In-aliter

APPROVED

Order of the Ministry of Health of Ukraine __________ № ______
Registration Certificate № UA/17135/01/01, UA/17135/01/02, UA/17135/01/03

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT
IN-ALITER (IN-ALITER)

Composition:

Active substances: perindopril, indapamide;

One 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 physicochemical characteristics: round, biconvex tablets, white to almost white in color.

Pharmacotherapeutic group.
Combined angiotensin-converting enzyme (ACE) inhibitors. Perindopril and diuretics.
ATC code: C09BA04.

Pharmacological Properties.

Pharmacodynamics. IN-ALITER is a combination of the angiotensin-converting enzyme (ACE) inhibitor perindopril tert-butylamine and the sulfonamide diuretic indapamide. Its pharmacological action is determined by the properties of each component (perindopril and indapamide) and their additive synergism.

Mechanism of action. IN-ALITER exerts an additive synergistic effect of two antihypertensive components.

Mechanism of action of perindopril. Perindopril is an ACE inhibitor that converts angiotensin I into angiotensin II (a vasoconstrictor substance), additionally stimulates aldosterone secretion by the adrenal cortex, and promotes bradykinin (a vasodilating 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; decreased total peripheral vascular resistance due to predominant effects on muscle and renal vessels; and no water and salt retention or reflex tachycardia, even during long-term treatment. Moreover, 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 decreased 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, decreased 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. IN-ALITER produces 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 the concomitant administration of perindopril and indapamide results in synergistic antihypertensive action, arising from the individual effects of the drug components.

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

ADVANCE — an international, multicenter, randomized study with a 2×2 factorial design aimed at evaluating the benefits of lowering blood pressure with a fixed combination of perindopril/indapamide versus placebo, against the background of current standard 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. The mean age of patients was 66 years, body mass index (BMI) 28 kg/m², duration of diabetes — 8 years, HbA1c 7.5%, and SBP/DBP 145/81 mm Hg. Among them, 83% of patients 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%, primarily statins — 28%), and acetylsalicylic acid or other antiplatelet agents (47%). During the 6-week run-in period, patients received the combination of perindopril/indapamide and continued their usual glucose-lowering therapy. Then, patients were randomized to receive either placebo (n = 5,571) or the combination of perindopril/indapamide (n = 5,569). Perindopril/indapamide 5 mg/1.25 mg film-coated tablets are not suitable for initiating therapy. Treatment was started 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 the perindopril/indapamide combination 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 compared to placebo were due to: a significant 14% relative risk reduction in overall mortality (95% CI [0.75; 0.98], p = 0.025); a significant 18% relative risk reduction in cardiovascular mortality (95% CI [0.68; 0.98], p = 0.027); and a 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, a significant 9% relative risk reduction in major macro- and microvascular complications was observed (95% CI [0.82; 1.0], p = 0.052) compared to the placebo group. In the subgroup of patients receiving perindopril/indapamide compared to placebo, there was also: a significant 16% relative risk reduction in overall mortality (95% CI [0.73; 0.97], p = 0.019); a significant 20% relative risk reduction in cardiovascular mortality (95% CI [0.66; 0.97], p = 0.023); and a significant 20% relative risk reduction in all types of renal complications (95% CI [0.73; 0.87], p < 0.001). The benefits of blood pressure-lowering treatment were independent of the benefits achieved in patients treated according to the intensive glycemic control strategy.

Pharmacodynamic effects related to perindopril. Perindopril effectively reduces BP at all stages of arterial hypertension: mild, moderate, and severe. Reduction in SBP and DBP is observed both in supine and standing positions. The maximum antihypertensive effect develops 4–6 hours after a single dose and lasts more than 24 hours. Perindopril achieves a high level of ACE inhibition (approximately 80%) 24 hours after administration. In patients who respond to treatment, normalization of BP is achieved within one month and is 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 arterial resistance, and reduces left ventricular hypertrophy. Adding a thiazide diuretic when necessary leads to 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 is evident at doses where diuretic properties are minimal. The antihypertensive effect of indapamide is proportional to improved arterial elasticity and reduced arteriolar resistance and total peripheral vascular resistance. Indapamide reduces left ventricular hypertrophy. For thiazide and thiazide-like diuretics, antihypertensive effects plateau beyond a certain dose, while the number of adverse effects increases. If treatment is insufficiently effective, the drug dose should not be increased. Moreover, studies of varying duration (short, medium, and long-term) in patients with arterial hypertension have shown that indapamide does not affect lipid metabolism (triglycerides, low- and high-density lipoproteins) and does not affect carbohydrate metabolism, even in patients with arterial hypertension and diabetes mellitus.

Pharmacokinetics. The pharmacokinetic properties of perindopril and indapamide in the IN-ALITER medicinal product do not differ from those when used separately.

Pharmacokinetic properties of perindopril.

Absorption and bioavailability. After oral administration, perindopril is rapidly absorbed, with maximum 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 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 depends on concentration.

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

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

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

Special patient populations

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

Renal function impairment. Dosage adjustment is required for patients with renal impairment depending on the degree of renal function (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. The elimination half-life is 14–24 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. In patients with renal insufficiency, pharmacokinetic parameters do not change.

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 in a dose of 8 mg and indapamide in 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 lactation"); concomitant use with medicinal products containing aliskiren 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. IN-ALITER must not be administered earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction"); extracorporeal treatment methods leading to blood contact with negatively charged surfaces (see section "Interaction with other medicinal products and other forms of interaction"); significant bilateral renal artery stenosis or stenosis of the artery of a solitary functioning kidney (see section "Special precautions").

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

Related to IN-ALITER: hypersensitivity to any excipient. Due to lack of sufficient clinical experience, IN-ALITER should not be used in patients undergoing hemodialysis; 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 concentrations and 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 necessary, serum lithium concentrations should be closely monitored (see section "Special precautions").

Concomitant use requiring particular 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). Concomitant use of ACEIs and NSAIDs, such as acetylsalicylic acid at anti-inflammatory doses, COX-2 inhibitors, and non-selective NSAIDs, may result in reduced antihypertensive effect. Concomitant use of ACEIs and NSAIDs may increase the risk of worsening renal function, including development of acute renal failure, and increase serum potassium levels, particularly in patients with renal impairment. Such combination should be used with caution, especially in elderly patients. Patients should be adequately hydrated prior to initiation of treatment and renal function should be monitored at the start 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 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. 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 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 IN-ALITER. Some medicinal products or therapeutic classes such as aliskiren, potassium salts, potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), ACE inhibitors, angiotensin II receptor antagonists, NSAIDs, heparins, 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 with these agents increases the risk of hyperkalemia. Therefore, concomitant use of IN-ALITER with the above-mentioned medicinal products is not recommended. If concomitant use is necessary, it should be done with caution and frequent monitoring of serum potassium levels.

Concomitant use contraindicated (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 low-density lipoprotein (LDL) apheresis using dextran sulfate, due to increased risk of severe anaphylactoid reactions (see section "Contraindications"). If such treatment is necessary, consideration should be given to using a different type of dialysis membrane or 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 patients with target organ damage, concomitant therapy with ACE inhibitors and angiotensin receptor blockers has been associated with increased incidence of hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to use of a single RAAS-acting agent. Dual blockade (i.e., combination of ACE inhibitor and angiotensin II receptor antagonist) may be considered only in selected cases with 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 unavoidable, it should be done with caution and frequent monitoring of serum potassium levels. Information on use of spironolactone in patients with heart failure is provided under "Concomitant use requiring particular attention".

Concomitant use requiring particular 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 the diuretic, increasing circulating volume, or salt intake prior to starting perindopril therapy, which should be initiated at a low dose with gradual dose escalation. In patients with hypertension, where prior diuretic therapy may have caused volume/sodium depletion, the diuretic should be discontinued prior to 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 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 doses of 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 of this combination are not followed. Before initiating such combination, absence of hyperkalemia and renal impairment should be confirmed. Close monitoring of serum potassium and creatinine is recommended weekly during the first month and monthly thereafter.

Concomitant use requiring attention

Antihypertensive agents and vasodilators. Concomitant use 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").

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

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

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

Interactions related to indapamide.

Concomitant use requiring particular 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 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, thiamylal, 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 vinca alkaloids, methadone, astemizole, terfenadine). Plasma potassium levels should be maintained 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). Serum potassium levels should be monitored and corrected if necessary, particularly during concomitant treatment with cardiac glycosides. Non-stimulant laxatives should be used.

Cardiac glycosides. Hypokalemia and/or hypomagnesemia may predispose to digitalis toxicity. Monitoring of plasma potassium and magnesium levels and ECG control is 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). Serum potassium levels should be monitored, ECG monitoring performed, and therapy reviewed if necessary.

Metformin. May cause lactic acidosis due to development of 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 and 12 mg/L (110 µmol/L) in women.

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

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

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

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

Special precautions for use.

Special warnings.

Special warnings common to perindopril and indapamide.

For the low-dose combination of the medicinal product IN-ALITER, a significant reduction in adverse reactions has not been demonstrated compared to the administration of equivalent doses of its components as monotherapies, except for hypokalemia (see section "Side effects"). When a patient starts 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

Dual blockade of the renin-angiotensin-aldosterone system (RAAS). Data indicate that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of arterial hypotension, hyperkalemia, and impaired kidney 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"). However, if dual RAAS blockade therapy is considered absolutely necessary, it should be conducted only under specialist supervision and with frequent, careful monitoring of kidney function, electrolyte levels, and blood pressure. Patients with diabetic nephropathy should not receive concomitant treatment with ACE inhibitors and angiotensin II receptor blockers.

Potassium-sparing agents, potassium-containing supplements or salt substitutes. The combination of perindopril with potassium-sparing agents, potassium-containing supplements, or 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 receiving ACE inhibitors. Neutropenia is rare in patients with normal renal function and no other risk factors. Perindopril should be used with extreme caution in patients with collagen vascular diseases, those receiving immunosuppressive therapy, allopurinol, or procainamide, or in patients with a combination of these risk factors, especially if renal function is impaired. In some of these patients, severe infections have been observed, sometimes resistant to intensive antibiotic therapy. Periodic monitoring of white blood cell count is recommended in such patients during perindopril therapy. 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 "Side effects").

Renovascular hypertension. In patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney, treatment with ACE inhibitors increases the risk of arterial hypotension and renal failure (see section "Contraindications"). Diuretic use may be a contributing factor. Impaired kidney 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 receiving ACE inhibitors, including perindopril (see section "Side effects"). This may occur at any time during treatment. In such cases, the drug must be discontinued immediately, and medical supervision should be maintained until symptoms completely resolve. If swelling is limited to the face and lips, the patient's condition usually improves without treatment, although antihistamines may be helpful in reducing symptoms. Angioedema involving laryngeal edema may be fatal. If swelling involves the tongue, glottis, or larynx, potentially leading to airway obstruction, emergency treatment is required, which may include subcutaneous administration of 1:1000 epinephrine solution (0.3–0.5 mL) and/or measures to ensure airway patency. Angioedema has been reported more frequently in patients of African descent receiving ACE inhibitors compared to other racial groups. Patients with a history of angioedema unrelated to ACE inhibitor use are at increased risk of developing angioedema during ACE inhibitor therapy. Rare cases of intestinal angioedema have been reported in patients receiving ACE inhibitor therapy. These patients experienced abdominal pain (with or without nausea and vomiting); intestinal angioedema sometimes occurred without prior facial angioedema, and serum C1 esterase inhibitor levels were within normal limits. The diagnosis of angioedema was confirmed by procedures such as abdominal computed tomography, ultrasound, or during surgical intervention; symptoms resolved after discontinuation of the ACE inhibitor. In patients taking ACE inhibitors who develop abdominal pain, differential diagnosis should be performed to exclude intestinal angioedema.

Concomitant use of perindopril with sacubitril/valsartan is contraindicated due to an increased risk of angioedema. Initiation of sacubitril/valsartan therapy should not occur earlier than 36 hours after the last dose of perindopril. If sacubitril/valsartan therapy 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 neprilysin inhibitors (NEP) (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 receiving ACE inhibitors during desensitization therapy with bee venom-containing agents. ACE inhibitors should be used with caution in patients with allergies undergoing desensitization and should be 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 starting desensitization therapy.

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

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

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

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

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

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

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

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 patients with severe renal impairment (creatinine clearance < 30 mL/min).

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

If laboratory blood tests in some patients with arterial hypertension but no signs of renal impairment show signs of functional renal impairment, treatment should be discontinued, possibly to be resumed at a lower dose or with one of its components alone. Such patients require frequent monitoring of potassium and creatinine levels in blood: 2 weeks after initiation of therapy and then every 2 months during therapeutic stabilization. Cases of renal impairment have been observed predominantly in patients with severe heart failure or renal impairment, 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 episodes of vomiting or diarrhea, is required. In such patients, plasma electrolyte levels should be monitored regularly. In cases of significant arterial hypotension, intravenous infusion of isotonic sodium chloride solution may be necessary. Transient hypotension is not a contraindication for continuing therapy. 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, especially in patients with diabetes mellitus or renal impairment. As with any antihypertensive agent combined with a diuretic, regular monitoring of plasma potassium levels is required.

Excipients. The medicinal product 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, a possible iatrogenic etiology should be considered. If ACE inhibitor therapy is necessary for the patient, a decision may be made to continue treatment.

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

Elderly patients. Renal function and blood potassium levels should be checked before starting therapy. To reduce the risk of sudden arterial hypotension, especially in the presence of 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 IN-ALITER is prescribed to patients with known renal artery stenosis or suspected stenosis, treatment should be initiated in a hospital setting with a low dose 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: IN-ALITER should not be prescribed to patients with known renal artery stenosis or suspected stenosis. In such cases, treatment should be initiated in a hospital setting with a dose lower 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-blocker therapy.

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

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

Surgery/anesthesia. ACE inhibitors may cause arterial hypotension during anesthesia, especially when anesthetics with hypotensive potential are used. Therefore, it is recommended to discontinue long-acting ACE inhibitors, such as perindopril, 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 inhibitor use has been associated with a syndrome beginning with cholestatic jaundice and progressing to fulminant hepatic necrosis, sometimes fatal. Patients who develop jaundice with elevated liver enzymes during ACE inhibitor therapy should discontinue the drug and receive appropriate medical supervision (see section "Side effects").

Hyperkalemia. Increased serum potassium levels have been observed in some patients receiving ACE inhibitors, including perindopril. ACE inhibitors may cause hyperkalemia by inhibiting aldosterone release. This effect is usually minor in patients with normal renal function. Risk factors for hyperkalemia include renal impairment, worsening renal function, age over 70 years, diabetes mellitus, intercurrent conditions (especially dehydration), acute heart decompensation, metabolic acidosis, and concomitant use with potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, amiloride), potassium-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 particularly aldosterone antagonists or angiotensin receptor blockers, other ACE inhibitors, angiotensin II receptor antagonists, acetylsalicylic acid at doses ≥ 3 g/day, COX-2 inhibitors and nonselective 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 a significant increase in serum potassium levels. Hyperkalemia may cause serious, sometimes fatal, arrhythmias. Patients receiving ACE inhibitors should use potassium-sparing diuretics and angiotensin receptor blockers with caution and undergo careful monitoring of serum potassium levels and renal function. If concomitant use of the above-mentioned drugs is considered appropriate, they should be used with caution and with frequent monitoring of 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. Hyponatremia may initially be asymptomatic, necessitating regular monitoring. Monitoring should be more frequent in elderly patients and patients with liver cirrhosis (see sections "Side effects" and "Overdose"). Any diuretic therapy may cause hyponatremia, sometimes with very serious consequences. Hyponatremia combined with hypovolemia may lead to dehydration and orthostatic hypotension. Concomitant chloride ion loss may lead to secondary compensatory metabolic alkalosis: the frequency and severity of this effect are low.

Potassium levels. Decreased 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 with concomitant severe hypokalemia, have been reported. Prevention of potassium depletion (< 3.4 mmol/L) is essential in certain high-risk patient groups, such as elderly patients and/or those with poor nutrition, regardless of concomitant medication use, patients with liver cirrhosis accompanied by edema and ascites, and patients with ischemic heart disease and heart failure. In these cases, hypokalemia increases the cardiotoxicity of cardiac glycosides and the risk of cardiac arrhythmias. Patients with congenital or iatrogenic long QT interval also belong to the risk group. Hypokalemia, like bradycardia, is a predisposing factor for severe cardiac arrhythmias, particularly paroxysmal torsades de pointes tachycardia, which may be fatal. More frequent monitoring of blood potassium levels is required. The first determination of plasma potassium levels should be performed within the first week of treatment. If low potassium levels are detected, correction is necessary.

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. 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 "Side effects").

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

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

Kidney function and diuretics. Thiazide and thiazide-like diuretics are most effective when kidney function is normal or only mildly impaired (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, potentially leading 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 pre-existing renal impairment.

Choroidal effusion, acute myopia (nearsightedness), and secondary angle-closure glaucoma. Medicinal products containing sulfonamide or sulfonamide derivatives may cause an idiosyncratic reaction leading to choroidal effusion with visual field defects, transient myopia, and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or eye pain and usually occur within several hours or weeks after starting the drug. Untreated acute angle-closure glaucoma may lead to permanent vision loss. The primary treatment is immediate discontinuation of the drug. If intraocular pressure remains uncontrolled, surgical or medical treatment may be necessary. Risk factors for developing 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 inhibitor use during the first trimester of pregnancy is lacking; however, a small increase in this risk cannot be excluded. If continued ACE inhibitor therapy is considered mandatory, women planning pregnancy should be switched to alternative antihypertensive drugs with established safety data during pregnancy. If pregnancy is confirmed during treatment, ACE inhibitor therapy should be immediately discontinued and, if necessary, replaced with another drug permitted 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 kidney function, oligohydramnios, delayed skull ossification) and on the newborn (renal failure, arterial hypotension, hyperkalemia). If ACE inhibitors were used during the second and third trimesters of pregnancy, ultrasound examination of kidney function and skull structure in the newborn is recommended. Newborns whose mothers received ACE inhibitors during pregnancy should be monitored for timely detection and correction of arterial hypotension.

Warnings related to indapamide. Data on indapamide use in pregnant women are lacking or limited (fewer than 300 cases). Prolonged use of a thiazide diuretic during the third trimester of pregnancy may lead to reduced circulating blood volume in the pregnant woman 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. IN-ALITER is not recommended during breastfeeding. A decision should be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the importance of the therapy for the mother.

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

Warnings related to indapamide. Data on indapamide/metabolite 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 not recommended during breastfeeding.

Fertility

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

Ability to affect reaction speed when driving or operating machinery.

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

Dosage and Administration

For oral use.

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

IN-ALITER 4 mg/1.25 mg: The recommended dose of IN-ALITER 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 IN-ALITER 4 mg/1.25 mg may be considered.

IN-ALITER 8 mg/2.5 mg: The recommended dose of IN-ALITER is 1 tablet once daily, preferably in the morning before meals.

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

IN-ALITER 2 mg/0.625 mg: Treatment should be initiated with the recommended dose of IN-ALITER 2 mg/0.625 mg – 1 tablet once daily.

IN-ALITER 4 mg/1.25 mg: In elderly patients, treatment should be prescribed taking into account blood pressure levels and renal function.

IN-ALITER 8 mg/2.5 mg: In elderly patients, plasma creatinine levels should be determined considering age, body weight, and gender. Treatment in elderly patients may be initiated if renal function is normal and after assessing blood pressure response to therapy.

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

IN-ALITER 2 mg/0.625 mg: IN-ALITER 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 IN-ALITER 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.

IN-ALITER 4 mg/1.25 mg: IN-ALITER 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.

IN-ALITER 8 mg/2.5 mg: IN-ALITER 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").

IN-ALITER is contraindicated in patients with severe hepatic impairment. Patients with moderate hepatic impairment do not require dose adjustment.

Pediatric population.

IN-ALITER should not be used for the treatment of children and adolescents. The 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, somnolence, confusion, oliguria, which may progress to anuria (due to hypovolemia), and circulatory shock. Electrolyte and fluid imbalances (decreased plasma potassium and sodium levels), renal failure, hyperventilation, tachycardia, palpitations, bradycardia, anxiety, and cough may also occur.

Treatment. Emergency measures include rapid elimination of the drug from the body – gastric lavage and/or administration of activated charcoal, 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 elevation of the head. If necessary, intravenous administration of isotonic sodium chloride solution or other measures to restore blood volume should be performed. Perindoprilat, the active metabolite of perindopril, may be removed from the body by hemodialysis (see section "Pharmacokinetics").

Adverse reactions.

The use of perindopril inhibits the renin-angiotensin-aldosterone system and helps reduce potassium loss in blood plasma caused by indapamide. Hypokalemia (potassium level < 3.4 mmol/L) occurs in 2–6% of patients treated with perindopril/indapamide. The most commonly reported adverse reactions are as follows: with perindopril — dizziness, headache, paresthesia, dysgeusia, visual disturbances, vertigo, tinnitus, arterial hypotension, cough, dyspnea, abdominal pain, constipation, dyspepsia, diarrhea, nausea, vomiting, pruritus, rash, muscle cramps, and asthenia; with indapamide — hypokalemia, hypersensitivity reactions, predominantly dermatological, in individuals 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, categorized by frequency as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), 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 anemia (very rare — indapamide); pancytopenia (very rare — perindopril); leukopenia (very rare — perindopril and indapamide); neutropenia (see section "Special precautions for use") (very rare — perindopril); hemolytic anemia (very rare — perindopril and indapamide); thrombocytopenia (see section "Special precautions for use") (very rare — perindopril and indapamide).

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

Metabolism and nutrition disorders: hypokalemia (see section "Special precautions for use") (common — indapamide); hypoglycemia (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction") (uncommon* — perindopril); hyperkalemia, reversible upon discontinuation of the drug (see section "Special precautions for use") (uncommon* — perindopril); hyponatremia (see section "Special precautions for use") (uncommon* — perindopril, uncommon — indapamide); hypochloremia (rare — indapamide); hypomagnesemia (rare — indapamide); hypercalcemia (very rare — indapamide).

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

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

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

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

Cardiac disorders: palpitations (uncommon* — perindopril); tachycardia (uncommon* — perindopril); angina pectoris (see section "Special precautions for use") (very rare — perindopril); arrhythmia (including bradycardia, ventricular tachycardia, atrial fibrillation) (very rare — perindopril and indapamide); myocardial infarction due to excessive arterial hypotension in high-risk patients (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); hot flushes (rare* — perindopril); Raynaud's phenomenon (frequency not known — perindopril).

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

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

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

Skin and subcutaneous tissue disorders: pruritus (common — perindopril); rash (common — perindopril); maculopapular rash (common — indapamide); urticaria (see section "Special precautions for use") (uncommon — perindopril, very rare — indapamide); angioedema (see section "Special precautions for use") (uncommon — perindopril, very rare — indapamide); purpura (uncommon — indapamide); hyperhidrosis (uncommon — perindopril); photosensitivity reactions (uncommon* — perindopril, frequency not known — indapamide); pemphigoid (uncommon* — perindopril); exacerbation of existing psoriasis symptoms (rare* — perindopril); erythema multiforme (very rare — perindopril); toxic epidermal necrolysis (very rare — indapamide); Stevens-Johnson syndrome (very rare — indapamide).

Musculoskeletal and connective tissue disorders: muscle cramps (common — perindopril, frequency not known — indapamide); possible worsening of existing systemic lupus erythematosus (frequency not known — indapamide); arthralgia (uncommon* — perindopril); myalgia (uncommon* — perindopril, frequency not known — indapamide); muscle weakness (frequency not known — indapamide); rhabdomyolysis (frequency not known — indapamide).

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

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

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

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

Injury, poisoning and procedural complications: falls (uncommon* — perindopril).

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

Reporting suspected adverse reactions

Reporting of adverse reactions after medicinal product authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at the following link: 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.

30 tablets (10 × 3) in a blister pack in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

LLC NPF "MIKROKHEM" (responsible for batch release, excluding batch control/testing).

JSC "FARMAC" (full-cycle manufacturing)

Manufacturer's location and address of place of business.

Ukraine, 01013, Kyiv, Budynstustriyi St., 5.

Ukraine, 04080, Kyiv, Kyrylivska St., 74

Marketing Authorization Holder.

LLC NPF "MIKROKHEM".

Address of Marketing Authorization Holder.

Ukraine, 01013, Kyiv, Budynstustriyi St., 5.

To report an adverse event during the use of the medicinal product, please call +38 (050) 309-83-54 (24/7).

INSTRUCTION

for medical use of the medicinal product

IN-ALITER

(IN-ALITER)

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 hydrogencarbonate; colloidal anhydrous silicon dioxide; magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white to almost white, round, biconvex tablets.

Pharmacotherapeutic group.

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

Pharmacological properties.

Pharmacodynamics. IN-ALITER is a combination of the angiotensin-converting enzyme (ACE) inhibitor perindopril tert-butylamine and the sulfonamide diuretic indapamide. Its pharmacological action is determined by the properties of each component (perindopril and indapamide) and their additive synergism.

Mechanism of action. IN-ALITER exerts 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) degradation into inactive heptapeptides. Inhibition of ACE leads to: reduced aldosterone secretion; increased plasma renin activity, while aldosterone does not exert a negative feedback effect; decreased total peripheral vascular resistance due to predominant effects on muscle and renal vessels; meanwhile, water and salt retention or reflex tachycardia are not observed, even during long-term treatment. In addition, 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 decreased total peripheral vascular resistance — reducing afterload on the heart. Studies conducted in patients with heart failure have demonstrated that perindopril use leads to reduced filling pressures in the left and right ventricles, decreased total peripheral vascular resistance, increased cardiac output, improved cardiac index, and increased regional blood flow in muscles. Exercise test parameters are improved.

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

Pharmacodynamic effects. IN-ALITER 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 in less than one month without development of tachyphylaxis; discontinuation of treatment does not cause withdrawal syndrome. Clinical studies have demonstrated that concomitant administration of perindopril and indapamide results in synergistic antihypertensive action, resulting from the individual effects of the drug components.

PICXEL — a multicenter, randomized, double-blind, placebo-controlled study in which the effect of the combination of perindopril and indapamide on left ventricular hypertrophy was evaluated by echocardiography compared to enalapril monotherapy. In the PICXEL study, patients with arterial hypertension and left ventricular hypertrophy (with 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) values: perindopril tert-butylamine dose was increased up to 8 mg (equivalent to 10 mg perindopril arginine), indapamide up to 2.5 mg, and enalapril up to 40 mg once daily. Starting doses were continued in 34% of patients in the perindopril/indapamide group (2 mg perindopril and 0.625 mg indapamide) and 20% in the enalapril group (10 mg). At the end of treatment, the left ventricular mass index decreased significantly more in patients receiving perindopril/indapamide (–10.1 g/m²) than in the enalapril group (–1.1 g/m²). The difference between the two groups was –8.3 (95% confidence interval [CI] from –11.5 to –5.0, p < 0.0001). Better reduction in 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 evaluating the benefits of blood pressure reduction with fixed-dose combination perindopril/indapamide versus placebo on top 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 evaluation]) 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. The mean age of patients 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%), and acetylsalicylic acid or other antiplatelet agents (47%). During the 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 = 5,571) or perindopril/indapamide combination (n = 5,569). Perindopril/indapamide 5 mg/1.25 mg film-coated tablets are not suitable for initiating 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 combination 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: a significant 14% relative risk reduction in overall mortality (95% CI [0.75; 0.98], p = 0.025); a significant 18% relative risk reduction in cardiovascular mortality (95% CI [0.68; 0.98], p = 0.027); and a 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, a significant 9% relative risk reduction in major macro- and microvascular complications was observed (95% CI [0.82; 1.0], p = 0.052) compared to the placebo group. In the subgroup of patients receiving perindopril/indapamide versus placebo, there were also significant reductions in: overall 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 treated 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. The maximum antihypertensive effect develops 4–6 hours after a single dose and persists for over 24 hours. Perindopril achieves a high level of sustained ACE inhibition (approximately 80%) 24 hours after administration. In patients who respond to treatment, BP normalization is achieved within one month and 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 arterial resistance, 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 antihypertensive effects 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 reach a plateau with increasing doses, while the number of adverse effects increases. If treatment is insufficiently effective, the dose should not be increased. Moreover, studies of varying duration (short, medium, and long-term) in patients with arterial hypertension have shown that indapamide does not affect lipid metabolism (triglycerides, low- and high-density lipoproteins) and does not affect carbohydrate metabolism, even in patients with arterial hypertension and diabetes mellitus.

Pharmacokinetics. The pharmacokinetic properties of perindopril and indapamide in the IN-ALITER medicinal product do not differ from those observed with their individual administration.

Pharmacokinetic properties of perindopril.

Absorption and bioavailability. After oral administration, perindopril is rapidly absorbed, with maximum 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 taken orally as a single daily dose in the morning before meals.

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

Biotransformation. Perindopril is a prodrug. Thus, 27% of the administered perindopril dose 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 excreted in urine; the terminal elimination 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 those with cardiac or renal insufficiency.

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

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

Liver cirrhosis. Perindopril kinetics are altered in patients with liver cirrhosis: hepatic clearance of the parent compound is halved. However, the amount of perindoprilat formed is not reduced; 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 administration 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. In patients with renal insufficiency, pharmacokinetic parameters are not altered.

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 treatment with perindopril tert-butylamine 8 mg and indapamide 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 ACE inhibitor therapy (see section "Special precautions"); hereditary or idiopathic angioedema; pregnancy or planned pregnancy (see section "Use in pregnancy or breastfeeding"); concomitant use with aliskiren-containing medicinal products in patients with diabetes mellitus or renal impairment (glomerular filtration rate < 60 mL/min/1.73 m²) (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacodynamics"); concomitant use with sacubitril/valsartan. IN-ALITER must not be initiated 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 contact of blood 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 to a single functioning kidney (see section "Special precautions").

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

Related to IN-ALITER: hypersensitivity to any excipient. Due to lack of sufficient clinical experience, IN-ALITER 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 concentrations 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 combination is necessary, serum lithium concentrations should be monitored carefully (see section "Special precautions").

Concomitant use requiring special attention

Baclofen. Antihypertensive effect is enhanced. Blood pressure should be monitored and antihypertensive dosage adjusted as needed.

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, or non-selective NSAIDs, the antihypertensive effect may be attenuated. Concomitant use of ACEIs and NSAIDs may increase the risk of worsening renal function, including acute renal failure, and hyperkalemia, particularly in patients with renal impairment. Such combinations should be prescribed 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 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), or 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 IN-ALITER. 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, immunosuppressants (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 with these agents increases the risk of hyperkalemia. Therefore, concomitant use of IN-ALITER with the above-mentioned drugs is not recommended. If concomitant use is necessary, it should be done with caution and frequent monitoring of serum potassium levels.

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 contact of blood with negatively charged surfaces, such as dialysis or hemofiltration using certain high-flux membranes (e.g., polyacrylonitrile) and LDL apheresis with 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 dialysis membrane or another class of antihypertensive agents.

Concomitant use not recommended

Aliskiren. In all other patient groups, as in patients 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 an ACE inhibitor and an angiotensin receptor blocker has been associated with increased incidence of hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to use of a single RAAS-acting agent. Dual blockade (i.e., combination of ACE inhibitor and angiotensin II receptor antagonist) may be considered only in selected cases under strict 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 agents is not recommended (see section "Special precautions"). If concomitant use is nevertheless indicated, it should be done with caution and frequent monitoring of serum potassium levels. Information on use of spironolactone in patients with heart failure is provided under "Concomitant use requiring special attention".

Concomitant use requiring special attention

Antidiabetic agents (insulin, oral hypoglycemics). Concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemics) may enhance 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 receiving 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 can be reduced by discontinuing diuretic therapy, increasing circulating volume, or salt intake prior to starting perindopril, which should be initiated at a low dose with gradual titration. In patients with hypertension, if prior diuretic therapy may have caused volume/sodium depletion, diuretic therapy should be discontinued before starting ACE inhibitor (diuretic therapy may be resumed later) or ACE inhibitor therapy should be initiated at a low dose with gradual titration. In patients with congestive heart failure receiving diuretics, ACE inhibitor therapy should be initiated at the lowest dose, possibly after reducing the diuretic dose. In all cases, renal function (creatinine 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%, 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, absence of hyperkalemia and renal dysfunction should be confirmed. Close monitoring of serum potassium and creatinine is recommended weekly during the first month and monthly thereafter.

Concomitant use requiring attention

Antihypertensives 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 blood pressure reduction.

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

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

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

Gold preparations. Rarely, when patients are treated with injectable gold preparations (sodium aurothiomalate) and concomitantly receive ACE inhibitors, including perindopril, 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. 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 (the list is not exhaustive): Class IA antiarrhythmics (e.g., quinidine, hydroquinidine, disopyramide); Class III antiarrhythmics (e.g., amiodarone, dofetilide, ibutilide, bretylium, sotalol); certain antipsychotics: phenothiazines (e.g., chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine), benzamides (e.g., amisulpride, sulpiride, sultopride, tiapride), butyrophenones (e.g., droperidol, haloperidol), other antipsychotics (e.g., pimozide); other substances (e.g., bepridil, cisapride, difemanil, intravenous erythromycin, halofantrine, mizolastine, moxifloxacin, pentamidine, sparfloxacin, intravenous vinca alkaloids, 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), tetracosactide, stimulant laxatives increase the risk of reduced serum potassium levels (additive effect). Serum potassium levels should be monitored and corrected if necessary, particularly during concomitant treatment with cardiac glycosides. Non-stimulant laxatives should be used.

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

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). Serum potassium levels should be monitored, ECG monitoring performed, and therapy reviewed if necessary.

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

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

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

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

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

Special precautions.

Special warnings.

Special warnings common to perindopril and indapamide.

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

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

Dual blockade of the renin-angiotensin-aldosterone system (RAAS). Data indicate that simultaneous use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of arterial hypotension, hyperkalemia, and impaired kidney function (including acute renal failure). Therefore, dual RAAS blockade resulting from concomitant use 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 kidney function, electrolyte levels, and blood pressure. Patients with diabetic nephropathy should not use ACE inhibitors and angiotensin II receptor blockers simultaneously.

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

Neutropenia/agranulocytosis/thrombocytopenia/anemia. Cases of neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported in patients taking ACE inhibitors. Neutropenia is rare in patients with normal kidney function and no other risk factors. Perindopril should be used with extreme caution in patients with collagen diseases, those receiving immunosuppressants, allopurinol, or procainamide, or in combination with these risk factors, especially if kidney 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 treatment in such patients. Patients should also be informed about the need to report any signs of infection (e.g., sore throat, fever) to their physician (see sections "Interaction with other medicinal products and other 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 kidney 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 should 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 help relieve symptoms. Angioedema involving laryngeal edema 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 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 treatment. These patients experienced abdominal pain (with or without nausea and vomiting); sometimes intestinal angioedema occurred without prior facial angioedema, and C1-esterase inhibitor levels were normal. The diagnosis of angioedema was confirmed by procedures such as abdominal computed tomography or ultrasound, or during surgical intervention; symptoms resolved after discontinuation of the ACE inhibitor. In patients taking ACE inhibitors who develop abdominal pain, differential diagnosis should be performed to exclude intestinal angioedema.

Concomitant use of perindopril with sacubitril/valsartan is contraindicated due to an increased risk of angioedema. Sacubitril/valsartan therapy should not be initiated 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., airway or tongue swelling, with or without respiratory impairment) (see section "Interaction with other medicinal products and other forms of interaction"). Caution should be exercised when initiating treatment 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 preparations. ACE inhibitors should be used with caution in patients with allergies after desensitization and should be avoided during immunotherapy with bee venom-containing preparations. However, in patients requiring both ACE inhibitors and desensitization, such reactions can be avoided by temporarily discontinuing ACE inhibitors at least 24 hours before starting desensitization therapy.

Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis. Rare, 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 using high-flux polyacrylonitrile membranes (e.g., AN 69®). Such patients should use a different type of dialysis membrane or be prescribed another class of antihypertensive agents.

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

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

Arterial hypotension. Symptomatic arterial hypotension has been reported in patients with symptomatic heart failure, with or without concomitant renal impairment. The occurrence of symptomatic arterial hypotension is more likely in patients with more severe heart failure, those taking high-dose loop diuretics, those with hyponatremia, or those with functional renal impairment. During initial therapy and dose titration, patients should be under close medical supervision to reduce the risk of symptomatic arterial hypotension. Similar precautions apply to patients with ischemic heart disease or cerebrovascular disorders, in whom excessive reduction in blood pressure 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 trigger hepatic encephalopathy, which may progress to hepatic coma. In such cases, diuretic use should be discontinued immediately.

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

Precautionary measures.

Precautionary measures common to perindopril and indapamide

Renal impairment. 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 moderate to severe renal impairment (creatinine clearance < 60 ml/min).

If laboratory blood tests in some patients with arterial hypertension but no signs of impaired kidney function show signs of functional renal impairment, treatment should be discontinued, possibly to be resumed at a lower dose or with only one of its components. 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 kidney 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 deficiency. 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 deficiency, which may occur during intercurrent vomiting or diarrhea, is necessary. Such patients should have regular plasma electrolyte level monitoring. In cases of significant arterial hypotension, intravenous infusion of isotonic sodium chloride solution may be required. Transient hypotension is not a contraindication for continuing treatment. After restoration of circulating blood volume and normalization of blood pressure, treatment may be resumed at a reduced dose or with only one of the components.

Potassium levels. The combination of perindopril and indapamide does not exclude the possibility of hypokalemia, especially in patients with diabetes mellitus or renal impairment. As with any antihypertensive agent used in combination 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 galactose intolerance, 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 appears, its iatrogenic etiology should be considered. If ACE inhibitor treatment is necessary for the patient, a decision may be made to continue therapy.

Risk of arterial hypotension and/or renal impairment (in cases of heart failure, water and electrolyte deficiency). Significant stimulation of the RAAS has been observed during acute water and electrolyte deficiency (strict salt-free diet or prolonged diuretic therapy) in patients with low blood pressure, renal artery stenosis, congestive heart failure, or cirrhosis with edema and ascites. Blocking this system with ACE inhibitors, especially during initial use and the first 2 weeks of treatment, may cause a sudden drop in blood pressure and/or an increase in plasma creatinine levels, 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. Kidney function and blood potassium levels should be checked before starting treatment. To reduce the risk of sudden arterial hypotension, especially in cases of water or electrolyte deficiency, the initial dose should be adjusted according to the blood pressure response.

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

Renovascular hypertension. The treatment of renovascular hypertension is revascularization. However, ACE inhibitors may be beneficial for patients with renovascular hypertension awaiting surgery or for whom surgery is not possible.

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

For dosage 8 mg/2.5 mg: IN-ALITER 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 of the drug.

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 treatment in patients with arterial hypertension and coronary insufficiency should not be discontinued; ACE inhibitors should be added to β-blockers.

Patients with diabetes mellitus. Treatment of patients with insulin-dependent diabetes mellitus (with a spontaneous tendency to increased blood potassium levels) should be initiated under medical supervision with a reduced initial dose. Patients with diabetes mellitus previously treated with oral hypoglycemic agents or insulin require careful monitoring of blood glucose levels, especially during the first month of ACE inhibitor treatment (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 races, 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, long-acting ACE inhibitors such as perindopril should preferably be discontinued 1 day before surgery.

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

Hepatic impairment. Rarely, ACE inhibitor use has been associated with a syndrome beginning with cholestatic jaundice and progressing to rapidly developing liver necrosis, sometimes fatal. Patients who develop jaundice with elevated liver enzymes during ACE inhibitor use 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 inhibiting aldosterone release. This effect is usually insignificant in patients with normal kidney function. Risk factors for hyperkalemia include renal impairment, worsening kidney function, age over 70 years, diabetes mellitus, intercurrent conditions (especially dehydration), acute heart decompensation, metabolic acidosis, and concomitant use with potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, amiloride), potassium supplements or potassium-containing salt substitutes, or other drugs associated with 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, non-selective NSAIDs, immunosuppressants such as cyclosporine or tacrolimus, trimethoprim). Use of potassium-containing supplements or salt substitutes and potassium-sparing diuretics, especially in patients with impaired kidney function, may lead to a significant increase in serum potassium levels. Hyperkalemia may cause serious, sometimes fatal arrhythmias. Patients taking ACE inhibitors should use potassium-sparing diuretics and angiotensin receptor blockers with caution and undergo careful monitoring of serum potassium levels and kidney function. If concomitant use of the above-mentioned drugs is considered appropriate, they should be used with caution and 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. Hyponatremia may initially be asymptomatic, so regular monitoring is necessary. Monitoring should be performed more frequently in elderly patients and patients with liver cirrhosis (see sections "Adverse reactions" and "Overdose"). Any diuretic treatment may cause hyponatremia, sometimes with very serious consequences. Hyponatremia combined with hypovolemia may lead to dehydration and orthostatic hypotension. Concomitant chloride ion loss may lead to secondary compensatory metabolic alkalosis: the frequency and severity of this effect are insignificant.

Potassium levels. Decreased blood potassium levels leading to hypokalemia are the main risk factor associated with thiazide and thiazide-like diuretics. Hypokalemia may cause muscle disorders. Cases of rhabdomyolysis, mainly with concomitant severe hypokalemia, have been reported. Hypokalemia (< 3.4 mmol/l) should be prevented in certain high-risk patient categories, such as elderly patients and/or those with poor nutrition, regardless of other drug use, patients with liver cirrhosis with 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 arrhythmias. Patients with congenital or iatrogenic prolonged QT interval also belong to the risk group. Hypokalemia, as well as bradycardia, is a favorable factor for the development of severe 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. If low blood potassium levels are detected, correction is necessary.

Detection of hypokalemia requires its correction. Hypokalemia caused by 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, temporary 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 gland function should be monitored.

Plasma magnesium levels. Thiazides and related diuretics, including indapamide, have been shown to increase magnesium excretion in urine, 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 mellitus, 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 level < 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 effects 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 primary treatment is to discontinue the drug as quickly as possible. If intraocular pressure remains uncontrolled, medical or surgical treatment may be necessary. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

Athletes. Athletes should be aware that this drug contains an active substance that may cause a positive result in doping tests.

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 inhibitor use during the first trimester of pregnancy is lacking; however, a small increased risk cannot be excluded. If continued ACE inhibitor treatment is considered mandatory, women planning pregnancy should be switched to alternative antihypertensive drugs with proven 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 in pregnant women. It is known that ACE inhibitor use during the second and third trimesters of pregnancy has toxic effects on the fetus (impaired kidney function, oligohydramnios, delayed formation of skull bone tissue) 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 the newborn's 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 did not reveal direct or indirect toxic effects on reproductive function. As a precaution, indapamide use during pregnancy should be avoided.

Breastfeeding. IN-ALITER 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 a newborn or premature infant.

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

Fertility

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

Ability to affect reaction speed when driving or operating machinery.

The active ingredients perindopril and indapamide, separately or in combination as the medicinal product IN-ALITER, do not affect the ability to drive or operate machinery; however, individual reactions related to reduced blood pressure may occur in some patients, especially at the beginning of treatment or when used concomitantly with other antihypertensive drugs. As a result, the ability to drive or operate machinery may be impaired.

Dosage and Administration

For oral use.

IN-ALITER 2 mg/0.625 mg: The recommended dose of IN-ALITER 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.

IN-ALITER 4 mg/1.25 mg: The recommended dose of IN-ALITER is 1 tablet once daily, preferably in the morning before meals. Individual dose titration of the individual components may be recommended. In cases of clinical necessity, transition from monotherapy directly to treatment with IN-ALITER 4 mg/1.25 mg may be considered.

IN-ALITER 8 mg/2.5 mg: The recommended dose of IN-ALITER is 1 tablet once daily, preferably in the morning before meals.

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

IN-ALITER 2 mg/0.625 mg: Treatment should be initiated with the recommended dose of IN-ALITER 2 mg/0.625 mg – 1 tablet once daily.

IN-ALITER 4 mg/1.25 mg: Treatment in elderly patients should be initiated considering blood pressure levels and renal function.

IN-ALITER 8 mg/2.5 mg: Plasma creatinine levels should be determined 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 Warnings and Precautions for Use").

IN-ALITER 2 mg/0.625 mg: IN-ALITER 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 IN-ALITER 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.

IN-ALITER 4 mg/1.25 mg: IN-ALITER 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 with appropriate doses of the individual components. 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.

IN-ALITER 8 mg/2.5 mg: IN-ALITER 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").

IN-ALITER is contraindicated in patients with severe hepatic impairment. Patients with moderate hepatic impairment do not require dose adjustment.

Children.

IN-ALITER 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, seizures, dizziness, somnolence, confusion, oliguria, which may progress to anuria (due to hypovolemia), and circulatory shock. Electrolyte and fluid imbalances (decreased plasma potassium and sodium levels), renal failure, hyperventilation, tachycardia, palpitations, bradycardia, anxiety, and cough may also occur.

Treatment. Emergency measures include rapid elimination of the drug from the body – gastric lavage and/or administration of activated charcoal, 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 low head elevation. If necessary, intravenous administration of isotonic sodium chloride solution or other volume replacement measures should be performed. Perindoprilat, the active metabolite of perindopril, can be removed from the body by hemodialysis (see section "Pharmacokinetics").

Adverse reactions.

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

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

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

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

Blood and lymphatic system disorders: eosinophilia (uncommon* — perindopril); agranulocytosis (see section "Special precautions") (very rare — perindopril and indapamide); aplastic anemia (very rare — indapamide); pancytopenia (very rare — perindopril); leukopenia (very rare — perindopril and indapamide); neutropenia (see section "Special precautions") (very rare — perindopril); hemolytic anemia (very rare — perindopril and indapamide); thrombocytopenia (see section "Special precautions") (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") (common — indapamide); hypoglycemia (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction") (uncommon* — perindopril); hyperkalemia, reversible upon discontinuation of the drug (see section "Special precautions") (uncommon* — perindopril); hyponatremia (see section "Special precautions") (uncommon* — perindopril, uncommon — indapamide); hypochloremia (rare — indapamide); hypomagnesemia (rare — indapamide); hypercalcemia (very rare — indapamide).

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

Nervous system disorders: dizziness (common — perindopril); headache (common — perindopril, rare — indapamide); paresthesia (common — perindopril, rare — indapamide); dysgeusia (common — perindopril); somnolence (uncommon* — perindopril); syncope (uncommon* — perindopril, frequency not known — indapamide); excessive arterial hypotension in high-risk patients may lead to stroke (see section "Special precautions") (very rare — perindopril); in patients with hepatic impairment, hepatic encephalopathy may occur (see sections "Contraindications" and "Special precautions") (frequency not known — indapamide).

Eye disorders: visual disturbances (common — perindopril, frequency not known — indapamide); myopia (see section "Special precautions") (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") (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") (very rare — perindopril); paroxysmal ventricular tachycardia of the "torsades de pointes" type (potentially fatal) (see sections "Special precautions" 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") (common — perindopril, very rare — indapamide); vasculitis (uncommon* — perindopril); hot flushes (rare* — perindopril); Raynaud's phenomenon (frequency not known — perindopril).

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

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

Hepatobiliary disorders: hepatitis (see section "Special precautions") (very rare — perindopril, frequency not known — indapamide); liver function abnormalities (very rare — indapamide).

Skin and subcutaneous tissue disorders: pruritus (common — perindopril); rash (common — perindopril); maculopapular rash (common — indapamide); urticaria (see section "Special precautions") (uncommon — perindopril, very rare — indapamide); angioedema (see section "Special precautions") (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 symptoms (rare* — perindopril); erythema multiforme (very rare — perindopril); toxic epidermal necrolysis (very rare — indapamide); Stevens-Johnson syndrome (very rare — indapamide).

Musculoskeletal and connective tissue disorders: muscle cramps (common — perindopril, frequency not known — indapamide); possible worsening of existing systemic lupus erythematosus (frequency not known — indapamide); arthralgia (uncommon* — perindopril); myalgia (uncommon* — perindopril, frequency not known — indapamide); muscle weakness (frequency not known — indapamide); rhabdomyolysis (frequency not known — indapamide).

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

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

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

Investigations: increased blood urea nitrogen (uncommon* — perindopril); increased blood creatinine (uncommon* — perindopril); increased blood bilirubin (rare — perindopril); increased liver enzymes (rare — perindopril, frequency not known — indapamide); decreased hemoglobin and hematocrit (see section "Special precautions") (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" 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 suspected adverse reactions after drug authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives are encouraged to report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: 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 of children.

Packaging.

30 tablets (10 × 3) in a blister pack in a cardboard carton.

Prescription status.

Prescription only.

Manufacturer.

MICROCHEM PHARMACEUTICAL RESEARCH AND PRODUCTION COMPANY LLC (production unit (all stages of the manufacturing process)).

Manufacturer's address.

24-V Promyslova Street, Severodonetsk, Luhansk region, 93400, Ukraine.

Marketing authorization holder.

MICROCHEM PHARMACEUTICAL RESEARCH AND PRODUCTION COMPANY LLC.

Address of the marketing authorization holder.

5 Budynstustriyi Street, Kyiv, 01013, Ukraine.

You can report any adverse event associated with the use of this medicinal product at +38 (050) 309-83-54 (24/7).