Perindopres® DUO

APPROVED

By the Order of the Ministry of Health of Ukraine

16.11.2021 No. 2537

Marketing Authorization

No. UA/19069/01/01

No. UA/19069/01/02

PACKAGE LEAFLET
​for medical use of a medicinal product

PRENDAMIN DUO

Qualitative and quantitative composition:

active substances: perindopril, indapamide;

Prendamin Duo, tablets 4 mg/1.25 mg

1 tablet contains perindopril tert-butylamine 4 mg (corresponding to 3.338 mg of perindopril) and indapamide 1.25 mg.

Prendamin Duo, tablets 8 mg/2.5 mg

1 tablet contains perindopril tert-butylamine 8 mg (corresponding to 6.676 mg of perindopril) and indapamide 2.5 mg.

excipients: lactose monohydrate, microcrystalline cellulose, crospovidone, colloidal hydrophobic silicon dioxide, magnesium stearate.

Pharmaceutical form. Tablets.

Basic physical and chemical properties: tablets of white or almost white color, flat cylindrical shape, with a bevel.

Pharmacotherapeutic group. Angiotensin-converting enzyme (ACE) inhibitors, combinations. Perindopril and diuretics. ATC code C09B A04.

Pharmacological properties.

Pharmacodynamic properties.

Prendamin Duo is a combination of the ACE inhibitor perindopril tert-butylamine and the sulfonamide diuretic indapamide. Its pharmacological action is determined by the properties of each component (perindopril and indapamide) and their additive synergism.

Mechanism of action:

Perindopril is an ACE inhibitor that converts angiotensin I into angiotensin II (a vasoconstrictor substance), additionally stimulates the secretion of aldosterone by the adrenal cortex and the breakdown of bradykinin (a vasodilating substance) into inactive heptapeptides. As a result of ACE inhibition, there is a decrease in aldosterone secretion, an increase in plasma renin activity without the negative effect of aldosterone, a decrease in the total peripheral vascular resistance due to the predominant effect on the vessels of the muscles and kidneys. At the same time, there is no retention of water and salts or reflex tachycardia, even in the case of long-term treatment. In addition, perindopril lowers arterial blood pressure (ABP) in patients with normal and low plasma renin levels. Perindopril works through its active metabolite perindoprilat. Other metabolites are inactive. Perindopril facilitates the work of the heart due to the vasodilatory effect on the veins (perhaps due to changes in prostaglandin metabolism) ‒ a decrease in preload and a decrease in total peripheral vascular resistance ‒ a decrease in afterload on the heart.

Studies conducted with patients with heart failure have proven 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, and an increase in regional blood flow in the muscles. The indicators of tests with physical load are improving.

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

Pharmacodynamic effects

The medicinal product Prendamin Duo has a dose-dependent antihypertensive effect on systolic blood pressure (SBP) and diastolic blood pressure (DBP) in patients of any age with arterial hypertension both in the supine and standing positions.

Perindopril. Perindopril effectively reduces ABP in all degrees of arterial hypertension: light, moderate and severe. A decrease in SBP and DBP is observed in both lying and standing positions. The maximum antihypertensive effect develops 4–6 hours after a single dose and lasts more than a day. Perindopril has a high rate of terminal ACE inhibitor blocking (approximately 80%) 24 hours after administration. In patients in whom the use of the medicinal product proved to be effective, ABP normalization is achieved after a month and persists without the occurrence of tachyphylaxis. Termination of therapy is not accompanied by a withdrawal syndrome. Perindopril has vasodilator properties, restores the elasticity of large arteries, corrects histomorphometric changes in arterial resistance, and reduces left ventricular hypertrophy. The addition of a thiazide diuretic, if necessary, results in additional synergism. The combined use of an ACE inhibitor and a thiazide diuretic reduces the risk of hypokalemia which can occur when using a diuretic as monotherapy.

Indapamide. When used as monotherapy, indapamide has an antihypertensive effect that lasts 24 hours. This effect is manifested in doses in which diuretic properties are minimal. The antihypertensive effect of indapamide is proportional to the improvement of arterial elasticity and decrease in arteriolar resistance and total peripheral vascular resistance. Indapamide reduces left ventricular hypertrophy. When the dose is exceeded, the antihypertensive effect of thiazide and thiazide-like diuretics reaches a plateau level, while the number of undesirable effects increases. If the treatment is not effective enough, you should not increase the dose of the medicinal product. In the course of studies of different duration (short, medium and long) involving patients with arterial hypertension, indapamide does not affect lipid metabolism (triglycerides, low and high density lipoproteins) and does not affect carbohydrate metabolism, even in patients with arterial hypertension and diabetes.

Pharmacokinetic properties.

The pharmacokinetic properties of perindopril and indapamide when used in combination do not differ from the properties of these components when used separately.

Pharmacokinetic properties of perindopril

Absorption and bioavailability. After oral administration, perindopril is rapidly absorbed, its maximum concentration is reached after 1 hour. The plasma elimination half-life of perindopril is 1 hour. Since food intake reduces the conversion of perindopril to perindoprilat and, consequently, reducing its bioavailability, perindopril tert-butylamine should be taken orally in a single daily dose in the morning before meals.

Distribution. The volume of distribution of unbound perindoprilat is approximately 0.2 L/kg. The binding of perindoprilat to blood plasma proteins is 20%, mainly with ACE, and is dose-dependent.

Biotransformation Perindopril is a prodrug. Thus, 27% of the accepted dose of perindopril enters the bloodstream in the form of an active metabolite of perindoprilat. In addition to the active perindoprilat, perindopril forms 5 more inactive metabolites. The maximum concentration of perindoprilat in blood plasma is reached after 3‒4 hours.

Excretion. Perindoprilat is excreted in the urine, the final elimination half-life of the unbound fraction is approximately 17 hours. The equilibrium state is reached within 4 days.

Linearity/non-linearity. A linear relationship has been demonstrated between the dose of perindopril and its plasma concentration.

Special categories of patients

Elderly patients The excretion of perindoprilat is reduced in elderly patients and in people with heart or kidney failure.

Impaired renal function. For patients with renal insufficiency, the dose should be adjusted depending on the degree of impaired renal function (creatinine clearance).

The necessity of dialysis. The dialysis clearance of perindoprilat is 70 ml/min.

Liver cirrhosis. The kinetics of perindopril changes in patients with liver cirrhosis: the hepatic clearance of the main molecule is reduced by half, but the amount of perindoprilat formed does not decrease (see the sections "Special warnings and precautions for use" and "Posology and method of administration").

Pharmacokinetic properties of indapamide

Absorption. Indapamide is rapidly and completely absorbed in the digestive tract. The maximum plasma concentration is reached approximately 1 hour after oral administration of the medicinal product.

Distribution. Plasma protein binding is 79%.

Biotransformation and excretion. The elimination half-life is 14–24 hours (average – 18 hours). Repeated reception does not lead to cumulation. Excretion mainly occurs with urine (70% of the dose) and faeces (22%) in the form of inactive metabolites.

Special categories of patients

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

Clinical particulars.
Therapeutic indications.
Essential hypertension.

Contraindications.
​Related to perindopril:

• hypersensitivity to perindopril or to any other ACE inhibitor;
• angioedema (Quincke's edema) in history associated with prior treatment with ACE inhibitors (see section "Special warnings and precautions for use");
• congenital or idiopathic angioedema;
• pregnancy or pregnancy planning (see the section "Fertility, pregnancy and lactation");
• simultaneous use with medicinal products containing aliskiren in patients with impaired renal function (glomerular filtration rate < 60 ml/min/1.73 m2) or with diabetes mellitus (see the section "Interaction with other medicinal products and other forms of interaction");
• simultaneous use with sacubitril/valsartan (see sections "Interaction with other medicinal products and other forms of interaction" and "Special warnings and precautions for use");
• extracorporeal therapies leading to contact of blood with negatively charged surfaces (see the section "Interaction with other medicinal products and other forms of interaction");
• significant bilateral stenosis of the renal arteries or stenosis of the artery of the only functioning kidney (see the section "Special warnings and precautions for use").

Related to indapamide:

• hypersensitivity to indapamide or to any other sulfonamides;
• severe renal impairment (creatinine clearance <30 ml/min) for a dosage of 4 mg/1.25 mg;
• severe renal impairment (creatinine clearance <60 ml/min) for a dosage of 8 mg/2.5 mg;
• hepatic encephalopathy;
• severe liver dysfunction;
• hypokalemia;
• as a general rule, this medicinal product should not be prescribed in combination with non-antiarrhythmic medicinal products that can cause the development of paroxysmal ventricular tachycardia of the "pirouette" type;
• the period of breastfeeding (see the section "Fertility, pregnancy and lactation").

Related to the medicinal product Prendamin Duo:

• hypersensitivity to any excipient of the medicinal product.

Due to the lack of sufficient clinical experience, Prendamin Duo should not be used:

• patients on hemodialysis;
• patients with untreated decompensated heart failure.

Interaction with other medicinal products and other forms of interaction

Interactions common to perindopril and indapamide

Simultaneous use is not recommended

Lithium. With the simultaneous use of lithium and ACE inhibitors, a reverse increase in the concentration of lithium in the blood serum and an increase in its toxicity have been reported. The simultaneous use of perindopril together with indapamide and lithium is not recommended, but if it is really necessary, the concentration of lithium in the blood serum should be carefully monitored (see the section "Special warnings and precautions for use").

Simultaneous use requiring special attention

Baclofen. The antihypertensive effect increases. It is necessary to monitor arterial blood pressure and, if necessary, adjust the dose of the antihypertensive medicinal product.

Non-steroidal anti-inflammatory medicinal products (NSAIDs) including acetylsalicylic acid ≥ 3 g/day. With the simultaneous use of ACE inhibitors and NSAIDs, for example, acetylsalicylic acid in anti-inflammatory doses, COX-2 inhibitors and non-selective NSAIDs, the antihypertensive effect may be weakened. The simultaneous use of ACE inhibitors and NSAIDs can lead to an increased risk of impaired renal function, including the development of acute renal failure, and an increase in the level of potassium in the blood serum, especially in patients with renal impairment. Such a combination should be prescribed with caution, especially to elderly patients. Patients should be rehydrated before starting treatment and monitor renal function at the beginning and during combined therapy.

Simultaneous use requiring attention

Imipramine Similar (tricyclic) antidepressants, antipsychotics. Enhance the antihypertensive effect and increase the risk of developing orthostatic hypotension (additive effect).

Interaction related to perindopril

Data from clinical studies indicate that dual blockade of the renin-angiotensin-aldosterone system (RAAS) due to the simultaneous use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with an increase in the frequency of such adverse reactions as hypotension, hyperkalemia, and impaired renal function (in particular acute renal failure), compared to the use of a single medicinal product that affects the RAAS (see sections "Pharmacodynamic properties", "Contraindications" and "Special warnings and precautions for use").

Medicinal products that cause hyperkalemia. Some medicinal products or therapeutic classes of medicinal products, such as aliskiren, potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, NSAIDs, heparins, immunosuppressants (such as cyclosporine or tacrolimus, trimethoprim), can cause hyperkalemia. The combination of these medicinal products increases the risk of hyperkalemia.

Simultaneous use is contraindicated (see section "Contraindications")

Aliskiren. Patients with diabetes or renal impairment have an increased risk of hyperkalemia, renal impairment, and cardiovascular morbidity and mortality.

Extracorporeal treatments. Extracorporeal therapies that result in blood coming into contact with negatively charged surfaces, such as dialysis or hemofiltration using certain membranes with high hydraulic permeability (e. g., polyacrylonitrile) and low-density lipoproteins (LDL) apheresis using dextran sulfate, due to the increased 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 agents.

Sacubitril/Valsartan. Simultaneous use of perindopril with sacubitril/valsartan is contraindicated because simultaneous inhibition of neprilysin and ACE may increase the risk of angioedema. Sacubitril/valsartan should not be started until 36 hours after the last dose of perindopril. Perindopril therapy should be initiated no earlier than 36 hours after the last dose of sacubitril/valsartan (see sections “Contraindications” and “Special warnings and precautions for use”).

Simultaneous use is not recommended

Aliskiren. In all other groups of patients, as well as in patients with diabetes mellitus or with impaired renal function, the risk of hyperkalemia, impaired renal function, and cardiovascular morbidity and mortality increases (see section "Special warnings and precautions for use").

Concomitant therapy with an ACE inhibitor and an angiotensin receptor blocker. Publications reported that in patients with established atherosclerosis, heart failure, or in patients with diabetes with target organ damage, concomitant therapy with an ACE inhibitor and an angiotensin receptor blocker was accompanied by an increase in the frequency of arterial hypotension, fainting, hyperkalemia, and renal dysfunction (in particular, acute renal insufficiency) compared to the use of a single medicinal product that affects the RAAS. The use of double blockade (that is, a combination of an ACE inhibitor and an angiotensin II receptor antagonist) is possible only in certain cases, with careful monitoring of kidney function of kidney function, blood potassium level and blood pressure (see section "Special warnings and precautions for use").

Estramustine. There is a risk of increased frequency of adverse reactions such as angioneurotic edema (angioedema).

Potassium-sparing diuretics (for example, triamterene, amiloride), potassium (salts). There is a risk of hyperkalemia (potentially fatal), especially in patients with renal impairment (additive hyperkalemia effect). The combination of perindopril with the above medicinal products is not recommended (see the section "Special warnings and precautions for use"). If the simultaneous use of these medicinal products is still indicated, they should be used with caution, often monitoring the level of potassium in the blood serum. Information on the use of spironolactone in patients with heart failure is given in the section "Simultaneous use requiring special attention”.

Co-trimoxazole (trimethoprim/sulfamethoxazole). In patients who simultaneously use co-trimoxazole, an increased risk of developing hyperkalemia is possible (see section "Special warnings and precautions for use").

Simultaneous use requiring special attention

Antidiabetic medicinal products (insulin, hypoglycemic medicinal products for oral administration). Epidemiological studies suggest that the simultaneous use of ACE inhibitors and antidiabetic medicinal products (insulins, hypoglycemic medicinal products for oral administration) may increase the hypoglycemic effect with the risk of hypoglycemia. It is more likely that this phenomenon can occur during the first weeks of combined treatment and in patients with impaired renal function.

Diuretics. In patients taking diuretics, especially in the presence of water and sodium deficiency, after the start of therapy with an ACE inhibitor, blood pressure may decrease excessively. The likelihood of developing hypotensive effects can be reduced by discontinuing the diuretic, increasing circulating blood volume, or salt intake before starting perindopril therapy, which should be started at a low dose and gradually increased. In patients with arterial hypertension, where previous diuretic therapy may have caused water/sodium depletion, the diuretic should be discontinued before starting the ACE inhibitor (in which case the diuretic may be restarted over time) or the ACE inhibitor should be started at a low dose and gradually increased. In patients with congestive heart failure who are using a diuretic, treatment with an ACE inhibitor should be started at the lowest dose, possibly after the diuretic dose has been reduced. In all cases, it is necessary to monitor kidney function (creatinine level) during the first few weeks of ACE inhibitor therapy.

Potassium-sparing diuretics (eplerenone, spironolactone). With the simultaneous use of eplerenone or spironolactone in doses from 12.5 mg to 50 mg per day with low doses of ACE inhibitors in patients with heart failure of II-IV functional classes according to the New York Heart Association (NYHA) scale and ejection fraction < 40%, who previously took ACE inhibitors and loop diuretics, there is a risk of hyperkalemia, potentially fatal, especially if the recommendations for prescribing such a combination are not followed. Before starting the use of such a combination, it is necessary to make sure that there is no hyperkalemia and renal function impairment Close monitoring of potassium and creatinine levels is recommended weekly during the first month of treatment and monthly thereafter.

Racecadotril. It is known that ACE inhibitors (for example, perindopril) can cause the development of angioedema. This risk may increase when used simultaneously with racecadotril (a medicinal product used to treat acute diarrhea).

mTOR inhibitors (e. g, sirolimus, everolimus, temsirolimus). In patients who simultaneously use mTOR inhibitors, an increased risk of developing angioedema is possible (see section "Special warnings and precautions for use").

Simultaneous use requiring attention

Antihypertensive medicinal products and vasodilators. The simultaneous use of these medicinal products can increase the hypotensive effects of perindopril. Simultaneous use with nitroglycerin and other nitrates or with other vasodilators may further reduce blood pressure.

Allopurinol, cytostatics, immunosuppressants, systemic corticosteroids or procainamide. Simultaneous use with ACE inhibitors can lead to an increased risk of leukopenia (see section "Special warnings and precautions for use").

Anesthetic agents. ACE inhibitors can increase the hypotensive effect of some anesthetic medicinal products (see section "Special warnings and precautions for use").

Gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin). With simultaneous use with an ACE inhibitor, the risk of angioedema increases due to inhibition of dipeptidyl peptidase-IV (DPP-IV) activity by gliptin.

Sympathomimetics. Sympathomimetics can weaken the antihypertensive effect of ACE inhibitors.

Medicinal products of gold. When treating patients with injectable medicinal products of gold (sodium aurothiomalate) and the simultaneous use of an ACE inhibitor, including perindopril, nitritoid reactions have been reported in rare cases (symptoms: facial flushing, nausea, vomiting and arterial hypotension).

Interaction related to indapamide

Simultaneous use requiring special attention

Medicinal products that can cause the development of paroxysmal ventricular tachycardia of the "pirouette" type. Due to the risk of hypokalemia, indapamide should be prescribed with caution in combination with medicinal products that can cause the development of paroxysmal ventricular tachycardia of the "pirouette" type, such as class IA antiarrhythmic medicinal products (quinidine, hydroquinidine, disopyramide); class III antiarrhythmic medicinal products (amiodarone, dofetilide, ibutilide, bretylium, sotalol); some antipsychotics (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine), benzamides (amisulpride, sulpiride, sultopride, tiapride), butyrophenones (droperidol, haloperidol), other antipsychotics (pimozide), other medicinal products such as bepridil, cisapride, diphemanil, erythromycin for intravenous use, halofantrine, mizolastine, moxifloxacin, pentamidine, sparfloxacin, vincamine for intravenous use, methadone, astemizole, terfenadine. A decrease in plasma potassium should be prevented and corrected if necessary, and the QT interval should be monitored.

Medicinal products that reduce the content of potassium in the blood. Amphotericin B for intravenous use, glucocorticoids and mineralocorticoids (systemic action), tetracosactide, laxatives that stimulate peristalsis, increase the risk of a decrease in the level of potassium in the blood serum (additive effect). It is necessary to monitor the content of potassium in the blood plasma and adjust it if necessary, in particular, during simultaneous treatment with digitalis medicinal products. It is necessary to use laxatives that do not stimulate peristalsis.

Digitalis medicinal products. Hypokalemia and/or hypomagnesemia increases the toxic effects of digitalis medicinal products. It is necessary to monitor the level of potassium, magnesium in the blood plasma and ECG, and if necessary, review the therapy.

Allopurinol. Simultaneous use with indapamide can lead to an increase in the frequency of hypersensitivity reactions to allopurinol.

Simultaneous use requiring attention

Potassium-sparing diuretics (amiloride, spironolactone, triamterene). Despite the rationality of prescribing this combination in some patients, hypokalemia or hyperkalemia may occur (especially in patients with renal insufficiency or diabetes mellitus). The level of potassium in the blood plasma should be controlled, ECG monitoring should be carried out and, if necessary, therapy should be reviewed.

Metformin. May cause lactic acidosis due to the development of functional renal failure associated with the use of diuretics, especially loop ones. Metformin should not be used if the plasma creatinine level is greater than 15 mg/l (135 μmol/l) in men and 12 mg/l (110 μmol/l) in women.

Iodinated contrast agents in the case of dehydration caused by the use of diuretics, the risk of developing acute renal failure increases, especially when using large doses of iodinated contrast agents. Before using iodocontrast medicinal products, it is necessary to restore the water balance.

Calcium (salts). There is a risk of an increase in the content of calcium in the blood due to a decrease in its excretion in the urine.

Cyclosporine, tacrolimus. There is a risk of an increase in blood creatinine without a change in the concentration of circulating cyclosporine, even in the absence of water and sodium deficits.

Corticosteroids, tetracosactide (systemic action). Reduce the antihypertensive effect (retention of water and sodium ions under the influence of corticosteroids).

Special warnings and precautions for use.

Special precautions

Special precautions common to perindopril and indapamide

Lithium. The simultaneous use of lithium and the combination of perindopril/indapamide is usually not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Special precautions related to perindopril

Double blockade of RAAS. There are data that the simultaneous use of ACE inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of arterial hypotension, hyperkalemia and decreased kidney function (in particular, acute renal failure). Therefore, the use of double RAAS blockade due to the simultaneous use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is not recommended (see section "Interaction with other medicinal products and other forms of interaction"). If therapy with double RAAS blockade is considered absolutely necessary, then it should be carried out only under the supervision of a specialist and under the condition of frequent and careful monitoring of kidney function, electrolyte levels and blood pressure. Patients with diabetic nephropathy should not use ACE inhibitors and angiotensin II receptor blockers at the same time.

Potassium-sparing agents, supplements or salt substitutes containing potassium. The combination of perindopril and potassium-sparing agents, supplements or salt substitutes containing potassium is usually not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Neutropenia/agranulocytosis/thrombocytopenia/anemia. Neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported in patients receiving ACE inhibitors. Neutropenia rarely occurs in patients with normal renal function in the absence of other risk factors. Perindopril should be used very carefully in patients with collagenosis, during therapy with immunosuppressants, allopurinol, or procainamide, or when these risk factors are combined, especially in the presence of renal function impairment. The development of serious infectious diseases, sometimes resistant to intensive antibiotic therapy, was noted in some of these patients. When using perindopril, such patients are recommended to periodically monitor the number of leukocytes in the blood. In addition, patients should be informed about the need to inform their doctor of any manifestation of an infectious disease (e. g., sore throat, fever) (see sections "Interaction with other medicinal products and other forms of interaction" and "Undesirable effects").

Renovascular hypertension. In patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney during treatment with ACE inhibitors, the risk of arterial hypotension and renal failure increases (see section "Contraindication"). The use of diuretics may be a contributing factor. Decreased renal function may be accompanied by only minor changes in serum creatinine even in patients with unilateral renal artery stenosis.

Hypersensitivity/angioneurotic edema (angioedema). In patients treated with ACE inhibitors, in particular perindopril, there have been rare cases of angioedema of the face, extremities, lips, tongue, glottis and / or larynx (see section “Undesirable effects”). This can happen at any time during the treatment. In such cases, it is necessary to immediately stop taking the medicinal product and establish medical supervision of the patient's condition until the symptoms completely disappear. If the swelling was limited to the face and lips, the patient's condition usually improved without treatment, although the use of antihistamines was helpful in reducing symptoms. Angioedema associated with laryngeal edema can be fatal. If swelling extends to the tongue, glottis, or larynx, which may lead to airway obstruction, immediate emergency treatment is required, which may include subcutaneous administration of solution epinephrine 1:1000 (0.3‒0.5 ml) and/or measures to provide airway patency. The occurrence of angioedema was more often reported in black race patients who used ACE inhibitors, compared to representatives of other races. Patients with a history of angioedema that was not associated with taking ACE inhibitors are at increased risk of developing angioedema while taking ACE inhibitors. There have been reports of rare cases of intestinal angioedema in patients treated with ACE inhibitors. Such patients had abdominal pain (with or without nausea and vomiting); sometimes intestinal angioedema was not accompanied by the manifestation of previous facial angioedema and the level of C1-esterase inhibitor was normal. The diagnosis of angioedema was established by procedures such as abdominal computed tomography or ultrasound or during surgery; after withdrawal of the ACE inhibitor, the symptoms of angioedema disappeared. If abdominal pain occurs in patients taking ACE inhibitors, a differential diagnosis should be made to rule out intestinal angioedema. The simultaneous use of perindopril with sacubitril/valsartan is contraindicated due to the increased risk of angioedema (see section "Contraindication"). Sacubitril/valsartan should not be started until 36 hours after the last dose of perindopril. In case of discontinuation of treatment with sacubitril / valsartan, perindopril therapy should be started no earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindication" and "Interaction with other medicinal products and other forms of interaction"). The simultaneous use of other neutral endopeptidase (NEP) inhibitors (e. g., racecadotril) and ACE inhibitors may also lead to an increased risk of angioedema (see section "Interaction with other medicinal products and other forms of interaction"). Therefore, before starting treatment with NEP inhibitors (e. g., racecadotril) for patients using perindopril, a careful assessment of the benefit / risk ratio should be carried out. Simultaneous use of mTOR inhibitors (example, sirolimus, everolimus, temsirolimus). Patients concomitantly using mTOR inhibitors may have an increased risk of developing angioedema, in particular swelling of the airways or tongue, with or without respiratory dysfunction (see section "Interaction with other medicinal products and other forms of interactions").

Anaphylactoid reactions during desensitization. Isolated cases of life-threatening, prolonged anaphylactoid reactions have been reported in patients receiving ACE inhibitors during desensitizing therapy with bee venom-containing medicinal products. ACE inhibitors should be used with caution in allergic patients after desensitization and should be avoided during immunotherapy with medicinal products containing bee venom. However, in patients requiring both ACE inhibitors and desensitization, such reactions can be avoided by temporarily discontinuing the ACE inhibitor at least 24 hours before starting desensitization therapy.

Anaphylactoid reactions during LDL plasmapheresis. Rarely, life-threatening anaphylactoid reactions have occurred in patients treated with ACE inhibitors during LDL plasmapheresis using dextran sulfate. The development of the latter can be avoided by temporarily stopping treatment with an ACE inhibitor before each plasmapheresis.

Patients undergoing hemodialysis. Anaphylactoid reactions have been reported in patients receiving ACE inhibitors during hemodialysis using high-flux polyacrylic membranes (e. g., AN 69®). Such patients should have treated with a different type of dialysis membrane or prescribe a different class of antihypertensive agents.

Primary aldosteronism. Patients with primary hyperaldosteronism usually do not respond to treatment with antihypertensive medicinal products that act by inhibiting the renin-angiotensin system. Therefore, it is not recommended to use this medicinal product in such patients.

Patients after kidney transplantation. There is no experience with prescribing perindopril tert-butylamine in patients who have recently undergone kidney transplantation.

Hypotension. Symptomatic hypotension has been reported in patients with symptomatic heart failure and concomitant renal failure or without it. The occurrence of symptomatic arterial hypotension is more likely in patients with more severe heart failure, taking high doses of loop diuretics, hyponatremia, or renal failure of a functional nature. To reduce the risk of symptomatic arterial hypotension at the beginning of therapy and at the stage of dose selection, patients should be under close supervision of a doctor. The same precautions apply to people with coronary heart disease or cerebrovascular disease, in whom excessive decrease in blood pressure can cause myocardial infarction or stroke.

Ischemic heart disease. If during the first month of treatment with perindopril there was an episode of unstable angina (of any severity), it is necessary to carefully weigh the risk/benefit ratio before deciding whether to continue therapy.

Special precautions related to indapamide

Hepatic encephalopathy. In patients with impaired liver function, the use of thiazide and thiazide-like diuretics can cause hepatic encephalopathy. Hepatic encephalopathy is a contraindication to the use of the medicinal product.

Photosensitization. Photosensitivity reactions have been reported when using thiazide and thiazide-like diuretics (see section “Undesirable effects”). If a photosensitivity reaction occurs during treatment, it is recommended to stop taking the medicinal product. If there is a need to resume its use, it is recommended to protect vulnerable areas from the sun or artificial ultraviolet sources.

Preventive measures.

Precautionary measures common to perindopril and indapamide

Impaired renal function. In the presence of severe renal insufficiency (creatinine clearance <30 ml/min), the use of the medicinal product Prendamin Duo dosed 4 mg/1.25 mg is contraindicated. In the presence of severe and moderate renal insufficiency (creatinine clearance <60 ml/min), the use of the medicinal product Prendamin Duo dosed 8 mg/2.5 mg is contraindicated. If in some patients with arterial hypertension without signs of impaired renal function, the results of laboratory blood tests show signs of functional renal failure, treatment with the medicinal product should be discontinued with the possibility of its restoration at a lower dose or only one of its components.

Such patients need frequent monitoring of the level of potassium and creatinine in the blood: 2 weeks after initiation of treatment and every two months thereafter during the period of therapeutic stabilization. Cases of renal failure were observed mainly in patients with severe heart failure or renal dysfunction, in particular with renal artery stenosis. This medicinal product should not be used in patients with significant bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney.

Arterial hypotension and water and electrolyte deficiency. Patients with sodium deficiency (especially in the presence of renal artery stenosis) are at risk of a sudden decrease in blood pressure. Therefore, systematic monitoring for clinical signs of water and electrolyte deficiency, which may occur with intercurrent cases of vomiting or diarrhea, is necessary. Such patients should regularly monitor the level of electrolytes in the blood plasma. If significant arterial hypotension occurs, intravenous infusion of isotonic sodium chloride solution may be required. Temporary hypotension is not a contraindication for continued treatment. After restoring the volume of circulating blood and normalizing blood pressure, the treatment can be resumed in a reduced dose or only one of the components of the medicinal product.

Potassium level. The combination of perindopril and indapamide does not exclude the possibility of hypokalemia, especially in patients with diabetes mellitus or renal failure. As with the use of any antihypertensive agent in combination with a diuretic, regular monitoring of the level of potassium in the blood plasma should be carried out.

Precautionary measures associated with perindopril

Cough. Dry cough has been reported during therapy with ACE inhibitors. This cough is persistent and stops after withdrawal of the medicinal product. If this symptom appears, it is necessary to take into account the possibility of its iatrogenic etiology. If the appointment of an ACE inhibitor for the treatment of the patient is necessary, a decision may be made to continue the therapy.

Risk of arterial hypotension and/or renal failure (in case of heart failure, water and electrolyte deficiency). Significant stimulation of the RAAS has been observed during acute water and electrolyte deficiency (strict salt-free diet or long-term treatment with diuretics) in patients with low blood pressure, in the presence of renal artery stenosis, congestive heart failure, or liver cirrhosis with edema and ascites. Blockade of this system by an ACE inhibitor, especially at initial use and during the first 2 weeks of treatment, may cause a sudden decrease in blood pressure and/or an increase in plasma creatinine, which confirms the presence of functional renal failure. Sometimes, although rarely, it can occur at any time and have an acute onset. In such cases, treatment should be started with a lower dose and gradually increased.

Elderly patients. Before starting treatment, it is necessary to check the function of the kidneys and the level of potassium in the blood. To reduce the risk of sudden arterial hypotension, especially in the presence of water or electrolyte deficiency, the initial dose of the medicinal product should be adjusted depending on the blood pressure response to treatment.

Atherosclerosis. The risk of arterial hypotension is present in all groups of patients, but in patients with coronary heart disease or cerebral circulatory insufficiency, the medicinal product should be used with extreme caution, starting treatment with a low dose.

Renovascular hypertension. The treatment for renovascular hypertension is revascularization. However, ACE inhibitors may be useful in patients with renovascular hypertension who are awaiting surgery or if such surgery is not possible.

If the medicinal product Prendamin Duo dosed 4 mg/1.25 mg is prescribed to patients with existing or suspected renal artery stenosis, treatment should be initiated in a hospital setting at a low dose with monitoring of renal function and blood potassium levels, as some functional renal failure was observed in patients, which was reversible upon discontinuation of treatment.

The medicinal product Prendamin Duo dosed 8 mg/2.5 mg should not be prescribed to patients with known or suspected renal artery stenosis. In this case, treatment should be started in hospital setting with a lower dose than the recommended dose of the medicinal product.

Heart failure/severe heart failure. Prendamin Duo should not be prescribed to patients with severe heart failure (class IV), as treatment must be started under medical supervision with a reduced initial dose. It is not necessary to stop treatment with β-blockers of patients with arterial hypertension and coronary insufficiency, it is necessary to add an ACE inhibitor to the β-blocker.

Patients with diabetes. Treatment of patients with insulin-dependent diabetes mellitus (spontaneous tendency to increase the level of potassium in the blood) should be started under medical supervision with a reduced initial dose.

The medicinal product Prendamin Duo dosed 8 mg/2.5 mg should not be prescribed to patients with insulin-dependent diabetes mellitus, since treatment must be started under medical supervision with a reduced initial dose.

Patients with diabetes mellitus who have previously taken oral hypoglycemic agents or insulin should have their blood glucose levels closely monitored, especially during the first month of ACE inhibitor therapy.

Race features. Perindopril, like other ACE inhibitors, lowers blood pressure less effectively in in patients of the black race with hypertension than in people of other races, which may be explained by the low level of renin in the blood plasma of such patients.

Surgery/anesthesia. ACE inhibitors can cause arterial hypotension during anesthesia, especially when using an anesthetic with hypotensive potential. Therefore, treatment with a long-acting ACE inhibitor, such as perindopril, should be discontinued 1 day before surgery, if possible.

Aortic or mitral valve stenosis/hypertrophic cardiomyopathy ACE inhibitors should be used with caution in patients with left ventricular outflow obstruction.

Hepatic insufficiency. Rarely, the use of ACE inhibitors has been associated with a syndrome that begins with cholestatic jaundice and progresses to transient hepatic necrosis, sometimes fatal. The mechanism of this syndrome is unclear. Patients who develop jaundice with elevated liver enzymes while taking an ACE inhibitor should have the ACE inhibitor discontinued and receive appropriate medical supervision (see section “Undesirable effects”).

Hyperkalemia In some patients who used ACE inhibitors, including perindopril, an increase in the level of potassium in the blood serum was noted. Risk factors for hyperkalemia include renal insufficiency, impaired renal function, age > 70 years, diabetes, intercurrent conditions, especially dehydration, acute cardiac decompensation, metabolic acidosis, and concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, amiloride ), additives or substitutes for salt containing potassium; or the use of other medicinal products associated with an increase in the level of potassium in the blood serum (for example, heparin, co-trimoxazole, also known as trimethoprim/sulfamethoxazole, other ACE inhibitors, angiotensin II receptor antagonists, acetylsalicylic acid at a dose of ≥ 3 g/day, COX-2 inhibitors and non-selective NSAIDs, immunosuppressants such as cyclosporine or tacrolimus, trimethoprim). The use of supplements or salt substitutes containing potassium, potassium-sparing diuretics, especially in patients with impaired renal function, can lead to significant increases in serum potassium. Hyperkalemia can cause serious, sometimes fatal, arrhythmia. If the simultaneous use of these drugs is considered appropriate, they should be used with caution, with frequent monitoring of serum potassium (see section "Interaction with other medicinal products and other forms of interaction").

Precautionary measures associated with indapamide

Balance of water and electrolytes

Sodium level. Before starting treatment and thereafter at regular intervals, the level of sodium in the blood plasma should be determined. Decreased sodium levels in the blood may initially be asymptomatic, so regular monitoring is necessary. Control should be carried out more often in elderly patients and patients with liver cirrhosis (see sections "Overdose" and "Undesirable effects"). Any treatment with diuretics can cause hyponatremia, sometimes with very serious consequences. Hyponatremia combined with hypovolemia can lead to dehydration and orthostatic hypotension. The concomitant loss of chloride ions can lead to secondary compensatory metabolic alkalosis: the frequency and severity of this effect are insignificant.

Potassium level. A decrease in the level of potassium in the blood with the occurrence of hypokalemia is the main risk factor when using thiazide and thiazide-like diuretics. A decrease in potassium levels (<3.4 mmol/l) should be avoided in certain categories of high-risk patients, such as elderly patients and/or those who are malnourished, regardless of the use of other medicinal products, patients with cirrhosis accompanied by edema and ascites, patients with coronary artery disease and heart failure. In such cases, hypokalemia increases the cardiotoxicity of cardiac glycosides and the risk of cardiac arrhythmias. Patients with a prolonged QT interval of congenital or iatrogenic origin are also at risk. Hypokalemia, like bradycardia, is a predisposing factor in the occurrence of severe heart rhythm disturbances, especially paroxysmal ventricular tachycardia of the "pirouette" type, which can be fatal. In all cases, more frequent monitoring of the level of potassium in the blood is necessary. The first determination of the level of potassium in the blood plasma should be carried out during the first week of treatment. Identification of hypokalemia requires its correction. Hypokalemia associated with low serum magnesium may be refractory to treatment unless serum magnesium levels are corrected.

Magnesium level. It has been proven that thiazides and related diuretics, including indapamide, increase the excretion of magnesium in the urine, which can cause hypomagnesemia (see sections "Interaction with other medicinal products and other forms of interaction" and "Undesirable effects").

Calcium level. Thiazide and thiazide-like diuretics can reduce urinary calcium excretion and lead to a slight transient increase in blood calcium levels. A significant increase in the level of calcium in the blood can be associated with undiagnosed hyperparathyroidism. In such cases, treatment should be discontinued and parathyroid function should be monitored.

Blood glucose level. Blood glucose control is very important for patients with diabetes, especially when potassium levels are low.

Uric acid. In patients with elevated levels of uric acid in the blood, an increase in the number of gout attacks is possible.

Renal function and diuretics. Thiazide and thiazide-like diuretics are most effective if there is no or minor impairment of renal function (creatinine levels are approximately below 25 mg/l, that is, 220 μmol/l, in adults).

In elderly patients, the blood plasma creatinine level should be determined according to the Cockroft formula, taking into account age, body weight and gender: creatinine clearance (clcr) = (140 – age) × body weight/0.814 × creatinine level in blood plasma, where age is expressed in years, body weight in kilograms, creatinine level in blood plasma in micromoles/liter.

This formula is acceptable for determining plasma creatinine levels in elderly men, but for women it should be adapted by multiplying the result by 0.85. Hypovolemia caused by loss of water and sodium as a result of taking diuretics at the beginning of treatment reduces glomerular filtration, which can lead to an increase in the level of urea and creatinine in the blood. This transient functional renal insufficiency has no adverse effects in patients without impaired renal function, but may worsen existing renal insufficiency.

Athletes. Athletes should remember that this medicinal product contains an active substance that can cause a positive reaction during doping control.

Choroidal effusion, acute myopia (short-sightedness) and secondary angle-closure glaucoma. Medicinal products containing sulfonamide or sulfonamide derivatives can cause an idiosyncratic reaction causing choroidal effusion with visual field defect, transient myopia, and acute angle-closure glaucoma. Symptoms include an acute onset of decreased visual acuity or eye pain and usually occur within hours or weeks of starting the medicinal product. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The main treatment is to stop using the medicinal products as soon as possible. If intraocular pressure remains uncontrolled, it may be necessary to use operative medical or surgical methods of treatment. A history of sulfonamide or penicillin allergy may be a risk factor for the development of acute angle-closure glaucoma.

Important information about excipients.

Each tablet contains 55.45 mg or 110.90 mg of lactose monohydrate, respectively. It should not be prescribed to patients with rare hereditary galactose intolerance, glucose-galactose malabsorption syndrome, Lapp lactase deficiency. Use with caution in patients with diabetes mellitus.

Fertility, pregnancy and lactation.

Pregnancy

The medicinal product is contraindicated for pregnant women or women who plan to become pregnant.

Precautions related to perindopril

There is no convincing epidemiological evidence of a teratogenic risk when using ACE inhibitors during the first trimester of pregnancy, but a small increase in this risk is possible. If continued treatment with ACE inhibitors is considered mandatory, patients planning pregnancy should be switched to alternative antihypertensive medicinal products with proven safety data during pregnancy. If pregnancy is confirmed during the treatment period, ACE inhibitor therapy should be discontinued immediately and, if necessary, replaced with another medicinal product approved for use in pregnant women. It is known that taking ACE inhibitors during the II and III trimesters of pregnancy has a toxic effect on the fetus (reduced kidney function, hypohydramnios, slowing of the formation of bone tissue of the skull) and on the body of the newborn child (kidney failure, arterial hypotension, hyperkalemia). If ACE inhibitors were used in the II and III trimesters of pregnancy, an ultrasound examination of kidney functions and the structure of the newborn's skull is recommended.

Newborns whose mothers took ACE inhibitors during pregnancy should be monitored for timely detection and correction of arterial hypotension.

Precautions related to indapamide

Data on the use of indapamide in pregnant women are absent or limited (less than 300 cases). The consequence of long-term use of a thiazide diuretic during the III trimester of pregnancy can be a decrease in the volume of circulating blood of a pregnant woman and uteroplacental blood filling, which can cause fetoplacental ischemia and delay in fetal development. Animal studies did not reveal direct or indirect toxic effects on reproduction. As a precautionary measure, it is advisable to avoid using indapamide during pregnancy.

Period of breast feeding.

The medicinal product Prendamin Duo is contraindicated during period of breast feeding. It is necessary to make a decision to stop breastfeeding for the duration of treatment or to discontinue the medicinal product during breastfeeding, given the importance of therapy for the mother.

Precautions related to perindopril

The use of perindopril during period of breast feeding is not recommended due to the lack of data. Alternative treatment with a proven safety profile should be preferred, especially period of breast feeding of a newborn or premature infant.

Precautions related to indapamide

Data on the penetration of indapamide / metabolites into breast milk are insufficient. Hypersensitivity to sulfonamide derivatives and hypokalemia may develop. A risk to newborns/infants cannot be excluded. Indapamide belongs to thiazide-like diuretics, the use of which during breast feeding is associated with a decrease or even inhibition of lactation. Indapamide is contraindicated during period of breast feeding.

Fertility:

Precautions common to perindopril and indapamide

Reproductive toxicity studies have shown no effect on fertility in male and female animals Effects on human fertility are not expected.

Effects on ability to drive and use machines.

The two active substances, when used separately or in combination in the form of the medicinal product Prendamin Duo, do not affect the ability to drive vehicles or work with other mechanisms, but in some patients, individual reactions associated with a decrease in blood pressure may occur, especially at the beginning of treatment or at simultaneous use with other antihypertensive medicinal products. As a result, the ability to drive a vehicle or work with other mechanisms may deteriorate.

Posology and method of administration.

For oral administration.

Prendamin Duo is prescribed once, 1 tablet per day, preferably in the morning before meals

The medicinal product Prendamin Duo dosed 8 mg/2.5 mg should be prescribed if the blood pressure does not change when using the medicinal product Prendamin Duo dosed 4 mg/1.25 mg:

Special categories of patients

Elderly patients (see section "Special warnings and precautions for use"). Elderly patients should determine the level of plasma creatinine, taking into account age, body weight and sex. Treatment of elderly patients can be started with normal renal function and after taking into account the response of blood pressure to therapy.

Patients with impaired renal function (see the section "Special warnings and precautions for use")

Prendamin Duo dosed 4 mg/1.25 mg: in the presence of severe impaired renal function (creatinine clearance <30 ml/min), the use of the medicinal product is contraindicated. Patients with moderate renal dysfunction (creatinine clearance 30‒60 ml/min) are recommended to start treatment with an appropriate dose of the components of the combination. Patients with creatinine clearance ≥ 60 ml/min do not require dose adjustment.

Prendamin Duo dosed 8 mg/2.5 mg: in the presence of severe and moderate renal dysfunction (creatinine clearance <60 ml/min), the use of the medicinal product is contraindicated.

Routine medical supervision should include frequent monitoring of plasma creatinine and potassium levels.

Patients with hepatic impairment (see sections "Pharmacokinetic properties", "Contraindications" and "Special warnings and precautions for use"). In the presence of severe liver function disorders, the use of the medicinal product is contraindicated. Patients with hepatic impairment disorders do not need dose adjustment.

Children.

The medicinal product Prendamin Duo should not be used for the treatment of children and adolescents. The safety and efficacy of perindopril tert-butylamine/indapamide in pediatric patients have not been established. No data available.

Overdose.

Symptoms. In case of overdose, the most common adverse reaction is arterial hypotension, which can sometimes be accompanied by nausea, vomiting, convulsions, dizziness, drowsiness, confusion, oliguria, which can progress to anuria (due to hypovolemia), as well as circulatory shock. There may be a violation of the water and electrolyte balance (decrease in the level of potassium and sodium in the blood plasma), renal failure, hyperventilation, tachycardia, rapid heartbeat (palpitation), bradycardia, anxiety, cough.

Treatment. First aid measures include rapid removal of the medicinal product from the body - gastric lavage and/or the use of activated charcoal, after which the water-electrolyte balance should be normalized in hospital conditions. In case of significant arterial hypotension, the patient must be provided with a horizontal position with a low headboard. If necessary, intravenous administration of isotonic sodium chloride solution or any other method of blood volume restoration should be used. Perindoprilat, the active form of perindopril, can be removed from the body by hemodialysis (see section "Pharmacokinetic properties").

Undesirable effects.

The use of perindopril inhibits the RAAS and helps to reduce the loss of potassium in the blood plasma caused by indapamide. Hypokalaemia (potassium level <3.4 mmol/l) may occur in 6% of treated patients. The following adverse reactions were most often reported: when using perindopril, dizziness, headache, paresthesia, dysgeusia, visual disturbances, vertigo, ringing in the ears, arterial hypotension, cough, shortness of breath, abdominal pain, constipation, dyspepsia, diarrhea, nausea, vomiting, itching, rash, muscle cramps muscles and asthenia; when using indapamide, hypokalemia**, hypersensitivity reactions, mainly dermatological, in people with a tendency to allergic and asthmatic reactions, and maculopapular rashes.

The patient should be warned about the need to consult a doctor in the event of signs of anuria/oliguria, hot flushes, as well as depression, darkening of urine, nausea, vomiting, muscle spasms, confusion of consciousness, which may indicate the occurrence of the syndrome of inadequate secretion of antidiuretic hormone (SIADH).

During treatment with perindopril and indapamide, the following adverse reaction were observed, which are distributed as follows by frequency: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, <1/100); rare (≥ 1/10000, <1/1000); very rare (<1/10000), not known (cannot be estimated from the available data).

Eye disorders: visual disturbances (common - perindopril, not known - indapamide); myopia (see the section "Special warnings and precautions for use") (not known - indapamide); blurred vision (not known - indapamide); choroidal effusion (not known - indapamide).

Ear and labyrinth disorders: vertigo (common - perindopril, rare - indapamide); ringing in the ears (common - perindopril).

Respiratory, thoracic and mediastinal disorders: cough (see section "Special warnings and precautions for use") (common - perindopril); shortness of breath (common - perindopril); bronchospasm (uncommon - perindopril); eosinophilic pneumonia (very rare - perindopril), rhinitis (very rare - perindopril).

Gastrointestinal disorders: pain in the abdominal area (common - perindopril); constipation (common - perindopril, rare - indapamide); diarrhea (common - perindopril); dyspepsia (common - perindopril); nausea (common - perindopril, rare - indapamide); vomiting (common - perindopril, rare - indapamide); dry mouth (rare - perindopril, rare - indapamide); pancreatitis (very rare - perindopril and indapamide).

Hepatobiliary disorders: hepatitis (see the section "Special warnings and precautions for use.") (very rare - perindopril, not known - indapamide); liver-function abnormalities (very rare - indapamide).

Renal and urinary disorders: renal failure (uncommon - perindopril); acute renal failure (rare - perindopril, very rare - indapamide); anuria/oliguria (rare - perindopril).

Endocrine disorders: SIADH (rare - perindopril).

Metabolism and nutrition disorders: hypoglycemia (see sections "Interaction with other medicinal products and other forms of interaction" and "Special warnings and precautions for use") (uncommon* - perindopril); hyperkalemia, reversible when the medicinal product is discontinued (see the section "Special warnings and precautions for use") (uncommon* - perindopril); hyponatremia (see section "Special warnings and precautions for use") (uncommon* - perindopril and indapamide); hypercalcemia (very rare - indapamide); a decrease in the level of potassium in the blood to the state of hypokalemia**, including serious in some high-risk patients (see section "Special warnings and precautions for use") (common - indapamide), hypochloremia (uncommon - indapamide), hypomagnesemia (uncommon - indapamide).

Nervous system disorders: dizziness (common - perindopril); headache (common - perindopril, rare - indapamide); paresthesia (common - perindopril, rare - indapamide); dysgeusia (common - perindopril); drowsiness (uncommon* - perindopril); fainting (uncommon* - perindopril, not known - indapamide); as a result of excessive arterial hypotension, a stroke may occur in patients of a high-risk group (see section "Special warnings and precautions for use") (very rare - perindopril); in case of liver failure, hepatic encephalopathy may occur (see sections "Contraindications" and "Special warnings and precautions for use") (not known - indapamide).

Psychiatric disorders mood changes (uncommon - perindopril); sleep disturbance (uncommon - perindopril); depression (uncommon - perindopril); confusion of consciousness (very rare - perindopril).

Cardiac disorders: palpitations (uncommon* - perindopril); tachycardia (uncommon* - perindopril); angina pectoris (see section "Special warnings and precautions for use") (very rare - perindopril); arrhythmia, including bradycardia, ventricular tachycardia, atrial fibrillation (very rare - perindopril and indapamide); as a result of excessive arterial hypotension, myocardial infarction is possible in patients of a high-risk group (see the section "Special warnings and precautions for use") (very rare - perindopril); paroxysmal ventricular tachycardia of the "pirouette" type (potentially fatal) (see the sections "Special warnings and precautions for use" and "Interactions with other medicinal products and other forms of interaction") (not known - indapamide).

Vascular disorders arterial hypotension (and manifestations related to hypotension) (see section "Special warnings and precautions for use") (common - perindopril, very rarely - indapamide); vasculitis (common* - perindopril); Raynaud's phenomenon (not known - perindopril).

Blood and lymphatic system disorders: eosinophilia (uncommon* - perindopril); agranulocytosis (see section "Special warnings and precautions for use") (very rare - perindopril and indapamide); aplastic anemia (very rare - indapamide); pancytopenia (very rare - perindopril); leukopenia (very rare - perindopril and indapamide); neutropenia (see section "Special warnings and precautions for use") (very rare - perindopril); hemolytic anemia (very rare - perindopril and indapamide); thrombocytopenia (see section "Special warnings and precautions for use") (very rare - perindopril and indapamide).

Immune system disorders: hypersensitivity (mainly dermatological reactions in patients prone to the development of allergic and asthmatic reactions) (common - indapamide).

Skin and subcutaneous tissue disorders: itching (common - perindopril); rash (common - perindopril); maculopapular rashes (common - indapamide); urticaria (see section "Special warnings and precautions for use") (uncommon - perindopril, very rare - indapamide); angioneurotic edema (see section "Special warnings and precautions for use") (uncommon - perindopril, very rare - indapamide); purpura (uncommon - indapamide); hyperhidrosis (uncommon - perindopril); photosensitivity reactions (uncommon* - perindopril, not known - indapamide); pemphigoid (uncommon* - perindopril); increased symptoms of psoriasis (rarely* - perindopril); erythema multiforme (very rare - perindopril); toxic epidermal necrolysis (very rare - indapamide); Stevens-Johnson syndrome (very rarely - indapamide).

Musculoskeletal and connective tissue disorders: muscle spasms (common - perindopril); possible worsening of existing acute systemic lupus erythematosus (not known - indapamide); arthralgia (uncommon* - perindopril); myalgia (uncommon* - perindopril).

Reproductive system and breast disorders: erectile dysfunction (uncommon - perindopril and indapamide).

General disorders: asthenia (common - perindopril); chest pain (uncommon* - perindopril); malaise (uncommon* - perindopril); peripheral edema (uncommon* - perindopril); pyrexia (uncommon* - perindopril); fatigue (rare - indapamide).

Investigations: increase in the level of urea in the blood (uncommon* - perindopril); an increase in the level of creatinine in the blood (uncommon* - perindopril); increase in the level of bilirubin in the blood (rarely - perindopril); increase in the level of liver enzymes (rare - perindopril, not known - indapamide); decrease in the level of hemoglobin and hematocrit (see section "Special warnings and precautions for use") (very rare - perindopril); increase in the level of glucose in the blood (not known - indapamide); increase in the level of uric acid in the blood (not known - indapamide); prolongation of the QT interval on the ECG (see sections "Special warnings and precautions for use" and "Interaction with other medicinal products and other forms of interaction") (not known - indapamide).

Damage, poisoning and complications during procedures: falling (uncommon* - perindopril).

* Frequencies of adverse reactions reported through spontaneous reporting are calculated from clinical trial data.

**During Phase II and III studies comparing 1.5 and 2.5 mg of indapamide, plasma potassium analysis showed a dose-dependent effect of indapamide:

Indapamide 1.5 mg: plasma potassium <3.4 mmol/l was observed in 10% of patients and <3.2 mmol/l in 4% of patients after 4‒6 weeks of treatment. After 12 weeks of treatment, the average drop in potassium in blood plasma was 0.23 mmol/l.

Indapamide 2.5 mg: plasma potassium <3.4 mmol/l was observed in 25% of patients and <3.2 mmol/l in 10% of patients after 4‒6 weeks of treatment. After 12 weeks of treatment, the average drop in potassium in blood plasma was 0.41 mmol/l.

With the use of other ACE inhibitors, cases of SIADH have been reported. Therefore, SIADH can be regarded as a probable complication associated with the use of ACE inhibitors, including perindopril, with a "very rare" frequency of occurrence.

Reported suspected adverse reactions

Reporting suspected adverse reactions after registration of the medicinal product is an important procedure. This allows for continued monitoring of the benefit/risk ratio for the respective drug. Healthcare providers should be informed of any suspected adverse reactions through the national alert system.

Shelf life. 2 years.

Special precautions for storage.

Store in the original package at a temperature not exceeding 25°C.

Keep out of the reach of children.

Nature and contents of container.

10 tablets in a blister; 3 blisters in a pack.

Category of release. Prescription only medicine.

Manufacturer. PrJSC “Pharmaceutical firm “Darnitsa”.

The manufacturer's location and address of the place of business.

13, Boryspilska Street, Kyiv, 02093, Ukraine.

Date of last revision. 16.11.2021.