Corderia duo

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CORDERIA DUO (Corderia DUO)

Composition:

Active substances: perindopril, indapamide;

1 tablet contains:

2 mg of perindopril tert-butylamine, equivalent to 1.669 mg of perindopril, and 0.625 mg of indapamide;

or 4 mg of perindopril tert-butylamine, equivalent to 3.338 mg of perindopril, and 1.25 mg of indapamide;

or 8 mg of perindopril tert-butylamine, equivalent to 6.676 mg of perindopril, and 2.5 mg of indapamide;

Excipients: lactose monohydrate; microcrystalline cellulose; crospovidone; sodium hydrogen carbonate; colloidal anhydrous silicon dioxide; magnesium stearate.

Pharmaceutical form. Tablets.

Main physico-chemical properties: round, biconvex tablets, white to almost white in color.

Pharmacotherapeutic group. Cardiovascular system agents.

Combined preparations of angiotensin-converting enzyme (ACE) inhibitors. Perindopril and diuretics. ATC code C09BA04.

Pharmacological Properties.

Pharmacodynamics.

Cordaria DUO is a combination of the angiotensin-converting enzyme (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. Cordaria DUO has an additive synergistic effect of two antihypertensive components.

Mechanism of action of perindopril. Perindopril is an ACE inhibitor that converts angiotensin I to angiotensin II (a vasoconstrictor substance), additionally stimulates aldosterone secretion by the adrenal cortex, and promotes bradykinin (a vasodilator substance) breakdown into inactive heptapeptides. Inhibition of ACE leads to: reduced aldosterone secretion; increased plasma renin activity, while aldosterone does not exert a negative feedback effect; reduction in total peripheral vascular resistance due to predominant effects on muscular and renal vessels; without water and salt retention or reflex tachycardia, even during prolonged treatment. Furthermore, perindopril reduces blood pressure (BP) in patients with normal and low plasma renin levels. Perindopril acts via its active metabolite, perindoprilat. Other metabolites are inactive. Perindopril reduces cardiac workload through vasodilatory effects on veins (possibly due to changes in prostaglandin metabolism)—reducing preload—and through reduction in total peripheral vascular resistance—reducing afterload on the heart. Studies conducted in patients with heart failure have demonstrated that perindopril use leads to reduced filling pressure in the left and right ventricles, reduced total peripheral vascular resistance, increased cardiac output, improved cardiac index, and increased regional blood flow in muscles. Exercise test performance improves.

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

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

PICXEL — a multicenter, randomized, double-blind, controlled study evaluating the effect of the combination of perindopril and indapamide on left ventricular hypertrophy compared to enalapril monotherapy, assessed by echocardiography. In the PICXEL study, patients with arterial hypertension and left ventricular hypertrophy (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 blood pressure (BP) levels: perindopril tert-butylamine dose was increased up to 8 mg (equivalent to 10 mg perindopril arginine), indapamide up to 2.5 mg, and enalapril up to 40 mg once daily. Starting doses were continued in 34% of patients in the perindopril/indapamide group (2 mg perindopril and 0.625 mg indapamide) and 20% in the enalapril group (10 mg). At the end of treatment, left ventricular mass index decreased significantly more in patients receiving perindopril/indapamide (–10.1 g/m²) compared to the enalapril group (–1.1 g/m²). The difference between the two groups was –8.3 (95% confidence interval [CI] from –11.5 to –5.0, p < 0.0001). Greater efficacy in reducing left ventricular mass index was achieved with maximum doses of perindopril/indapamide (10 mg/2.5 mg). Blood pressure reduction was more effective in the perindopril/indapamide group: the mean difference in 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.

ADVANCE — an international, multicenter, randomized study with a 2×2 factorial design, aimed at determining the benefits of blood pressure reduction using fixed-dose perindopril/indapamide combination versus placebo, against the background of standard ongoing therapy (double-blind comparison), and the benefits of an intensive glycemic control strategy (HbA1c ≤ 6.5%) based on gliclazide MR ("Diabeton® MR") versus standard glycemic control (PROBE design [prospective randomized open-label blinded-endpoint]) on major macro- and microvascular events in patients with type 2 diabetes. The primary endpoint consisted of major macrovascular (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke) and microvascular (new onset or worsening of nephropathy, retinopathy) events. The study included 11,140 patients with type 2 diabetes. Mean patient age was 66 years, body mass index (BMI) 28 kg/m², diabetes duration 8 years, HbA1c 7.5%, and SBP/DBP 145/81 mm Hg. Among them, 83% had arterial hypertension, 32% and 10% had a history of micro- and macrovascular disease respectively, and 27% had microalbuminuria. Concomitant therapy included antihypertensive agents (75%), lipid-lowering agents (35%, predominantly statins — 28%), acetylsalicylic acid or other antiplatelet agents (47%). During a 6-week run-in period, patients received perindopril/indapamide combination and continued their usual glucose-lowering therapy. Subsequently, patients were randomized to receive either placebo (n = 5571) or perindopril/indapamide combination (n = 5569). Perindopril/indapamide 5 mg/1.25 mg film-coated tablets are not suitable for initiation of therapy. Treatment was initiated with perindopril 2.5 mg/indapamide 0.625 mg, one tablet once daily. After 3 months, if well tolerated, the dose was increased to perindopril/indapamide 5 mg/1.25 mg film-coated tablets, one tablet once daily. Treatment with perindopril/indapamide for 4.3 years led to a significant 9% relative risk reduction in the primary endpoint (95% CI [0.828; 0.996], p = 0.041). The benefits of perindopril/indapamide treatment versus placebo were due to: significant 14% relative risk reduction in all-cause mortality (95% CI [0.75; 0.98], p = 0.025); significant 18% relative risk reduction in cardiovascular mortality (95% CI [0.68; 0.98], p = 0.027); significant 21% relative risk reduction in all types of renal complications (95% CI [0.74; 0.86], p < 0.001). In the subgroup of patients with arterial hypertension treated with perindopril/indapamide, there was a significant 9% relative risk reduction in major macro- and microvascular complications (95% CI [0.82; 1.0], p = 0.052) compared to the placebo group. In the subgroup receiving perindopril/indapamide versus placebo, there were also significant reductions in: all-cause mortality by 16% (95% CI [0.73; 0.97], p = 0.019); cardiovascular mortality by 20% (95% CI [0.66; 0.97], p = 0.023); and all types of renal complications by 20% (95% CI [0.73; 0.87], p < 0.001). The benefits of blood pressure-lowering treatment were independent of benefits achieved in patients managed according to the intensive glycemic control strategy.

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. Maximum antihypertensive effect develops within 4–6 hours after a single dose and persists for more than 24 hours. Perindopril achieves a high level of sustained ACE inhibition (approximately 80%) 24 hours after dosing. In patients responding to treatment, BP normalization is achieved within one month and maintained without tachyphylaxis. Discontinuation of therapy is not associated with withdrawal syndrome. Perindopril has vasodilatory properties, restores elasticity of large arteries, corrects histomorphometric changes in resistance arteries, and reduces left ventricular hypertrophy. Addition of a thiazide diuretic, if necessary, results in additional synergism. Combined use of an ACE inhibitor and a thiazide diuretic reduces the risk of hypokalemia that may occur with diuretic monotherapy.

Pharmacodynamic effects related to indapamide. When used as monotherapy, indapamide exerts an antihypertensive effect lasting 24 hours. This effect occurs at doses where diuretic properties are minimal. The antihypertensive effect of indapamide is proportional to improved arterial elasticity and reduced arteriolar resistance and total peripheral vascular resistance. Indapamide reduces left ventricular hypertrophy. For thiazide and thiazide-like diuretics, antihypertensive effects plateau at higher doses, while adverse effects increase. If treatment is insufficiently effective, the dose should not be increased. Moreover, studies of varying durations (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 in the Cordaria DUO formulation do not differ from those observed when administered separately.

Pharmacokinetic properties of perindopril.

Absorption and bioavailability. After oral administration, perindopril is rapidly absorbed, with peak concentration reached within 1 hour. The elimination half-life of perindopril in plasma is 1 hour. Since food intake reduces the conversion of perindopril to perindoprilat, thereby decreasing its bioavailability, perindopril 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.

Biotransformation. Perindopril is a prodrug. About 27% of the administered dose of perindopril reaches the systemic circulation 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 eliminated via urine; the terminal half-life of the unbound fraction is approximately 17 hours. Steady-state is achieved within 4 days.

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

Special patient populations.

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

Renal function 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. Perindopril kinetics are altered in patients with hepatic cirrhosis: hepatic clearance of the parent compound is halved. 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 precautions").

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%.

Biotransformation and elimination. 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 dose) and feces (22%) as inactive metabolites.

Special patient populations.

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

Clinical characteristics.

Indications.

Dosing 2 mg/0.625 mg:

− essential hypertension in adult patients.

Dosing 4 mg/1.25 mg:

− essential hypertension in adult patients;

− additional blood pressure control required when perindopril is used as monotherapy.

Dosing 8 mg/2.5 mg:

− arterial hypertension in patients requiring perindopril tert-butylamine at a dose of 8 mg and indapamide at a dose of 2.5 mg.

Contraindications.

Related to perindopril: hypersensitivity to the active substance or to any other angiotensin-converting enzyme (ACE) inhibitor; history of angioedema (Quincke's edema) associated with previous treatment with ACE inhibitors (see section "Special precautions"); hereditary or idiopathic angioedema; pregnancy or planned pregnancy (see section "Use during pregnancy or breastfeeding"); concomitant use with aliskiren-containing products in patients with diabetes mellitus or renal impairment (glomerular filtration rate < 60 mL/min/1.73 m²) (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacodynamics"); concomitant use with sacubitril/valsartan. Cordaria DUO 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 treatments 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").

Related to indapamide: hypersensitivity to the active substance or to any other sulfonamides; severe renal failure (creatinine clearance < 30 mL/min); hepatic encephalopathy; severe hepatic dysfunction; hypokalemia.

Related to Cordaria DUO: hypersensitivity to any excipient. Due to insufficient clinical experience, Cordaria DUO should not be used in patients undergoing hemodialysis or in patients with untreated decompensated heart failure.

Interaction with other medicinal products and other forms of interaction.

Interactions common to perindopril and indapamide

Concomitant use not recommended

Lithium. Reversible increases in serum lithium concentration and lithium toxicity have been reported during concomitant use with ACE inhibitors (ACEIs). Concomitant use of perindopril with indapamide and lithium is not recommended; however, if such use is truly 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.

Non-steroidal anti-inflammatory drugs (NSAIDs) (including acetylsalicylic acid at doses ≥ 3 g/day). When ACEIs are used concomitantly with NSAIDs, such as acetylsalicylic acid at anti-inflammatory doses, COX-2 inhibitors, and non-selective NSAIDs, the antihypertensive effect may be attenuated. Concomitant use of ACEIs and NSAIDs may lead to an increased risk of worsening renal function, including acute renal failure, and elevated serum potassium levels, particularly in patients with renal impairment. Such combinations should be prescribed with caution, especially in elderly patients. Patients should have their fluid status restored before initiation of treatment, and renal function should be monitored at the beginning and throughout combination therapy.

Concomitant use requiring attention

Tricyclic antidepressants, neuroleptics. Enhance antihypertensive action 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) resulting from 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 renal function (including acute renal failure), compared to use of a single RAAS-acting agent (see sections "Contraindications", "Special precautions", and "Pharmacodynamics").

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

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

Medicinal products causing hyperkalemia. Serum potassium levels usually remain within normal limits, but hyperkalemia may occur in some patients treated with Cordaria DUO. Certain drugs 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, immunosuppressive agents (e.g., cyclosporine or tacrolimus), and co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim acts as a potassium-sparing diuretic similar to amiloride, may cause hyperkalemia. Combination of these drugs increases the risk of hyperkalemia. Therefore, concomitant use of Cordaria DUO with the above-mentioned drugs is not recommended. If concomitant use is necessary, they should be used with caution and serum potassium levels should be frequently monitored.

Concomitant use contraindicated (see section "Contraindications")

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

Extracorporeal treatments leading to blood contact with negatively charged surfaces, such as dialysis or hemofiltration using certain high-flux membranes (e.g., polyacrylonitrile) and LDL apheresis using dextran sulfate, 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 patient groups, including those with diabetes mellitus or renal impairment, increased risk of hyperkalemia, worsening renal function, cardiovascular morbidity, and mortality (see section "Special precautions").

Concomitant therapy with ACE inhibitor and angiotensin receptor blocker. In patients with established atherosclerosis, heart failure, or diabetic end-organ damage, concomitant therapy with ACE inhibitors and angiotensin receptor blockers has been associated with increased incidence of arterial hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to use of a single RAAS-acting agent. Dual blockade (i.e., combination of ACE inhibitor and angiotensin II receptor antagonist) may be considered only in exceptional 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 agents is not recommended (see section "Special precautions"). If concomitant use is nevertheless indicated, they should be used with caution and serum potassium levels should be frequently monitored. Information on use of spironolactone in patients with heart failure is provided under "Concomitant use requiring special attention".

Concomitant use requiring special attention

Antidiabetic agents (insulin, oral hypoglycemic agents). Concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemic agents) may enhance the glucose-lowering effect with risk of hypoglycemia. This phenomenon may occur during the first weeks of combination therapy and in patients with renal impairment.

Diuretics. In patients taking diuretics, especially those with volume and sodium depletion, excessive reduction in blood pressure may occur after initiation of ACE inhibitor therapy. The likelihood of hypotensive effects may be reduced by discontinuing diuretic therapy, increasing circulating blood volume, or increasing salt intake before starting perindopril therapy, which should be initiated at a low dose with gradual dose escalation. In hypertensive patients whose prior diuretic therapy may have caused volume/sodium depletion, diuretic therapy should be discontinued before initiating ACE inhibitor therapy (diuretic therapy may later be resumed) or ACE inhibitor therapy should be initiated at a low dose with gradual dose escalation. In patients with congestive heart failure taking diuretics, ACE inhibitor therapy should be initiated at the lowest dose, possibly after reducing the diuretic dose. In all cases, renal function (creatinine level) 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 of this combination are not followed. Before initiating such combination therapy, absence of hyperkalemia and renal dysfunction should be confirmed. Careful monitoring of serum potassium and creatinine is recommended weekly during the first month and monthly thereafter.

Concomitant use requiring attention

Antihypertensive agents and vasodilators. Concomitant use 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 potentiate the hypotensive effect of certain anesthetic agents (see section "Special precautions").

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

Gold preparations. In patients treated with injectable gold preparations (sodium aurothiomalate) and concomitantly using ACE inhibitors, including perindopril, rare cases of nitritoid reactions (facial flushing, nausea, vomiting, and arterial hypotension) have been reported.

Interactions related to indapamide.

Concomitant use requiring special attention

Medicinal products that may induce torsades de pointes. Indapamide should be used with caution in combination with medicinal products that may induce torsades de pointes due to the risk of hypokalemia, such as (the following 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 substances (e.g., bepridil, cisapride, difemanil, intravenous erythromycin, halofantrine, mizolastine, moxifloxacin, pentamidine, sparfloxacin, intravenous vincamine, methadone, astemizole, terfenadine). Plasma potassium levels should be prevented from decreasing and corrected if necessary, and QT interval should be monitored.

Medicinal products reducing blood potassium levels. Intravenous amphotericin B, glucocorticoids and mineralocorticoids (systemic action), tetracosactide, stimulant laxatives increase the risk of reduced 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 favor cardiac glycoside toxicity. Monitoring of plasma potassium and magnesium levels and ECG monitoring are recommended, with treatment adjustment if necessary.

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

Concomitant use requiring attention

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

Metformin. May cause lactic acidosis due to functional renal impairment associated with diuretic use, particularly 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. In cases of dehydration caused by diuretic use, the risk of acute renal failure increases, especially with high doses of iodinated contrast agents. Fluid balance should be restored 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 action). Reduce antihypertensive effect (water and sodium retention induced by corticosteroids).

Special precautions for use.

Special warnings.

Special warnings common to perindopril and indapamide

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

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

Special warnings related to 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 arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure). Therefore, dual blockade of the RAAS by concomitant administration of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacodynamics"). If dual RAAS blockade therapy is considered absolutely necessary, it should be conducted only under specialist supervision and with frequent, careful monitoring of renal function, electrolyte levels, and blood pressure. Patients with diabetic nephropathy should not receive concomitant treatment with ACE inhibitors and angiotensin II receptor blockers.

Potassium-sparing agents, 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. Cases of neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported in patients taking 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 collagenosis, during immunosuppressive therapy, allopurinol, or procainamide treatment, or when these risk factors are combined, especially 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. Patients should also be informed about the necessity 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 arterial hypotension and renal failure (see section "Contraindications"). The use of diuretics may be a contributing factor. Impaired renal function may be accompanied by only minor changes in serum creatinine levels, even in patients with unilateral renal artery stenosis.

Hypersensitivity/angioedema (angioedema). Rare cases of angioedema of the face, extremities, lips, tongue, glottis, and/or larynx have been reported in patients taking 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 the patient must be placed under medical supervision until symptoms completely resolve. If swelling is limited to the face and lips, the patient's condition usually improves without treatment, although antihistamines may be helpful in reducing symptoms. Angioedema associated with laryngeal swelling may be fatal. If swelling spreads to the tongue, glottis, or larynx, potentially causing airway obstruction, emergency treatment is required, which may include subcutaneous administration of epinephrine 1:1000 solution (0.3–0.5 mL) and/or measures to ensure airway patency. Angioedema has been reported more frequently in patients of non-Caucasian race taking ACE inhibitors compared to other racial groups. Patients with a history of angioedema unrelated to ACE inhibitor use are at increased risk of developing angioedema during ACE inhibitor therapy. Rare cases of intestinal angioedema have been reported in patients receiving ACE inhibitor therapy. These patients experienced abdominal pain (with or without nausea and vomiting); intestinal angioedema sometimes occurred without prior facial angioedema, and C1-esterase inhibitor levels were within normal range. The diagnosis of angioedema was confirmed by procedures such as abdominal computed tomography, ultrasound, or during surgical intervention; symptoms resolved after discontinuation of the ACE inhibitor. In patients taking ACE inhibitors who develop abdominal pain, differential diagnosis should be performed to rule out intestinal angioedema.

Concomitant use of perindopril with sacubitril/valsartan is contraindicated due to an increased risk of angioedema. Initiation of sacubitril/valsartan should not occur earlier than 36 hours after the last dose of perindopril. If sacubitril/valsartan treatment 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) may increase the risk of angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) (see section "Interaction with other medicinal products and other forms of interaction"). Caution should be exercised when initiating therapy with racecadotril, mTOR inhibitors, or gliptins in patients already receiving ACE inhibitors.

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

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

Patients undergoing hemodialysis. Cases of anaphylactoid reactions have been reported in patients taking 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 aldosteronism. Patients with primary hyperaldosteronism generally do not respond to antihypertensive drugs acting via inhibition of the renin-angiotensin system. Therefore, this drug is not recommended for such patients.

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

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

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

Special warnings related to indapamide.

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

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

Precautionary measures.

Precautionary measures common to perindopril and indapamide

Renal impairment. For dosages 2 mg/0.625 mg and 4 mg/1.25 mg: treatment with the drug is contraindicated in cases of severe renal impairment (creatinine clearance < 30 mL/min).

For dosage 8 mg/2.5 mg: treatment with the drug is contraindicated in cases of severe and moderate renal impairment (creatinine clearance < 60 mL/min).

If laboratory blood tests in some patients with arterial hypertension but no apparent signs of renal impairment show signs of functional renal impairment, treatment should be discontinued, with the possibility of resuming at a lower dose or with only one component. Such patients require frequent monitoring of potassium and creatinine levels in blood: 2 weeks after initiation of treatment and then every 2 months during therapeutic stabilization. Cases of renal impairment occurred predominantly in patients with severe heart failure or impaired renal function, including renal artery stenosis. This drug 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 deficiency (especially with renal artery stenosis) are at risk of a sudden drop in blood pressure. Systematic monitoring for clinical signs of water and electrolyte depletion, which may occur during intercurrent vomiting or diarrhea, is required. Such patients should have regular monitoring of plasma electrolyte levels. In cases of significant arterial hypotension, intravenous infusion of isotonic sodium chloride solution may be necessary. Transient hypotension is not a contraindication for continuing treatment. After restoration of circulating blood volume and normalization of blood pressure, treatment may be resumed at a reduced dose or with only one component.

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

Excipients. The drug contains lactose; therefore, its use is contraindicated in patients with rare hereditary intolerance to galactose, glucose-galactose malabsorption syndrome, or lactase deficiency.

Precautionary measures related to perindopril

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

Risk of arterial hypotension and/or renal impairment (in cases of 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 hepatic cirrhosis with edema and ascites. Blockade of this system by ACE inhibitors, especially during initial use and the first 2 weeks of treatment, may cause a sharp drop in blood pressure and/or an increase in 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, gradually increasing it.

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

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

Renovascular hypertension. Revascularization is the treatment for renovascular hypertension. However, ACE inhibitors may be beneficial for patients with renovascular hypertension awaiting surgery or when surgery is not possible.

For dosages 2 mg/0.625 mg and 4 mg/1.25 mg: if Corderia DUO is prescribed to patients with existing renal artery stenosis or suspected stenosis, treatment should be initiated in a hospital setting with a low dose and under potassium level monitoring, as functional renal impairment, reversible upon discontinuation of treatment, has been observed in some patients.

For dosage 8 mg/2.5 mg: Corderia DUO should not be prescribed to patients with existing renal artery stenosis or suspected 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. Treatment of patients with severe heart failure (Class IV) should be initiated under medical supervision with a reduced initial dose. β-blocker therapy in patients with arterial hypertension and coronary insufficiency should not be discontinued; ACE inhibitors should be added to β-blockers.

Patients with diabetes. Treatment of patients with insulin-dependent diabetes (with a spontaneous tendency to increased blood potassium levels) should be initiated under medical supervision with a reduced initial dose. Patients with diabetes previously treated with oral hypoglycemic agents or insulin require careful monitoring of blood glucose levels, especially during the first month of ACE inhibitor therapy (see section "Interaction with other medicinal products and other forms of interaction").

Racial characteristics. Perindopril, like other ACE inhibitors, is less effective in lowering blood pressure in hypertensive patients of non-Caucasian race compared to other racial groups, possibly due to low plasma renin levels in these patients.

Surgery/anesthesia. ACE inhibitors may cause arterial hypotension during anesthesia, especially when anesthetics with hypotensive potential are used. Therefore, it is recommended to discontinue long-acting ACE inhibitors, such as perindopril, at least 1 day before surgery, if possible.

Stenosis of aortic or mitral valves/hypertrophic cardiomyopathy. ACE inhibitors should be used with caution in patients with left ventricular outflow tract obstruction.

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

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

Precautionary measures related to indapamide

Water and electrolyte balance

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

Potassium levels. Decreased blood potassium levels leading to hypokalemia are the main risk factor with thiazide and thiazide-like diuretics. Hypokalemia may cause muscle disorders. Cases of rhabdomyolysis, mainly associated with severe concomitant hypokalemia, have been reported. Prevention of decreased potassium levels (< 3.4 mmol/L) is required in certain high-risk patient groups, such as elderly patients and/or those with poor nutrition, regardless of concomitant drug use, patients with liver cirrhosis accompanied by edema and ascites, 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 drug-induced prolonged QT interval also belong to the risk group. Hypokalemia, like bradycardia, is a predisposing factor for severe cardiac arrhythmias, especially paroxysmal torsades de pointes tachycardia, which may be fatal. More frequent monitoring of blood potassium levels is required. The first determination of plasma potassium levels should be performed within the first week of treatment. Low blood potassium levels must be corrected.

Detection of hypokalemia requires its correction. Hypokalemia due to low serum magnesium levels may be refractory to treatment unless magnesium levels are corrected.

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

Plasma magnesium. It has been shown that thiazides and related diuretics, including indapamide, increase urinary magnesium excretion, which may lead to hypomagnesemia (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

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

Uric acid. In patients with elevated blood uric acid levels, the frequency of gout attacks may increase.

Kidney function and diuretics. Thiazide and thiazide-like diuretics are most effective when kidney function is normal or only slightly impaired (blood 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 µmol/L. This formula is suitable for determining plasma creatinine levels in elderly men, but for women, the result should be multiplied by 0.85. Hypovolemia caused by water and sodium loss due to diuretic use at the beginning of treatment reduces glomerular filtration, which may lead to increased blood urea and creatinine levels. This transient functional renal impairment has no adverse consequences in patients with normal kidney function but may worsen existing renal impairment.

Choroidal effusion, acute myopia (nearsightedness), and secondary angle-closure glaucoma. Drugs 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 main treatment is immediate discontinuation of the drug. If intraocular pressure remains uncontrolled, medical, surgical, or other interventions may be necessary. Risk factors for acute angle-closure glaucoma may include a history of allergy to sulfonamides or penicillin.

Athletes. Athletes should be aware that this drug contains an active substance that may lead to a positive doping test.

Use during pregnancy or breastfeeding.

Pregnancy. The drug is contraindicated in pregnant women or women planning to become pregnant.

Warnings related to perindopril. Convincing epidemiological evidence of teratogenic risk with ACE inhibitors during the first trimester of pregnancy is lacking; however, a small increase in this risk cannot be excluded. If continued treatment with ACE inhibitors is considered mandatory, women planning pregnancy should be switched to alternative antihypertensive drugs with established safety data during pregnancy. If pregnancy is confirmed during treatment, ACE inhibitor therapy should be discontinued immediately and, if necessary, replaced with another drug 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 bone formation) and on the newborn (renal failure, arterial hypotension, hyperkalemia). If ACE inhibitors were used during the second and third trimesters of pregnancy, ultrasound examination of newborn kidney function and skull structure is recommended. Newborns whose mothers took ACE inhibitors during pregnancy should be monitored for timely detection and correction of arterial hypotension.

Warnings related to indapamide. Data on indapamide use in pregnant women are lacking or limited (fewer than 300 cases). Prolonged use of a thiazide diuretic during the third trimester of pregnancy may reduce the pregnant woman's circulating blood volume and uteroplacental perfusion, potentially causing fetoplacental ischemia and 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. Corderia DUO is not recommended during breastfeeding. A decision should be made whether to discontinue breastfeeding or discontinue the drug, taking into account the importance of therapy for the mother.

Warnings related to perindopril. Perindopril use during breastfeeding is not recommended due to lack of data. Alternative treatment with a proven safety profile should be preferred, especially during breastfeeding of newborns or premature infants.

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

Fertility

Warnings common to perindopril and indapamide. Reproductive toxicity studies showed no effect on fertility in male and female animals. No effect on human fertility is expected.

Ability to affect reaction speed when driving vehicles or operating machinery.

The active substances perindopril and indapamide, individually or in combination as the medicinal product Corderia DUO, do not affect the ability to drive vehicles or operate machinery. However, in some patients, individual reactions related to decreased blood pressure may occur, especially at the beginning of treatment or when used concomitantly with other antihypertensive drugs. As a result, the ability to drive vehicles or operate machinery may be impaired.

Method of Administration and Dosage.

For oral use.

Coderea DUO 2 mg/0.625 mg. The recommended dose of Coderea DUO is 1 tablet once daily, preferably in the morning before meals. If blood pressure is not adequately controlled after 1 month of treatment, the dose may be doubled.

Coderea DUO 4 mg/1.25 mg. The recommended dose of Coderea DUO is 1 tablet once daily, preferably in the morning before meals. Individual dose titration of the individual components of the drug may be recommended. If clinically appropriate, transition from monotherapy directly to treatment with Coderea DUO 4 mg/1.25 mg may be considered.

Coderea DUO 8 mg/2.5 mg. The recommended dose of Coderea DUO is 1 tablet once daily, preferably in the morning before meals.

Elderly patients (see section "Special Warnings and Precautions for Use").

Coderea DUO 2 mg/0.625 mg. Treatment should be initiated with the recommended dose of Coderea DUO 2 mg/0.625 mg – 1 tablet daily.

Coderea DUO 4 mg/1.25 mg: treatment in elderly patients should be prescribed taking into account blood pressure levels and renal function.

Coderea DUO 8 mg/2.5 mg: in elderly patients, plasma creatinine levels should be determined, taking into account age, body weight, and gender. Treatment in elderly patients may be initiated only if renal function is normal and after considering the blood pressure response to therapy.

Patients with renal impairment (see section "Special Warnings and Precautions for Use").

Coderea DUO 2 mg/0.625 mg. Coderea DUO is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min). For patients with moderate renal impairment (creatinine clearance 30–60 mL/min), the maximum daily dose is 1 tablet of Coderea DUO 2 mg/0.625 mg. Patients with creatinine clearance ≥ 60 mL/min do not require dose adjustment. Routine medical monitoring should include frequent assessment of plasma creatinine and potassium levels.

Coderea DUO 4 mg/1.25 mg. Coderea DUO is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min). For patients with moderate renal impairment (creatinine clearance 30–60 mL/min), treatment should be initiated using appropriate doses of the individual components of the drug. Patients with creatinine clearance ≥ 60 mL/min do not require dose adjustment. Routine medical monitoring should include frequent assessment of plasma creatinine and potassium levels.

Coderea DUO 8 mg/2.5 mg. Coderea DUO is contraindicated in patients with moderate to severe renal impairment (creatinine clearance < 60 mL/min). Routine medical monitoring should include frequent assessment of plasma creatinine and potassium levels.

Patients with hepatic impairment (see sections "Contraindications", "Special Warnings and Precautions for Use", and "Pharmacokinetics").

Coderea DUO is contraindicated in patients with severe hepatic impairment. Patients with moderate hepatic impairment do not require dose adjustment.

Children.

Coderea DUO should not be used for the treatment of children and adolescents. Safety and efficacy of perindopril/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, vertigo, 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. First aid measures include rapid elimination of the drug from the body – gastric lavage and/or administration of activated charcoal, followed by correction of fluid and electrolyte imbalances under hospital conditions. In case of significant arterial hypotension, the patient should be placed in a supine position with low head elevation. If necessary, intravenous administration of isotonic sodium chloride solution or other measures to restore blood volume should be performed. Perindoprilat, the active metabolite of perindopril, may be removed from the body by hemodialysis (see section "Pharmacokinetics").

Adverse reactions.

Administration of perindopril inhibits the renin-angiotensin-aldosterone system (RAAS) and helps reduce potassium loss in blood plasma caused by indapamide. Hypokalemia (potassium level < 3.4 mmol/L) occurs in 2–6% of patients treated with perindopril/indapamide combination. The most commonly reported adverse reactions were: with perindopril — dizziness, headache, paraesthesia, dysgeusia, visual disturbances, vertigo, tinnitus, arterial hypotension, cough, dyspnoea, abdominal pain, constipation, dyspepsia, diarrhoea, nausea, vomiting, pruritus, rash, muscle cramps, and asthenia; with indapamide — hypokalemia, hypersensitivity reactions (mainly dermatological) in patients predisposed to allergic and asthmatic reactions, and maculopapular rash.

During clinical trials and/or post-marketing use of the medicinal product, the following adverse reactions have been observed, listed according to frequency categories: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from the 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 anaemia (very rare — indapamide); pancytopenia (very rare — perindopril); leukopenia (very rare — perindopril and indapamide); neutropenia (see section "Special precautions for use") (very rare — perindopril); haemolytic anaemia (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); hypoglycaemia (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction") (uncommon* — perindopril); hyperkalaemia, reversible upon discontinuation of the drug (see section "Special precautions for use") (uncommon* — perindopril); hyponatraemia (see section "Special precautions for use") (uncommon* — perindopril, uncommon — indapamide); hypochloraemia (rare — indapamide); hypomagnesaemia (rare — indapamide); hypercalcaemia (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); paraesthesia (common — perindopril, rare — indapamide); dysgeusia (common — perindopril); somnolence (uncommon* — perindopril); loss of consciousness (uncommon* — perindopril, frequency not known — indapamide); excessive arterial hypotension in high-risk patients may lead to stroke (see section "Special precautions for use") (very rare — perindopril); in patients with hepatic impairment, hepatic encephalopathy may occur (see sections "Contraindications" and "Special precautions for use") (frequency not known — indapamide).

Eye disorders: visual disturbances (common — perindopril, frequency not known — indapamide); myopia (see section "Special precautions for use") (frequency not known — indapamide); blurred vision (frequency not known — indapamide), choroidal effusion (frequency not known — indapamide); acute angle-closure glaucoma (frequency not known — indapamide).

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

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

Vascular disorders: arterial hypotension (and symptoms associated with hypotension) (see section "Special precautions for use") (common — perindopril, very rare — indapamide); vasculitis (uncommon* — perindopril); flushing (rare* — perindopril); Raynaud's phenomenon (frequency not known — perindopril).

Respiratory, thoracic and mediastinal disorders: cough (see section "Special precautions for use") (common — perindopril); dyspnoea (common — perindopril); bronchospasm (uncommon — perindopril); eosinophilic pneumonia (very rare — perindopril).

Gastrointestinal disorders: abdominal pain (common — perindopril); constipation (common — perindopril, rare — indapamide); diarrhoea (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 rash (common — indapamide); urticaria (see section "Special precautions for use") (uncommon — perindopril, very rare — indapamide); angioedema (see section "Special precautions for use") (uncommon — perindopril, very rare — indapamide); purpura (uncommon — indapamide); hyperhidrosis (uncommon — perindopril); photosensitivity reactions (uncommon* — perindopril, frequency not known — indapamide); pemphigoid (uncommon* — perindopril); 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, 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 impairment (uncommon — perindopril, very rare — indapamide); acute renal failure (rare — perindopril); anuria/oliguria (rare* — perindopril).

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

General disorders and administration site conditions: asthenia (common — perindopril); chest pain (uncommon* — perindopril); malaise (uncommon* — perindopril); peripheral oedema (uncommon* — perindopril); pyrexia (uncommon* — perindopril); fatigue (rare — indapamide).

Investigations: increased blood urea (uncommon* — perindopril); increased blood creatinine (uncommon* — perindopril); increased blood bilirubin (rare — perindopril); increased liver enzymes (rare — perindopril, frequency not known — indapamide); decreased haemoglobin and haematocrit (see section "Special precautions for use") (very rare — perindopril); increased blood glucose (frequency not known — indapamide); increased blood uric acid (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 authorization is important. It allows continued 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.

2 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging.

Keep out of reach and sight of children.

Packaging.

10 tablets per blister. 3 blisters per cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

JSC "FARMAC".

Manufacturer's address and location of business activity.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.