Indapamide, 1.5 mg, extended-release film-coated tablets, 30 pcs.

Diuretics are one of the groups of drugs used in the treatment of hypertension. Indapamide is often prescribed in the complex treatment of arterial hypertension and some cardiovascular diseases; it allows achieving stable and long-term results, including in the elderly.

Composition and release form

Indapamide is produced by different pharmaceutical companies under several names (for example, Indapamide Stada or Teva) in the form:

• long-acting tablets (their name contains the word retard or the letters MB);
• tablets with a special film coating;
• capsules

In all dosage forms, the active ingredient is the same - indapamide. In long-acting tablets, its dosage can be 1.5 mg, and in regular tablets and capsules - only 2.5 mg. Sold in cardboard boxes of 30 or 60 pieces, complete with instructions.

Auxiliary components are represented by colloidal silicon dioxide, magnesium stearate, lactose, microcrystalline cellulose. But each manufacturer has the right to produce medicine using its own technology, so the composition must be specified in the instructions for the product being purchased.

Renaissance of diuretic therapy for long-acting indapamide

Cardiovascular pathology is a leading cause of morbidity and mortality throughout the world, and in Russia in particular. Poor blood pressure control is responsible for 29% of deaths annually and is responsible for the development of up to 62% of cerebrovascular diseases and 49% of coronary heart disease (CHD). Arterial hypertension (HTN) is the most important risk factor for cardiovascular diseases (CVD), and proper control of HTN can reduce the risks of cerebral stroke by 35–40% and coronary heart disease by 20–25% [1].

Of all the classes of drugs used in the long-term treatment of hypertension, diuretics are one of the oldest. Potentiating the effect of all other drug groups (except calcium antagonists), they are an integral part of combination antihypertensive therapy, which is very often prescribed already at the initial stages of treatment of patients with hypertension. In European [2] and American [3] cardiological guidelines, thiazide-like diuretics are also primarily recommended for use in the treatment of hypertension in monotherapy or combination regimens. Recent studies indicate that systolic blood pressure (SBP) is a stronger predictor of death, stroke, and myocardial infarction than diastolic blood pressure (DBP) in populations over 55 years of age, and diuretics remain the drug of choice among older patients and patients with systolic hypertension [ 4]. At the same time, during certain periods there was some “cooling” towards thiazide-like diuretics due to a suboptimal safety profile and lack of effectiveness, as well as the introduction of a large number of new antihypertensive drugs of other classes. The presence of frequent complications of diuretic therapy, such as impaired glucose tolerance, deterioration of the lipid profile, and increased uric acid levels, forced the abandonment of high doses (50–100 mg) of the classical diuretic hydrochlorothiazide (HCTZ) [5, 6]. However, in the last 20 years, antihypertensive drug therapy based on the use of diuretics has been reintroduced, and one of the most important reasons for this is the introduction of newer thiazide-like diuretics, such as indapamide.

Indapamide is part of a new generation of thiazide-like diuretics derived from chlorosulfonamide and has a clinical history as an effective and well-tolerated antihypertensive drug. Its short-term action is mediated by the influence on the proximal part of the distal tubules of the nephron, which causes the presence of a natriuretic effect characteristic of representatives of the diuretic class. However, this representative of the diuretic family also has additional antihypertensive activity, manifested primarily by a vasodilating effect [7]. This property is due to a decrease in vascular reactivity to angiotensin, angiotensin II, adrenaline, norepinephrine, thromboxane A2, as well as inhibition of free radical oxidation processes [8, 9]. In addition, the antisclerotic effect of the drug has been described [10].

Despite the less pronounced diuretic effect of this group of drugs in comparison with HCTZ and, especially, loop diuretics, standard indapamide during long-term therapy can also cause electrolyte disturbances. Specifically, in Australia, 87 cases of hyponatremia and hypokalemia were reported with indapamide use over a 15-year period; Moreover, the number of such cases was greater than with the use of HCTZ [11].

As is known, a modern antihypertensive drug should combine, on the one hand, high efficiency and duration of blood pressure control throughout the day, and on the other, be prescribed only once a day (to achieve optimal compliance). In addition, the European Cardiological Guidelines emphasize the desirability of using lower doses of drugs for hypertension to achieve the required blood pressure level in order to ensure the safety of therapy [2]. In accordance with the above recommendations, a new slow-release dosage form of indapamide was first created about 20 years ago. This form reduces and “smoothes out” the peak concentration of the drug in the blood plasma, which allows it to achieve a constant level and at the same time control blood pressure for 24 hours. For example, one of the generics (the drug "Ravel SR") with the original design of a hydrophobic matrix in the structure of the drug prolongs its effect, increasing the release time of the active substance up to 16 times! The slow-release form used a much lower dosage of the drug - 1.5 mg instead of 2.5 mg. The theoretical basis for dosage reduction was data from laboratory studies and two fairly large randomized clinical trials (RCTs). In animal models, indapamide retard at a dosage of 1 mg/kg increased natriuresis by 3 times, and kaliuresis by 1.2 times; at the same time, its higher doses did not lead to an increase in natriuresis, increasing the risk of hypokalemia, i.e., the natriuretic effect was achieved in much lower doses than the kaliuretic effect [8].

The first RCT involved 285 people who were randomized to receive immediate-release indapamide 2.5 mg or extended-release indapamide 1.5, 2.0, or 2.5 mg [12]. The drugs were prescribed for 2 months after a 1-month washout period. The study concluded that there was no dose-dependent effect in reducing SBP and DBP between the fast release form of indapamide 1.5 mg and its slow release form 2.5 mg.

In a second blinded study in 405 patients with moderate hypertension, the effect of immediate-release indapamide compared with the extended-release form was monitored within three months [12]. The endpoints in this study were not only blood pressure levels, but also the level of side effects such as hypokalemia. With an almost identical decrease in blood pressure at the end of three months in both groups to 69% and 66%, respectively, the frequency of hypokalemia less than 3.4 mmol/l in blood plasma was significantly less common in the group of patients receiving the prolonged form (9%) compared with using an immediate release drug (24%, p < 0.001). When the study was extended for another 9 months, such negative metabolic complications as increased levels of blood glucose, cholesterol, triglycerides, uric acid, and creatinine were not recorded.

In addition, other RCTs compared the new form of indapamide with the classic diuretic HCTZ, as well as other antihypertensive agents. In a 3-month RCT of the antihypertensive activity of indapamide retard 1.5 mg, amlodipine 5 mg and HCTZ 25 mg in 605 elderly patients with systolic hypertension, indapamide retard and amlodipine showed a more pronounced hypotensive effect than HCTZ [13]. When using long-acting indapamide, patients have a lower incidence of side effects (back pain, peripheral edema) than comparators. In the double-blind, controlled X-CELLENT trial, the effects of indapamide retard were compared with the effects of candesartan 8 mg/day, amlodipine 5 mg/day and placebo in 1750 people with essential hypertension [14]. Each drug was equally effective in controlling blood pressure when compared with placebo, and the diuretic was more effective than amlodipine in reducing SBP. As is known, left ventricular hypertrophy (LVH) is an unfavorable marker of the development of hypertension and correlates with cardiovascular mortality [13]. In the multicenter RCT LIVE (LVH: Indapamide Versus Enalapril) [16], in 411 patients, the therapeutic efficacy of standard dosage indapamide retard was compared with enalapril 20 mg/day in patients with essential hypertension and LVH. When observed for one year, a significant decrease in the left ventricular myocardial mass index according to echocardiography was noted in the retard indapamide group, despite the fact that the decrease in blood pressure occurred to the same extent. The combination of type 2 diabetes mellitus and hypertension quite often leads to the development of kidney damage and its early marker - microalbuminuria. It is believed that angiotensin-converting factor inhibitors significantly reduce the level of microalbuminuria in these conditions [17]. In the NESTOR study [18] on 570 patients with arterial hypertension, indapamide retard 1.5 mg to the same extent with enalapril 20 mg in patients with hypertension, type 2 diabetes mellitus and microalbuminuria reduced the level of blood pressure and albuminuria (35% and 39%, respectively). Finally, a meta-analysis of three controlled, double-blind studies with a total of 1195 patients examined the short- and long-term metabolic effects of treatment [19]. All studies were conducted in patients with mild to moderate hypertension. After 9–12 months of treatment with indapamide retard at a dosage of 1.5 mg/day, no significant changes in blood glucose and blood lipid levels were noted. No renal dysfunction was observed in either the short or long term. In the first months, an increase in uric acid levels was detected in the blood serum, which returned to its previous level by the end of the year. In addition, a significant decrease in LVH during therapy was shown.

Several large Russian studies have shown the effectiveness of the original drug indapamide retard in the treatment of people with arterial hypertension (ARGUS [20], MINOTAVR [21]). Considering some national characteristics of the population of the Russian Federation, in particular, the high level of CVD diseases, research in our country is of particular value. Recently, Russian and foreign studies were completed with the first European generic drug, Ravel SR, which studied the effectiveness, safety profile and compliance of this retard form of the drug in comparison with other antihypertensive drugs, such as HCTZ. When creating generics, a mandatory condition is to test the drug in terms of bioequivalence to the original. Tests conducted in the Czech Republic several years ago showed the identity of the dosage form of the generic and the original.

The effectiveness of Ravel CP sustained release at a standard dosage of 1.5 mg was studied in a study conducted in Slovenia in 2005–2006. in patients with mild and moderate arterial hypertension in a fairly large sample of patients (n = 1419). Moreover, 74% of patients had previously received antihypertensive therapy. In addition to Ravel SR, 77.2% of patients continued taking previously prescribed medications (enalapril in 15.1% of cases, ramipril in 11.5%, aspirin in 10.9% and simvastatin in 7.5%). At a follow-up visit after 4–6 months, the level of initial systolic blood pressure decreased by 14.1% (p < 0.005), and DBP by 11.1% (p < 0.005). At the same time, a very good safety profile of the drug was established: in 62.4% of cases, the target blood pressure level was achieved without any side effects, and mild adverse events (dry mouth, dizziness) were noted only in 2.5% of patients.

The BOLERO study (“Basic treatment and antihypertensive effect: Ravel SR in patients with arterial hypertension”) [22] also studied the safety profile and impact on quality of life of indapamide retard and standard indapamide over a two-month period. The study was simple, open-label, controlled, sequential, prospective and fairly large (n = 1068). All patients with essential hypertension were prescribed the drug "Ravel SR" at a dosage of 1.5 mg/day. After 2 months of therapy, a significant decrease in both SBP and DBP was shown by 18% and 15%, respectively, as well as heart rate (by 6%), blood glucose levels (by 4%), creatinine (by 3%), total cholesterol (by 9%) and triglycerides (by 8%). An extremely important result of the study was the lack of a significant effect of the drug on the levels of potassium and uric acid in the blood. When comparing test results before and after a course of therapy, the 10-year risk of death from CVD according to the SCORE scale decreased by almost 2 times. The quality of life of patients, studied using the GQI (The Goeteborg Quality of the life Instruments) and SAM (well-being, activity, mood) questionnaire, also significantly improved.

Another open Russian randomized clinical trial observed 40 patients aged 18 to 60 years with an increased body mass index (BMI) (more than 27 kg/m2) [23]. Patients were randomized into 2 groups: in the first group, Ravel SR was taken at a standard dosage of 1.5 mg, and in the second, HCTZ was taken for 12 weeks, followed by a transfer to Ravel SR for another 12 weeks. During the study, 24-hour blood pressure monitoring (ABPM), echocardiography was carried out, and the speed of pulse wave propagation and the amount of fat deposits were determined. The data obtained as a result of the study were generally consistent with international RCTs: with monotherapy with indapamide retard, a greater number of patients were able to achieve the target blood pressure level in a larger number of patients than with HCTZ. When analyzing ABPM data, Ravel SR was more effective in controlling the daily blood pressure profile - the T/P (through-peak ratio) indicator turned out to be significantly lower in the long-acting drug. Functional research methods also showed a beneficial effect of Ravel SR on vascular elasticity and, very importantly, on reducing LVH when compared with the group with HCTZ. With regard to the effect on lipid and carbohydrate profiles, in the case of HCTZ, hyperglycemia significantly increased and a tendency to increase uric acid was observed, while the reference drug (Ravel SR) did not cause such changes. A very interesting result was the fact that body fat decreased during therapy with a long-acting drug, despite the fact that body mass index (BMI) decreased equally in both groups.

Thus, according to both large multicenter international studies with the original long-acting indapamide, and several Russian projects with the generic Ravel SR, the effectiveness of indapamide retard in the treatment of mild and moderate arterial hypertension, especially in elderly people with systolic hypertension, was shown and obesity. In addition, indapamide retard showed better safety when compared with hydrochlorothiazide and short-acting indapamide, in particular, a neutral metabolic effect and a low level of kaliuresis. The nephroprotective effectiveness of the drug was also shown in the presence of microalbuminuria and diabetes mellitus, and the cardioprotective effect was demonstrated by reducing the degree of left ventricular hypertrophy.

Thus, Ravel SR is a modern low-dose and at the same time very effective drug, which allows us to consider it the drug of choice for mild to moderate hypertension, in the elderly (with systolic hypertension), in people with left ventricular hypertrophy, as well as concomitant diabetes mellitus and high body mass index.

Literature

1. Collins R., MacMahon S. et al. Blood pressure, stroke, and coronary heart disease. Part 2, short term reductions in blood pressure: overview of randomized drug trials in their epidemiological context // Lancet 1990; 335(8693):827–838.
2. European Society of Hypertention-European Society of Cardiology guidelines for the management of arterial hypertention // J. Hypertens. 2003: 21; 1011–1053.
3. Chobanian AV, Bakris GJ, Black HR et al. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, Hypertension. 2003: 42; 1206–1252.
4. Systolic Hypertension in the Elderly Program Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP) // JAMA. 1991; 265:3255–3264.
5. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT) // JAMA. 2000: 283 (15); 1967–1975.
6. Psaty BM, Smith NL, Siscovick DS et al. Health outcomes associated with antihypertensive therapies used as first-line agents // JAMA. 1997; 277:739–745.
7. Calder JA Mechanism of antihypertensive action of thiazide diuretics and related drugs: direct vascular effects // J. Drug Dev. 1992; 4 (4): 189–198.
8. Bataillard A., Schiavi P., Sassard J. Pharmacological properties of indapamide: rationale for use in hypertension // Clin. Pharmacokinet. 1999; 37 (Supp. l): 7–12.
9. Campbell DB, Brackman F. Cardiovascular protective properties of indapamide // Am J. Cardiol. 1990: 65; 11–27H.
10. Janeca P., Kojsova S., Jendekova L. et al. Indapamide-Induced Prevention of Myocardial Fibrosis in Spontaneous Hypertension Rats Is Not Nitric Oxide-Related // Physiol Res. 2007: 56; 825–828.
11. Chapman M., Hanrahan R., McEwen J., Marley J. Hyponatraemia and hypokalaemia due to indapamide // MJA. 2002; 176(5):219–221.
12. Ambrosini E., Safar M., Degaute J.-P. et al. Low dose antihypertensive thrapy with 1.5 mg sustained-release indapamide: results of randomized double-blind controlled studies. European Study Group // J. Hypertens. 1998; 16:1677–1684.
13. Emeriau JP, Knauf H, Pujadas JO et al. A comparison of indapamide SR 1.5 mg with both amlodipine 5mg and hydrochlorothiazide 25mg in elderly hypertensive patients: a randomized double-blind controlled study // J. Hypertens. 200:19(2):343–350.
14. London GM, Schmeider R, Calvo C et al. On behalf of the X-CELLENT study investgators. Indapamide SR versus candesartan and amlodipine in hypertension: the X-CELLENT study // Am J. Hypertens. 2006: 19; 113–121.
15. Levy D., Garrison RJ, Savage DD et al. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study // N. Engl. J. Med. 1990. 322. 1561–1566.
16. Gosse P., Sheridan DJ, Zannad F. et al. Regression of left ventricular hypertrophy in hypertensive patients treated with indapamide SR 1.5mg versus enalapril 20 mg: the LIVE study // J. Hypertens. 2000: 18 (10); 1465–1475.
17. Mattock MB, Viberti G, Keen H et al. Prospective study of microalbuminurea as a predictor of mortality in NIDDM // Diabetes.1992. 41. 736–741.
18. Marre M., Garcia-Puig J., Kokot F. et al. Equivalence of indapamide SR and enalapril on microalbuminuria reduction hypertensive patients with type 2 diabetic: the NESTOR study // J. Hypertens. 2004: 22; 1613–1622.
19. Wiedermann P. Metabolic Profile of Indapamide Sustained-Release in Patients with Hypertention // Drug Safety.2001: 24; 1156–1165.
20. Kobalava Zh. D., Kotovskaya Yu. V., Vereshchagina G. N. et al. Efficacy and tolerability of indapamide in the treatment of arterial hypertension in elderly patients (results of a multicenter open non-comparative study within the framework of the Russian research program ARGUS) // Journal. 2002; 42 (7): 25–5.
21. Mychka V. B., Mamyrbaeva K. M., Masenko V. P. et al. Possibilities of a fixed form of combination of perindopril with indapamide in the primary prevention of cerebrovascular complications in patients with metabolic syndrome and arterial hypertension // Cardiovascular Therapy and Prevention. 2006. 5 (1). 31–36.
22. Glezer M. G. Results of the program “Basic treatment and antihypertensive effect: the drug “Ravel SR” in patients with arterial hypertension” (BOLERO) // Gender aspects. Women's health problems. 2007. 3 (2). pp. 3–10.
23. Nedogoda S.V., Barykina I.N., Brel U.A., Chelyabi T.A. Possibility of Ravel correction of risk factors for arterial hypertension due to obesity // Systemic hypertension, supplement to Consilium Medicum. 2007. No. 1. pp. 17–21.

N. Sh. Zagidullin , Candidate of Medical Sciences Sh. Z. Zagidullin , Doctor of Medical Sciences, Professor BSMU , Ufa

Effect of the drug

Indapamide has a triple effect:

• has a diuretic effect;
• reduces blood pressure;
• dilates blood vessels.

When taking 1.5-2.5 mg of the drug, a hypotensive effect appears, but without a noticeable diuretic effect. This feature allows the drug to be used to lower blood pressure for a long time.

When the dosage is increased, the hypotensive effect does not increase, but the diuretic effect appears.

A noticeable decrease in blood pressure occurs only after 7 days of taking the medicine; a lasting effect can be expected no earlier than after 3 months.

Thanks to the drug, vascular resistance is reduced by reducing the force of contraction of the smooth muscles of the arteries, and the size of the left ventricle of the heart returns to normal.

Indications for use

The instructions for use contain information about what Indapamide helps with. It is prescribed for arterial hypertension, as well as for chronic heart failure caused by sodium and water retention in the body.

The drug does not affect the metabolism of carbohydrates and fats, therefore it is indicated:

• people diagnosed with diabetes;
• patients with high cholesterol;
• people with one kidney or on hemodialysis.

Indapamide

Undesirable drug combinations

— Lithium preparations:

With the simultaneous use of indapamide and lithium preparations, as well as when following a salt-free diet, an increase in the concentration of lithium in the blood plasma may be observed due to a decrease in its excretion, accompanied by the appearance of signs of overdose. If necessary, diuretics can be used in combination with lithium preparations, and the lithium content in the blood plasma should be monitored and the dose of the drug should be adjusted accordingly.

Combinations of drugs requiring special attention

- Drugs that can cause aritis:

• class I A antiarrhythmic drugs (quinidine, hydroquinidine, disopyramide);
• class III antiarrhythmic drugs (amiodarone, sotalol, dofetilide, ibutilide);
• some neuroleptics: phenothiazines (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoroperazine), benzamides (amisulpride, sulpiride, sultopride, tiapride). butyrophenones (droperidol, haloperidol);
• others: bepridil, cisapride, difemanil, erythromycin (iv), halofantrine, mizolastine, pentamidine, sparfloxacin, moxifloxacin, vincamine (iv), astemizole.

Increased risk of developing ventricular arrhythmias, especially arrhythmias (hypokalemia is a risk factor).

It is necessary to determine the potassium content in the blood plasma and. if necessary, adjust it before starting combination therapy with indapamide and the above drugs. It is necessary to monitor the patient’s clinical condition, monitor the level of electrolytes in the blood plasma, and ECG indicators.

In patients with hypokalemia, drugs that do not cause ari should be used.

— Systemic non-steroidal anti-inflammatory drugs, including selective cyclooxygenase-2 (COX-2) inhibitors, high doses of acetylsalicylic acid (≥ 3 g/day):

The antihypertensive effect of indapamide may be reduced. There is a risk of developing acute renal failure due to a decrease in glomerular filtration rate. Patients need to compensate for fluid loss and carefully monitor renal function at the beginning of therapy.

— Angiotensin-converting enzyme (ACE) inhibitors:

Prescribing ACE inhibitors to patients with low sodium levels in the blood (especially patients with renal artery stenosis) is accompanied by a risk of sudden arterial hypotension and/or acute renal failure.

For patients with arterial hypertension

and, possibly, due to the reduced content of sodium ions in the blood plasma due to the use of diuretics, it is necessary to:

- 3 days before starting therapy with an ACE inhibitor, stop taking the diuretic. In the future, if necessary, the diuretic can be resumed;

- or start ACE inhibitor therapy with low doses, followed by a gradual increase in dose if necessary.

For chronic heart failure

Therapy with ACE inhibitors should be started with low doses, with a possible preliminary reduction in diuretic doses.

In all cases, in the first week of taking ACE inhibitors in patients, it is necessary to monitor renal function (plasma creatinine content).

— Other drugs that can cause hypokalemia: amphotericin B (iv), gluco- and mineralocorticosteroids when used systemically, tetracosactide, laxatives that stimulate intestinal motility:

Increased risk of hypokalemia (additive effect). Constant monitoring of potassium concentration in the blood plasma and, if necessary, its correction is necessary. It is recommended to use laxatives that do not stimulate intestinal motility.

- Baclofen:

There is an increase in the hypotensive effect. Patients need to compensate for fluid loss and carefully monitor renal function at the beginning of treatment.

— Cardiac glycosides:

Hypokalemia enhances the toxic effect of cardiac glycosides. With the simultaneous use of indapamide and cardiac glycosides, the content of potassium in the blood plasma, ECG parameters should be monitored and, if necessary, therapy should be adjusted.

Drug combinations requiring attention

— Potassium-sparing diuretics (amiloride, spironolactone, triamterene):

Combination therapy with indapamide and potassium-sparing diuretics is advisable in some patients, but the possibility of developing hypokalemia or hyperkalemia cannot be excluded (especially in patients with renal failure or in patients with diabetes mellitus).

It is necessary to monitor the potassium content in the blood plasma, ECG indicators and, if necessary, adjust therapy.

— Metformin:

Functional renal failure, which can occur against the background of diuretics, especially loop diuretics, with simultaneous administration of metformin increases the risk of developing lactic acidosis. Metformin should not be used if creatinine levels exceed 15 mg/L (135 µmol/L) in men and 12 mg/L (110 µmol/L) in women.

— Iodine-containing contrast agents:

In case of dehydration while taking diuretics, the risk of developing acute renal failure increases, especially when using high doses of iodine-containing contrast agents. Before using iodinated contrast agents, patients need to compensate for fluid loss.

— Tricyclic antidepressants, antipsychotics (neuroleptics):

Drugs in these classes enhance the antihypertensive effect of indapamide and increase the risk of orthostatic hypotension (additive effect).

— Calcium salts:

With simultaneous administration, hypercalcemia may develop due to a decrease in the excretion of calcium ions by the kidneys.

- Cyclosporine, tacrolimus:

It is possible to increase the creatinine content in the blood plasma without changing the concentration of circulating cyclosporine, even with normal fluid and sodium ion levels.

— Corticosteroid drugs, tetracosactide (for systemic use):

Reduced hypotensive effect (retention of fluid and sodium ions as a result of the action of corticosteroids).

Indapamide: how and in what doses to take

The method and regimen of use depend on the prescribed dosage of the drug.

• A 2.5 mg tablet is taken once a day in the morning. If the hypotensive effect does not appear within 14 days, then the dose is increased to 2-3 tablets per day. The maximum daily dose is 10 mg, which should be divided into two doses;
• a long-acting tablet of 1.5 mg is taken once a day in the morning, but if the effectiveness is weak, after 1.5-2 months the treatment should be supplemented with a drug that is not a diuretic. With long-term therapy, increasing the dose is not advisable due to the increased risk of side effects without normalizing blood pressure.

To eliminate edema in chronic heart failure, Indapamide is prescribed at a dose of 5-7.5 mg per day for 7-14 days.

Clinical efficacy of indapamide in patients with hypertension

G

Hypertension (HD) is one of the leading causes of disability and mortality. A prolonged increase in blood pressure (BP) leads to target organ damage and the development of cardiovascular complications (heart failure, myocardial infarction, cerebral stroke and renal failure) [2, 3, 8].

Drugs for the treatment and prevention of complications of hypertension should have high therapeutic efficacy, a long-lasting antihypertensive effect throughout the day, and the absence of metabolic side effects [3, 4, 8].

The listed requirements are fully met by the drug belonging to the second generation of thiazide and thiazide-like diuretics, indapamide

. The mechanism of its antihypertensive action is associated with inhibition of sodium reabsorption in the distal convoluted tubules and the development of peripheral vasodilation [6]. Unlike hydrochlorothiazide, indapamide does not affect lipid and carbohydrate metabolism [7, 9]. One of the advantages of the drug is the ability to reduce the mass of hypertrophied left ventricular myocardium [5].

Indapamide has high bioavailability (90–95%) and a long half-life (15–25 hours), which allows for a stable antihypertensive effect throughout the day [4].

The purpose of the study conducted in our clinic was to evaluate the effectiveness and safety of indapamide under conditions of 24-hour blood pressure monitoring (ABPM), studying central hemodynamics under the control of a number of parameters of the biochemical spectrum of blood.

The study included 30 patients (12 men and 18 women) with stage I and II hypertension (according to WHO classification). The average age of the group was 47.1±11.5 years, the duration of the disease was 8.0±7.05 years. 10 patients had mild and 20 had moderate arterial hypertension (AH). Patients with symptomatic hypertension, unstable angina, previous myocardial infarction or acute cerebrovascular accident in the last 6 months, a history of liver and kidney diseases, and intolerance to sulfonamides were excluded from the study. The duration of observation was 8 weeks.

After an introductory period, during which patients did not receive antihypertensive therapy, indapamide (Hemofarm, Yugoslavia) was prescribed at a daily dose of 2.5 mg, once in the morning. If monotherapy was ineffective for 1 month, enalapril (Hemofarm, Yugoslavia) was added at a daily dose of 5–20 mg. At baseline and after 8 weeks of treatment, antihypertensive efficacy using ABPM, the effect on central hemodynamic parameters, and levels of electrolytes and blood lipids were assessed in all patients.

ABPM was carried out using a portable recorder ABRM-04 from Meditech (Hungary), which records blood pressure and heart rate during the decompression phase using the oscillometric method. Measurements began at 9–10 am. The intervals between blood pressure and heart rate measurements were 15 minutes during the day and 30 minutes at night. Based on ABPM data, we analyzed the average indicators of systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate during periods of wakefulness, sleep and for the day as a whole, standard deviation to assess the variability of blood pressure and heart rate; degree of nocturnal reduction in blood pressure (SNS – percentage of reduction in blood pressure at night); percentage of blood pressure measurements exceeding the upper limit of normal in the total number of registrations; variability index. Blood pressure levels below 140/90 mmHg are considered normal. Art. during the day and below 120/70 mm Hg. Art. at night. Central hemodynamics were studied using an Acuson apparatus (USA).

Results and discussion

Before starting treatment, patients complained of headache (63%), dizziness (37%), pain in the heart of various types (27%), decreased performance (50%). 23% of patients had no complaints. According to ABPM data (Table 1), there was an increase in the average daytime, average nighttime and average daily values ​​of SBP and DBP. The proportion of measurements that exceeded the norm, as well as the variability index, exceeded the permissible normative values, which indicated an increase in hypertensive load. The degree of nocturnal decrease (NNR) for SBP was 10.0±6.0%, for DBP – 13.0±7.5%, which corresponds to the “dipper” group. Initially, indicators of central hemodynamics (Table 2) such as average blood pressure per day and total peripheral vascular resistance (TPVR) were significantly increased.

After 8 weeks of therapy, clear positive dynamics were noted in the patients’ condition. The general well-being of the patients improved, dizziness decreased or disappeared (in 82%), headaches (in 58%), cardialgia (in 100%), and performance increased (in 80%). All patients had good tolerability of treatment, there were no side effects.

When assessing the data obtained, normalization of DBP (decrease to 90 mm Hg or lower) was considered a good result of treatment; a satisfactory result was a decrease in DBP by 10 mm Hg. Art. and more (but not to normal values), unsatisfactory - a decrease in DBP by less than 10 mm Hg. Art. or increased blood pressure. In 16 patients receiving monotherapy with indapamide, the antihypertensive result was assessed as good, in 2 patients - as satisfactory. Thus, 60% of patients achieved an effect during treatment with indapamide, which corresponds to the available literature data on the effectiveness of monotherapy [8].

There was a significant decrease in SBP per day, day, night by 14.5, 14.9 and 18 mm Hg. Art., respectively. Average daily, daytime, and nighttime DBP decreased by 8.8, 8.9, and 14.3 mmHg, respectively. Art. A significant decrease in the blood pressure variability index was revealed. Particularly noteworthy is the decrease in the absolute value of DBP and the DBP variability index, since changes in these indicators correlate with target organ damage [10]. During treatment, an unreliable increase in the SNS was noted, not exceeding 20%. The above indicates that a single dose of indapamide 2.5 mg is sufficient to maintain normal blood pressure throughout the day without affecting the physiological circadian rhythm of blood pressure.

When analyzing central hemodynamics during monotherapy with indapamide, a significant decrease in average blood pressure per day (p <0.01) and total peripheral resistance (p <0.05) was revealed, which largely explains the predominant effect of indapamide on DBP (Table 2). The dynamics of shock and cardio indices were statistically insignificant.

Twelve patients received combination therapy (indapamide 2.5 mg/day + enalapril 5–20 mg/day). At the same time, there was a significant decrease in SBP and DBP per day, day and night (Table 1), and the BP variability index. SNS increased slightly within the “dipper” group, that is, there was also no change in the circadian rhythm of blood pressure. According to echocardiography, there was a significant decrease in average blood pressure per day by 7.2% (p<0.01), peripheral vascular resistance by 13.3% (p<0.05), other indicators changed unreliably (Table 2). In 8 patients receiving combination therapy with indapamide and enalapril, the antihypertensive result was assessed as good, in 2 patients as satisfactory, in 2 patients as unsatisfactory, and therefore required the addition of verapamil at a dose of 120 mg per day. After 8 weeks of indapamide therapy, an insignificant decrease in the levels of sodium (from 142.4±2.9 to 140.4±2.3 mmol/l) and potassium (from 4.4±0.4 to 3.96±0.3) was noted mmol/l) in blood serum. Not a single patient had electrolyte levels (and, most importantly, potassium) that dropped below normal values. There were also no significant changes in the content of cholesterol and triglycerides compared to the initial level.

conclusions

1. Indapamide is a highly effective antihypertensive drug for the treatment of patients with mild and moderate forms of hypertension.

2. Considering the effect of indapamide on the peripheral vascular resistance, the drug can be prescribed primarily for diastolic hypertension.

3. The metabolic inertness of indapamide, unlike thiazides, makes it possible to recommend it to patients with hypertension in combination with metabolic disorders.

4. Adding enalapril to indapamide (if monotherapy is insufficiently effective) allows you to achieve the target blood pressure level.

Indapamide -

Indapamide (trade name)

(Hemofarm)
Literature:
1. Bulkina O.S., Dobrovolsky A.B., Britareva V.V., Marenich A.V., Karpov Yu.A. Ross. cardiol. magazine 1999; 1:39–42.

2. Gogin E.E. Hypertonic disease. M.; 1997.

3. Makolkin V.I., Podzolkov V.I. Hypertonic disease. – M.; 2000.

4. Sidorenko B.A., Preobrazhensky D.V. Diagnosis and treatment of arterial hypertension. Part two. Diuretics. M.; 2000.

5. Campbell DB, Brackman FJ Clin. Pharmacol. 1991; 31: 751–757.

6. Campbell DB, Moore R. Am. J. Hypertens. 1981; 57: 7–17.

7. FuJii S., Kaku K., Andou S., Nakayama H. ​​et al. Clin. Ther. 1993; 15:6.

8. Hanson L., Hedner T. Hypertension Manual. 3rd ed., 2000.

9. Weidmann P., M. De Courten, P. Ferrari, Lorenz Bohlen. J. Cardiovasc. Pharmacol. 1993; 22(Suppl. 6): 98–105.

10. White WB, Dey HM, Schulman P. Am. Heart J 1989; 118:782–795.

Is Indapamide safe for pregnant women?

Due to the fact that no serious studies have been conducted on the effect of the drug on pregnant women, tablets and capsules are prohibited during pregnancy. There is a risk of fetoplacental insufficiency, leading to slower fetal development.

The substance can pass into breast milk, therefore, when treating with the drug during lactation, breastfeeding should be stopped.

Indapamide is not suitable for the treatment of physiological edema in pregnancy.

Contraindications and side effects

According to the instructions for use of Indapamide, the drug is contraindicated in:

• hypersensitivity to the main substance;
• acute cerebrovascular accident;
• severe diabetes mellitus;
• advanced form of gout;
• serious renal dysfunction;
• severe liver diseases.

Since the substance removes fluid from the body, it can cause dehydration and a decrease in the concentration of potassium and sodium in the body. In rare cases, arrhythmia and hemolytic anemia may occur.

Main side effects:

• allergies (in the form of skin itching, rash, photosensitivity);
• arrhythmia or tachycardia;
• dry mouth and nausea;
• headache and sleep disturbances;
• epigastric pain;
• constipation or diarrhea.

Taking the drug may provoke changes in well-being due to a decrease in blood pressure, so it is better to avoid activities that require special care.

Perindopril + Indapamide 2.5 mg + 8 mg 30 pcs ➤ instructions for use

Common to perindopril and indapamide Lithium preparations

The simultaneous use of Perindopril PLUS Indapamide with lithium preparations is usually not recommended (see section “Interaction with other drugs”).

Renal dysfunction

Therapy with the drug Perindopril PLUS Indapamide is contraindicated in patients with severe renal failure (creatinine clearance less than 30 ml/min). In some patients with arterial hypertension without previous obvious renal impairment, laboratory signs of functional renal failure may appear during therapy. In this case, treatment with Perindopril PLUS Indapamide should be discontinued. In the future, you can resume combination therapy using low doses of a combination of perindopril and indapamide, or use only one of the drugs.

Such patients require regular monitoring of the content of potassium and creatine ions in the blood serum - 2 weeks after the start of therapy and then every 2 months. Renal failure occurs more often in patients with severe chronic heart failure or underlying renal impairment, including renal artery stenosis.

The drug Perindopril PLUS Indapamide is not recommended for use in cases of bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney.

Arterial hypotension and water-electrolyte imbalance

In the case of initial hyponatremia, there is a risk of sudden development of arterial hypotension (especially in patients with renal artery stenosis). Therefore, when monitoring patients, attention should be paid to possible symptoms of dehydration and decreased plasma electrolytes, for example, after diarrhea or vomiting. Such patients require regular monitoring of blood plasma electrolyte levels.

In case of severe arterial hypotension, intravenous administration of 0.9% sodium chloride solution may be required.

Transient arterial hypotension is not a contraindication for continued therapy. After restoration of blood volume and blood pressure, therapy can be resumed using low doses of a combination of perindopril and indapamide, or only one of the drugs.

Potassium content

The combined use of perindopril and indapamide does not prevent the development of hypokalemia, especially in patients with diabetes mellitus or renal failure. As with the use of other antihypertensive drugs in combination with a diuretic, regular monitoring of the content of potassium ions in the blood plasma is necessary.

Childhood

The drug Perindopril PLUS Indapamide should not be prescribed to children and adolescents under the age of 18 years due to the lack of data on the effectiveness and safety of the use of perindopril and indapamide both in monotherapy and in combination use in patients of this age group

Indapamide

Hepatic encephalopathy

In the presence of liver dysfunction, taking thiazide and thiazide-like diuretics can lead to the development of hepatic encephalopathy. In such a situation, you should immediately stop taking the diuretic.

Photosensitivity

Cases of photosensitivity reactions have been reported with thiazide and thiazide-like diuretics (see section “Side Effects”). If a photosensitivity reaction develops while taking the drug, treatment should be discontinued. If it is necessary to continue diuretic therapy, it is recommended to protect the skin from exposure to sunlight or artificial ultraviolet rays.

Water and electrolyte balance

Content of sodium ions in blood plasma

The content of sodium ions in the blood plasma must be determined before starting treatment, and then regularly monitored while taking the drug. Hyponatremia at the initial stage may not be accompanied by clinical symptoms, so regular laboratory monitoring is necessary. More frequent monitoring of sodium ion levels is indicated for patients with liver cirrhosis and elderly patients (see sections “Side effects” and “Overdose”). Treatment with any diuretics can cause hyponatremia, sometimes with very serious consequences. Hyponatremia accompanied by hypovolemia can lead to dehydration and orthostatic hypotension. A simultaneous decrease in the content of chloride ions can lead to the development of secondary compensatory metabolic alkalosis: the frequency of its occurrence and severity are insignificant.

Content of potassium ions in blood plasma

Therapy with thiazide and thiazide-like diuretics is associated with a high risk of developing hypokalemia. Hypokalemia (less than 3.4 mmol/L) should be avoided in the following high-risk patients: elderly patients, malnourished patients (both those receiving and not receiving concomitant drug therapy), patients with cirrhosis (with edema and ascites) , coronary heart disease, chronic heart failure. Hypokalemia in these patients increases the toxic effect of cardiac glycosides and increases the risk of developing arrhythmia.

Patients with a prolonged QT interval, either congenital or drug-induced, are also at increased risk.

Hypokalemia, like bradycardia, contributes to the development of severe cardiac arrhythmias, especially arrhythmias, which can be fatal. In all the cases described above, more frequent monitoring of the content of potassium ions in the blood plasma is necessary. The first measurement of potassium ion content should be carried out within the first week from the start of therapy.

If hypokalemia is detected, appropriate correction should be made.

Content of calcium ions in blood plasma

Thiazide and thiazide-like diuretics can reduce the excretion of calcium ions by the kidneys, leading to a slight and temporary increase in the content of calcium ions in the blood plasma. Severe hypercalcemia may be a consequence of previously undiagnosed hyperparathyroidism. Before studying the function of the parathyroid glands, you should stop taking diuretics.

Plasma glucose concentration

It is necessary to monitor blood glucose concentrations in patients with diabetes mellitus, especially in the presence of hypokalemia.

Uric acid

When the concentration of uric acid in the blood plasma increases during therapy, the frequency of gout attacks may increase.

Diuretics and kidney function

Thiazide and thiazide-like diuretics are fully effective only in patients with normal or slightly impaired renal function (plasma creatinine clearance in adult patients below 25 mg/l or 220 µmol/l). In elderly patients, plasma creatinine levels should be assessed taking into account age, weight and gender according to the Cockroft formula:

CC = (140 – age) × weight/0.814 × plasma creatinine concentration,

where: age – in years, weight – in kg, plasma creatinine concentration – in µmol/l.

The formula is suitable for elderly men; for elderly women, the result should be multiplied by a factor of 0.85.

At the beginning of treatment with diuretics, patients due to hypovolemia (due to the excretion of water and sodium ions) may experience a temporary decrease in glomerular filtration rate and an increase in the concentration of urea and creatinine in the blood plasma. This transient functional renal failure is not dangerous for patients with normal renal function, but its severity may increase in patients with renal failure.

Athletes

Indapamide may give a positive reaction during doping control.

Acute myopia and secondary angle-closure glaucoma

Sulfonamides and their derivatives can cause the development of idiosyncratic reactions leading to temporary (transient) myopia and acute angle-closure glaucoma. Without proper treatment, acute angle-closure glaucoma can lead to vision loss. The first step is to stop taking the drug as soon as possible. If intraocular pressure continues to be high, immediate medical or surgical treatment may be required. Risk factors that may lead to the development of acute angle-closure glaucoma include a history of allergies to sulfonamides or penicillin.

Perindopril

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

There is evidence of an increased risk of arterial hypotension, hyperkalemia and renal dysfunction (including acute renal failure) when ACE inhibitors are used simultaneously with ARB II or aliskiren. Therefore, double blockade of the RAAS by combining an ACE inhibitor with ARA II or aliskiren is not recommended (see sections “Interaction with other drugs” and “Pharmacodynamics”). If a double blockade is absolutely necessary, it should be performed under the strict supervision of a specialist with regular monitoring of renal function, plasma electrolytes and blood pressure.

The use of ACE inhibitors in combination with ARA II receptor antagonists is contraindicated in patients with diabetic nephropathy and is not recommended in other patients (see section "Contraindications").

Potassium-sparing diuretics, potassium supplements, potassium-containing table salt substitutes and food supplements

The simultaneous use of perindopril and potassium-sparing diuretics, as well as potassium preparations, potassium-containing table salt substitutes and food additives is not recommended (see section “Interaction with other drugs”).

Neutropenia/agranulocytosis/thrombocytopenia

There are reports of the development of neutropenia/agranulocytosis, thrombocytopenia and anemia while taking ACE inhibitors. In patients with normal renal function and without concomitant risk factors, neutropenia rarely occurs. Perindopril should be used with extreme caution against the background of systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma), as well as while taking immunosuppressants, allopurinol, procainamide, or a combination of these factors, especially in patients with initially impaired renal function.

Some patients developed severe infectious diseases, in some cases resistant to intensive antibiotic therapy. When prescribing perindopril to such patients, it is recommended to periodically monitor the number of leukocytes in the blood. Patients should tell their doctor about any signs of infectious diseases (for example, sore throat, fever) (see sections "Interaction with other drugs" and "Side effects").

Anemia

Anemia may develop in patients after kidney transplantation or in patients undergoing hemodialysis. In this case, the decrease in hemoglobin is greater, the higher its initial value. This effect does not appear to be dose-dependent, but may be related to the mechanism of action of ACE inhibitors.

A slight decrease in hemoglobin occurs during the first 6 months, then it remains stable and is completely restored after discontinuation of the drug. In such patients, treatment can be continued, but hematological tests should be carried out regularly.

Hypersensitivity/angioedema

When taking ACE inhibitors, including perindopril, in rare cases, the development of angioedema of the face, extremities, lips, tongue, vocal folds and/or larynx may occur (see section “Side effects”). This can happen at any time during therapy. If symptoms occur, Perindopril PLUS Indapamide should be discontinued immediately and the patient should be observed until signs of swelling have completely resolved. If the swelling affects only the face and lips, it usually goes away on its own, although antihistamines can be used as symptomatic therapy.

Angioedema, accompanied by swelling of the larynx, can be fatal. Swelling of the tongue, vocal folds, or larynx can lead to airway obstruction. If such symptoms appear, appropriate therapy should be started immediately, for example, epinephrine (adrenaline) administered subcutaneously at a dilution of 1:1000 (0.3 or 0.5 ml) and/or ensure airway patency.

A higher risk of developing angioedema has been reported in black patients.

Patients with a history of angioedema not associated with taking ACE inhibitors may have an increased risk of developing it when taking drugs of this group (see section “Contraindications”).

In rare cases, angioedema of the intestine develops during therapy with ACE inhibitors. In this case, patients experience abdominal pain as an isolated symptom or in combination with nausea and vomiting, in some cases without previous angioedema of the face and with normal activity of the C-1 esterase enzyme. The diagnosis is made using computed tomography of the abdominal cavity, ultrasound, or at the time of surgery. Symptoms disappear after stopping ACE inhibitors. In patients with abdominal pain receiving ACE inhibitors, when carrying out differential diagnosis, it is necessary to take into account the possibility of developing angioedema of the intestine.

mTOR (mammalian Target of Rapamycin) inhibitors (eg, temsirolimus, sirolimus, everolimus)

In patients receiving concomitant therapy with mTOR inhibitors, the risk of developing angioedema (including swelling of the airways or tongue with or without impairment of respiratory function) may be increased (see section "Interaction with other drugs").

Anaphylactoid reactions during desensitization

There are isolated reports of the development of prolonged, life-threatening anaphylactoid reactions in patients receiving ACE inhibitors during desensitizing therapy with hymenoptera venom (bees, wasps). ACE inhibitors should be used with caution in patients with a history of allergies or a tendency to allergic reactions undergoing desensitization procedures. The use of an ACE inhibitor should be avoided in patients receiving immunotherapy with hymenoptera venom. However, an anaphylactoid reaction can be avoided by temporarily discontinuing the ACE inhibitor at least 24 hours before the start of the desensitization procedure.

Anaphylactoid reactions during LDL apheresis

In rare cases, life-threatening anaphylactoid reactions have developed in patients receiving ACE inhibitors during LDL apheresis using dextran sulfate. To prevent an anaphylactoid reaction, ACE inhibitor therapy should be temporarily discontinued before each apheresis procedure.

Hemodialysis

Anaphylactoid reactions have been reported in patients receiving ACE inhibitors during hemodialysis using high-flux membranes (eg, AN69®). Therefore, it is advisable to use a different type of membrane or use an antihypertensive agent of a different pharmacotherapeutic group.

Cough

During therapy with an ACE inhibitor, a dry persistent cough may occur. The cough persists for a long time while taking drugs of this group and disappears after their discontinuation. If a patient develops a dry cough, one should be aware of the possible iatrogenic nature of this symptom. If the doctor believes that ACE inhibitor therapy is necessary for the patient, the drug may be continued.

Risk of arterial hypotension and/or renal failure (in patients with chronic heart failure, fluid and electrolyte imbalance, etc.)

In some pathological conditions, significant activation of the RAAS may be observed, especially with severe hypovolemia and a decrease in the content of electrolytes in the blood plasma (due to a salt-free diet or long-term use of diuretics), in patients with initially low blood pressure, renal artery stenosis, chronic heart failure or cirrhosis of the liver with edema and ascites.

The use of ACE inhibitors causes blockade of the RAAS and therefore may be accompanied by a sharp decrease in blood pressure and/or an increase in plasma creatinine clearance, indicating the development of functional renal failure. These phenomena are more often observed when taking the first dose of the drug and during the first two weeks of therapy. In rare cases, these conditions develop acutely and during other periods of therapy. In such cases, it is recommended to restart therapy at a lower dose and then gradually increase the dose.

Elderly age

Before starting to take perindopril, it is necessary to assess the functional activity of the kidneys and the content of potassium ions in the blood plasma. At the beginning of therapy, the dose of the drug is selected taking into account the degree of reduction in blood pressure, especially in the case of a decrease in blood volume and loss of electrolytes. Such measures help to avoid a sharp decrease in blood pressure.

Atherosclerosis

The risk of arterial hypotension exists in all patients, however, special care should be taken when using the drug in patients with coronary heart disease and cerebrovascular insufficiency. In such patients, treatment should begin with low doses of the drug.

Renovascular hypertension

The treatment method for renovascular hypertension is revascularization. However, the use of ACE inhibitors may have a beneficial effect in patients both awaiting surgery and in cases where surgery is not possible.

Treatment with the drug Perindopril PLUS Indapamide is not indicated in patients with diagnosed or suspected renal artery stenosis, because Therapy should be started in a hospital setting with lower doses of the combination of perindopril and indapamide.

Heart failure/severe heart failure

In patients with chronic heart failure (functional class IV according to the NYHA classification), treatment with the drug Perindopril PLUS Indapamide is not indicated, because Therapy should begin with lower doses of the combination of perindopril and indapamide under close medical supervision.

Patients with arterial hypertension and coronary heart disease should not stop taking beta-blockers: an ACE inhibitor should be added to beta-blocker therapy.

Diabetes

In patients with type 1 diabetes mellitus, a spontaneous increase in potassium levels in the blood is possible. Treatment of such patients with the drug Perindopril PLUS Indapamide is not indicated, because it should start with minimal doses and be under constant medical supervision. Patients receiving oral hypoglycemic agents or insulin require regular monitoring of plasma glucose concentrations during the first month of therapy with ACE inhibitors (see section “Interaction with other drugs”).

Ethnic differences

Perindopril, like other ACE inhibitors, have a clearly less pronounced antihypertensive effect in patients of the Negroid race compared to representatives of other races. This difference may be due to the fact that black patients with arterial hypertension are more likely to have low renin activity.

Surgery/general anesthesia

Carrying out general anesthesia while taking ACE inhibitors can lead to a significant decrease in blood pressure, especially when using general anesthesia agents that have an antihypertensive effect. It is recommended, if possible, to stop taking long-acting ACE inhibitors, including perindopril, the day before surgery. It is necessary to warn the anesthesiologist that the patient is taking an ACE inhibitor.

Aortic or mitral stenosis/hypertrophic obstructive cardiomyopathy

ACE inhibitors should be prescribed with caution to patients with left ventricular outflow tract obstruction.

Liver failure

In rare cases, cholestatic jaundice occurs while taking ACE inhibitors. As this syndrome progresses, fulminant liver necrosis develops, sometimes with death. The mechanism of development of this syndrome is unclear. If jaundice appears or if there is a significant increase in the activity of liver enzymes while taking ACE inhibitors, the patient should stop taking the ACE inhibitor and consult a doctor (see section “Side Effects”).

Hyperkalemia

Hyperkalemia may develop during treatment with ACE inhibitors, including perindopril. Risk factors for hyperkalemia are renal failure, impaired renal function, advanced age over 70 years, diabetes mellitus, some concomitant conditions (dehydration, acute cardiac decompensation, metabolic acidosis), concomitant use of potassium-sparing diuretics (such as spironolactone and its derivative eplerenone, triamterene, amiloride), as well as potassium preparations or potassium-containing substitutes for table salt, as well as the use of other drugs that help increase the content of potassium ions in the blood plasma (for example, heparins, AFP inhibitors, angiotensin II receptor antagonists, acetylsalicylic acid at a dose of 3 g/day or more , COX-2 inhibitors and non-selective NSAIDs, immunosuppressants such as cyclosporine or tacrolimus, and trimethoprim). The use of potassium supplements, potassium-sparing diuretics, and potassium-containing table salt substitutes can lead to a significant increase in potassium levels in the blood, especially in patients with reduced renal function. Hyperkalemia can lead to serious, sometimes fatal, heart rhythm disturbances. If combined use of the above drugs is necessary, treatment should be carried out with caution, against the background of regular monitoring of the content of potassium ions in the blood serum (see section “Interaction with other drugs”).

Impact on the ability to drive vehicles and machinery

Care must be taken when driving vehicles and other technical devices that require increased attention and speed of psychomotor reactions (risk of dizziness and fainting).