INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Noliprel® arginine (Noliprel® arginine)

Composition:

Active substances: perindopril arginine, indapamide;

One tablet contains 2.5 mg of perindopril arginine, equivalent to 1.6975 mg of perindopril, and 0.625 mg of indapamide;

Excipients: lactose monohydrate, magnesium stearate (E 470 B), maltodextrin, colloidal anhydrous silicon dioxide (E 551), sodium starch glycolate (type A), macrogol 6000, glycerin (E 422), hypromellose (E 464), titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Manufactured by "Laboratoires Servier Industrie", France: white, elongated-shaped, film-coated tablets, embossed with a line on both sides;

Manufactured by "Servier (Ireland) Industries Ltd", Ireland: white, elongated-shaped, film-coated tablets, embossed with “” on one side and a line on both sides.

Pharmacotherapeutic group. Perindopril and diuretics. ATC code C09BA04.

Pharmacological Properties.

Pharmacodynamics.

Noliprel® arginine is a combination of the ACE inhibitor perindopril arginine 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

Noliprel® arginine has an additive synergistic effect of two antihypertensive components.

Mechanism of action of perindopril

Perindopril is an ACE inhibitor that converts angiotensin I to angiotensin II (a vasoconstrictive substance), additionally stimulates aldosterone secretion by the adrenal cortex, and promotes bradykinin (a vasodilatory substance) degradation into inactive heptapeptides. Inhibition of ACE leads to: reduced aldosterone secretion; increased plasma renin activity, while aldosterone does not exert a negative effect; decreased total peripheral vascular resistance due to predominant effects on muscular and renal vessels; and no water and salt retention or reflex tachycardia, even during long-term treatment. Furthermore, perindopril reduces arterial pressure (BP) in patients with normal and low plasma renin levels. Perindopril acts via its active metabolite perindoprilat. Other metabolites are inactive. Perindopril reduces cardiac workload through vasodilatory effects on veins (possibly due to changes in prostaglandin metabolism) – reducing preload, and by decreasing total peripheral vascular resistance – reducing afterload on the heart. Studies conducted in patients with heart failure have demonstrated that perindopril use leads to reduced filling pressures in the left and right ventricles, decreased total peripheral vascular resistance, increased cardiac output and cardiac index, and increased regional blood flow in muscles. Exercise test parameters are improved.

Mechanism of action of indapamide

Indapamide is a sulfonamide derivative with an indole ring, pharmacologically related to thiazide diuretics. Indapamide inhibits sodium reabsorption in the cortical segment of the kidneys. This increases urinary excretion of sodium and chloride, and to a lesser extent potassium and magnesium, thereby increasing diuresis and providing antihypertensive action.

Pharmacodynamic effects

Noliprel® arginine exerts dose-dependent antihypertensive effects on systolic (SBP) and diastolic (DBP) arterial pressure in patients with arterial hypertension of any age, both in supine and standing positions. The antihypertensive effect lasts for 24 hours. Reduction in arterial pressure is achieved in less than one month without development of tachyphylaxis; discontinuation of treatment does not cause withdrawal syndrome. Clinical studies have demonstrated that concomitant administration of perindopril and indapamide results in a synergistic antihypertensive effect, resulting from the individual effects of the components.

PICXEL – a multicenter, randomized, double-blind, controlled study evaluating the effect of the combination of perindopril and indapamide on left ventricular hypertrophy compared to enalapril monotherapy, based on echocardiographic results. In the PICXEL study, patients with arterial hypertension and left ventricular hypertrophy (with a left ventricular mass index >120 g/m² in men and >100 g/m² in women) were randomized into two groups: one group received 2 mg of perindopril tert-butylamine (equivalent to 2.5 mg perindopril arginine)/0.625 mg indapamide, and the other received 10 mg enalapril once daily for one year. Doses were adjusted according to BP values: perindopril tert-butylamine dose was increased up to 8 mg (equivalent to 10 mg perindopril arginine), indapamide up to 2.5 mg, and enalapril up to 40 mg once daily. Starting doses were continued in 34% of patients in the perindopril/indapamide group (2 mg perindopril and 0.625 mg indapamide) and 20% in the enalapril group (10 mg). At the end of treatment, among all randomized patients, the left ventricular mass index decreased significantly more in patients receiving perindopril/indapamide (−10.1 g/m²) compared to the enalapril group (−1.1 g/m²). The difference between the two groups was −8.3 (95% confidence interval [CI] from −11.5 to −5.0, p < 0.0001). Better efficacy in reducing left ventricular mass index was achieved with perindopril/indapamide doses higher than those approved for Noliprel® arginine and Noliprel® arginine forte. Arterial pressure was more effectively reduced in the perindopril/indapamide group: the difference in mean BP reduction between the two patient groups was −5.8 mm Hg (95% CI from −7.9 to −3.7, p < 0.0001) for SBP and −2.3 mm Hg (95% CI from −3.6 to −0.9, p = 0.0004) for DBP.

Pharmacodynamic effects related to perindopril

Perindopril effectively reduces BP in all stages of arterial hypertension: mild, moderate, and severe. Reduction in SBP and DBP is observed both in supine and standing positions. The maximum antihypertensive effect develops 4–6 hours after a single dose and persists for more than 24 hours. Perindopril achieves a high level of ACE inhibition (approximately 80%) 24 hours after administration. In patients responding to treatment, BP normalization is achieved within one month and maintained without tachyphylaxis. Discontinuation of therapy is not associated with withdrawal syndrome. Perindopril has vasodilatory properties, restores elasticity of large arteries, corrects histomorphometric changes in resistance arteries, and reduces left ventricular hypertrophy. Addition of a thiazide diuretic, if necessary, results in additional synergism. Combined use of an ACE inhibitor and a thiazide diuretic reduces the risk of hypokalemia that may occur with diuretic monotherapy.

Pharmacodynamic effects related to indapamide

When used as monotherapy, indapamide exerts an antihypertensive effect lasting 24 hours. This effect occurs at doses where diuretic properties are minimal. The antihypertensive effect of indapamide is proportional to improved arterial elasticity and reduced 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, while the number of adverse effects increases. If treatment is insufficiently effective, the dose should not be increased. Moreover, studies of varying duration (short, medium, and long-term) in patients with arterial hypertension have shown that 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 mellitus.

Pharmacokinetics.

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

Pharmacokinetic properties of perindopril

Absorption and bioavailability. After oral administration, perindopril is rapidly absorbed, with peak concentration reached within 1 hour. The elimination half-life of perindopril in plasma is 1 hour. Since food intake reduces the conversion of perindopril to perindoprilat, thereby decreasing its bioavailability, perindopril arginine should be taken orally as a single daily dose in the morning before meals.

Distribution. The volume of distribution of unbound perindoprilat is approximately 0.2 L/kg. Perindoprilat binding to plasma proteins is 20%, primarily to ACE, and depends on concentration.

Biotransformation. Perindopril is a prodrug. Thus, 27% of the administered perindopril dose enters the bloodstream as the active metabolite perindoprilat. In addition to the active perindoprilat, perindopril forms five other inactive metabolites. Maximum plasma concentration of perindoprilat is reached within 3–4 hours.

Elimination. Perindoprilat is excreted in urine; the terminal half-life of the unbound fraction is approximately 17 hours. Steady state is achieved within 4 days.

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

Special patient populations

Elderly patients. Elimination of perindoprilat is reduced in elderly patients and in individuals with heart or renal failure.

Renal impairment. Dose adjustment is required for patients with renal impairment depending on the degree of renal dysfunction (creatinine clearance).

Dialysis requirement. Dialysis clearance of perindoprilat is 70 mL/min.

Liver cirrhosis. Perindopril kinetics are altered in patients with liver cirrhosis: hepatic clearance of the parent compound is halved. However, the amount of perindoprilat formed is not reduced, and therefore dose adjustment is not required in these patients (see sections "Dosage and administration" and "Special precautions").

Pharmacokinetic properties of indapamide

Absorption. Indapamide is rapidly and completely absorbed in the gastrointestinal tract. Peak plasma concentration is reached approximately 1 hour after oral administration.

Distribution. Protein binding in plasma is 79%.

Biotransformation and elimination. Elimination half-life ranges from 14 to 24 hours (on average, 18 hours). Repeated dosing does not lead to accumulation. Excretion occurs mainly in urine (70% of dose) and feces (22%) as inactive metabolites.

Special patient populations

Renal impairment. Pharmacokinetic parameters are not altered in patients with renal impairment.

Clinical characteristics.

Indications.

Noliprel® arginine is indicated for the treatment of essential hypertension in adult patients.

Contraindications.

Related to perindopril:

Hypersensitivity to the active substance or to any other angiotensin-converting enzyme (ACE) inhibitor;
History of angioedema (Quincke's edema) associated with previous treatment with ACE inhibitors (see section "Special precautions");
Hereditary or idiopathic angioedema;
Pregnancy or planned pregnancy (see section "Use during pregnancy or breastfeeding");
Concomitant use with aliskiren-containing medicinal products in patients with diabetes mellitus or renal impairment (glomerular filtration rate < 60 mL/min/1.73 m²) (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacodynamics");
Concomitant use with sacubitril/valsartan. Noliprel® arginine must not be used earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction");
Extracorporeal treatment methods leading to blood contact with negatively charged surfaces (see section "Interaction with other medicinal products and other forms of interaction");
Severe bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney (see section "Special precautions").

Related to indapamide:

Hypersensitivity to the active substance or to any other sulfonamides;
Severe renal impairment (creatinine clearance < 30 mL/min);
Hepatic encephalopathy;
Severe hepatic impairment;
Hypokalemia.

Related to Noliprel® arginine:

Hypersensitivity to any excipient.

Due to lack of sufficient clinical experience, Noliprel® arginine should not be used:

In patients undergoing hemodialysis;
In patients with untreated decompensated heart failure.

Interaction with other medicinal products and other forms of interaction.

Interactions common to perindopril and indapamide

Concomitant use not recommended

Lithium. Reversible increases in serum lithium concentration and lithium toxicity have been reported during concomitant use with angiotensin-converting enzyme inhibitors (ACE inhibitors). Concomitant use of perindopril with indapamide and lithium is not recommended; however, if this combination is necessary, serum lithium concentrations should be closely monitored.

Concomitant use requiring special attention

Baclofen. Antihypertensive effect is enhanced. Blood pressure should be monitored and dosage of antihypertensive therapy adjusted if necessary.

Nonsteroidal anti-inflammatory drugs (NSAIDs) (including acetylsalicylic acid at doses ≥ 3 g/day). Concomitant use of ACE inhibitors and NSAIDs, such as acetylsalicylic acid at anti-inflammatory doses, COX-2 inhibitors, and nonselective NSAIDs, may reduce the antihypertensive effect. Concomitant use of ACE inhibitors and NSAIDs may increase the risk of worsening renal function, including acute renal failure, and hyperkalemia, particularly in patients with impaired renal function. This combination should be used with caution, especially in elderly patients. Patients should be adequately hydrated before starting treatment, and renal function should be monitored at the beginning and throughout combination therapy.

Concomitant use requiring attention

Tricyclic antidepressants, neuroleptics. May enhance antihypertensive effects and increase the risk of orthostatic hypotension (additive effect).

Interactions related to perindopril

Clinical trial data indicate that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with increased incidence of adverse reactions such as hypotension, hyperkalemia, and worsening renal function (including acute renal failure), compared to use of a single RAAS-acting agent (see sections "Contraindications" and "Special precautions").

Medicinal products increasing the risk of angioedema. Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema. Initiation of sacubitril/valsartan should not occur earlier than 36 hours after the last dose of perindopril. Perindopril therapy should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Special precautions").

Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) may increase the risk of angioedema (see "Special precautions").

Medicinal products causing hyperkalemia. Serum potassium levels usually remain within normal limits, but hyperkalemia may occur in some patients treated with Noliprel® arginine. Certain medicinal products or therapeutic classes, such as aliskiren, potassium salts, potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), ACE inhibitors, angiotensin II receptor antagonists, NSAIDs, heparins, immunosuppressants such as cyclosporine or tacrolimus, trimethoprim, and co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim acts as a potassium-sparing diuretic similar to amiloride, may cause hyperkalemia. Combination with these agents increases the risk of hyperkalemia. Therefore, concomitant use of Noliprel® arginine with the above-mentioned medicinal products is not recommended. If concomitant use is necessary, it should be done with caution and frequent monitoring of serum potassium levels.

Concomitant use contraindicated

Aliskiren. In patients with diabetes mellitus or renal impairment, increased risk of hyperkalemia, worsening renal function, cardiovascular morbidity, and mortality.

Extracorporeal treatments leading to blood contact with negatively charged surfaces, such as dialysis or hemofiltration using certain high-flux membranes (e.g., polyacrylonitrile) and low-density lipoprotein apheresis using dextran sulfate, due to increased risk of severe anaphylactoid reactions (see section "Contraindications"). If necessary, consider using a different type of dialysis membrane or another class of antihypertensive agents.

Concomitant use not recommended

Aliskiren. In all other patient groups, including those with diabetes mellitus or impaired renal function, increased risk of hyperkalemia, worsening renal function, cardiovascular morbidity, and mortality (see section "Special precautions").

Concomitant therapy with ACE inhibitor and angiotensin receptor blocker. In patients with established atherosclerosis, heart failure, or diabetes with target organ damage, concomitant therapy with an ACE inhibitor and an angiotensin receptor blocker has been associated with increased incidence of hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to use of a single RAAS-acting agent. Dual blockade (i.e., combination of ACE inhibitor and angiotensin II receptor antagonist) may be considered only in selected cases with careful monitoring of renal function, serum potassium, and blood pressure (see section "Special precautions").

Estramustine. Risk of increased adverse reactions such as angioedema.

Potassium-sparing diuretics (e.g., triamterene, amiloride), potassium (salts). Risk of hyperkalemia (potentially fatal), especially in patients with impaired renal function (additive hyperkalemic effect). Combination of perindopril with the above-mentioned medicinal products is not recommended (see section "Special precautions"). If concomitant use is unavoidable, it should be done with caution and frequent monitoring of serum potassium levels. Information on use of spironolactone in patients with heart failure is provided under "Concomitant use requiring special attention".

Concomitant use requiring special attention

Antidiabetic agents (insulin, oral hypoglycemic agents). Concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemic agents) may enhance hypoglycemic effects with risk of hypoglycemia. This phenomenon is more likely during the first weeks of combination therapy and in patients with impaired renal function.

Diuretics. In patients receiving diuretics, particularly those with volume and sodium depletion, excessive reduction in blood pressure may occur after initiation of ACE inhibitor therapy. The risk of hypotensive effects may be reduced by discontinuing diuretic therapy, increasing circulating volume, or increasing salt intake prior to initiating perindopril, which should be started at a low dose with gradual dose escalation. In patients with hypertension, if prior diuretic therapy may have caused volume/sodium depletion, diuretic therapy should be discontinued prior to starting ACE inhibitors (diuretic therapy may be resumed later), or ACE inhibitor therapy should be initiated at a low dose with gradual dose escalation. In patients with congestive heart failure receiving diuretics, ACE inhibitor therapy should be initiated at the lowest dose, possibly after reducing the diuretic dose. In all cases, renal function (serum creatinine) should be monitored during the first few weeks of ACE inhibitor therapy.

Potassium-sparing diuretics (eplerenone, spironolactone). When eplerenone or spironolactine (12.5–50 mg daily) is used concomitantly with low-dose ACE inhibitors in patients with NYHA class II–IV heart failure and ejection fraction < 40%, previously treated with ACE inhibitors and loop diuretics, there is a risk of potentially fatal hyperkalemia, especially if recommendations for use are not followed. Before initiating such combination therapy, absence of hyperkalemia and renal impairment should be confirmed. Close monitoring of serum potassium and creatinine is recommended weekly during the first month and monthly thereafter.

Concomitant use requiring attention

Antihypertensive agents and vasodilators. Concomitant use may enhance the hypotensive effects of perindopril. Concomitant use with nitroglycerin and other nitrates or other vasodilators may lead to additional blood pressure reduction.

Allopurinol, cytostatics, immunosuppressants, systemic corticosteroids, or procainamide. Concomitant use with ACE inhibitors may increase the risk of leukopenia (see section "Special precautions").

Anesthetics. ACE inhibitors may enhance the hypotensive effect of some anesthetic agents (see section "Special precautions").

Sympathomimetics. Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.

Gold compounds. Rare cases of nitritoid reactions (facial flushing, nausea, vomiting, and hypotension) have been reported in patients receiving injectable gold compounds (sodium aurothiomalate) and concomitant ACE inhibitors, including perindopril.

Interactions related to indapamide

Concomitant use requiring special attention

Medicinal products that may induce torsades de pointes. Due to the risk of hypokalemia, indapamide should be used cautiously in combination with medicinal products that may induce torsades de pointes, such as (the list is not exhaustive): Class IA antiarrhythmics (e.g., quinidine, hydroquinidine, disopyramide); Class III antiarrhythmics (e.g., amiodarone, dofetilide, ibutilide, bretylium, sotalol); certain antipsychotics: phenothiazines (e.g., chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine), benzamides (e.g., amisulpride, sulpiride, sulthiapride, tiapride), butyrophenones (e.g., droperidol, haloperidol), other antipsychotics (e.g., pimozide); other substances (e.g., bepridil, cisapride, difemanil, intravenous erythromycin, halofantrine, mizolastine, moxifloxacin, pentamidine, sparfloxacin, intravenous vinca alkaloids, methadone, astemizole, terfenadine). Plasma potassium levels should be maintained and corrected if necessary, and QT interval should be monitored.

Medicinal products that reduce serum potassium levels. Intravenous amphotericin B, glucocorticoids, mineralocorticoids (systemic), tetracosactide, stimulant laxatives increase the risk of hypokalemia (additive effect). Serum potassium levels should be monitored and corrected if necessary, particularly during concomitant treatment with cardiac glycosides. Non-stimulant laxatives should be used.

Cardiac glycosides. Hypokalemia and/or hypomagnesemia may predispose to digitalis toxicity. Monitoring of serum potassium and magnesium levels and ECG monitoring are recommended, with treatment adjustment if necessary.

Allopurinol. Concomitant use with indapamide may increase the frequency of hypersensitivity reactions to allopurinol.

Concomitant use requiring attention

Potassium-sparing diuretics (amiloride, spironolactone, triamterene). Hypokalemia or hyperkalemia may occur (particularly in patients with renal impairment or diabetes mellitus). Serum potassium levels should be monitored, ECG monitoring performed, and therapy reviewed if necessary.

Metformin. May cause lactic acidosis due to functional renal impairment associated with diuretic use, especially loop diuretics. Metformin should not be used if plasma creatinine exceeds 15 mg/L (135 µmol/L) in men or 12 mg/L (110 µmol/L) in women.

Iodinated contrast agents. Dehydration caused by diuretic use increases the risk of acute renal failure, especially with high doses of iodinated contrast agents. Adequate hydration should be ensured before administration of iodinated contrast agents.

Calcium (salts). Risk of increased serum calcium levels due to reduced urinary excretion.

Cyclosporine, tacrolimus. Risk of increased serum creatinine without changes in circulating cyclosporine concentration, even in the absence of volume or sodium depletion.

Corticosteroids, tetracosactide (systemic). May reduce antihypertensive effect (due to water and sodium retention caused by corticosteroids).

Special precautions for use.

Special warnings

Special warnings common to perindopril and indapamide

For the Noliprel® arginine combination, a significant reduction in adverse reactions has not been demonstrated compared to the use of equivalent doses of its components as monotherapies, except for hypokalemia (see section "Adverse reactions"). When a patient begins treatment with two new antihypertensive active substances simultaneously, an increased frequency of idiosyncratic reactions cannot be excluded. To minimize this risk, careful monitoring of the patient's condition is required.

Lithium. Concomitant use with the perindopril/indapamide combination is generally not recommended (see section "Interaction with other medicinal products and other types of interactions").

Special warnings related to perindopril

Dual blockade of the renin-angiotensin-aldosterone system (RAAS). Data indicate that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure). Therefore, dual blockade of the RAAS by concomitant administration of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see sections "Interaction with other medicinal products and other types of interactions" and "Pharmacodynamics"). If dual RAAS blockade therapy is considered absolutely necessary, it should be conducted only under specialist supervision and with frequent, careful monitoring of renal function, electrolyte levels, and blood pressure. Patients with diabetic nephropathy should not receive concomitant treatment with ACE inhibitors and angiotensin II receptor blockers.

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

Neutropenia/agranulocytosis/thrombocytopenia/anemia. Cases of neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported in patients treated with ACE inhibitors. Neutropenia is rare in patients with normal renal function and no other risk factors. Perindopril should be used with extreme caution in patients with collagen diseases, those receiving immunosuppressive therapy, allopurinol, or procainamide, or in patients with a combination of these risk factors, especially if renal function is impaired. Some of these patients have developed severe infectious diseases, sometimes resistant to intensive antibiotic therapy. Periodic monitoring of white blood cell count is recommended during perindopril therapy in such patients. Additionally, patients should be informed of the need to report any signs of infection (e.g., sore throat, fever) to their physician (see sections "Interaction with other medicinal products and other types of interactions" and "Adverse reactions").

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

Hypersensitivity/angioedema (angioedema). Rare cases of angioedema of the face, extremities, lips, tongue, glottis, and/or larynx have been reported in patients treated with ACE inhibitors, including perindopril (see section "Adverse reactions"). This may occur at any time during treatment. In such cases, the drug must be discontinued immediately, and medical supervision should be maintained until symptoms completely resolve. If swelling is limited to the face and lips, the patient's condition usually improves without treatment, although antihistamines may be helpful in reducing symptoms. Angioedema involving the larynx may be fatal. If swelling spreads to the tongue, glottis, or larynx, potentially causing airway obstruction, emergency treatment is required, which may include subcutaneous administration of 1:1000 epinephrine solution (0.3–0.5 mL) and/or measures to ensure airway patency. Angioedema has been reported more frequently in patients of African descent receiving ACE inhibitors compared to other racial groups. Patients with a history of angioedema unrelated to ACE inhibitor use are at increased risk of developing angioedema during ACE inhibitor therapy. Rare cases of intestinal angioedema have been reported in patients receiving ACE inhibitor therapy. These patients experienced abdominal pain (with or without nausea and vomiting); intestinal angioedema sometimes occurred without prior facial angioedema, and serum C1-esterase inhibitor levels were within normal limits. The diagnosis of angioedema was confirmed by procedures such as abdominal computed tomography, ultrasound, or during surgical intervention; symptoms resolved after discontinuation of the ACE inhibitor. In patients taking ACE inhibitors who develop abdominal pain, differential diagnosis should be performed to exclude intestinal angioedema. Concomitant use of perindopril with sacubitril/valsartan is contraindicated due to an increased risk of angioedema. Sacubitril/valsartan should not be initiated earlier than 36 hours after the last dose of perindopril. If treatment with sacubitril/valsartan is discontinued, perindopril therapy should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Interaction with other medicinal products and other types of interactions"). Concomitant use of ACE inhibitors with neutral endopeptidase (NEP) inhibitors (e.g., racecadotril), mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) may increase the risk of angioedema (e.g., airway or tongue swelling, with or without respiratory impairment) (see "Interaction with other medicinal products and other types of interactions"). Caution is advised when initiating treatment with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) in patients already receiving ACE inhibitors.

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

Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis. Rare cases of life-threatening anaphylactoid reactions have been reported in patients receiving ACE inhibitors during LDL apheresis using dextran sulfate. These reactions may be avoided by temporarily withholding ACE inhibitor therapy before each apheresis session.

Patients undergoing hemodialysis. Cases of anaphylactoid reactions have been reported in patients receiving ACE inhibitors during hemodialysis with high-flux polyacrylonitrile membranes (e.g., AN 69®). Such patients should use a different type of dialysis membrane or be prescribed another class of antihypertensive agents.

Primary hyperaldosteronism. Patients with primary hyperaldosteronism generally do not respond to antihypertensive drugs acting via inhibition of the renin-angiotensin system. Therefore, this medication is not recommended for such patients.

Patients after kidney transplantation. Experience with perindopril arginine in patients after recent kidney transplantation is lacking.

Arterial hypotension. Symptomatic arterial hypotension has been reported in patients with symptomatic heart failure, with or without concomitant renal impairment. The risk of symptomatic arterial hypotension is higher in patients with more severe heart failure, those receiving high-dose loop diuretics, those with hyponatremia, or those with functional renal impairment. Close medical supervision is required at the beginning of therapy and during dose titration to reduce the risk of symptomatic arterial hypotension. Similar precautions apply to patients with ischemic heart disease or cerebrovascular disease, in whom excessive blood pressure reduction may lead to myocardial infarction or stroke.

Ischemic heart disease. If an episode of unstable angina (of any severity) occurs within the first month of perindopril treatment, the risk-benefit ratio should be carefully evaluated before deciding whether to continue therapy.

Special warnings related to indapamide

Hepatic encephalopathy. In patients with impaired liver function, the use of thiazide and thiazide-like diuretics, especially in the presence of electrolyte imbalance, may precipitate hepatic encephalopathy, which may progress to hepatic coma. In such cases, diuretic therapy should be discontinued immediately.

Photosensitivity. Photosensitivity reactions have been reported with thiazide and thiazide-like diuretics (see section "Adverse reactions"). If a photosensitivity reaction occurs during treatment, drug administration should be discontinued. If reinitiation is necessary, protection of vulnerable areas from sunlight or artificial ultraviolet sources is recommended.

Precautionary measures

Precautionary measures common to perindopril and indapamide

Renal impairment. Treatment with this medication is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min). In some patients with arterial hypertension but no signs of renal impairment, laboratory blood tests may reveal signs of functional renal impairment; in such cases, treatment should be discontinued, possibly to be resumed at a lower dose or with only one of its components. These patients require frequent monitoring of serum potassium and creatinine levels: 2 weeks after initiation of treatment and then every 2 months during therapeutic stabilization. Cases of renal impairment have primarily occurred in patients with severe heart failure or pre-existing renal impairment, including renal artery stenosis. This medication should not be used in patients with significant bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney.

Arterial hypotension and fluid and electrolyte depletion. Patients with sodium deficiency (especially those with renal artery stenosis) are at risk of a sudden drop in blood pressure. Therefore, systematic monitoring for clinical signs of fluid and electrolyte depletion, which may occur during intercurrent episodes of vomiting or diarrhea, is necessary. Serum electrolyte levels should be regularly monitored in such patients. In cases of significant arterial hypotension, intravenous infusion of isotonic sodium chloride solution may be required. Transient hypotension is not a contraindication for continuing treatment. After restoration of circulating blood volume and normalization of blood pressure, treatment may be resumed at a reduced dose or with only one component of the drug.

Potassium levels. The combination of perindopril and indapamide does not exclude the possibility of hypokalemia, especially in patients with diabetes mellitus or renal impairment. As with any antihypertensive agent combined with a diuretic, regular monitoring of serum potassium levels is required.

Excipients. Patients with rare hereditary lactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medication.

Sodium content. Noliprel® arginine contains less than 1 mmol of sodium (23 mg) per tablet, i.e., it is nearly sodium-free.

Precautionary measures related to perindopril

Cough. Dry cough has been reported during ACE inhibitor therapy. This cough is persistent and resolves after discontinuation of the drug. If this symptom occurs, its iatrogenic etiology should be considered. If ACE inhibitor therapy is necessary for the patient, a decision may be made to continue treatment.

Risk of arterial hypotension and/or renal impairment (in the presence of heart failure, fluid and electrolyte depletion). Significant stimulation of the renin-angiotensin-aldosterone system occurs during acute fluid and electrolyte depletion (strict salt-free diet or prolonged diuretic therapy) in patients with low blood pressure, renal artery stenosis, congestive heart failure, or cirrhosis with edema and ascites. Blocking this system with ACE inhibitors, especially during initial use and the first 2 weeks of treatment, may cause a sudden drop in blood pressure and/or an increase in plasma creatinine levels, indicating functional renal impairment. Occasionally, although rarely, this may occur at any time and have an acute onset. In such cases, treatment should be initiated with a lower dose and gradually increased.

Elderly patients. Renal function and serum potassium levels should be checked before initiating treatment. To reduce the risk of sudden arterial hypotension, especially in the presence of fluid or electrolyte depletion, the initial dose should be adjusted according to the blood pressure response.

Atherosclerosis. The risk of arterial hypotension exists in all patient groups, but the drug should be used with particular caution in patients with ischemic heart disease or cerebral circulation insufficiency, starting treatment with a low dose.

Renovascular hypertension. The treatment of renovascular hypertension is revascularization. However, ACE inhibitors may be beneficial for patients with renovascular hypertension awaiting surgery or for whom surgery is not feasible. If Noliprel® arginine is prescribed to patients with known or suspected renal artery stenosis, treatment should be initiated in a hospital setting with a low dose and under potassium level monitoring, as functional renal impairment, reversible upon discontinuation of treatment, has been observed in some patients.

Heart failure/severe heart failure. Treatment of patients with severe heart failure (Class IV) should be initiated under medical supervision with a reduced initial dose. Treatment with β-blockers in patients with arterial hypertension and coronary insufficiency should not be discontinued; ACE inhibitors should be added to β-blocker therapy.

Patients with diabetes mellitus. Treatment of patients with insulin-dependent diabetes mellitus (with a spontaneous tendency to elevated serum potassium) should be initiated under medical supervision with a reduced initial dose. In patients with diabetes mellitus previously treated with oral hypoglycemic agents or insulin, blood glucose levels should be carefully monitored, especially during the first month of ACE inhibitor therapy (see section "Interaction with other medicinal products and other types of interactions").

Racial characteristics. Perindopril, like other ACE inhibitors, is less effective in lowering blood pressure in hypertensive patients of African descent compared to other racial groups, possibly due to lower plasma renin levels in these patients.

Surgery/anesthesia. ACE inhibitors may cause arterial hypotension during anesthesia, especially when anesthetics with hypotensive potential are used. Therefore, long-acting ACE inhibitor therapy, such as perindopril, should preferably be discontinued 1 day before surgery.

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

Hepatic impairment. Rarely, ACE inhibitor use has been associated with a syndrome beginning with cholestatic jaundice and progressing to rapidly progressive hepatic necrosis, sometimes with fatal outcome. The mechanism of this syndrome is unclear. Patients who develop jaundice with elevated liver enzymes during ACE inhibitor therapy should discontinue the drug and receive appropriate medical supervision (see section "Adverse reactions").

Hyperkalemia. Increased serum potassium levels have been observed in some patients treated with ACE inhibitors, including perindopril. ACE inhibitors may cause hyperkalemia by inhibiting aldosterone release. This effect is usually mild in patients with normal renal function. Risk factors for hyperkalemia include renal impairment, worsening renal function, age over 70 years, diabetes mellitus, intercurrent conditions (especially dehydration), acute heart decompensation, metabolic acidosis, and concomitant use with potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, amiloride), potassium supplements or potassium-containing salt substitutes, or other drugs associated with elevated serum potassium (e.g., heparin, co-trimoxazole, also known as trimethoprim/sulfamethoxazole, other ACE inhibitors, angiotensin II receptor antagonists, acetylsalicylic acid at doses ≥ 3 g/day, COX-2 inhibitors and non-selective NSAIDs, immunosuppressants such as cyclosporine or tacrolimus, trimethoprim), and particularly aldosterone antagonists or angiotensin II receptor blockers. Use of potassium-containing supplements or salt substitutes and potassium-sparing diuretics, especially in patients with impaired renal function, may lead to significant increases in serum potassium. Hyperkalemia may cause serious, sometimes fatal, arrhythmias. Patients receiving ACE inhibitors should use potassium-sparing diuretics and angiotensin II receptor blockers with caution and undergo careful monitoring of serum potassium levels and renal function. If concomitant use of the above-mentioned drugs is considered appropriate, they should be used with caution and with frequent monitoring of serum potassium levels (see "Interaction with other medicinal products and other types of interactions").

Precautionary measures related to indapamide

Water and electrolyte balance

Sodium levels. Serum sodium levels should be determined before starting treatment and at regular intervals thereafter. Hyponatremia may initially be asymptomatic, so regular monitoring is necessary. Monitoring should be more frequent in elderly patients and patients with liver cirrhosis (see sections "Adverse reactions" and "Overdose"). Any diuretic therapy may cause hyponatremia, sometimes with very serious consequences. Hyponatremia combined with hypovolemia may lead to dehydration and orthostatic hypotension. Concomitant chloride ion loss may lead to secondary compensatory metabolic alkalosis: the frequency and severity of this effect are low.

Potassium levels. Decreased serum potassium levels leading to hypokalemia are a major risk factor with thiazide and thiazide-like diuretics. Hypokalemia may cause muscle disorders. Cases of rhabdomyolysis, mainly associated with severe concomitant hypokalemia, have been reported. Hypokalemia (< 3.4 mmol/L) should be prevented in certain high-risk patient groups, such as elderly patients and/or those with poor nutrition, regardless of concomitant medication use, patients with cirrhosis with edema and ascites, and patients with ischemic heart disease and heart failure. In these cases, hypokalemia increases the cardiotoxicity of cardiac glycosides and the risk of cardiac arrhythmias. Patients with congenital or iatrogenic long QT syndrome also belong to the risk group. Hypokalemia, like bradycardia, is a predisposing factor for severe cardiac arrhythmias, particularly paroxysmal torsades de pointes tachycardia, which may be fatal. More frequent monitoring of serum potassium levels is required in all such cases. The first determination of plasma potassium levels should be performed within the first week of treatment. Hypokalemia requires correction. Hypokalemia associated with low serum magnesium levels may be refractory to treatment unless serum magnesium levels are corrected.

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

Plasma magnesium levels. Thiazides and related diuretics, including indapamide, have been shown to increase urinary magnesium excretion, potentially leading to hypomagnesemia (see "Interaction with other medicinal products and other types of interactions" and "Adverse reactions").

Blood glucose levels. Monitoring blood glucose levels is very important in diabetic patients, especially when serum potassium levels are low.

Uric acid. In patients with elevated serum uric acid levels, an increased frequency of gout attacks is possible.

Kidney function and diuretics. Thiazide and thiazide-like diuretics are most effective when kidney function is normal or only mildly impaired (serum creatinine < 25 mg/L, i.e., 220 µmol/L in adults). In elderly patients, plasma creatinine levels should be determined using the Cockcroft formula, taking into account age, body weight, and sex: creatinine clearance (CrCl) = (140 – age) × body weight / 0.814 × plasma creatinine level, where age is in years, body weight in kilograms, and plasma creatinine in µmol/L. This formula is suitable for determining plasma creatinine levels in elderly men, but for women, the result should be multiplied by 0.85. Hypovolemia caused by fluid and sodium loss due to diuretic use at the beginning of treatment reduces glomerular filtration, potentially leading to increased blood urea and creatinine levels. This transient functional renal impairment has no adverse effects in patients with normal kidney function but may worsen pre-existing renal impairment.

Athletes. Athletes should be aware that this medication contains an active substance that may cause a positive doping test.

Choroidal effusion, acute myopia (nearsightedness), and secondary angle-closure glaucoma. Medicinal products containing sulfonamide or sulfonamide derivatives may cause an idiosyncratic reaction leading to choroidal effusion with visual field defects, transient myopia, and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or eye pain and usually occur within hours or weeks of starting the medication. Untreated acute angle-closure glaucoma may lead to permanent vision loss. The primary treatment is immediate discontinuation of the medication. If intraocular pressure remains uncontrolled, medical or surgical intervention may be necessary. Risk factors for acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

Use during pregnancy or breastfeeding.

Pregnancy

The medication is contraindicated in pregnant women or women planning to become pregnant.

Warnings related to perindopril

There are no convincing epidemiological data on teratogenic risk with ACE inhibitor use during the first trimester of pregnancy; however, a small increase in risk cannot be excluded. If continued ACE inhibitor therapy is considered mandatory, women planning pregnancy should be switched to alternative antihypertensive drugs with established safety data during pregnancy. If pregnancy is confirmed during treatment, ACE inhibitor therapy should be discontinued immediately and, if necessary, replaced with another medication approved for use in pregnant women. It is known that ACE inhibitor use during the second and third trimesters of pregnancy has toxic effects on the fetus (impaired renal function, oligohydramnios, delayed skull ossification) and on the newborn (renal failure, arterial hypotension, hyperkalemia). If ACE inhibitors were used during the second and third trimesters of pregnancy, ultrasound assessment of renal function and skull structure in the newborn is recommended. Newborns whose mothers received ACE inhibitors during pregnancy should be monitored for timely detection and correction of arterial hypotension.

Warnings related to indapamide

Data on indapamide use in pregnant women are lacking or limited (fewer than 300 cases). Prolonged use of a thiazide diuretic during the third trimester of pregnancy may reduce the pregnant woman's circulating blood volume and uteroplacental perfusion, potentially causing fetoplacental ischemia and fetal growth retardation. Animal studies have not revealed direct or indirect toxic effects on reproductive function. As a precaution, indapamide use during pregnancy should be avoided.

Breastfeeding

Noliprel® arginine is not recommended during breastfeeding. A decision should be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the importance of the therapy for the mother.

Warnings related to perindopril

Perindopril use during breastfeeding is not recommended due to lack of data. Alternative therapy with a proven safety profile should be preferred, especially during breastfeeding of a newborn or premature infant.

Warnings related to indapamide

Data on indapamide/metabolite transfer into breast milk are insufficient. Hypersensitivity to sulfonamide derivatives and hypokalemia may develop. Risk to newborns/infants cannot be excluded. Indapamide belongs to thiazide-like diuretics, whose use during breastfeeding is associated with reduced or even suppressed lactation. Indapamide is not recommended during breastfeeding.

Fertility

Warnings common to perindopril and indapamide

Reproductive toxicity studies showed no effect on fertility in male and female animals. No effect on human fertility is expected.

Ability to affect reaction speed when driving or operating machinery.

The two active substances, when used separately or in combination as Noliprel® arginine, do not affect the ability to drive or operate machinery; however, individual reactions related to reduced blood pressure may occur in some patients, especially at the beginning of treatment or when used concomitantly with other antihypertensive drugs. As a result, the ability to drive or operate machinery may be impaired.

Method of Administration and Dosage

For oral use.

The recommended dose of the medicinal product Noliprel® arginine is 1 tablet daily, taken once, preferably in the morning before meals. If blood pressure has not been adequately controlled after 1 month of treatment, the dose may be doubled.

Special Patient Categories

Geriatric patients (see section "Special Warnings and Precautions for Use"). Treatment should be initiated with the recommended dose of Noliprel® arginine – 1 tablet daily.

Renal impairment (see section "Special Warnings and Precautions for Use"). Noliprel® arginine is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min). For patients with moderate renal impairment (creatinine clearance 30–60 mL/min), the maximum daily dose is 1 tablet of Noliprel® arginine. Patients with creatinine clearance ≥ 60 mL/min do not require dose adjustment. Routine medical monitoring should include frequent assessment of plasma creatinine and potassium levels.

Hepatic impairment (see sections "Contraindications", "Special Warnings and Precautions for Use", and "Pharmacokinetics"). Noliprel® arginine is contraindicated in patients with severe hepatic impairment. Patients with moderate hepatic impairment do not require dose adjustment.

Children

Noliprel® arginine should not be used for the treatment of children and adolescents. The safety and efficacy of perindopril arginine/indapamide in pediatric patients have not been established. Data are lacking.

Overdose

Symptoms. In case of overdose, the most common adverse reaction is arterial hypotension, which may sometimes be accompanied by nausea, vomiting, convulsions, dizziness, somnolence, confusion, oliguria, potentially progressing to anuria (due to hypovolemia), and circulatory shock. Electrolyte and fluid imbalances (decreased plasma potassium and sodium levels), renal failure, hyperventilation, tachycardia, palpitations, bradycardia, anxiety, and cough may also occur.

Treatment. First aid measures include rapid elimination of the drug from the body – gastric lavage and/or administration of activated charcoal, followed by correction of fluid and electrolyte imbalances under hospital conditions. In case of significant arterial hypotension, the patient should be placed in a supine position with low head elevation. If necessary, intravenous administration of isotonic sodium chloride solution or other measures to restore blood volume should be performed. Perindoprilat, the active metabolite of perindopril, may be removed from the body by hemodialysis (see section "Pharmacokinetics").

Adverse Reactions

The use of perindopril inhibits the renin-angiotensin-aldosterone system and helps reduce potassium loss in blood plasma caused by indapamide. Hypokalemia (potassium level < 3.4 mmol/L) occurs in 2% of patients treated with Noliprel® Arginine. The most commonly reported adverse reactions are as follows: with perindopril – dizziness, headache, paresthesia, dysgeusia, visual disturbances, vertigo, tinnitus, arterial hypotension, cough, dyspnea, abdominal pain, constipation, dyspepsia, diarrhea, nausea, vomiting, pruritus, rash, muscle cramps, and asthenia; with indapamide – hypokalemia, hypersensitivity reactions (mainly dermatological), particularly in patients predisposed to allergic and asthmatic reactions, and maculopapular rash.

During clinical trials and/or post-marketing use of the medicinal product, the following adverse reactions have been observed and are categorized by frequency as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), and frequency not known (cannot be estimated from available data).

Infections and infestations:
Rhinorrhea (very rare – perindopril).

Endocrine system:
Syndrome of inappropriate antidiuretic hormone secretion (SIADH) (rare – perindopril).

Blood and lymphatic system:
Eosinophilia (uncommon* – perindopril);
Agranulocytosis (see section "Special 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 precautions for use") (very rare – perindopril);
Hemolytic anemia (very rare – perindopril and indapamide);
Thrombocytopenia (see section "Special precautions for use") (very rare – perindopril and indapamide).

Immune system:
Hypersensitivity (mainly dermatological reactions in patients predisposed to allergic and asthmatic reactions) (common – indapamide).

Metabolism and nutrition disorders:
Hypokalemia (see section "Special precautions for use") (common – indapamide);
Hypoglycemia (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction") (uncommon* – perindopril);
Hyperkalemia (reversible upon discontinuation of the drug) (see section "Special precautions for use") (uncommon* – perindopril);
Hyponatremia (see section "Special precautions for use") (uncommon* – perindopril, uncommon – indapamide);
Hypochloremia (rare – indapamide);
Hypomagnesemia (rare – indapamide);
Hypercalcemia (very rare – indapamide).

Psychiatric disorders:
Mood changes (uncommon – perindopril);
Sleep disturbances (uncommon – perindopril);
Depression (uncommon* – perindopril);
Confusion (very rare – perindopril).

Nervous system:
Dizziness (common – perindopril);
Headache (common – perindopril, rare – indapamide);
Paresthesia (common – perindopril, rare – indapamide);
Dysgeusia (common – perindopril);
Somnolence (uncommon* – perindopril);
Syncope (uncommon* – perindopril, frequency not known – indapamide);
Excessive arterial hypotension in high-risk patients may lead to stroke (see section "Special precautions for use") (very rare – perindopril);
In patients with hepatic insufficiency, hepatic encephalopathy may occur (see sections "Contraindications" and "Special precautions for use") (frequency not known – indapamide).

Eye disorders:
Visual disturbances (common – perindopril, frequency not known – indapamide);
Myopia (see section "Special precautions for use") (frequency not known – indapamide);
Blurred vision (frequency not known – indapamide);
Choroidal effusion (frequency not known – indapamide);
Acute angle-closure glaucoma (frequency not known – indapamide).

Ear and labyrinth disorders:
Vertigo (common – perindopril, rare – indapamide);
Tinnitus (common – perindopril).

Cardiac disorders:
Palpitations (uncommon* – perindopril);
Tachycardia (uncommon* – perindopril);
Angina pectoris (see section "Special precautions for use") (very rare – perindopril);
Arrhythmia (including bradycardia, ventricular tachycardia, atrial fibrillation) (very rare – perindopril and indapamide);
Excessive arterial hypotension in high-risk patients may lead to myocardial infarction (see section "Special precautions for use") (very rare – perindopril);
Paroxysmal ventricular tachycardia of the "torsades de pointes" type (potentially fatal) (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction") (frequency not known – indapamide).

Vascular disorders:
Arterial hypotension (and symptoms related to hypotension) (see section "Special precautions for use") (common – perindopril, very rare – indapamide);
Vasculitis (uncommon* – perindopril);
Hot flushes (rare* – perindopril);
Raynaud’s phenomenon (frequency not known – perindopril).

Respiratory, thoracic and mediastinal disorders:
Cough (see section "Special precautions for use") (common – perindopril);
Dyspnea (common – perindopril);
Bronchospasm (uncommon – perindopril);
Eosinophilic pneumonia (very rare – perindopril).

Gastrointestinal disorders:
Abdominal pain (common – perindopril);
Constipation (common – perindopril, rare – indapamide);
Diarrhea (common – perindopril);
Dyspepsia (common – perindopril);
Nausea (common – perindopril, rare – indapamide);
Vomiting (common – perindopril, uncommon – indapamide);
Dry mouth (uncommon – perindopril, rare – indapamide);
Pancreatitis (very rare – perindopril and indapamide).

Hepatobiliary disorders:
Hepatitis (see section "Special precautions for use") (very rare – perindopril, frequency not known – indapamide);
Liver function abnormalities (very rare – indapamide).

Skin and subcutaneous tissue disorders:
Pruritus (common – perindopril);
Rash (common – perindopril);
Maculopapular rash (common – indapamide);
Urticaria (see section "Special precautions for use") (uncommon – perindopril, very rare – indapamide);
Angioedema (see section "Special precautions for use") (uncommon – perindopril, very rare – indapamide);
Purpura (uncommon – indapamide);
Hyperhidrosis (uncommon – perindopril);
Photosensitivity reactions (uncommon* – perindopril, frequency not known – indapamide);
Pemphigoid (uncommon* – perindopril);
Worsening of psoriasis symptoms (rare* – perindopril);
Erythema multiforme (very rare – perindopril);
Toxic epidermal necrolysis (very rare – indapamide);
Stevens-Johnson syndrome (very rare – indapamide).

Musculoskeletal and connective tissue disorders:
Muscle cramps (common – perindopril, frequency not known – indapamide);
Possible exacerbation of existing systemic lupus erythematosus (frequency not known – indapamide);
Arthralgia (uncommon* – perindopril);
Myalgia (uncommon* – perindopril, frequency not known – indapamide);
Muscle weakness (frequency not known – indapamide);
Rhabdomyolysis (frequency not known – indapamide).

Renal and urinary disorders:
Renal impairment (uncommon – perindopril, very rare – indapamide);
Acute renal failure (rare – perindopril);
Anuria/oliguria (rare* – perindopril).

Reproductive system and breast disorders:
Erectile dysfunction (uncommon – perindopril and indapamide).

General disorders and administration site conditions:
Asthenia (common – perindopril);
Chest pain (uncommon* – perindopril);
Malaise (uncommon* – perindopril);
Peripheral edema (uncommon* – perindopril);
Pyrexia (uncommon* – perindopril);
Fatigue (rare – indapamide).

Investigations:
Increased blood urea levels (uncommon* – perindopril);
Increased serum creatinine levels (uncommon* – perindopril);
Increased serum bilirubin levels (rare – perindopril);
Increased liver enzymes (rare – perindopril, frequency not known – indapamide);
Decreased hemoglobin and hematocrit (see section "Special precautions for use") (very rare – perindopril);
Increased blood glucose levels (frequency not known – indapamide);
Increased serum uric acid levels (frequency not known – indapamide);
Prolongation of QT interval on ECG (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction") (frequency not known – indapamide).

Injury, poisoning and procedural complications:
Falls (uncommon* – perindopril).

* Frequency of adverse reactions identified from spontaneous reports, calculated based on clinical trial data.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store tablets in a tightly closed container. No special storage conditions required. Keep out of reach and sight of children.

Packaging.

14 tablets per container; 1 container per cardboard box.

30 tablets per container; 1 or 3 containers per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Les Laboratoires Servier Industrie / Laboratoires Servier Industrie.

Manufacturer's address.

905 route de Saran, 45520 Gidy, France.

Manufacturer.

Servier (Ireland) Industries Ltd.

Manufacturer's address.

Gorey Road, Arklow, Co. Wicklow, Y14 E284, Ireland.

Marketing Authorization Holder.

Les Laboratoires Servier.

Address of Marketing Authorization Holder.

50, rue Carnot, 92284 Suresnes Cedex, France.

For inquiries, please contact LLC "Servier Ukraine" at phone number (044) 490 3441.