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Composition:


active ingredients: perindopril TERT-butylamine, indapamide, amlodipine;


1 tablet contains: 2 mg of perindopril TERT-butylamine, 0.625 mg of indapamide and 5 mg of amlodipine (in the form of amlodipine besylate) or


4 mg perindopril TERT-butylamine, 1.25 mg indapamide and 5 mg amlodipine (as amlodipine besylate), or


4 mg perindopril TERT-butylamine, 1.25 mg indapamide and 10 mg amlodipine (as amlodipine besylate), or


8 mg perindopril TERT-butylamine, 2.5 mg indapamide and 5 mg amlodipine (as amlodipine besylate), or


8 mg perindopril TERT-butylamine, 2.5 mg indapamide and 10 mg amlodipine (as amlodipine besylate);


excipients:


microcrystalline cellulose; calcium chloride, hexahydrate; pre-chelated starch; sodium starch glycolate (Type A); sodium bicarbonate; colloidal water Silicon Dioxide; Magnesium Stearate.


Dosage form. Pills.


Basic physical and chemical properties:


2 mg/0.625 mg/5 mg: white to almost white, oval, biconvex tablets with a risk on one side;


4 mg/1.25 mg/5 mg: white to almost white, round, slightly biconvex tablets with beveled edges;


4 mg/1.25 mg/10 mg: white to almost white, oval, biconvex tablets with a risk on one side. The tablet can be divided into equal doses;


8 mg/2.5 mg/5 mg: white to Off-White, Round, biconvex tablets with beveled edges;


8 mg/2.5 mg/10 mg: white to almost white in color, round, biconvex tablets with beveled edges, with a risk on one side. The tablet can be divided into equal doses.


Pharmacotherapeutic group. Angiotensin-converting enzyme (ACE) inhibitors, other combinations. Perindopril, indapamide, and amlodipine. ATX code C09B X01.


Pharmacological properties.

Pharmacodynamics.


Co-Amless is a combination of three antihypertensive components whose mechanism of action complements each other to control blood pressure in patients with arterial hypertension. Perindopril TERT - butylamine is an angiotensin – converting enzyme inhibitor, indapamide is a sulfonamide diuretic, and amlodipine is a calcium ion antagonist.


The pharmacological effect of co-Amless is determined by the properties of each of the components separately. In addition, the combination of perindopril/indapamide has an additive synergistic effect of the antihypertensive effects of the two components.


Mechanism of action


Perindopril


Perindopril is an ACE inhibitor that converts angiotensin I to angiotensin II (vasoconstrictor substance), additionally stimulates the secretion of aldosterone by the adrenal cortex and the breakdown of bradykinin (vasodilator substance) to inactive heptapeptides. Due to ace inhibition, there is: a decrease in aldosterone secretion; an increase in renin activity in blood plasma, while aldosterone does not have a negative effect; reduction of total peripheral vascular resistance due to the predominant effect on the vessels of the muscles and kidneys, while there is no water and salt retention or reflex tachycardia, even in the case of long-term treatment.


Perindopril also reduces blood pressure in patients with normal and low plasma renin levels.


Perindopril acts through its active metabolite perindoprilate. Other metabolites are inactive.


Perindopril reduces heart function due to: vasodilating effect on the veins (possibly due to changes in prostaglandin metabolism) – reducing the preload on the heart; reducing the total resistance of peripheral vessels – reducing the afterload on the heart.


Studies conducted with patients with heart failure have shown that the use of perindopril leads to: a decrease in the filling pressure of the left and right ventricles; a decrease in the total resistance of peripheral vessels; an increase in cardiac output and an improvement in the cardiac index; an increase in regional blood circulation in the muscles.


In addition, the performance of physical activity tests is significantly improved.


Indapamide


Indapamide is a sulfonamide derivative with an indole ring, pharmacologically related to thiazide diuretics. Indapamide inhibits sodium reabsorption in the cortical segment of the kidneys. This increases the excretion of sodium and chlorides in the urine and, to a lesser extent, the excretion of potassium and magnesium, thus increasing diuresis. This mechanism provides an antihypertensive effect.


Amlodipine


Amlodipine is a calcium ion antagonist, and blocks the transmembrane flow of calcium ions to the smooth muscle cells of the myocardium and blood vessels.


Pharmacodynamic effects


Perindopril / indapamide


The combination of perindopril/indapamide reduces systolic and diastolic blood pressure in patients of any age with arterial hypertension, both in the supine and standing positions. The antihypertensive effect of the drug is dose-dependent. In the course of clinical studies, it has been proven that the simultaneous administration of perindopril and indapamide causes an antihypertensive effect of synergistic origin, which is the result of individual effects of the components of the drug.


Perindopril


Perindopril effectively reduces blood pressure in patients with arterial hypertension of any degree: mild, moderate and severe. A decrease in systolic and diastolic blood pressure is observed both in the supine and standing positions. The maximum antihypertensive effect develops 4-6 hours after taking a single dose and persists for more than a day. Perindopril has a high level of final ACE inhibitor blocking (approximately 80 %) 24 hours after administration.


In patients who responded to treatment, normalization of blood pressure occurs within a month and persists without the occurrence of tachyphylaxis.


Discontinuation of therapy is not accompanied by a withdrawal effect.


Perindopril has vasodilating properties, restores the elasticity of large arteries, corrects histomorphometric changes in arterial resistance and reduces left ventricular hypertrophy. As a result of the addition of a thiazide diuretic, if necessary, additional synergy develops.


The combination of an ACE inhibitor and a thiazide diuretic reduces the risk of hypokalemia that may occur when a diuretic is prescribed as monotherapy.


Indapamide


The antihypertensive effect of indapamide as monotherapy lasts 24 hours. This effect is manifested in doses in which the diuretic properties are minimal.


The antihypertensive effect of indapamide is associated with an improvement in arterial elasticity and a decrease in arteriole resistance and total peripheral vascular resistance.


Indapamide reduces left ventricular hypertrophy.


If the recommended dose is exceeded, the therapeutic effect of thiazide and thiazide-like diuretics does not increase, while the number of undesirable effects increases. If the treatment is not effective enough, it is not recommended to increase the dose.


Moreover, as shown in studies of various durations (short, medium and long) involving patients with arterial hypertension, indapamide: does not affect the metabolism of lipids (triglycerides, low-and high-density lipoproteins); does not affect the metabolism of carbohydrates, even in patients with arterial hypertension and diabetes mellitus.


Amlodipine


The mechanism of the antihypertensive effect of amlodipine is due to the direct relaxing effect on vascular smooth muscles. The exact mechanism by which amlodipine reduces the manifestations of angina is not fully determined, but it is known that the drug helps to reduce overall load ischemia due to such actions:


- amlodipine dilates the peripheral arterioles and thus reduces total peripheral resistance (afterload); since the heart rate does not change, reducing the load on the heart reduces the energy consumption of the myocardium and its oxygen demand;


- amlodipine partially promotes dilation of the main coronary arteries and arterioles in both unchanged and ischemic areas of the myocardium; this dilation increases oxygen supply to the myocardium in patients with Prinzmetal angina.

In patients with arterial hypertension, taking amlodipine 1 time a day provides a clinically pronounced decrease in blood pressure for 24 hours both in the supine and standing positions.


In patients with angina pectoris, taking amlodipine once a day prolongs the total active time, the time to the onset of angina pectoris, and the time to 1 mm ST-segment depression. Amlodipine reduces the incidence of angina and reduces the need for Nitroglycerin tablets.


The appointment of amlodipine is not associated with negative metabolic manifestations or changes in the level of lipids in blood plasma, so it can be used in patients with asthma, diabetes mellitus and gout.


Clinical efficacy and safety.


Studies of co-Amless on morbidity and mortality have not been conducted. Perindopril


Concomitant use of ACE inhibitors and angiotensin II receptor blockers was investigated in two large-scale randomized controlled trials [ONTARGET (ongoing Telmisartan Alone and Ramipril Global endpoint Trial) and VA NEPHRON-D (the Veterans Affairs Nephropathy in Diabetes)].


ONTARGET-a study involving patients with a history of cardiovascular or cerebrovascular disease or type II diabetes mellitus, accompanied by signs of damage to the target organ. VA NEPHRON-D is a study involving patients with Type II diabetes mellitus and diabetic nephropathy.


Studies have not found a significant positive effect for patients with kidney and/or cardiovascular diseases and on mortality from them, while compared with monotherapy, there was an increased risk of hyperkalemia, acute kidney damage and/or hypotension. Given the similarity of pharmacodynamic properties, these results are also applicable to other ACE inhibitors and angiotensin II receptor blockers.


Concomitant use of ACE inhibitors and angiotensin II receptor blockers is contraindicated in patients with diabetic nephropathy.


Aliskiren (study of aliskiren in Type II diabetes using the endpoints of cardiovascular disease (CVD) and kidney disease) — a study of the benefits of treatment when adding aliskiren to standard therapy with an ACE inhibitor or angiotensin II receptor blocker in patients with Type II diabetes mellitus and/or chronic kidney disease, CVD. The study was terminated prematurely due to an increased risk of undesirable consequences. CVD mortality, stroke cases, and reports of adverse events and serious complications (hyperkalemia, hypotension, or impaired renal function) were the most frequent in the aliskiren group compared to the placebo group.


Perindopril / indapamide


PICXEL is a multicenter randomized double-blind controlled trial that evaluated the effect of a combination of perindopril and indapamide on left ventricular hypertrophy compared to enalapril in monotherapy (based on echocardiography results).


In the PICXEL study, patients with arterial hypertension and left ventricular hypertrophy (with a left ventricular mass index > 120 g/m2 in men and > 100 g/m2 in women) were randomized into two groups: some patients took 2 mg of perindopril tertbutylamine/0.625 mg of indapamide, the rest – 10 mg of enalapril once a day for a year. Doses were adapted according to blood pressure indicators: the dose of perindopril tertbutylamine was increased to 8 mg, indapamide – to 2.5 mg, enalapril – to 40 mg once a day. 34% of patients in the perindopril/indapamide Group (2 mg perindopril and 0.625 mg indapamide) and 20% in the enalapril Group (10 mg) continued to take drugs at the starting dose.


At the end of treatment, the left ventricular mass index decreased significantly more in patients treated with perindopril/indapamide (-10.1 g/m2) than in the enalapril group (-1.1 g/m2). The difference between the two groups was -8.3 (95% confidence interval [CI] -11.5 to -5.0, p


The best effect on reducing the left ventricular mass index was achieved with perindopril/indapamide.


Blood pressure decreased more effectively in the perindopril/indapamide group: the difference in mean blood pressure reduction between the two groups of patients was -5.8 mm Hg. art. (95% CI from -7.9 to -3.7, p


ADVANCE is an international multicenter randomized trial with a bifactorial (2×2) design aimed at determining the benefits of lowering blood pressure with a fixed combination of perindopril/indapamide compared to placebo against the background of current standard therapy [double - blind comparison (prospective randomized open-label study with blind determination)]. The primary endpoint consisted of major macrovascular events (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke) and microvascular events (new cases or increased nephropathy, retinopathy). The study included 11,140 patients with Type II diabetes. Among them, 83% of patients had arterial hypertension, 32% and 10% of patients had a history of micro - and macrovascular diseases, respectively, and 27% had microalbuminuria. Concomitant therapy included medications to lower blood pressure (75 %), lipid – lowering medications (35 %, mainly statins-28 %), aspirin, or other antiplatelet medications (47 %).


Treatment for 4.3 years with the combination of perindopril/indapamide contributed to a significant 9% reduction in the relative risk of primary endpoint indicators (95% confidence interval (CI) [0.828; 0.996], P = 0.041). The advantages of treatment with perindopril / indapamide over the placebo group were due to: a significant reduction in the relative risk of total mortality by 14 % (95% CI [0.75; 0.98], p = 0.025); a significant reduction in the relative risk of cardiovascular mortality by 18 % (95% CI [0.68; 0.98], p = 0.027); a significant reduction in the relative risk of all renal events by 21 % (95% CI [0.74; 0.86], p


In the subgroup of hypertensive patients taking perindopril/indapamide, there was a significant 9% reduction in the relative risk of major macro - and microvascular events (95% CI [0.82; 1.00], p = 0.052) compared to the placebo group. In the subgroup among patients taking perindopril / indapamide, compared with the placebo group, there was also: a significant decrease in the relative risk of overall mortality by 16 % (95% CI [0.73; 0.97], p = 0.019); a significant decrease in the relative risk of cardiovascular mortality by 20 % (95% CI [0.66; 0.97], p = 0.023); significant reduction in the relative risk of all renal events by 20 % (95% CI [0.73; 0.87], p


The benefits of blood pressure reduction treatment were independent of those observed with intensive glucose control.


Amlodipine


A randomized double-blind clinical trial on morbidity and mortality "clinical trial for the Prevention of myocardial infarction with blood pressure and lipid reduction" (allhat) was conducted to compare newer treatments: amlodipine 2.5-10 mg/day (calcium channel blocker) or lisinopril 10-40 mg/day (ACE inhibitor) as first-line therapy compared to treatment with the thiazide diuretic chlorotalidone 12.5-25 mg / day for mild to moderate hypertension.


A total of 33,357 hypertensive patients aged 55 years and older were randomized and followed up for an average of 4.9 years. Patients had at least one additional risk factor for coronary heart disease, including myocardial infarction or stroke (> 6 months prior to inclusion in the study) or confirmed other atherosclerotic cardiovascular diseases (CVD) (overall 51.5%), type 2 diabetes (36.1%), HDL cholesterol


The primary endpoint consisted of fatal coronary heart disease or non-fatal myocardial infarction. The relative risk (BP) of 0.98, 95% CI (0.90-1.07), p=0.65. among the secondary endpoints, the incidence of heart failure (part of the combined cardiovascular index) was significantly higher in the amlodipine group compared to the chlorotalidone group (10.2% vs. 7.7%, BP of 1.38, 95% CI [1.25]. -1,52],


Use for children


There are no data on the use of co-Amless in children (see the section "dosage and administration").


Pharmacokinetics.


Co-Amless


Administration of perindopril/indapamide and amlodipine in a fixed combination does not change their pharmacokinetic properties compared to the use of monopreparations.


Perindopril


After oral administration, absorption of perindopril occurs rapidly, and the peak concentration is reached within 1 hour. The plasma half-life of perindopril is 1 hour. Since food intake reduces conversion to perindoprilate, hence bioavailability, perindopril should be administered orally in one daily dose in the morning before meals.


Distribution


The volume of distribution of free perindopril is approximately 0.2 L/kg. The Binding of perindopril proteins to plasma proteins is 20 %, especially with ace, but depends on the concentration.


Metabolism


Perindopril is a prodrug. 27% of the total amount of perindopril absorbed is converted to the active metabolite perindoprilate. In addition, five more inactive metabolites are formed. The maximum concentration of perindoprilate in blood plasma is reached within 3-4 hours.


Output


Perindoprilat is excreted in the urine, and the Half-Life of the unbound fraction is approximately 17 hours, causing a stable condition for 4 days.


Linearity/nonlinearity


A linear relationship between the dose of perindopril and its plasma concentration was demonstrated.


Special patient groups


Elderly patients


In the elderly and patients with heart or renal insufficiency, the excretion of perindoprilate decreases.


Patients with impaired renal function


In case of impaired renal function, it is recommended to change the dose depending on the degree of violation (creatinine clearance).


Patients undergoing dialysis

Perindoprilat is eliminated from the circulation by dialysis, its clearance is 70 ml/min.


Patients with cirrhosis of the liver


With cirrhosis of the liver, the kinetics of perindopril changes, while the hepatic clearance of the initial molecule decreases by half, but the amount of perindoprilate formed does not change, so in this disease, the dose of the drug can not be changed (see the sections "dosage and administration" and "application features").


Indapamide


Absorption and distribution


Indapamide is rapidly and completely absorbed in the digestive tract. The maximum concentration in blood plasma is reached approximately 1 hour after oral administration. Binding to plasma proteins is 79 %.


Biotransformation and elimination


The elimination Half – Life is 14 to 24 hours (an average of 18 hours). Repeated administration does not cause accumulation.


Indapamide is mainly excreted in the urine (70% of the dose) and feces (22 %) as inactive metabolites.


Special patient groups


Patients with impaired renal function


In patients with renal insufficiency, the pharmacokinetic parameters do not change.


Amlodipine


Absorption and bioavailability


When using therapeutic doses orally, amlodipine is well absorbed and reaches its maximum concentration in the blood 6-12 hours after administration. Absolute bioavailability ranges from 64 to 80%. Food intake does not affect the bioavailability of amlodipine.


Distribution


The volume of distribution is approximately 21 l/kg. In vitro studies have shown that about 97.5% of circulating amlodipine binds to plasma proteins.


Biotransformation


Amlodipine is mainly metabolized in the liver to form inactive metabolites, 60% of the administered dose is excreted in the urine, and 10% is unchanged.


Output


The Half-Life of amlodipine from blood plasma is approximately 35-50 hours, which allows you to prescribe the drug 1 time a day.


Special patient groups


Elderly patients


The time to reach the maximum concentration of amlodipine in blood plasma in elderly and younger patients is the same. In elderly patients, there is a tendency to decrease the clearance of amlodipine, which leads to an increase in AUC and Half-Life. The increase in AUC and Half-Life in patients with congestive heart failure corresponded to the age characteristics of the patients.


Patients with impaired renal function


The pharmacokinetics of amlodipine do not change in patients with renal insufficiency.


Patients with impaired liver function


There is a very limited amount of clinical data regarding the administration of amlodipine to patients with impaired liver function. In patients with hepatic insufficiency, the clearance of amlodipine decreases, which leads to an extension of the Half-Life and an increase in AUC by approximately 40-60 %.


Clinical characteristics.


Indications.


Co-Amlessa is intended for the treatment of arterial hypertension in patients who need treatment with perindopril, indapamide and amlodipine in doses available in a fixed combination.


Contraindications.


- Hypersensitivity to perindopril or any other ACE inhibitor, to indapamide or any other sulfonamides, to amlodipine or dihydropyridine and to any of the excipients;


- a history of angioedema (angioedema) associated with previous treatment with ACE inhibitors;


- congenital or idiopathic angioedema;


- hepatic encephalopathy;


- severe liver dysfunction;


- hypokalemia;


- severe hypotension;


- shock, including cardiogenic shock;


- left ventricular exit obstruction (for example, severe aortic stenosis);


- heart failure with unstable hemodynamics after acute myocardial infarction;


- untreated decompensated heart failure;


- concomitant administration with drugs containing the active substance aliskiren to patients with diabetes mellitus or renal insufficiency (glomerular filtration rate 2) (see the sections "application features" and "interaction with other drugs and other types of interactions");


- use in patients undergoing hemodialysis;


- severe renal failure (creatinine clearance


- moderate renal failure (creatinine clearance 8 mg/2.5 mg/5 mg or 8 mg/2.5 mg/10 mg;


- pregnancy or pregnancy planning period;


- breast-feeding period;


- children's age;


- concomitant use with sacubitril/valsartan therapy – due to the increased risk of angioedema. The drug should not be used within 36 hours after the last dose of sacubitril/valsartan or after switching from it to another drug containing a neprilysin inhibitor (see the sections "application features" and "interactions with other drugs and other types of interactions").;


- extracorporeal methods of treatment that lead to blood contact with negatively charged surfaces (see the section "interactions with other drugs and other types of interactions");


- significant bilateral stenosis of the renal arteries or stenosis of the artery of the only functioning kidney (see the section "application features").


Interactions with other drugs and other types of interactions.


Medications that cause hyperkalemia


Certain medications or therapeutic classes of drugs can cause hyperkalemia, namely: aliskiren, potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, nonsteroidal anti-inflammatory drugs (NSAIDs), heparins, immunosuppressants such as cyclosporine or tacrolimus, trimethoprim. Concomitant use of these medications increases the risk of hyperkalemia.


Concomitant use is contraindicated (see the section "contraindications")


Aliskiren


In patients with diabetes mellitus or patients with impaired renal function, the risk of hyperkalemia, deterioration of renal function, and cardiovascular morbidity and mortality increases (see the section "application features").


Extracorporeal treatments that result in blood contact with negatively charged surfaces, such as high — flow dialysis or hemofiltration membranes (for example, polyacrylic membranes) and low-density lipoprotein apheresis with dextran sulfate, increase the risk of severe anaphylactoid reactions (see Section "contraindications"). If such treatment is necessary, consideration should be given to using a different type of dialysis membrane or using a different class of antihypertensive drugs.


Sacubitril / valsartan


Concomitant use of perindopril with sacubitril/valsartan is contraindicated, as it increases the risk of angioedema. Start using sacubitrile / valsartan no earlier than 36 hours after taking the last dose of perindopril. Perindopril therapy should be started no earlier than 36 hours after taking the last dose of sacubitril/valsartan (see the sections "contraindications" and "application features").


Concomitant use is not recommended


Perindopril / indapamide

Application features.


All the warnings listed below regarding individual components also apply to the Drug Co-Amless as a whole.


Special warnings and precautions


Lithium


Concomitant use of lithium and a combination of perindopril/indapamide is usually not recommended (see "interactions with other drugs and other types of interactions").


Potassium-sparing medicines, dietary supplements containing potassium, or salt substitutes with potassium


Concomitant use of perindopril with potassium-sparing drugs or dietary supplements containing potassium is not recommended (see the section "interactions with other drugs and other types of interactions").


Neutropenia / agranulocytosis/thrombocytopenia/anemia


Neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported among patients taking ACE inhibitors. Neutropenia is rare in patients with normal renal function and in the absence of other risk factors. Perindopril should be administered very carefully to patients with collagenosis, during therapy with immunosuppressants, allopurinol, procainamide, or with a combination of these factors, especially if there is impaired renal function. Some of these patients developed serious infectious diseases, and in some cases they were resistant to intensive antibiotic therapy. If perindopril is prescribed to such patients, it is recommended to periodically monitor the number of white blood cells in the blood. They should also notify you of any manifestation of an infectious disease (sore throat, fever) (see the section "adverse reactions").


Hypersensitivity/angioedema


Rare cases of angioedema of the face, extremities, lips, tongue, glottis, and/or larynx have been reported with ACE inhibitors, including perindopril. This can happen at any time during treatment.


In such cases, it is necessary to immediately stop taking perindopril and establish the necessary monitoring of the patient's condition until the symptoms completely disappear. If the swelling spreads only to the face and lips, the patient's condition usually improves without therapy, and prescribing antihistamines may be useful to reduce symptoms.


Angioedema, accompanied by laryngeal edema, can be fatal. If the edema spreads to the tongue, glottis or larynx with the possibility of airway obstruction, emergency therapy is urgently needed, which may include subcutaneous administration of a 1:1000 epinephrine solution (0.3–0.5 ml) and/or ensuring airway patency.


It has been reported that ACE inhibitors are more likely to cause angioedema in black patients than in patients of other races.


Patients with a history of angioedema that was not associated with the use of ACE inhibitors have an increased risk of its occurrence while taking ACE inhibitors (see the section "contraindications").


Rare cases of intestinal angioedema have been reported in patients treated with ACE inhibitors. These patients experienced abdominal pain (with or without nausea and vomiting); in some cases, previous angioedema of the face was not observed, and C-1 esterase levels were normal. The diagnosis of intestinal angioedema was established during computed tomography, ultrasound, or surgery. After discontinuation of the ACE inhibitor, the symptoms of angioedema disappeared. When conducting a differential diagnosis of abdominal pain that occurs in patients taking ACE inhibitors, it is necessary to take into account the likelihood of intestinal angioedema.


Sacubitril / valsartan


Concomitant use of perindopril with sacubitril/valsartan is contraindicated, as it increases the risk of angioedema. Start using sacubitrile / valsartan no earlier than 36 hours after taking the last dose of perindopril. Perindopril therapy should be started no earlier than 36 hours after taking the last dose of sacubitril/valsartan (see the sections "contraindications" and "application features").


MTOR inhibitors


Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (for example: sirolimus, everolimus, temsirolimus) and Vildagliptin increases the risk of angioedema (for example, edema of the respiratory tract or tongue, with or without respiratory disorders) (see the section "interactions with other drugs and other types of interactions").


Caution should be exercised when starting the use of racecadotril, mTOR inhibitors (for example, sirolimus, everolimus, temsirolimus) and Vildagliptin in patients who are already taking an ACE inhibitor.


Anaphylactoid reactions during desensitizing therapy


Isolated cases of prolonged, life-threatening anaphylactoid reactions have been reported in patients taking ACE inhibitors during desensitizing treatment with drugs containing bee venom, OS. 


However, in patients requiring both ACE inhibitors and desensitizing therapy, such reactions can be avoided by temporarily stopping the use of an ACE inhibitor at least 24 hours before desensitization.


Anaphylactoid reactions during low-density lipoprotein (LDL)plasmapheresis


Occasionally, life-threatening anaphylactoid reactions were observed in patients taking ACE inhibitors during LDL plasmapheresis using dextran sulfate. The development of the latter can be avoided if treatment with an ACE inhibitor is temporarily discontinued before each plasmapheresis.


Patients undergoing hemodialysis


Anaphylactoid reactions have been reported in patients taking ACE inhibitors while undergoing hemodialysis using high-flow polyacrylic membranes (e.g. an 69®). Such patients should use a different type of dialysis membrane or be prescribed a different class of antihypertensive medications.


Primary aldosteronism


Patients with primary hyperaldosteronism usually do not respond to treatment with antihypertensive drugs that act by inhibiting RAAS. Therefore, it is not recommended for such patients to use this medicine.


Hepatic encephalopathy


Indapamide: in patients with impaired liver function, the use of thiazide and thiazide-like diuretics may cause hepatic encephalopathy. In this case, the use of diuretics should be stopped immediately.


Photosensitization


Photosensitization reactions have been reported in patients taking thiazide and thiazide-like diuretics (see Section "adverse reactions"). In case of such reactions, treatment with diuretics is recommended to be discontinued. If it is necessary to resume taking diuretics, protect vulnerable areas from the sun or artificial ultraviolet sources.

Overdose.


There are no data on overdose of co-Amless.


When using the combination of perindopril/indapamide, the most common adverse reaction in case of overdose is hypotension, reflex tachycardia is also possible, which is sometimes accompanied by nausea, vomiting, convulsions, dizziness, drowsiness, confusion, oliguria, which can progress to anuria (due to hypovolemia). There may be violations of the water-electrolyte balance (a decrease in the level of potassium and sodium in the blood plasma).


First aid measures include rapid elimination of the drug from the body: gastric lavage and/or administration of activated charcoal, and then restoration of water and electrolyte balance in a hospital setting until these indicators return to normal.


In case of significant hypotension, the patient should be given a horizontal position with a low headboard. If necessary, an isotonic solution is administered intravenously or any other method of restoring blood volume is used.


Perindoprilate, the active form of perindopril, can be removed from the body by hemodialysis. Since amlodipine is tightly bound to proteins, dialysis is unlikely to be beneficial.


Data on deliberate overdose of amlodipine are limited.


According to the available data, it can be assumed that taking very high doses will lead to excessive peripheral vasodilation and reflex tachycardia. A pronounced, presumably long-term systemic hypothesis and fatal shock were reported.


Clinically expressed hypotension caused by an overdose of amlodipine requires active cardiovascular care, in particular frequent monitoring of heart and respiratory function, lifting of tender limbs, as well as monitoring of BCC and urination.


Prescribing a vasoconstrictor can be useful for restoring vascular tone and blood pressure, if there are no contraindications. Intravenous administration of calcium gluconate can help eliminate the effects of calcium channel blockage.


In some cases, gastric lavage is recommended. A study involving healthy volunteers showed that due to the use of activated charcoal 2 hours after taking 10 mg of amlodipine, the rate of absorption of amlodipine in the body decreases. Since amlodipine has a high level of binding to blood proteins, hemodialysis is considered ineffective.

Tags: Amlodipine, Indapamide, Perindopril