to monitor blood pressure and kidney function, if necessary, adjust the dose of antihypertensive drugs.
Simultaneous application that requires attention
Antihypertensive agents (e.g. beta-blockers) and vasodilators. When used simultaneously with antihypertensive drugs, the antihypertensive effect may increase. Caution should be exercised when used concomitantly with nitroglycerin, other nitrates or other vasodilators, as this may further reduce blood pressure.
Corticosteroids (mineral-and glucocorticosteroids), tetracosactide. Reduced antihypertensive effects (fluid retention and sodium retention as a result of corticosteroids).
Alpha-blockers (prazosin, alfuzosin, doxazosin, tamsulosin, terazosin). Increased antihypertensive effect and increased risk of orthostatic hypotension.
Amifostine. It is possible to increase the antihypertensive effect of amlodipine.
Tricyclic antidepressants/antipsychotics/general anaesthetics. Increased antihypertensive effect and increased risk of orthostatic hypotension (additive effect).
WHO classification of the frequency of side effects: 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.
| MedDRA Classification | Undesirable effects | Frequency | |
| Amlodipine | Perindopril/Indapamide | ||
| From the blood and lymphatic system | Leukopenia/neutropenia | Very rare | Very rare |
| Agranulocytosis or pancytopenia | — | Very rare | |
| Thrombocytopenia | Very rare | Very rare | |
| Aplastic anemia | — | Very rare | |
| Hemolytic anemia | — | Very rare | |
| When treated with ACE inhibitors in certain situations (after kidney transplantation, during dialysis), the development of anemia was observed | — | Very rare | |
| On the part of the immune system | Hypersensitivity reactions in patients predisposed to bronchoobstructive and allergic reactions | — | Infrequently |
| Allergic reactions | Very rare | — | |
| From the side of metabolism and nutrition | Hyperglycemia | Very rare | — |
| Increase or decrease in body weight | Infrequently | — | |
| Mental disorders | Insomnia | Infrequently | — |
| Mood lability (including anxiety) | Infrequently | Infrequently | |
| Depression | Infrequently | — | |
| Sleep disturbance | — | Infrequently | |
| Confusion of consciousness | Rarely | Very rare | |
| From the nervous system | Drowsiness (especially at the beginning of treatment) | Often | — |
| Dizziness (especially at the beginning of treatment) | Often | Often | |
| Headache | Often | Often | |
| Tremor | Infrequently | — | |
| Hypesthesia | Infrequently | — | |
| Paresthesia | Infrequently | Often | |
| Muscle hypertension | Very rare | — | |
| Peripheral neuropathy | Very rare | — | |
| Vertigo | — | Often | |
| Fainting | Infrequently | Frequency unknown | |
| On the part of the visual organ | Visual impairment (including diplopia) | Infrequently | Often |
| On the part of the organ of hearing and labyrinth disorders | Noise (ringing) in the ears | Infrequently | Often |
| From the heart | Heartbeat sensation | Often | — |
| Angina pectoris | — | Very rare | |
| Myocardial infarction, possibly due to excessive blood pressure reduction in high-risk patients | Very rare | Very rare | |
| Cardiac arrhythmias (including bradycardia, ventricular tachycardia, and atrial fibrillation) | Very rare | Very rare | |
| Polymorphic ventricular tachycardia of the "pirouette" type (possibly fatal) | — | Frequency unknown | |
| From the side of the vessels | Feeling of blood rush to the skin of the face | Often | — |
| Marked decrease in blood pressure (including orthostatic hypotension) | Infrequently | Infrequently | |
| Vasculitis (including hemorrhagic vasculitis) | Very rare | Infrequently | |
| From the respiratory system, chest and mediastinal organs | Shortness of breath | Infrequently | Often |
| Rhinitis | Infrequently | Very rare | |
| Cough | Very rare | Often | |
| Bronchospasm | — | Infrequently | |
| Eosinophilic pneumonia | — | Very rare | |
| From the gastrointestinal tract | Gum hyperplasia | Very rare | — |
| Abdominal pain, nausea | Often | Often | |
| Epigastric pain | — | Often | |
| Vomiting | Infrequently | Often | |
| Dyspepsia | Infrequently | Often | |
| Changes in the mode of defecation (including diarrhea, constipation) | Infrequently | Often | |
| Dryness of the oral mucosa | Infrequently | Often | |
| Violation of taste perception | — | Often | |
| Pancreatitis | Very rare | Very rare | |
| Gastritis | Very rare | — | |
| Loss of appetite | — | Often | |
| Angioedema of the intestine | — | Very rare | |
| From the liver and biliary tract | Hepatitis* | Very rare | — |
| Jaundice* | Very rare | Very rare | |
| Hepatic encephalopathy in patients with hepatic insufficiency | — | Frequency unknown | |
| From the skin and subcutaneous tissues | Urticaria | Infrequently | Infrequently |
| Angioedema of the face, limbs, lips, mucous membrane of the tongue, vocal folds and / or larynx (see " Special instructions») | Very rare | Infrequently | |
| Exudative erythema multiforme | Very rare | Very rare | |
| Rash | Infrequently | — | |
| Alopecia | Infrequently | — | |
| Purple | Infrequently | — | |
| Change the color of the skin | Infrequently | — | |
| Increased sweating | Infrequently | Infrequently | |
| Itchy skin | Infrequently | Often | |
| Skin rash | Infrequently | Often | |
| Exfoliative dermatitis | Very rare | — | |
| Stevens-Johnson Syndrome | Very rare | Very rare | |
| Photosensitivity | Very rare | Frequency unknown | |
| Maculopapular rash | — | Often | |
| Toxic epidermal necrolysis | — | Very rare | |
| Possible deterioration of the course of acute systemic lupus erythematosus | — | Infrequently | |
| From the musculoskeletal system and connective tissue | Arthralgia, myalgia | Infrequently | — |
| Swelling of the ankles | Often | — | |
| Muscle spasms | Infrequently | Often | |
| Back pain | Infrequently | — | |
| From the kidneys and urinary tract | Painful urination, nocturia, frequent urination | Infrequently | — |
| Kidney failure | — | Infrequently | |
| Acute renal failure | — | Very rare | |
| From the genitals and breast | Impotence | Infrequently | Infrequently |
| Gynecomastia | Infrequently | — | |
| General disorders and disorders at the injection site | Peripheral edema | Often | — |
| Increased fatigue | Often | — | |
| Pain in the chest | Infrequently | — | |
| Asthenia | Infrequently | Often | |
| Pain of different localization | Infrequently | — | |
| General malaise | Infrequently | — | |
| Laboratory and instrumental data | Increased serum bilirubin concentration, liver enzyme activity (ALT*, AST*) | Very rare | Frequency unknown |
| Increasing the QT interval on the ECG | — | Frequency unknown | |
| Increased creatinine concentration in urine and blood plasma after discontinuation of therapy | — | Frequency unknown | |
| Hypokalemia | — | Frequency unknown | |
| Hyponatremia and hypovolemia leading to dehydration and orthostatic hypotension | — | Frequency unknown | |
| Increased concentration of uric acid and glucose in the blood plasma | — | Frequency unknown | |
| Hyperkalemia | — | Frequency unknown | |
| Hypercalcemia | — | Rarely | |
* In most cases, it is associated with cholestasis.
Arterial hypertension (if necessary, simultaneous therapy with amlodipine, indapamide and perindopril in doses used in monotherapy of individual components).
Arterial hypertension (if necessary, simultaneous therapy with amlodipine, indapamide and perindopril in doses used in monotherapy of individual components).
Ko Dulneva® - a combination drug containing perindopril erbumin( ACE inhibitor), indapamide (thiazide-like diuretic) and amlodipine (BCC).
Ko Dulneva® it combines the properties of each of the active substances, which have a potentiating effect.
Amlodipine
Amlodipine-BCC, a dihydropyridine derivative. Amlodipine inhibits the transmembrane transfer of calcium ions to cardiomyocytes and vascular wall smooth muscle cells. 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, presumably it is associated with the following effects:
- causes the expansion of peripheral arterioles, reducing the OPSS-postload on the heart, which leads to a decrease in the 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 angina.
In patients with hypertension, taking amlodipine once a day provides a clinically significant reduction in blood pressure (in the supine and standing positions) for 24 hours. The antihypertensive effect develops slowly, and therefore the development of acute arterial hypotension is uncharacteristic. In patients with angina, taking amlodipine once a day increases exercise tolerance, the time before the development of an angina attack and before ST-segment ischemic depression, reduces the frequency of angina attacks and the need for taking nitroglycerin (short-acting forms). Amlodipine does not affect the parameters of the lipid profile and does not cause changes in the lipid-lowering parameters of blood plasma. The drug can be used in patients with bronchial asthma( BA), diabetes and gout
Indapamide
Indapamide is a derivative of sulfonamide. In terms of pharmacological properties, it is close to thiazide diuretics. Indapamide inhibits the reabsorption of sodium ions in the cortical segment of the Henle loop, which leads to increased renal excretion of sodium and chlorine ions, and to a lesser extent potassium and magnesium ions, thereby increasing diuresis and reducing blood pressure.
In the 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, a decrease in OPSS. Against the background of taking indapamide, LVH decreases. Indapamide does not affect the concentration of lipids in the blood plasma (triglycerides, total cholesterol, HDL, LDL), on the indicators of carbohydrate metabolism (including in patients with diabetes mellitus (DM).
Perindopril
Perindopril-ACE inhibitor, or kininase II-is an exopeptidase that converts angiotensin I to the vasoconstrictor angiotensin II, and also destroys bradykinin, which has vasodilating properties, to an inactive heptapeptide.
As a result, perindopril provides the following effects:
- reduces the secretion of aldosterone,
- increases the activity of blood plasma renin on the principle of negative feedback,
- with prolonged use, it reduces the OPSS-post-load on the heart, which is mainly due to the effect on the muscle and kidney vessels.
The decrease in OPSS is not accompanied by sodium and water retention and does not cause reflex tachycardia.
The study of hemodynamic parameters in patients with CHF revealed:
- reduced filling pressure in the left and right ventricles of the heart,
- reduction of OPSS,
- increased cardiac output and cardiac index,
- increased peripheral blood flow in the muscles.
In addition, there was an improvement in the results of the exercise test. The action is carried out by means of perindopril to the active metabolite of perindoprilat. 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 sAD and dBP in the supine and standing positions.
The antihypertensive effect reaches a maximum in 4-6 hours after a single oral administration and persists for 24 hours.
Antihypertensive effect 24 hours after a single oral administration is about 87-100% of the maximum antihypertensive effect. Perindopril has an antihypertensive effect in patients with both low and normal renin activity in blood plasma.
The therapeutic effect occurs less than 1 month after the start of therapy and is not accompanied by tachyphylaxis. Discontinuation of therapy does not cause withdrawal syndrome.
Perindopril has vasodilating properties and helps to 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 hypokalemia while taking diuretics.
Perindopril/Indapamide
The combination of perindopril / indapamide has a dose-dependent antihypertensive effect on both sAD and dBP (standing and lying down), regardless of the patient's age. The antihypertensive effect persists for 24 hours. The therapeutic effect occurs less than 1 month after 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 to monotherapy with each drug. The combination of perindopril tert-butylamine (perindopril erbumin)/indapamide resulted in a significantly more pronounced decrease in LVH than enalapril monotherapy. The most significant effect on LVH is achieved with the use of perindopril tert-butylamine (perindopril erbumin) 8 mg/indapamide 2.5 mg.
Co-Amlessa® - a combination drug containing perindopril erbumin( ACE inhibitor), indapamide (thiazide-like diuretic) and amlodipine (BCC).
Co-Amlessa® it combines the properties of each of the active substances, which have a potentiating effect.
Amlodipine
Amlodipine-BCC, a dihydropyridine derivative. Amlodipine inhibits the transmembrane transfer of calcium ions to cardiomyocytes and vascular wall smooth muscle cells. 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, presumably it is associated with the following effects:
- causes the expansion of peripheral arterioles, reducing the OPSS-postload on the heart, which leads to a decrease in the 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 angina.
In patients with hypertension, taking amlodipine once a day provides a clinically significant reduction in blood pressure (in the supine and standing positions) for 24 hours. The antihypertensive effect develops slowly, and therefore the development of acute arterial hypotension is uncharacteristic. In patients with angina, taking amlodipine once a day increases exercise tolerance, the time before the development of an angina attack and before ST-segment ischemic depression, reduces the frequency of angina attacks and the need for taking nitroglycerin (short-acting forms). Amlodipine does not affect the parameters of the lipid profile and does not cause changes in the lipid-lowering parameters of blood plasma. The drug can be used in patients with bronchial asthma( BA), diabetes and gout
Indapamide
Indapamide is a derivative of sulfonamide. In terms of pharmacological properties, it is close to thiazide diuretics. Indapamide inhibits the reabsorption of sodium ions in the cortical segment of the Henle loop, which leads to increased renal excretion of sodium and chlorine ions, and to a lesser extent potassium and magnesium ions, thereby increasing diuresis and reducing blood pressure.
In the 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, a decrease in OPSS. Against the background of taking indapamide, LVH decreases. Indapamide does not affect the concentration of lipids in the blood plasma (triglycerides, total cholesterol, HDL, LDL), on the indicators of carbohydrate metabolism (including in patients with diabetes mellitus (DM).
Perindopril
Perindopril-ACE inhibitor, or kininase II-is an exopeptidase that converts angiotensin I to the vasoconstrictor angiotensin II, and also destroys bradykinin, which has vasodilating properties, to an inactive heptapeptide.
As a result, perindopril provides the following effects:
- reduces the secretion of aldosterone,
- increases the activity of blood plasma renin on the principle of negative feedback,
- with prolonged use, it reduces the OPSS-post-load on the heart, which is mainly due to the effect on the muscle and kidney vessels.
The decrease in OPSS is not accompanied by sodium and water retention and does not cause reflex tachycardia.
The study of hemodynamic parameters in patients with CHF revealed:
- reduced filling pressure in the left and right ventricles of the heart,
- reduction of OPSS,
- increased cardiac output and cardiac index,
- increased peripheral blood flow in the muscles.
In addition, there was an improvement in the results of the exercise test. The action is carried out by means of perindopril to the active metabolite of perindoprilat. 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 sAD and dBP in the supine and standing positions.
The antihypertensive effect reaches a maximum in 4-6 hours after a single oral administration and persists for 24 hours.
Antihypertensive effect 24 hours after a single oral administration is about 87-100% of the maximum antihypertensive effect. Perindopril has an antihypertensive effect in patients with both low and normal renin activity in blood plasma.
The therapeutic effect occurs less than 1 month after the start of therapy and is not accompanied by tachyphylaxis. Discontinuation of therapy does not cause withdrawal syndrome.
Perindopril has vasodilating properties and helps to 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 hypokalemia while taking diuretics.
Perindopril/Indapamide
The combination of perindopril / indapamide has a dose-dependent antihypertensive effect on both sAD and dBP (standing and lying down), regardless of the patient's age. The antihypertensive effect persists for 24 hours. The therapeutic effect occurs less than 1 month after 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 to monotherapy with each drug. The combination of perindopril tert-butylamine (perindopril erbumin)/indapamide resulted in a significantly more pronounced decrease in LVH than enalapril monotherapy. The most significant effect on LVH is achieved with the use of perindopril tert-butylamine (perindopril erbumin) 8 mg/indapamide 2.5 mg.
Amlodipine
The absorption, distribution. After oral administration, amlodipine is slowly absorbed from the gastrointestinal tract. Food intake does not affect the bioavailability of amlodipine. Cmax amlodipine in the blood plasma is reached in 6-12 hours after oral administration. The absolute bioavailability is about 64-80%. Vd it is approximately 21 l/kg. In research in vitro The degree of binding of amlodipine to plasma proteins was about 97.5%.
Metabolism/excretion. Final T1/2 from the blood plasma is about 35-50 hours, which allows you to take amlodipine 1 time a day.
Amlodipine is metabolized in the liver to form inactive metabolites, while 10% of the oral dose of amlodipine is excreted unchanged, about 60% by the kidneys — in the form of metabolites. Amlodipine is not eliminated from the body by hemodialysis.
Time to reach Cmax amlodipine does not differ in 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. Dose adjustment in elderly patients is not required, but the dose of amlodipine should be increased with caution. Increase in AUC and T1/2 In patients with CHF, it 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. Slight elongation of T is possible1/2.
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 T1/2 and the AUC is about 40-60%.
Indapamide
The absorption, distribution. Indapamide is rapidly and completely absorbed from the gastrointestinal tract. Cmax the blood plasma level is reached approximately 1 h after oral administration of the drug. The degree of binding to plasma proteins is 79%.
Metabolism, excretion. T1/2 it is 14-24 hours (18 hours on average). Repeated administration of indapamide does not lead to its accumulation. It is eliminated mainly by the kidneys (70% of the oral dose) and through the intestine (22%) in the form of inactive metabolites.
The pharmacokinetics of indapamide do not change in patients with renal insufficiency.
Perindopril
Absorption, metabolism. When taken orally, perindopril is rapidly absorbed. Cmaxin the blood plasma, it is reached 1 h after oral administration.
Perindopril is a prodrug, i.e. it has no pharmacological activity. About 27% of the oral dose of perindopril enters the bloodstream in the form of the active metabolite — perindoprilat. In addition to the active metabolite-perindoprilate, 5 more metabolites are formed that do not have pharmacological activity. Cmax perindoprilat in blood plasma is reached in 3-4 hours after oral administration. Eating slows down the conversion of perindopril to perindoprilat, thus affecting bioavailability. Therefore, perindopril should be taken 1 time a day, in the morning, before meals.
There is a linear dependence of the concentration of perindopril in the blood plasma on the oral dose.
Distribution. Vd the amount of free perindoprilate is approximately 0.2 l/kg. The degree of binding of perindoprilat to plasma proteins (mainly ACE) is about 20% and is dose-dependent.
Output. T1/2 Perindopril from the blood plasma is 1 h. Perindopril is eliminated from the body by the kidneys. Final T1/2 the free fraction is about 17 h, the equilibrium state is reached within 4 days. The elimination of perindoprilat is delayed in elderly patients, as well as in patients with heart and kidney failure. Dose adjustment in patients with renal insufficiency is carried out taking into account the degree of impaired renal function (creatinine clearance). Dialysis clearance of perindoprilat is 70 ml/min.
The pharmacokinetics of perindopril changes in patients with cirrhosis of the liver: hepatic clearance decreases by 2 times. However, the amount of perindoprilate formed does not decrease, so no dose adjustment is required (see "Method of administration and doses" and "Special instructions").
Co-Amlessa
Amlodipine, Indapamid, Perindopril
Inside, 1 table. 1 time a day, preferably in the morning, before meals.
The dose of the drug Co-Dulneva® it is selected after the previously performed titration of the doses of the active components of the drug. The maximum daily dose of the drug Ko-Dalneva® it is 8 mg of perindopril 2.5 mg of indapamide 10 mg of amlodipine.
Elderly patients and patients with impaired renal function. The Drug Co-Dulneva® It is contraindicated in patients with moderate to severe renal impairment (creatinine Cl less than 60 ml / min). The drug Co-Dalneva can be used in patients with a creatinine Cl equal to or greater than 60 ml / min. Such patients are recommended individual selection of doses of amlodipine, indapamide, perindopril. Amlodipine, used in equivalent doses, is equally well tolerated by patients of both older and younger age. It is not necessary to change the dosage regimen in elderly patients, but increasing the dose should be carried out with caution, which is associated with age-related changes and lengthening of the T1/2.
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-Dulneva® it is contraindicated in patients with severe hepatic insufficiency.
Caution should be exercised when using the drug in patients with mild to moderate hepatic impairment.
Inside, 1 table. 1 time a day, preferably in the morning, before meals.
Dose of Co-Amlessa® it is selected after the previously performed titration of the doses of the active components of the drug. Maximum daily dose of Co-Amlessa® it is 8 mg of perindopril 2.5 mg of indapamide 10 mg of amlodipine.
Elderly patients and patients with impaired renal function. Co-Amlessa preparation® It is contraindicated in patients with moderate to severe renal impairment (creatinine Cl less than 60 ml / min). Co-Amlessa can be used in patients with a creatinine Cl equal to or greater than 60 ml / min. Such patients are recommended individual selection of doses of amlodipine, indapamide, perindopril. Amlodipine, used in equivalent doses, is equally well tolerated by patients of both older and younger age. It is not necessary to change the dosage regimen in elderly patients, but increasing the dose should be carried out with caution, which is associated with age-related changes and lengthening of the T1/2.
Changes in the concentration of amlodipine in the blood plasma do not correlate with the severity of renal failure.
Patients with impaired liver function. Co-Amlessa preparation® it is contraindicated in patients with severe hepatic insufficiency.
Caution should be exercised when using the drug in patients with mild to moderate hepatic impairment.
