Co-pranelia®

Ukraine
Brand name Co-pranelia®
Form tablets
Active substance / Dosage
perindopril · 3.338 mg
indapamide · 1.25 mg
Prescription type prescription only
ATC code
C09BA04
Registration number UA/17442/01/01
Manufacturer PJSC "Kyivmedpreparat" (manufacturing of bulk products from the manufacturer Atlantic Pharma Produsios Farmaceuticas S.A., Portugal or Medinfar Manufacturing S.A., Portugal)
Co-pranelia® tablets

Table of Contents

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CO-PRENELIA® (CO-PRENELIA)

Composition:

Active substances: perindopril, indapamide;

One tablet contains: perindopril tert-butylamine — 4 mg (equivalent to 3.338 mg of perindopril) and indapamide — 1.25 mg, or perindopril tert-butylamine — 8 mg (equivalent to 6.676 mg of perindopril) and indapamide — 2.5 mg;

Excipients: microcrystalline cellulose; lactose monohydrate; colloidal anhydrous silicon dioxide; magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

Tablets 4 mg / 1.25 mg: white, oval-shaped tablets with a groove on both sides and an embossed symbol “+” on each side of the groove on one side of the tablet;

Tablets 8 mg / 2.5 mg: white or almost white, round-shaped tablets with a groove on one side.

Pharmacotherapeutic group. Combined preparations of angiotensin-converting enzyme (ACE) inhibitors. Perindopril and diuretics.

ATC code C09B A04.

Pharmacological Properties

Pharmacodynamics

Co-Prenelia® is a combination of the angiotensin-converting enzyme (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

Mechanism of action of perindopril. Perindopril is an ACE inhibitor that converts angiotensin I to angiotensin II (a vasoconstrictor substance), stimulates aldosterone secretion from the adrenal cortex, and promotes bradykinin (a vasodilating substance) degradation into inactive heptapeptides. Inhibition of ACE leads to: reduced aldosterone secretion; increased plasma renin activity, while aldosterone does not exert a negative feedback 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 prolonged treatment. Additionally, perindopril reduces blood pressure (BP) in patients with normal or 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 via changes in prostaglandin metabolism), decreasing preload, and by reducing total peripheral resistance, thereby decreasing afterload on the heart. Studies in patients with heart failure have demonstrated that perindopril reduces filling pressures in both the left and right ventricles, decreases total peripheral resistance, increases cardiac output and cardiac index, and improves regional blood flow to muscles. Exercise tolerance tests show improved performance.

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 enhancing diuresis and providing antihypertensive effects.

Pharmacodynamic Effects

Co-Prenelia® exerts a dose-dependent antihypertensive effect on systolic blood pressure (SBP) and diastolic blood pressure (DBP) in patients with arterial hypertension of any age, both in supine and standing positions.

This antihypertensive effect lasts for 24 hours. Blood pressure reduction is achieved within less than 1 month without tachyphylaxis; discontinuation of treatment does not lead to rebound hypertension. In clinical trials, concomitant administration of perindopril and indapamide produced synergistic antihypertensive effects compared to each component used alone.

PICXEL — a multicenter, randomized, double-blind, controlled study that evaluated the effect of the combination of perindopril and indapamide on left ventricular hypertrophy compared to enalapril monotherapy, using echocardiography. 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 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 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 maintained 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, the left ventricular mass index decreased significantly more in patients receiving perindopril/indapamide (–10.1 g/m²) than in the enalapril group (–1.1 g/m²). The difference between the two groups was –8.3 (95% confidence interval [CI] from –11.5 to –5.0, p < 0.0001). Greater reduction in left ventricular mass index was achieved with the dose of 8 mg perindopril (equivalent to 10 mg perindopril arginine) / 2.5 mg indapamide. Blood pressure reduction was more effective in the perindopril/indapamide group: the difference in mean BP reduction between the two 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 in both supine and standing positions. The maximum antihypertensive effect develops 4–6 hours after a single dose and lasts more than 24 hours. Perindopril achieves a high level of sustained ACE inhibition (approximately 80%) 24 hours after administration. In patients who respond to treatment, BP normalization is achieved within one month and is maintained without tachyphylaxis. Discontinuation of therapy is not associated with a rebound effect. Perindopril has vasodilatory properties, restores elasticity of large arteries, corrects histomorphometric changes in resistance arteries, and reduces left ventricular hypertrophy. Adding a thiazide diuretic when necessary provides 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. Indapamide as monotherapy exerts an antihypertensive effect lasting 24 hours. This effect is evident 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 exceeds the optimal level, the antihypertensive effect of thiazide and thiazide-like diuretics reaches a plateau, while the incidence 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 plasma 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 tert-butylamine should be administered 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. Protein binding of perindoprilat to plasma proteins is 20%, primarily to ACE, and is concentration-dependent.

Biological transformation. Perindopril is a prodrug. About 27% of the administered dose of perindopril enters the circulation as the active metabolite perindoprilat. In addition to the active perindoprilat, perindopril forms five inactive metabolites. Peak 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 levels are achieved within 4 days.

Linearity/non-linearity. There is a linear relationship between perindopril dose and its plasma concentration.

Special patient populations

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

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

Need for dialysis. Dialysis clearance of perindoprilat is 70 mL/min.

Hepatic cirrhosis. The pharmacokinetics of perindopril are altered in patients with hepatic cirrhosis: hepatic clearance of the parent compound is reduced by half. However, the amount of perindoprilat formed is not reduced; therefore, dose adjustment is not required in these patients (see sections "Dosage and Administration" and "Special Warnings and 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 to plasma proteins is 79%.

Metabolism and elimination. The elimination half-life ranges from 14 to 24 hours (average 18 hours). Repeated administration does not lead to accumulation. Elimination occurs primarily via urine (70% of the dose) and feces (22%) as inactive metabolites.

Special patient populations

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

Clinical characteristics.

Indications.

Treatment of essential hypertension.

Contraindications.

Associated with 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 in pregnancy or breastfeeding");
  • concomitant use with aliskiren-containing products in patients with diabetes 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. Co-Prenelia® 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");
  • significant bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney (see section "Special precautions").

Associated with indapamide:

  • hypersensitivity to the active substance or to any other sulfonamides;
  • moderate to severe renal impairment (creatinine clearance < 60 mL/min);
  • hepatic encephalopathy;
  • severe hepatic impairment;
  • hypokalemia;
  • should not be used in combination with non-antiarrhythmic drugs that may induce torsades de pointes ventricular tachycardia;
  • breastfeeding period (see section "Use in pregnancy or breastfeeding").

Associated with the medicinal product Co-Prenelia®:

  • hypersensitivity to any excipient.

Due to lack of sufficient clinical experience, the medicinal product Co-Prenelia® 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 with perindopril and indapamide

Concomitant use not recommended

Lithium. Reversible increases in serum lithium concentration and increased lithium toxicity have been reported during concomitant use of lithium and ACE inhibitors. Concomitant use of perindopril with indapamide and lithium is not recommended; however, if this combination is truly necessary, serum lithium concentrations should be closely monitored (see section "Special precautions").

Concomitant use requires special attention

Baclofen. Antihypertensive effect is enhanced. Blood pressure should be monitored and the dose of antihypertensive agent adjusted as needed.

Non-steroidal 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 non-selective NSAIDs, may result in reduced antihypertensive effect. Concomitant use of ACE inhibitors and NSAIDs may lead to worsening of renal function, including acute renal failure, and increased serum potassium levels, particularly in patients with renal impairment. 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 requires attention

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

Interactions with perindopril

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

Medicinal products causing hyperkalemia. Serum potassium levels usually remain within normal limits, but hyperkalemia may occur in some patients treated with Co-Prenelia®. 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 cotrimoxazole [trimethoprim/sulfamethoxazole] (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 Co-Prenelia® with the above-mentioned agents is not recommended. If concomitant use is necessary, it should be done with caution and close monitoring of serum potassium levels.

Concomitant use contraindicated (see section "Contraindications")

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

Extracorporeal treatment methods 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, are contraindicated due to increased risk of severe anaphylactoid reactions (see section "Contraindications"). If such treatment is required, consideration should be given to using a different type of dialysis membrane or another class of antihypertensive agents.

Concomitant use not recommended

Aliskiren. In all other patients, including those with diabetes or renal impairment, increased risk of hyperkalemia, worsening of renal function, cardiovascular events, and mortality (see section "Special precautions").

Concomitant therapy with an ACE inhibitor and an angiotensin receptor blocker. Published data show that in patients with atherosclerosis, heart failure, or diabetic patients with target organ damage, concomitant therapy with an ACE inhibitor and an angiotensin receptor blocker is associated with increased incidence of arterial hypotension, syncope, hyperkalemia, and worsening of renal function (including acute renal failure) compared to use of a single agent affecting the renin-angiotensin-aldosterone system. Dual blockade (i.e., combination of an ACE inhibitor and an angiotensin II receptor antagonist) may be considered only in selected cases with strict monitoring of renal function, serum potassium levels, 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 renal impairment (additive hyperkalemic effect). Combination of perindopril with the above-mentioned medicinal products is not recommended (see section "Special precautions"). If concomitant use is indicated, it should be done with caution and frequent monitoring of serum potassium levels. For use of spironolactone in heart failure patients, see the section "Concomitant use requires special attention" below.

Concomitant use requires special attention

Antidiabetic agents (insulin, oral hypoglycemic agents). Epidemiological studies indicate that concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemic agents) may enhance the glucose-lowering effect, increasing the risk of hypoglycemia. This phenomenon is more likely during the first weeks of combination therapy and in patients with renal impairment.

Diuretics. In patients receiving diuretics, especially those with volume and sodium depletion, excessive reduction in blood pressure may occur after initiation of ACE inhibitor therapy. The risk of hypotensive effects can be reduced by discontinuing the diuretic, increasing circulating blood volume, or increasing salt intake before starting perindopril therapy, which should begin with a low dose and be gradually increased. For hypertensive patients in whom prior diuretic therapy may have caused volume/sodium depletion, diuretic therapy should be discontinued before starting ACE inhibitor therapy (diuretic therapy may be resumed later), or ACE inhibitor therapy should be initiated with a low dose and gradually increased. 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 (creatinine levels) should be monitored during the first few weeks of ACE inhibitor therapy.

Potassium-sparing diuretics (eplerenone, spironolactone). When eplerenone or spironolactone (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%, who have previously received ACE inhibitors and loop diuretics, there is a risk of potentially fatal hyperkalemia, especially if recommendations for use are not followed. Hyperkalemia and renal impairment should be excluded before initiating such combination therapy. Close monitoring of serum potassium and creatinine levels is recommended weekly during the first month and monthly thereafter.

Concomitant use requires 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 increases the risk of leukopenia (see section "Special precautions").

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

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

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

Interactions with indapamide

Concomitant use requires special attention

Medicinal products that may induce torsades de pointes ventricular tachycardia. Due to the risk of hypokalemia, indapamide should be used with caution in combination with medicinal products that may induce torsades de pointes ventricular tachycardia, namely (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, sultopride, tiapride), butyrophenones (e.g., droperidol, haloperidol), other antipsychotics (e.g., pimozide); other agents (e.g., bepridil, cisapride, difemanyl, 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 blood potassium levels. Intravenous amphotericin B, glucocorticoids and mineralocorticoids (systemic), tetracosactide, stimulant laxatives increase the risk of reduced serum potassium levels (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 enhance the toxic effects of cardiac glycosides. 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 requires attention

Potassium-sparing diuretics (amiloride, spironolactone, triamterene). Despite the rationale for using this combination in certain patients, hypokalemia or hyperkalemia may occur (especially in patients with renal impairment or diabetes). Serum potassium levels should be monitored, ECG monitoring performed, and therapy adjusted if necessary.

Metformin. May cause lactic acidosis due to functional renal impairment associated with diuretic use, particularly loop diuretics. Metformin should not be used if plasma creatinine levels exceed 15 mg/L (135 µmol/L) in men and 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 blood calcium levels due to reduced urinary excretion.

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

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

Special precautions for use.

Special warnings

Special warnings regarding the combination of perindopril and indapamide

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

Special warnings regarding perindopril

Double 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 hypotension, hyperkalaemia, and impaired renal function (including acute renal failure). Therefore, dual blockade of the RAAS by concomitant 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 dual RAAS blockade therapy is considered absolutely necessary, it should be administered 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, potassium supplements, or potassium-containing salt substitutes is generally 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 observed in patients receiving 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 vascular diseases, those receiving immunosuppressants, allopurinol, or procainamide, or in patients with a combination of these risk factors, especially in the presence of impaired renal function. Some of these patients have developed severe infections, sometimes resistant to intensive antibiotic therapy. Periodic monitoring of white blood cell counts 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) (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, treatment with ACE inhibitors increases the risk of hypotension and renal failure (see section "Contraindications"). Diuretic therapy may be an additional risk factor. Impaired renal function may be associated with only minor changes in serum creatinine levels, even in patients with unilateral renal artery stenosis.

Hypersensitivity / angioedema (angio-oedema). Rare cases of angioedema of the face, extremities, lips, tongue, glottis, and/or larynx have been observed in patients receiving ACE inhibitors, including perindopril (see section "Undesirable effects"). Angioedema 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, symptoms usually improve without treatment, although antihistamines may help relieve symptoms. Angioedema of the larynx may be fatal. If swelling involves the tongue, glottis, or larynx, potentially leading to airway obstruction, emergency treatment is required, which may include subcutaneous administration of epinephrine 1:1000 (0.3–0.5 mL) and/or measures to ensure airway patency. Angioedema occurs 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 presented with abdominal pain (with or without nausea and vomiting); intestinal angioedema sometimes occurred without prior facial angioedema, and C1-esterase inhibitor levels were within normal range. Diagnosis of angioedema was confirmed by abdominal computed tomography, ultrasound, or during surgical intervention; symptoms resolved after discontinuation of the ACE inhibitor. In patients receiving 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 (see section "Contraindications"). Sacubitril/valsartan should not be initiated earlier than 36 hours after the last dose of perindopril. If 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 forms of interaction"). 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) increases the risk of angioedema (e.g., airway or tongue swelling, with or without respiratory compromise) (see section "Interaction with other medicinal products and other forms of interaction"). Caution is advised when initiating therapy 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 life-threatening, prolonged anaphylactoid reactions have been reported in patients receiving ACE inhibitors during desensitization therapy with bee venom-containing preparations. ACE inhibitors should be used with caution in patients undergoing allergen desensitization and should be avoided during immunotherapy with bee venom-containing preparations. 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 low-density lipoprotein (LDL) apheresis. Life-threatening anaphylactoid reactions have rarely occurred in patients receiving ACE inhibitors during LDL apheresis using dextran sulfate. These reactions can be avoided by temporarily withholding ACE inhibitor therapy before each apheresis session.

Patients on haemodialysis. Cases of anaphylactoid reactions have been reported in patients receiving ACE inhibitors during haemodialysis 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 agents acting via inhibition of the renin-angiotensin system. Therefore, this medication is not recommended for such patients.

Patients after kidney transplantation. There is no experience with the use of perindopril arginine in patients following recent kidney transplantation.

Arterial hypotension. Symptomatic hypotension has been reported in patients with symptomatic heart failure, with or without concomitant renal impairment. The risk of symptomatic hypotension is higher in patients with more severe heart failure, those receiving high-dose loop diuretics, those with hyponatraemia, 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 hypotension. These precautions also apply to patients with ischaemic heart disease or cerebrovascular disease, in whom excessive blood pressure reduction may precipitate myocardial infarction or stroke.

Ischaemic heart disease. If an episode of unstable angina (of any severity) occurs during the first month of perindopril therapy, the risk-benefit ratio should be carefully evaluated before deciding on continuing therapy.

Special warnings regarding 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 "Undesirable effects"). If a photosensitivity reaction occurs during treatment, drug discontinuation is recommended. If reinitiation is necessary, protection of exposed skin from sunlight or artificial ultraviolet sources is advised.

Precautionary measures

Precautionary measures for the use of perindopril/indapamide combination

Renal impairment. The use of this medication is contraindicated in patients with moderate to severe renal impairment (creatinine clearance < 60 mL/min). In some patients with arterial hypertension and no signs of renal impairment, laboratory blood tests may reveal signs of functional renal impairment; in such cases, treatment should be discontinued and may be resumed at a lower dose or with one of the components alone. These patients require careful monitoring of serum potassium and creatinine levels: 2 weeks after initiation of therapy and every 2 months thereafter 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 depletion (especially those with renal artery stenosis) are at risk of a sudden drop in blood pressure. Regular monitoring for clinical signs of fluid and electrolyte depletion, which may occur during intercurrent vomiting or diarrhoea, is necessary. Plasma electrolyte levels should be monitored regularly in these patients. In cases of significant hypotension, intravenous infusion of isotonic sodium chloride solution may be required. Transient hypotension is not a contraindication to continuing therapy. After restoration of circulating blood volume and normalization of blood pressure, therapy may be resumed at a reduced dose or with one of the components alone.

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

Excipients. This medicinal product should not be administered to patients with rare hereditary galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.

Precautionary measures for the use of 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, an iatrogenic cause should be considered. If ACE inhibitor therapy is necessary for the patient, continuation of treatment may be considered.

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 in acute fluid and electrolyte depletion (e.g., strict salt-free diet or prolonged diuretic therapy) in patients with low blood pressure, renal artery stenosis, congestive heart failure, or cirrhosis with oedema and ascites. Blocking this system with an ACE inhibitor, especially during initial use and the first 2 weeks of treatment, may cause a marked drop in blood pressure and/or increased plasma creatinine levels, indicating functional renal impairment. This disorder may rarely occur at any time and may have an acute onset. In such cases, treatment should be initiated with a lower dose, gradually increasing it.

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 ischaemic heart disease or cerebral circulation insufficiency, starting treatment with a low dose.

Renovascular hypertension. Revascularization is the treatment of choice for renovascular hypertension. However, ACE inhibitors may be beneficial for patients with renovascular hypertension awaiting surgery or when surgery is not feasible. Co-Prenelia® should not be prescribed to patients with known or suspected renal artery stenosis. In such cases, treatment should be initiated in a hospital setting with a lower dose than the recommended dose.

Heart failure / severe heart failure. Co-Prenelia® should not be prescribed to patients with severe heart failure (class IV), as treatment should be initiated under medical supervision with a reduced initial dose. β-blocker therapy in patients with hypertension and coronary insufficiency should not be discontinued; an ACE inhibitor should be added to β-blocker therapy.

Patients with diabetes mellitus. Co-Prenelia® should not be prescribed to patients with insulin-dependent diabetes mellitus (due to a spontaneous tendency towards elevated serum potassium levels), as treatment should be initiated under medical supervision with a reduced initial dose. In patients with diabetes mellitus previously treated with oral hypoglycaemic agents or insulin, careful monitoring of blood glucose levels is required, especially during the first month of ACE inhibitor therapy (see section "Interaction with other medicinal products and other forms of interaction").

Racial factors. 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 / anaesthesia. ACE inhibitors may cause arterial hypotension during anaesthesia, particularly when anaesthetics with hypotensive potential are used. Therefore, therapy with long-acting ACE inhibitors such as perindopril should be discontinued, if possible, 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 inhibitors have been associated with a syndrome beginning with cholestatic jaundice and progressing to rapidly developing hepatic necrosis, sometimes fatal. The mechanism of this syndrome is unclear. Patients who develop jaundice with elevated liver enzymes during ACE inhibitor therapy should discontinue the ACE inhibitor and receive appropriate medical supervision (see section "Undesirable effects").

Hyperkalaemia. Increased serum potassium levels have been observed in some patients receiving ACE inhibitors, including perindopril—ACE inhibitors may cause hyperkalaemia due to aldosterone suppression. In patients with normal renal function, this effect is usually mild. Risk factors for hyperkalaemia include renal impairment, worsening renal function, age over 70 years, diabetes mellitus, intercurrent conditions (especially dehydration, acute heart decompensation, metabolic acidosis), and concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, amiloride), potassium supplements or potassium-containing salt substitutes, or other drugs associated with increased serum potassium levels (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 receptor blockers. Concomitant 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 levels. Hyperkalaemia may cause serious, sometimes fatal, arrhythmias. Patients receiving ACE inhibitors should use potassium-sparing diuretics and angiotensin receptor blockers with caution, and careful monitoring of serum potassium levels and renal function is required.

If concomitant use of the above-mentioned medicinal products is considered appropriate, they should be used with caution and with frequent monitoring of serum potassium levels (see section "Interaction with other medicinal products and other forms of interaction").

Precautionary measures for the use of indapamide

Water and electrolyte balance

Sodium levels. Plasma sodium levels should be determined regularly before and during treatment. Hyponatraemia may initially be asymptomatic, necessitating regular monitoring. Monitoring should be more frequent in elderly patients and patients with cirrhosis (see sections "Undesirable effects" and "Overdose"). Any diuretic therapy may cause hyponatraemia, sometimes with very serious consequences. Hyponatraemia combined with hypovolaemia may lead to dehydration and orthostatic hypotension. Concomitant loss of chloride ions may lead to secondary compensatory metabolic alkalosis: the frequency and severity of this effect are low.

Potassium levels. Hypokalaemia is the main risk factor associated with thiazide and thiazide-like diuretics. Hypokalaemia may cause muscle disorders. Cases of rhabdomyolysis, mainly associated with severe hypokalaemia, have been reported. Hypokalaemia (< 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 accompanied by oedema and ascites, and patients with ischaemic heart disease and heart failure. In these cases, hypokalaemia increases the cardiotoxicity of cardiac glycosides and the risk of cardiac arrhythmias.

Patients with congenital or iatrogenic prolonged QT interval also belong to the risk group. Hypokalaemia, as well as bradycardia, may predispose to severe cardiac arrhythmias, particularly paroxysmal torsades de pointes, 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. Detected hypokalaemia requires correction. Hypokalaemia 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 urinary calcium excretion and lead to a slight, transient increase in serum calcium levels. A marked increase in serum calcium levels 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 hypomagnesaemia (see sections "Interaction with other medicinal products and other forms of interaction" and "Undesirable effects").

Blood glucose levels. Monitoring blood glucose levels is very important for patients with diabetes mellitus, especially when potassium levels are low.

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

Renal function and diuretics. Thiazide and thiazide-like diuretics are most effective when renal function is normal or only slightly 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 (clcr) = (140 – age) × body weight / 0.814 × plasma creatinine level,

where age is in years, body weight in kilograms, and plasma creatinine level in micromoles per litre.

This formula is used to calculate plasma creatinine levels in elderly men; for women, the result should be multiplied by 0.85.

Hypovolaemia caused by loss of water and sodium 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 consequences in patients with normal renal function but may worsen pre-existing renal impairment.

For athletes. Athletes should be aware that this medicinal product contains an active substance that may lead to a positive result in doping controls.

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 drug. Untreated acute angle-closure glaucoma may lead to permanent vision loss. The primary treatment is immediate discontinuation of the drug. If intraocular pressure remains uncontrolled, medical or surgical intervention may be required. A risk factor for acute angle-closure glaucoma is a history of allergy to sulfonamides or penicillin.

Use during pregnancy or breastfeeding.

Pregnancy

This medicinal product is contraindicated in pregnant women or women planning to become pregnant.

Perindopril. Convincing epidemiological evidence of teratogenic risk with ACE inhibitors during the first trimester of pregnancy is lacking; however, a small increased risk cannot be excluded. If continued ACE inhibitor therapy is considered necessary, women planning pregnancy should be switched to alternative antihypertensive agents with established safety data during pregnancy. If pregnancy is confirmed during treatment, ACE inhibitor therapy should be discontinued immediately and, if necessary, replaced with a medicinal product approved for use during pregnancy. 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, hypotension, hyperkalaemia). If ACE inhibitors were used during the second and third trimesters of pregnancy, ultrasound examination of neonatal renal function and skull structure is recommended. Newborns whose mothers received ACE inhibitors during pregnancy should be monitored for timely detection and correction of hypotension.

Indapamide. Data on the use of indapamide 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 ischaemia and delayed fetal development. Animal studies did not reveal direct or indirect toxic effects on reproductive function. As a precaution, indapamide use during pregnancy should be avoided.

Breastfeeding

Co-Prenelia® is not recommended for women during breastfeeding. A decision should be made whether to discontinue breastfeeding or discontinue the medicinal product, taking into account the importance of therapy for the mother.

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 preterm infant.

Indapamide. Data on the passage of indapamide/metabolites into breast milk are insufficient. Hypersensitivity to sulfonamide derivatives and hypokalaemia 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

Perindopril/indapamide. Reproductive toxicity studies showed no effect on fertility in male and female animals. An effect on human fertility is not expected.

Ability to affect reaction speed when driving or operating machinery.

The active substances perindopril and indapamide, when used alone or in combination as the medicinal product Co-Prenelia®, do not affect the ability to drive or operate machinery. However, some patients may experience individual reactions related to decreased blood pressure, especially at the beginning of treatment or when used concomitantly with other antihypertensive agents. As a result, the ability to drive or operate machinery may be impaired.

Method of Administration and Dosage

For oral use.

Co-Pranelia®, tablets 4 mg / 1.25 mg is indicated for patients whose blood pressure is not adequately controlled by monotherapy with perindopril alone. The usual dose is 1 tablet of Co-Pranelia® 4 mg / 1.25 mg once daily, preferably in the morning before a meal.

Whenever possible, individual titration with the individual components is recommended.

Co-Pranelia® 4 mg / 1.25 mg should be prescribed when blood pressure is not controlled by lower doses of combined perindopril/indapamide preparations.

In the presence of clinical indications, a direct switch from perindopril monotherapy to Co-Pranelia® 4 mg / 1.25 mg tablets may be considered.

Co-Pranelia®, tablets 8 mg / 2.5 mg is indicated for the treatment of arterial hypertension as a replacement in patients already receiving perindopril and indapamide concomitantly at the same doses. The usual dose is 1 tablet of Co-Pranelia® 8 mg / 2.5 mg once daily, preferably in the morning before a meal.

The maximum daily dose is 1 tablet of Co-Pranelia® 8 mg / 2.5 mg.

Special Patient Categories

Elderly patients (see section "Special Warnings and Precautions for Use"). Plasma creatinine levels should be assessed in elderly patients, taking into account age, body weight, and gender. Treatment in elderly patients may be initiated if renal function is normal and after considering the blood pressure response to therapy.

Renal impairment (see section "Special Warnings and Precautions for Use"). The use of this medicinal product is contraindicated in patients with moderate to severe renal impairment (creatinine clearance < 60 mL/min).

For patients with moderate renal impairment (creatinine clearance 30–60 mL/min), treatment should be initiated with appropriate dose titration of the individual components of the combination.

Patients with creatinine clearance ≥ 60 mL/min do not require dose adjustment.

Regular medical monitoring should include careful monitoring of plasma creatinine and potassium levels.

Hepatic impairment (see sections "Contraindications", "Special Warnings and Precautions for Use", and "Pharmacokinetics"). The use of this medicinal product is contraindicated in patients with severe hepatic impairment. Patients with moderate hepatic impairment do not require dose adjustment.

Children

Co-Pranelia® should not be used in children and adolescents. The safety and efficacy of perindopril tert-butylamine / 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, which may progress 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. Emergency measures include rapid elimination of the drug from the body—gastric lavage and/or administration of activated charcoal. Subsequently, fluid and electrolyte balance should be normalized 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

Administration of perindopril inhibits the renin-angiotensin-aldosterone system and reduces potassium loss in blood plasma caused by indapamide. Hypokalemia (potassium level < 3.4 mmol/L) occurs in 6% of patients treated with Co-Perenelia®. The most commonly reported adverse reactions are:

With perindopril use — 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 use — hypokalemia, hypersensitivity reactions (mainly dermatological), particularly in patients predisposed to allergic and asthmatic reactions, and maculopapular rashes.

During clinical trials and/or post-marketing use of the medicinal product, the following adverse reactions have been observed, categorized by frequency: 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), frequency not known (cannot be estimated from available data).

Infections and infestations: rhinitis (very rare — perindopril).

Endocrine system disorders: syndrome of inappropriate antidiuretic hormone secretion (SIADH) (rare — perindopril).

Blood and lymphatic system disorders: 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 disorders: 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 disorders: 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); stroke may occur due to excessive arterial hypotension in high-risk patients (see section "Special precautions for use") (very rare — perindopril); hepatic encephalopathy may occur in patients with hepatic insufficiency (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); myocardial infarction may occur due to excessive arterial hypotension in high-risk patients (see section "Special precautions for use") (very rare — perindopril); paroxysmal torsades de pointes ventricular tachycardia (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 associated with 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); hepatic function abnormalities (very rare — indapamide).

Skin and subcutaneous tissue disorders: pruritus (common — perindopril); rash (common — perindopril); maculopapular rashes (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); exacerbation 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 worsening 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 failure (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 blood creatinine levels (uncommon* — perindopril); increased blood bilirubin levels (rare — perindopril); increased liver enzymes (rare — perindopril; frequency not known — indapamide); decreased hemoglobin and hematocrit levels (see section "Special precautions for use") (very rare — perindopril); increased blood glucose levels (frequency not known — indapamide); increased blood uric acid levels (frequency not known — indapamide); QT interval prolongation 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 from clinical trial data.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after medicinal product registration is of great importance. 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 from the date of manufacture in bulk.

Storage conditions.

Tablets 4 mg / 1.25 mg: store in original packaging at a temperature not exceeding 30 °C.

Keep out of reach and sight of children.

Tablets 8 mg / 2.5 mg: no special storage conditions required. Store in original packaging. Keep out of reach and sight of children.

Packaging.

10 tablets in a blister; 3 blisters per carton.

Prescription status. Prescription only.

Manufacturer. JSC "Kyivmedpreparat".

Manufacturer's address and location of business activity.

139 Saksaganskoho Street, Kyiv, 01032, Ukraine.