Perindopress® duo: detailed information

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PERINDOPRES® DUO (PERINDOPRES DUO)

Composition:

Active substances: perindopril, indapamide;

Perindopres® Duo, tablets 4 mg/1.25 mg

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

Perindopres® Duo, tablets 8 mg/2.5 mg

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

Excipients: lactose monohydrate, microcrystalline cellulose, crospovidone, colloidal anhydrous silica, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white or almost white, flat cylindrical tablets with a bevel.

Pharmacotherapeutic group. Combined angiotensin-converting enzyme (ACE) inhibitors. Perindopril and diuretics. ATC code C09B A04.

Pharmacological Properties.

Pharmacodynamics.

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

Mechanism of action

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) breakdown into inactive heptapeptides. By inhibiting ACE, perindopril reduces aldosterone secretion, increases plasma renin activity without negative effects from aldosterone, and decreases total peripheral vascular resistance due to its predominant effect on muscle and renal vessels. Water and salt retention or reflex tachycardia are not observed, even during long-term treatment. Furthermore, perindopril reduces arterial 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 due to its vasodilatory effect on veins (possibly via changes in prostaglandin metabolism), reducing preload, and by decreasing total peripheral resistance, thereby reducing afterload on the heart. Studies conducted in patients with heart failure have demonstrated that perindopril reduces filling pressures in the left and right ventricles, decreases total peripheral resistance, increases cardiac output and cardiac index, and improves regional blood flow in muscles. Exercise tolerance tests show improved performance.

Indapamide is a sulfonamide derivative with an indole ring, pharmacologically related to the thiazide diuretic group. 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, thus enhancing diuresis. This mechanism provides antihypertensive effects.

Pharmacodynamic effects

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

Perindopril. Perindopril effectively reduces BP in all stages of arterial hypertension: mild, moderate, and severe. Reductions in SBP and DBP are observed both in the supine and standing positions. The maximum antihypertensive effect develops 4–6 hours after a single dose and lasts more than 24 hours. Perindopril provides a high level of 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 withdrawal syndrome. Perindopril has vasodilatory properties, restores elasticity of large arteries, corrects histomorphometric changes in resistance arteries, and reduces left ventricular hypertrophy. Additional use of a thiazide diuretic, if necessary, results in further synergism. Combined use of an ACE inhibitor and a thiazide diuretic reduces the risk of hypokalemia that may occur with diuretic monotherapy.

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, reduced arteriolar resistance, and decreased total peripheral vascular resistance. Indapamide reduces left ventricular hypertrophy. For thiazide and thiazide-like diuretics, antihypertensive effects reach a plateau with dose escalation, while adverse effects increase. If treatment is insufficiently effective, the dose should not be increased. In short-, medium-, and long-term studies involving patients with arterial hypertension, indapamide did not affect lipid metabolism (triglycerides, low- and high-density lipoproteins) and had no effect on 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 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. Protein binding of perindoprilat to plasma proteins is 20%, primarily to ACE, and is dose-dependent.

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

Elimination. Perindoprilat is excreted in the 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 its plasma concentration has been demonstrated.

Special patient populations

Elderly patients. Elimination of perindoprilat is reduced in elderly patients and in individuals with cardiac or renal insufficiency.

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.

Hepatic cirrhosis. The kinetics of perindopril are altered in patients with hepatic cirrhosis: hepatic clearance of the parent compound is halved, but the amount of perindoprilat formed does not decrease (see sections "Special precautions for use" and "Dosage and administration").

Pharmacokinetic properties of indapamide

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

Distribution. Protein binding in plasma is 79%.

Biological transformation and elimination. The elimination half-life ranges from 14 to 24 hours (average 18 hours). Repeated dosing 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 insufficiency.

Clinical characteristics.

Indications.

Essential hypertension.

Contraindications.

Related to perindopril:

Hypersensitivity to perindopril 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 renal impairment (glomerular filtration rate < 60 mL/min/1.73 m²) or with diabetes mellitus (see section "Interaction with other medicinal products and other forms of interaction");
Concomitant use with sacubitril/valsartan (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions");
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 solitary functioning kidney (see section "Special precautions").

Related to indapamide:

Hypersensitivity to indapamide or to any other sulfonamides;
Severe renal impairment (creatinine clearance < 30 mL/min) for the 4 mg/1.25 mg dosage;
Moderate to severe renal impairment (creatinine clearance < 60 mL/min) for the 8 mg/2.5 mg dosage;
Hepatic encephalopathy;
Severe hepatic impairment;
Hypokalemia;
As a general rule, this medicinal product should not be prescribed in combination with non-antiarrhythmic drugs that may induce torsades de pointes;
Breastfeeding period (see section "Use during pregnancy or breastfeeding").

Related to the medicinal product Perindopres® Duo:

Hypersensitivity to any excipient of the medicinal product.

Due to insufficient clinical experience, Perindopres® Duo 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. Increased, reversible serum lithium concentrations and 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 necessary, serum lithium concentrations should be closely monitored (see section "Special precautions").

Concomitant use requiring special attention

Baclofen. Antihypertensive effect is enhanced. Blood pressure should be monitored and the dose of antihypertensive agent 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 non-selective NSAIDs, may result in attenuation of the antihypertensive effect. Concomitant use of ACE inhibitors and NSAIDs may increase the risk of renal impairment, including acute renal failure, and hyperkalemia, particularly in patients with pre-existing 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 requiring attention

Imipramine-like (tricyclic) antidepressants, neuroleptics. Enhance antihypertensive effect 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 renal dysfunction (including acute renal failure), compared to use of a single RAAS-acting agent (see sections "Pharmacodynamics", "Contraindications", and "Special precautions").

Medicinal products causing hyperkalemia. Certain medicinal products or therapeutic classes, such as aliskiren, potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, NSAIDs, heparins, immunosuppressants (e.g., cyclosporine or tacrolimus, trimethoprim), may cause hyperkalemia. Combination of these agents increases the risk of hyperkalemia.

Concomitant use contraindicated (see section "Contraindications")

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

Extracorporeal treatment methods. 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 (LDL) apheresis using dextran sulfate, are contraindicated due to increased risk of severe anaphylactoid reactions (see section "Contraindications"). If such treatment is necessary, consider using a different dialysis membrane or another class of antihypertensive agents.

Sacubitril/valsartan. Concomitant use of perindopril with sacubitril/valsartan is contraindicated, as simultaneous inhibition of neprilysin and ACE may increase the risk of angioedema. Initiation of sacubitril/valsartan should not occur earlier than 36 hours after the last dose of perindopril. Initiation of perindopril therapy should not occur earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Special precautions").

Concomitant use not recommended

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

Concomitant therapy with an ACE inhibitor and an angiotensin receptor blocker. Published reports indicate that in patients with established atherosclerosis, heart failure, or diabetes 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 renal dysfunction (including acute renal failure) compared to use of a single RAAS-acting agent. Dual blockade (i.e., combination of an ACE inhibitor and an 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 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 necessary, 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 in the section "Concomitant use requiring special attention".

Co-trimoxazole (trimethoprim/sulfamethoxazole). In patients receiving co-trimoxazole, increased risk of hyperkalemia may occur (see section "Special precautions").

Concomitant use requiring special attention

Antidiabetic agents (insulin, oral hypoglycemic agents). Epidemiological studies suggest that concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemic agents) may enhance the glucose-lowering effect with 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, 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 the diuretic, increasing intravascular volume, or increasing salt intake prior to starting perindopril therapy, which should be initiated at a low dose with gradual dose escalation. In hypertensive patients previously treated with diuretics who may have volume/sodium depletion, the diuretic should be discontinued before starting ACE inhibitor therapy (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 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%, 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. Careful monitoring of serum potassium and creatinine is recommended weekly during the first month and monthly thereafter.

Racecadotril. ACE inhibitors (e.g., perindopril) are known to cause angioedema. This risk may increase with concomitant use of racecadotril (a drug used to treat acute diarrhea).

mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus). In patients receiving mTOR inhibitors concomitantly, increased risk of angioedema may occur (see section "Special precautions").

Concomitant use requiring attention

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

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 certain anesthetic agents (see section "Special precautions").

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

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

Gold preparations. Rare cases of nitritoid reactions (symptoms: facial flushing, nausea, vomiting, and hypotension) have been reported in patients treated with injectable gold preparations (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 with caution in combination with medicinal products that may induce torsades de pointes, such as class IA antiarrhythmics (quinidine, hydroquinidine, disopyramide); class III antiarrhythmics (amiodarone, dofetilide, ibutilide, bretylium, sotalol); certain neuroleptics (chlorpromazine, zuclopenthixol, levomepromazine, thioridazine, trifluoperazine), benzamides ( amisulpride, sulpiride, sultopride, tiapride), butyrophenones (droperidol, haloperidol), other neuroleptics (pimozide), and other agents such as bepridil, cisapride, difemanil, intravenous erythromycin, halofantrine, mizolastine, moxifloxacin, pentamidine, sparfloxacin, intravenous vinpocetine, 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 decreased serum potassium levels (additive effect). Plasma 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. Plasma potassium and magnesium levels and ECG should be monitored, and therapy should be reviewed 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). Although this combination may be rational in some patients, hypokalemia or hyperkalemia may occur (especially in patients with renal impairment or diabetes mellitus). Plasma potassium levels should be monitored, ECG monitoring should be performed, and therapy should be 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 blood calcium levels due to reduced urinary excretion.

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

Corticosteroids, tetracosactide (systemic). Reduce antihypertensive effect (due to water and sodium retention induced by corticosteroids).

Special precautions for use.

Special warnings

Special warnings common to 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 related to perindopril

Dual blockade of the RAAS. Data indicate that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of hypotension, hyperkalaemia, and renal dysfunction (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 performed only under specialist supervision 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.

Drugs that retain potassium, potassium supplements, or potassium-containing salt substitutes. 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 forms of interaction").

Neutropenia/agranulocytosis/thrombocytopenia/anemia. 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 vascular diseases, those receiving immunosuppressants, allopurinol, or procainamide, or in patients with a combination of these risk factors, particularly if renal function is impaired. Some of these patients have developed severe infections, sometimes resistant to intensive antibiotic therapy. Periodic monitoring of white blood cell count is recommended during perindopril therapy in such patients. In addition, patients should be informed to report any signs of infection (e.g., sore throat, fever) to their physician (see sections "Interaction with other medicinal products and other forms of interaction" 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 hypotension and renal failure (see section "Contraindications"). Diuretic use may be a contributing factor. Impaired renal function may be accompanied only by 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 maintained until symptoms completely resolve. If swelling is limited to the face and lips, the condition usually resolves without treatment, although antihistamines may help relieve symptoms. Angioedema involving the larynx may be fatal. If swelling involves the tongue, glottis, or larynx, potentially causing airway obstruction, immediate 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 non-black race receiving ACE inhibitors compared to other races. 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 normal. Diagnosis of angioedema was confirmed by procedures such as abdominal computed tomography, ultrasound, or during surgery; symptoms resolved after discontinuation of the ACE inhibitor. In patients presenting with abdominal pain while taking ACE inhibitors, differential diagnosis should be performed to exclude intestinal angioedema. Concomitant use of perindopril with sacubitril/valsartan is contraindicated due to 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 other neutral endopeptidase (NEP) inhibitors (e.g., racecadotril) with ACE inhibitors may also increase the risk of angioedema (see section "Interaction with other medicinal products and other forms of interaction"). Therefore, a careful benefit-risk assessment should be performed before initiating NEP inhibitor therapy (e.g., racecadotril) in patients receiving perindopril.

Concomitant use of mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus). In patients receiving concomitant mTOR inhibitors, there may be an increased risk of angioedema, including swelling of the airways or tongue, with or without respiratory impairment (see section "Interaction with other medicinal products and other forms of interaction").

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 preparations. ACE inhibitors should be used cautiously in patients with allergies undergoing desensitization and avoided during immunotherapy with bee venom-containing preparations. However, in patients requiring both ACE inhibitors and desensitization, such reactions may be avoided by temporarily discontinuing the ACE inhibitor at least 24 hours before starting desensitization therapy.

Anaphylactoid reactions during LDL apheresis. Rare, life-threatening anaphylactoid reactions have occurred in patients receiving ACE inhibitors during LDL apheresis using dextran sulfate. These reactions may be avoided by temporarily discontinuing 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 usually 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. Experience with perindopril tert-butylamine in patients after recent kidney transplantation is lacking.

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

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

Special warnings related to indapamide

Hepatic encephalopathy. Thiazide and thiazide-like diuretics may precipitate hepatic encephalopathy in patients with impaired liver function. Hepatic encephalopathy is a contraindication to the use of the medicinal product.

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, vulnerable areas should be protected from sunlight or artificial ultraviolet sources.

Precautions.

Precautions common to perindopril and indapamide

Renal function impairment. Use of Perindopres® Duo 4 mg/1.25 mg is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min).

Use of Perindopres® Duo 8 mg/2.5 mg is contraindicated in patients with moderate to severe renal impairment (creatinine clearance < 60 mL/min). In some patients with arterial hypertension but no apparent signs of renal impairment, laboratory blood tests may reveal signs of functional renal impairment; in such cases, treatment should be discontinued with the possibility of resuming at a lower dose or with one of its components alone.

Such patients require frequent monitoring of serum potassium and creatinine levels: 2 weeks after initiation of treatment and then every 2 months during therapeutic stabilization. Renal impairment has been observed primarily in patients with severe heart failure or renal dysfunction, particularly with 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 water and electrolyte depletion. Patients with sodium depletion (especially with renal artery stenosis) are at risk of sudden blood pressure reduction. Systematic monitoring for clinical signs of water and electrolyte depletion, which may occur during intercurrent vomiting or diarrhea, is required. Plasma electrolyte levels should be regularly monitored in such patients. In cases of significant hypotension, intravenous infusion of isotonic sodium chloride solution may be required. Transient hypotension is not a contraindication to continuing treatment. After restoration of circulating blood volume and normalization of blood pressure, treatment 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 hypokalemia, 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.

Precautions 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, iatrogenic etiology should be considered. If ACE inhibitor therapy is necessary for patient management, a decision may be made to continue treatment.

Risk of arterial hypotension and/or renal impairment (in patients with heart failure, water and electrolyte depletion). Significant stimulation of the RAAS occurs during acute water 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. Blockade of this system by an ACE inhibitor, particularly during initial use and the first 2 weeks of treatment, may cause sudden blood pressure reduction and/or increased plasma creatinine levels, confirming 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 starting treatment. To reduce the risk of sudden hypotension, particularly with water or electrolyte depletion, the initial dose should be adjusted according to the blood pressure response to treatment.

Atherosclerosis. The risk of 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. Revascularization is the treatment for renovascular hypertension. However, ACE inhibitors may be beneficial for patients with renovascular hypertension awaiting surgery or for whom surgery is not feasible.

If Perindopres® Duo 4 mg/1.25 mg is prescribed to patients with known or suspected renal artery stenosis, treatment should be initiated in a hospital setting with a low dose, monitoring renal function and serum potassium levels, as functional renal impairment, reversible upon discontinuation, has been observed in some patients.

Perindopres® Duo 8 mg/2.5 mg 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. Perindopres® Duo should not be prescribed to patients with severe (class IV) heart failure, 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. Treatment of patients with insulin-dependent diabetes mellitus (with a spontaneous tendency to increased serum potassium) should be initiated under medical supervision with a reduced initial dose.

Perindopres® Duo 8 mg/2.5 mg should not be prescribed to patients with insulin-dependent diabetes mellitus, as treatment should be initiated under medical supervision with a reduced initial dose.

In diabetic patients previously treated with oral hypoglycemic agents or insulin, blood glucose levels should be carefully monitored, especially during the first month of ACE inhibitor therapy.

Racial factors. Perindopril, like other ACE inhibitors, is less effective in reducing blood pressure in black hypertensive patients compared to other races, possibly due to low plasma renin levels in these patients.

Surgery/anesthesia. ACE inhibitors may cause hypotension during anesthesia, particularly with anesthetics having hypotensive potential. Therefore, it is recommended to discontinue long-acting ACE inhibitor therapy, such as perindopril, at least 1 day before surgery if possible.

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

Hepatic impairment. Rarely, ACE inhibitors have been associated with a syndrome beginning with cholestatic jaundice and progressing to rapidly progressive liver necrosis, sometimes fatal. The mechanism of this syndrome is unclear. Patients who develop jaundice with elevated liver enzymes while taking ACE inhibitors should discontinue ACE inhibitor therapy 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. Risk factors for hyperkalemia include renal impairment, renal dysfunction, age > 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 (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). Concomitant use of potassium-containing supplements or salt substitutes and potassium-sparing diuretics, especially in patients with renal dysfunction, may lead to significant increases in serum potassium. Hyperkalemia may cause serious, sometimes fatal, arrhythmias. If concomitant use of these 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").

Precautions 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, necessitating regular monitoring. Monitoring should be more frequent in elderly patients and those with liver cirrhosis (see sections "Overdose" and "Adverse reactions"). Any diuretic therapy may cause hyponatremia, sometimes with very serious consequences. Hyponatremia combined with hypovolemia 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. Decreased serum potassium levels leading to hypokalemia are a major risk factor with thiazide and thiazide-like diuretics. 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 such cases, hypokalemia 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. Hypokalemia, like bradycardia, is a predisposing factor for 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 should be performed within the first week of treatment. Hypokalemia requires correction. Hypokalemia associated with low serum magnesium concentration may be refractory to treatment unless serum magnesium levels are corrected.

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

Calcium levels. Thiazide and thiazide-like diuretics may reduce urinary calcium excretion and cause slight transient increases in serum calcium. Marked increases in serum calcium may be associated with undiagnosed hyperparathyroidism. In such cases, treatment should be discontinued and parathyroid function monitored.

Blood glucose levels. Blood glucose monitoring is very important for diabetic patients, especially with low potassium levels.

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 there is no renal impairment or impairment is minimal (serum creatinine approximately below 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 in micromoles per liter.

This formula is acceptable for determining plasma creatinine levels in elderly men, but for women, the result should be multiplied by 0.85. Hypovolemia caused by water and sodium loss due to diuretic use at the beginning of treatment reduces glomerular filtration, potentially increasing blood urea and creatinine levels. This transient functional renal impairment has no adverse consequences in patients without pre-existing renal impairment but may worsen 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, 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. Primary treatment is prompt 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.

Important information about excipients.

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

Use during pregnancy or breastfeeding.

Pregnancy

The medicinal product is contraindicated during pregnancy or in 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, although a slight increase in risk is possible. If continued ACE inhibitor therapy is considered mandatory, women planning pregnancy should be switched to alternative antihypertensive agents with proven safety during pregnancy. If pregnancy is confirmed during treatment, ACE inhibitor therapy should be discontinued immediately and, if necessary, replaced with a medication 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, hyperkalemia). If ACE inhibitors were used during the second and third trimesters of pregnancy, ultrasound evaluation of newborn kidney function and skull structure is recommended. Newborns whose mothers received ACE inhibitors during pregnancy should be monitored for timely detection and correction of 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 delayed fetal development. Animal studies have not revealed direct or indirect toxic effects on reproductive function. As a precaution, indapamide use during pregnancy should be avoided.

Breastfeeding period

Perindopres® Duo is contraindicated during breastfeeding. A decision should be made whether to discontinue breastfeeding or discontinue the medication during breastfeeding, considering the importance of 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 passage 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 contraindicated 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 vehicles or operating machinery.

The two active substances, when used separately or in combination as Perindopres® Duo, do not affect the ability to drive vehicles or operate machinery, but individual reactions related to reduced blood pressure may occur in some patients, particularly at the beginning of treatment or when used concomitantly with other antihypertensive agents. As a result, the ability to drive vehicles or operate machinery may be impaired.

Dosage and Administration.

For oral use.

Perindopres® Duo should be administered once daily, one tablet per day, preferably in the morning before meals.

Perindopres® Duo 8 mg/2.5 mg should be prescribed only if blood pressure remains uncontrolled during treatment with Perindopres® Duo 4 mg/1.25 mg.

Special patient groups

Elderly patients (see section "Special instructions"). 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.

Patients with renal impairment (see section "Special instructions")

Perindopres® Duo 4 mg/1.25 mg: Contraindicated in patients with severe renal impairment (creatinine clearance <30 mL/min). For patients with moderate renal impairment (creatinine clearance 30–60 mL/min), treatment should be initiated with the appropriate dose of the combination components. Patients with creatinine clearance ≥60 mL/min do not require dose adjustment.

Perindopres® Duo 8 mg/2.5 mg: Contraindicated in patients with moderate to severe renal impairment (creatinine clearance <60 mL/min).

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

Patients with hepatic impairment (see sections "Pharmacokinetics", "Contraindications", and "Special instructions"). The use of the drug is contraindicated in patients with severe hepatic impairment. Patients with moderate hepatic impairment do not require dose adjustment.

Children

Perindopres® Duo should not be used in children and adolescents. Safety and efficacy of perindopril tert-butylamine/indapamide in pediatric patients have not been established. Data are lacking.

Overdose.

Symptoms. The most common adverse reaction in case of overdose is arterial hypotension, which may be accompanied by nausea, vomiting, convulsions, dizziness, somnolence, confusion, oliguria, potentially progressing to anuria (due to hypovolemia), and circulatory shock. Electrolyte 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, followed by correction of fluid and electrolyte balance under hospital conditions. In case of significant arterial hypotension, the patient should be placed in a supine position with the head slightly lowered. If necessary, intravenous administration of isotonic sodium chloride solution or other volume replacement therapy should be initiated. 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 RAAS and helps reduce potassium loss in blood plasma caused by indapamide. Hypokalemia (potassium level < 3.4 mmol/L) may occur in 6% of treated patients. The most commonly reported adverse reactions were: 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, predominantly dermatological, in individuals predisposed to allergic and asthmatic reactions, and maculopapular rash.

Patients should be warned to consult a physician if signs of anuria/oliguria, hot flushes, depression, darkening of urine, nausea, vomiting, muscle cramps, or confusion occur, as these may indicate the development of the syndrome of inappropriate antidiuretic hormone secretion (SIADH).

During treatment with perindopril and indapamide, the following adverse reactions have been observed, categorized by frequency as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), and frequency not known (cannot be estimated from available data).

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

Ear and labyrinth disorders: vertigo (common − perindopril, rare − indapamide); tinnitus (common − perindopril).

Respiratory, thoracic and mediastinal disorders: cough (see section "Special warnings and precautions for use") (common − perindopril); dyspnea (common − perindopril); bronchospasm (uncommon − perindopril); eosinophilic pneumonia (very rare − perindopril); rhinitis (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 warnings and precautions for use") (very rare − perindopril, frequency not known − indapamide); liver function abnormalities (very rare − indapamide).

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

Endocrine disorders: SIADH (rare − perindopril).

Metabolism and nutrition disorders: hypoglycemia (see sections "Interaction with other medicinal products and other forms of interaction" and "Special warnings and precautions for use") (uncommon* − perindopril); hyperkalemia, reversible upon discontinuation of the drug (see section "Special warnings and precautions for use") (uncommon* − perindopril); hyponatremia (see section "Special warnings and precautions for use") (uncommon* − perindopril and indapamide); hypercalcemia (very rare − indapamide); decreased blood potassium levels leading to hypokalemia**, including severe cases in some high-risk patients (see section "Special warnings and precautions for use") (common − indapamide); hypochloremia (rare − indapamide); hypomagnesemia (rare − indapamide).

Nervous system disorders: dizziness (common − perindopril); headache (common − perindopril, rare − indapamide); paresthesia (common − perindopril, rare − indapamide); dysgeusia (common − perindopril); somnolence (uncommon* − perindopril); loss of consciousness (uncommon* − perindopril, frequency not known − indapamide); stroke may occur due to excessive arterial hypotension in high-risk patients (see section "Special warnings and precautions for use") (very rare − perindopril); hepatic encephalopathy may occur in case of liver insufficiency (see sections "Contraindications" and "Special warnings and precautions for use") (frequency not known − indapamide).

Psychiatric disorders: mood changes (uncommon − perindopril); sleep disturbances (uncommon − perindopril); depression (uncommon − perindopril); confusion (very rare − perindopril).

Cardiac disorders: palpitations (uncommon* − perindopril); tachycardia (uncommon* − perindopril); angina pectoris (see section "Special warnings and precautions for use") (very rare − perindopril); arrhythmia, including bradycardia, ventricular tachycardia, atrial fibrillation (very rare − perindopril and indapamide); myocardial infarction may occur due to excessive arterial hypotension in high-risk patients (see section "Special warnings and precautions for use") (very rare − perindopril); paroxysmal ventricular tachycardia of the "torsades de pointes" type (potentially fatal) (see sections "Special warnings and 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 warnings and precautions for use") (common − perindopril, very rare − indapamide); vasculitis (uncommon* − perindopril); Raynaud's phenomenon (frequency not known − perindopril).

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

Immune system disorders: hypersensitivity (mainly dermatological reactions in patients predisposed to allergic and asthmatic reactions) (common − indapamide).

Skin and subcutaneous tissue disorders: pruritus (common − perindopril); rash (common − perindopril); maculopapular rash (common − indapamide); urticaria (see section "Special warnings and precautions for use") (uncommon − perindopril, very rare − indapamide); angioedema (see section "Special warnings and 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 existing psoriasis (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); possible worsening of existing systemic lupus erythematosus (frequency not known − indapamide); arthralgia (uncommon* − perindopril); myalgia (uncommon* − 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 warnings and 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 warnings and 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.

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

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

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

Cases of SIADH have been reported with other ACE inhibitors. Therefore, SIADH can be considered a possible complication associated with ACE inhibitors, including perindopril, with an incidence classified as "very rare."

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is an important procedure. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions through the national reporting system.

Shelf life. 2 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

10 tablets in a blister; 3 or 9 blisters in a carton.

Prescription status. Prescription only.

Manufacturer. JSC "Pharmaceutical company "Darnytsia".

Manufacturer's address and location of its business activities.

13, Boryspilska St., Kyiv, 02093, Ukraine.