Tri-aliter®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TRI-ALITER® (TRI-ALITER)

Composition:

Active substances: perindopril, indapamide, amlodipine;

One tablet contains:

perindopril tert-butylamine 4 mg (equivalent to 3.338 mg of perindopril), indapamide 1.25 mg and amlodipine besylate 6.935 mg (equivalent to 5 mg of amlodipine)

or perindopril tert-butylamine 4 mg (equivalent to 3.338 mg of perindopril), indapamide 1.25 mg and amlodipine besylate 13.870 mg (equivalent to 10 mg of amlodipine),

or perindopril tert-butylamine 8 mg (equivalent to 6.676 mg of perindopril), indapamide 2.5 mg and amlodipine besylate 6.935 mg (equivalent to 5 mg of amlodipine),

or perindopril tert-butylamine 8 mg (equivalent to 6.676 mg of perindopril), indapamide 2.5 mg and amlodipine besylate 13.870 mg (equivalent to 10 mg of amlodipine);

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

Pharmaceutical form. Tablets.

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

Pharmacotherapeutic group.

Agents acting on the renin-angiotensin system. ACE inhibitors, combinations. ACE inhibitors and other combinations. Perindopril, amlodipine and indapamide.

ATC code C09B X01.

Pharmacological properties.

Pharmacodynamics.

TRI-ALITRE® is a combination of three antihypertensive components whose mechanisms of action complement each other in controlling arterial pressure in patients with arterial hypertension. Perindopril is an angiotensin-converting enzyme (ACE) inhibitor, indapamide is a sulfonamide diuretic, and amlodipine is a calcium ion channel blocker belonging to the dihydropyridine class.

The pharmacological effect of TRI-ALITRE® is due to the properties of each individual component. In addition, the combination of perindopril/indapamide produces an additive synergism of the antihypertensive effects of these components.

Mechanism of action.

Perindopril. Perindopril is an angiotensin-converting enzyme inhibitor (ACE inhibitor). ACE converts angiotensin I into angiotensin II (a vasoconstrictor substance), additionally stimulates aldosterone secretion by the adrenal cortex, and promotes the breakdown of bradykinin (a vasodilator substance) into inactive heptapeptides. Inhibition of ACE leads to reduced aldosterone secretion; increased plasma renin activity without the negative effects of aldosterone; and decreased total peripheral vascular resistance due to predominant effects on vascular smooth muscle in skeletal muscles and kidneys, without water and salt retention or reflex tachycardia, even during long-term treatment.

Perindopril reduces arterial pressure in patients with normal and low plasma renin levels.

Perindopril acts via its active metabolite, perindoprilat. Other metabolites are inactive.

Perindopril reduces cardiac workload due to vasodilatory effects on veins (possibly via changes in prostaglandin metabolism), thereby reducing cardiac preload, and by decreasing total peripheral resistance, reduces cardiac afterload.

Studies conducted in patients with heart failure have demonstrated that perindopril leads to reduced filling pressures in the left and right ventricles; decreased total peripheral resistance; increased cardiac output and improved cardiac index; and increased regional muscle blood flow.

In addition, exercise tolerance test results are significantly improved.

Indapamide. Indapamide is a sulfonamide derivative with an indole ring, pharmacologically related to the thiazide diuretic group. Indapamide inhibits sodium reabsorption in the cortical segment of the nephron. This increases urinary excretion of sodium and chloride, and to a lesser extent, potassium and magnesium, thereby increasing diuresis. This mechanism underlies its antihypertensive effect.

Amlodipine. Amlodipine is a calcium ion channel blocker belonging to the dihydropyridine class (a slow calcium channel blocker or calcium antagonist) that blocks transmembrane calcium ion influx into myocardial and vascular smooth muscle cells.

Pharmacodynamic effects.

Perindopril/indapamide. The combination of perindopril/indapamide reduces systolic and diastolic blood pressure in hypertensive patients of any age, both in the supine and standing positions. The antihypertensive effect of the drug is dose-dependent. Clinical studies have demonstrated that concomitant administration of perindopril and indapamide results in synergistic antihypertensive effects compared to each component administered as a single agent.

Perindopril. Perindopril effectively reduces arterial pressure in patients with mild, moderate, and severe arterial hypertension. Reduction in both systolic and diastolic blood pressure is observed in both supine and standing positions. The maximum antihypertensive effect develops within 4–6 hours after a single dose and lasts for more than 24 hours. Perindopril achieves a high level of sustained ACE inhibition (approximately 80%) 24 hours after administration.

In patients who respond to treatment, normalization of arterial pressure occurs within one month and is maintained without tachyphylaxis.

Discontinuation of therapy is not associated with a rebound effect.

Perindopril has vasodilatory properties, restores elasticity of large arteries, corrects histomorphometric changes in resistance arteries, and reduces left ventricular hypertrophy. Additional synergism occurs when a thiazide diuretic is added if necessary.

The combination of an ACE inhibitor and a thiazide diuretic reduces the risk of hypokalemia that may occur when a diuretic is used as monotherapy.

Indapamide. The antihypertensive effect of indapamide, when used as monotherapy, lasts for 24 hours. This effect is evident at doses where diuretic properties are minimal.

The antihypertensive effect of indapamide is associated with improved arterial elasticity and reduced arteriolar resistance and total peripheral vascular resistance.

Indapamide reduces left ventricular hypertrophy.

When the recommended dose is exceeded, the antihypertensive effect of thiazide and thiazide-like diuretics reaches a plateau, while the incidence of adverse effects increases. If treatment is ineffective, 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.

Amlodipine. The mechanism of amlodipine’s antihypertensive effect is due to its direct relaxing effect on vascular smooth muscle. The exact mechanism by which amlodipine reduces angina symptoms is not fully elucidated, but it is known that the drug reduces overall myocardial ischemia through two actions:

• Amlodipine dilates peripheral arterioles, thereby reducing total peripheral resistance (afterload); as heart rate remains unchanged, reduced cardiac workload decreases myocardial energy consumption and oxygen demand;
• Amlodipine partially promotes dilation of major coronary arteries and arterioles in both normal and ischemic myocardial regions; this dilation increases oxygen delivery to the myocardium in patients with vasospastic angina (Prinzmetal’s angina or variant angina).

In patients with arterial hypertension, once-daily administration of amlodipine provides clinically significant blood pressure reduction over 24 hours, both in supine and standing positions. Due to its slow onset of action, amlodipine does not cause acute hypotension.

Amlodipine is not associated with negative metabolic effects or changes in plasma lipid levels, making it suitable for use in patients with asthma, diabetes mellitus, and gout.

Pharmacokinetics.

Administration of perindopril/indapamide and amlodipine in a fixed combination does not alter their pharmacokinetic properties compared to their use as monotherapies.

Perindopril. After oral administration, perindopril is rapidly absorbed, with peak concentration reached within 1 hour (perindopril is a prodrug, and perindoprilat is the active metabolite). The elimination half-life of perindopril in plasma is 1 hour. Approximately 27% of the administered dose reaches systemic circulation as the active metabolite, perindoprilat. In addition to the active perindoprilat, perindopril forms five inactive metabolites. Peak plasma concentration of perindoprilat is achieved within 3–4 hours.

Since food intake reduces the conversion of perindopril to perindoprilat, thereby decreasing its bioavailability, perindopril should be administered orally as a single daily dose in the morning before a meal. A linear relationship exists between perindopril dose and its plasma concentration.

The volume of distribution of unbound perindoprilat is approximately 0.2 L/kg. Protein binding of perindoprilat to plasma proteins is 20%, primarily to angiotensin-converting enzyme, and is dose-dependent. Perindoprilat is excreted in urine, and the terminal elimination half-life of the unbound fraction is approximately 17 hours. Steady-state is achieved within 4 days.

Elimination of perindoprilat is reduced in elderly patients and in patients with cardiac or renal impairment. Dose adjustment is required in patients with renal impairment based on the degree of renal dysfunction (creatinine clearance).

Dialysis clearance of perindoprilat is 70 mL/min.

Pharmacokinetics of perindopril is altered in patients with hepatic cirrhosis: hepatic clearance of the parent compound is reduced by half. However, the amount of perindoprilat formed is not reduced. Therefore, dose adjustment is not required in these patients (see sections "Dosage and administration" and "Special precautions").

Indapamide. Indapamide is rapidly and completely absorbed in the gastrointestinal tract. Peak plasma concentration is reached approximately 1 hour after oral administration. Protein binding in plasma is 79%. Elimination half-life ranges from 14 to 24 hours (average 18 hours). Repeated administration does not lead to accumulation.

Indapamide is primarily excreted in urine (70% of the dose) and feces (22%) as inactive metabolites. Pharmacokinetic parameters are not altered in patients with renal impairment.

Amlodipine. When administered orally at therapeutic doses, amlodipine is well absorbed and reaches peak blood concentration within 6–12 hours after administration. Absolute bioavailability ranges from 64% to 80%. Volume of distribution is approximately 21 L/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine in blood is protein-bound. Food intake does not affect amlodipine bioavailability. The elimination half-life of amlodipine in plasma is approximately 35–50 hours, allowing once-daily dosing. Amlodipine is primarily metabolized in the liver into inactive metabolites, with 60% of metabolites excreted in urine and 10% excreted unchanged.

Time to peak plasma concentration of amlodipine is similar in elderly and younger patients. In elderly patients, there is a tendency toward reduced amlodipine clearance, leading to increased AUC and prolonged elimination half-life. Increased AUC and elimination half-life in patients with congestive heart failure corresponded to the age characteristics of the studied patients.

There are very limited clinical data on amlodipine use in patients with hepatic impairment. In patients with hepatic insufficiency, amlodipine clearance is reduced, leading to prolonged elimination half-life and increased AUC by approximately 40–60%.

Clinical characteristics.

Indications.

TRI-ALITER® is indicated for the treatment of arterial hypertension in patients who require therapy with perindopril, indapamide, and amlodipine in doses available in fixed combination.

Contraindications.

• Hemodialysis;
• Untreated decompensated heart failure;
• Severe renal impairment (creatinine clearance below 30 mL/min);
• Moderate renal impairment (creatinine clearance below 60 mL/min) (applies to the medicinal product TRI-ALITER® containing the combination of active substances in doses of 8 mg / 2.5 mg / 5 mg or 8 mg / 2.5 mg / 10 mg);
• Hypersensitivity to the active substances, other sulfonamide drugs, dihydropyridine derivatives, any other angiotensin-converting enzyme (ACE) inhibitor, or to any excipients;
• Pregnancy or planned pregnancy (see section "Use in pregnancy or breastfeeding");
• History of angioedema (Quincke's edema) associated with previous ACE inhibitor therapy (see section "Special precautions");
• Hereditary or idiopathic angioedema;
• Hepatic encephalopathy;
• Severe hepatic impairment;
• Hypokalemia;
• Severe arterial hypotension;
• Shock, including cardiogenic shock;
• Obstruction of the left ventricular outflow tract (e.g., severe aortic stenosis);
• Heart failure with unstable hemodynamics following acute myocardial infarction;
• Concomitant use with medicinal products containing aliskiren in patients with diabetes or renal insufficiency (glomerular filtration rate < 60 mL/min/1.73 m²) (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction");
• Concomitant use with sacubitril/valsartan. Initiation of TRI-ALITER® therapy must not occur 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").

Interaction with other medicinal products and other forms of interaction.

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

Medicinal products increasing the risk of angioedema. Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema (see sections "Contraindications" and "Special precautions"). Initiation of sacubitril/valsartan therapy should not occur earlier than 36 hours after the last dose of perindopril. Perindopril therapy should be initiated no earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Special precautions").

Concomitant use of ACE inhibitors with racemethyldopril, 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 receiving TRI-ALITER®. Certain medicinal products or therapeutic classes may cause hyperkalemia: aliskiren, potassium salts, potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), ACE inhibitors, angiotensin II receptor antagonists, nonsteroidal anti-inflammatory drugs (NSAIDs), heparins, immunosuppressants such as cyclosporine or tacrolimus, trimethoprim, and co-trimoxazole (trimethoprim/sulfamethoxazole)—since trimethoprim acts as a potassium-sparing diuretic similar to amiloride. Concomitant use of these medicinal products increases the risk of hyperkalemia. Therefore, concomitant use of TRI-ALITER® with the above-mentioned agents is not recommended. If such concomitant use is necessary, it should be administered with caution and frequent monitoring of serum potassium levels is required.

Concomitant use is contraindicated (see section "Contraindications").

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

Extracorporeal treatments: Extracorporeal treatments leading to blood contact with negatively charged surfaces, such as dialysis or hemofiltration using certain high-flux membranes (e.g., polyacrylonitrile) and low-density lipoprotein apheresis using dextran sulfate, are associated with an 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.

Perindopril/indapamide. Reversible increases in serum lithium concentration and increased lithium toxicity have been reported with concomitant use of lithium and ACE inhibitors. Concomitant use of perindopril with indapamide and lithium is not recommended. However, if such combination is necessary, serum lithium concentration should be closely monitored (see section "Special precautions").

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

Published data show that in patients with established atherosclerosis, heart failure, or diabetes with target organ damage, concomitant use of ACE inhibitors and angiotensin receptor blockers is associated with increased incidence of arterial hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to monotherapy with RAAS-affecting drugs. Dual blockade (i.e., combination of an ACE inhibitor with angiotensin II receptor antagonists) may be considered only in selected cases under strict monitoring of renal function, potassium levels, and blood pressure (see section "Special precautions").

Estromustine: Increased risk of adverse reactions such as angioedema.

Potassium-sparing agents (e.g., triamterene, amiloride, etc.), potassium salts: Risk of hyperkalemia (potentially fatal), especially in patients with renal impairment (additive hyperkalemic effect). These agents are not recommended for concomitant use with perindopril (see section "Special precautions"). However, if concomitant use is necessary, they should be used with caution and frequent monitoring of serum potassium levels is required. For spironolactone use in heart failure, see below "Concomitant use requiring special attention."

Amlodipine.Dantrolene (infusion): Animal studies have shown ventricular fibrillation with fatal outcome and cardiovascular collapse combined with hyperkalemia after intravenous administration of verapamil and dantrolene. Due to the potential for hyperkalemia, concomitant use of calcium channel blockers such as amlodipine should be avoided in patients with established or suspected malignant hyperthermia.

Grapefruit or grapefruit juice: In some patients, increased bioavailability of amlodipine may occur, leading to enhanced hypotensive effect.

Concomitant use requiring special attention.

Perindopril/indapamide. Baclofen potentiates the antihypertensive effect. Blood pressure should be monitored and antihypertensive dose adjusted if necessary.

Perindopril/indapamide.Nonsteroidal anti-inflammatory drugs (NSAIDs), including high-dose acetylsalicylic acid. When ACE inhibitors are used concomitantly with NSAIDs such as acetylsalicylic acid at anti-inflammatory doses, COX-2 inhibitors, and nonselective NSAIDs, the antihypertensive effect may be attenuated. Concomitant use of ACE inhibitors and NSAIDs may increase the risk of worsening renal function, including possible development of acute renal failure, and elevated serum potassium levels, particularly in patients with pre-existing impaired renal function. This combination should be used with caution, especially in elderly patients. Patients should be adequately hydrated, and renal function should be monitored after initiation of concomitant therapy and during continued treatment.

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

In patients receiving diuretics, especially those with fluid and electrolyte imbalance, excessive reduction in blood pressure may occur after initiation of ACE inhibitor therapy. The risk of hypotensive effects can be reduced by discontinuing the diuretic, increasing circulating blood volume, and increasing salt intake before starting perindopril therapy, which should begin with low doses and gradually increase. In arterial hypertension, if a previously prescribed diuretic may have caused fluid/electrolyte deficiency, it should be discontinued before starting ACE inhibitor therapy (diuretic use may be resumed later) or the ACE inhibitor should be initiated at a low dose with gradual dose escalation. In congestive heart failure on background diuretic therapy, ACE inhibitor therapy should be initiated at the lowest dose, possibly after reducing the diuretic dose. Renal function (creatinine level) should be monitored during the first weeks of ACE inhibitor therapy.

Potassium-sparing diuretics (eplerenone, spironolactone). Concomitant use of eplerenone or spironolactone (12.5–50 mg daily) 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, carries a risk of hyperkalemia (potentially fatal), especially if recommendations for use of this combination are not followed. Before initiating such combination therapy, absence of hyperkalemia and renal impairment should be confirmed. Close monitoring of serum potassium and creatinine is recommended weekly during the first month and monthly thereafter.

Indapamide. Due to the risk of hypokalemia, indapamide should be used cautiously in combination with medicinal products that may induce torsades de pointes-type ventricular tachycardia, such as, but not limited to:

• Class Ia antiarrhythmics (e.g., quinidine, hydroquinidine, disopyramide);
• Class III antiarrhythmics (e.g., amiodarone, dofetilide, ibutilide, bretylium, sotalol);
• Certain antipsychotics: phenothiazines (e.g., chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine), benzamides (e.g., amisulpride, sulpiride, sultopride, tiapride), butyrophenones (e.g., droperidol, haloperidol), other antipsychotics (e.g., pimozide);
• Other agents (e.g., bepridil, cisapride, difemanil, intravenous erythromycin, halofantrine, mizolastine, moxifloxacin, pentamidine, sparfloxacin, intravenous vincamine, methadone, astemizole, terfenadine).

Serum potassium levels should be maintained; correction of potassium levels and QT interval monitoring are recommended when necessary.

Intravenous amphotericin B, glucocorticoids and mineralocorticoids (systemic), tetracosactide, stimulant laxatives increase the risk of hypokalemia (additive effect). Serum potassium levels should be monitored and corrected as needed, especially when used concomitantly with cardiac glycosides. Non-stimulant laxatives are recommended.

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

Allopurinol. Concomitant use with indapamide increases the risk of hypersensitivity reactions to allopurinol.

*Amlodipine. Concomitant use with known CYP3A4 inducers may alter plasma concentrations of amlodipine. Blood pressure should be monitored and dose adjustments made during and after concomitant use with CYP3A4 inducers, particularly strong CYP3A4 inducers (e.g., rifampicin, St. John's wort [Hypericum perforatum]).

Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin and clarithromycin, verapamil, or diltiazem) may cause significant increases in amlodipine concentration. The clinical manifestation of these pharmacokinetic changes may be more pronounced in elderly patients. Clinical monitoring and dose adjustment may be necessary.

There is an increased risk of hypotension in patients taking clarithromycin in combination with amlodipine. Close monitoring is recommended for such patients.

Concomitant use requiring attention.

Perindopril/indapamide/amlodipine.Tricyclic antidepressants, neuroleptics enhance antihypertensive effects and increase the risk of orthostatic hypotension (additive effect).

Concomitant use of other antihypertensive agents may cause additional blood pressure reduction.

Corticosteroids, tetracosactide. Reduced antihypertensive effect (due to water and salt retention by corticosteroids).

Perindopril. Antihypertensive agents and vasodilators: concomitant use with nitroglycerin and other nitrates or other vasodilators may lead to additional blood pressure reduction.

Allopurinol, cytostatics, immunosuppressants, systemic corticosteroids, or procainamide: concomitant use with ACE inhibitors increases the risk of leukopenia.

ACE inhibitors may enhance the hypotensive effect of certain anesthetic agents.

Diuretics (thiazide and loop diuretics): prior treatment with high-dose diuretics may cause dehydration, increasing the risk of hypotension at the start of perindopril therapy.

Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.

Rarely, concomitant use of ACE inhibitors, including perindopril, and injectable gold preparations (sodium aurothiomalate) has been associated with reactions similar to those seen with nitrates (symptoms: facial flushing, nausea, vomiting, and hypotension).

Indapamide. Metformin may cause lactic acidosis due to possible development of functional renal insufficiency associated with diuretic use, especially loop diuretics. Metformin should not be prescribed if plasma creatinine exceeds 15 mg/L (135 µmol/L) in men or 12 mg/L (110 µmol/L) in women.

Dehydration due to diuretic use increases the risk of acute renal failure, especially with high doses of iodinated contrast agents. Fluid balance should be restored before administration of contrast agents.

Calcium salts: risk of hypercalcemia due to reduced urinary calcium excretion.

Cyclosporine: risk of increased creatinine levels without affecting circulating cyclosporine levels, even in the absence of water and sodium deficiency.

Amlodipine: Clinical interaction studies have demonstrated that amlodipine does not affect the pharmacokinetics of atorvastatin, digoxin, or warfarin.

Tacrolimus: Risk of increased plasma tacrolimus concentration with concomitant use of amlodipine. Plasma tacrolimus levels should be monitored and dose adjusted if necessary to avoid toxicity.

mTOR inhibitors. mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are CYP3A substrates. Amlodipine is a weak CYP3A inhibitor. Concomitant use with mTOR inhibitors may potentiate their effects.

Cyclosporine: Interaction studies between cyclosporine and amlodipine have not been conducted in healthy volunteers or other populations, except in kidney transplant patients, where fluctuations in minimum cyclosporine concentration (on average from 0 to 40%) were observed. In kidney transplant patients receiving amlodipine, cyclosporine blood levels should be monitored and dose reduced if necessary.

Concomitant use of amlodipine at doses above 10 mg with 80 mg of simvastatin resulted in a 77% increase in simvastatin concentration compared to simvastatin monotherapy. Patients taking amlodipine should limit simvastatin dose to 20 mg daily.

Special precautions for use.

All the warnings below regarding the use of individual components of the medicinal product also apply to the fixed combination TRI-ALITRE®.

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

Double blockade of the renin-angiotensin-aldosterone system (RAAS). Data indicate that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of hypotension, hyperkalemia, and decreased renal function (including acute renal failure). Therefore, dual blockade of the RAAS by concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see section "Interaction with other medicinal products and other forms of interaction"). If dual RAAS blockade is considered absolutely necessary, it should be carried out only under specialist supervision and with frequent, careful monitoring of renal function, electrolyte levels, and blood pressure. ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Potassium-sparing agents, potassium-containing dietary supplements, or potassium-containing salt substitutes. Concomitant use of perindopril with potassium-sparing agents, potassium-containing dietary 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 receiving ACE inhibitors. Neutropenia is rare in patients with normal renal function and no risk factors. Perindopril should be used with extreme caution in patients with collagen vascular diseases, those receiving immunosuppressive therapy, allopurinol, procainamide, or a combination of these factors, especially if renal function is impaired. Some of these patients have developed severe infections, in several cases resistant to intensive antibiotic therapy. If perindopril is prescribed to such patients, periodic monitoring of white blood cell count is recommended. Patients should also be informed about the need to report any signs of infection (e.g., sore throat, fever) (see section "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"). The use of diuretics may be a contributing factor. Impaired renal function may manifest only as slight changes in serum creatinine levels, even in patients with unilateral renal artery stenosis.

Hypersensitivity / angioedema. Rare cases of angioedema of the face, extremities, lips, tongue, glottis, and/or larynx have been reported during treatment with ACE inhibitors, including perindopril. Angioedema may occur at any time during treatment.

In such cases, perindopril must be discontinued immediately, and appropriate monitoring of the patient should be maintained until symptoms completely resolve. If swelling is limited to the face and lips, the patient's condition usually improves without treatment, and antihistamines may help relieve symptoms.

Angioedema involving swelling of the larynx may be fatal. If swelling spreads to the tongue, glottis, or larynx, with a risk of airway obstruction, emergency treatment is required, which may include subcutaneous administration of epinephrine 1:1000 (0.3–0.5 mL) and/or securing airway patency.

It has been reported that ACE inhibitors cause angioedema more frequently in individuals of non-Caucasian race compared to patients of other races.

Patients with a history of angioedema unrelated to ACE inhibitor use have an increased risk of developing angioedema during ACE inhibitor therapy (see section "Contraindications").

Rare cases of intestinal angioedema have been reported in patients receiving ACE inhibitors. These patients experienced abdominal pain (with or without nausea and vomiting); in some cases, prior facial angioedema was not observed, and C-1 esterase levels were within normal limits. The diagnosis of intestinal angioedema was established by computed tomography, ultrasound, or surgical intervention. Symptoms of angioedema resolved after discontinuation of the ACE inhibitor. Intestinal angioedema should be considered in the differential diagnosis of abdominal pain occurring in patients receiving ACE inhibitors.

Concomitant use of perindopril with sacubitril/valsartan is contraindicated due to an increased risk of angioedema (see section "Contraindications").

Sacubitril/valsartan should not be initiated earlier than 36 hours after the last dose of perindopril. If treatment with sacubitril/valsartan is discontinued, perindopril therapy should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Concomitant use of ACE inhibitors with neutral endopeptidase (NEP) inhibitors (e.g., racecadotril), mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) may increase the risk of angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) (see section "Interaction with other medicinal products and other forms of interaction"). Caution is advised when initiating treatment with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) in patients already receiving ACE inhibitors.

Anaphylactoid reactions during desensitization therapy. Isolated cases of prolonged, life-threatening anaphylactoid reactions have been reported in patients receiving ACE inhibitors during desensitization therapy with insect venom (bee, wasp) preparations. ACE inhibitors should be used with caution in patients with allergies after desensitization and should be avoided during immunotherapy with animal-derived venom substances.

However, in patients requiring both ACE inhibitors and desensitization therapy, such reactions can be avoided by temporarily discontinuing the ACE inhibitor at least 24 hours before desensitization.

Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis. Rarely, life-threatening anaphylactoid reactions have occurred in patients receiving ACE inhibitors during LDL apheresis using dextran sulfate. These reactions can be avoided by temporarily discontinuing ACE inhibitor treatment before each apheresis session.

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

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

Pregnancy. ACE inhibitors should not be prescribed during pregnancy. If continued treatment with ACE inhibitors is considered mandatory, patients planning pregnancy should be switched to alternative antihypertensive agents with confirmed safety data during pregnancy. If pregnancy is diagnosed, treatment with an ACE inhibitor should be immediately discontinued and, if necessary, replaced with another alternative medicinal product approved for use in pregnant women (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

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 coma. In such cases, diuretic therapy should be discontinued immediately.

Photosensitization. Cases of photosensitization reactions have been reported in patients receiving thiazide and thiazide-like diuretics (see section "Side effects"). If such reactions occur, diuretic therapy is recommended to be discontinued. If diuretic therapy must be resumed, vulnerable areas should be protected from sunlight or artificial ultraviolet sources.

Renal function. The use of the drug is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min). Treatment with the TRI-ALITRE® medicinal product containing the perindopril/indapamide combination at doses of 8 mg / 2.5 mg (i.e., TRI-ALITRE® 8 mg / 2.5 mg / 5 mg and 8 mg / 2.5 mg / 10 mg) is contraindicated in patients with moderate renal impairment (creatinine clearance < 60 mL/min). If, in some patients with arterial hypertension without signs of kidney damage, laboratory blood tests show signs of functional renal failure, treatment with the drug should be discontinued; resumption of treatment at a lower dose or with one of its components may be possible. These patients require frequent monitoring of potassium and creatinine: 2 weeks after initiation of treatment and subsequently every two months during therapeutic stabilization. Cases of renal failure have been observed primarily in patients with severe heart failure or impaired renal function, including renal artery stenosis.

This combination is not recommended for patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney.

Risk of arterial hypotension and/or renal failure (in heart failure, water and electrolyte deficiency, etc.): significant stimulation of the renin-angiotensin-aldosterone system was observed mainly due to perindopril in cases of pronounced water and electrolyte deficiency (strict salt-free diet or prolonged diuretic therapy), in patients with initially low blood pressure, in cases of renal artery stenosis, congestive heart failure, or in patients with cirrhosis of the liver with edema and ascites.

Blocking this system with an ACE inhibitor, especially during the first dose and the first two weeks of treatment, may cause a sharp decrease in blood pressure and/or an increase in plasma creatinine levels, indicating functional renal failure. This may sometimes have an acute onset and very rarely may occur at any time during treatment. In such cases, treatment should be initiated with a lower dose, gradually increasing it. In patients with ischemic heart disease or cerebrovascular diseases, significant reduction in blood pressure may lead to myocardial infarction or stroke.

Thiazide and thiazide-like diuretics demonstrate the greatest efficacy when there is no renal impairment or impairment is insignificant (serum creatinine approximately below 25 mg/L, i.e., 220 μmol/L, in adults).

In elderly patients, plasma creatinine levels should correspond to age, body weight, and gender. Hypovolemia caused by loss of water and sodium due to diuretic use at the beginning of treatment leads to decreased glomerular filtration. This may result in increased blood urea and creatinine levels. This transient functional renal failure has no adverse consequences in patients with normal renal function but may exacerbate pre-existing renal impairment.

Amlodipine can be used in patients with renal impairment at usual doses. Changes in amlodipine plasma concentration do not correlate with the degree of renal function impairment.

Studies on the use of the fixed combination TRI-ALITRE® in patients with renal dysfunction have not been conducted. For patients with impaired renal function, the dosage of the fixed combination TRI-ALITRE® should correspond to individually adjusted doses of the monocomponents.

Hypotension, water and electrolyte deficiency. There is a risk of sudden decrease in blood pressure in patients with existing sodium deficiency (particularly in patients with renal artery stenosis). Therefore, systematic monitoring for clinical signs of water and electrolyte deficiency, which may occur due to intercurrent vomiting or diarrhea, is necessary. In such patients, serum electrolyte levels should be regularly monitored.

In case of pronounced hypotension, intravenous administration of isotonic sodium chloride solution may be required. Transient hypotension is not a contraindication for further use of the drug. After restoration of circulating blood volume (CBV) and normalization of blood pressure, treatment may be resumed at a lower dose or with one of the drug's components.

Initial decrease in sodium concentration may be asymptomatic, so regular laboratory monitoring of this parameter is very important. More frequent monitoring is necessary for elderly patients and patients with liver cirrhosis (see sections "Side effects" and "Overdose").

Any diuretic treatment may cause hyponatremia, sometimes with very serious consequences. Hyponatremia combined with hypovolemia may lead to dehydration and orthostatic arterial hypotension. Concomitant loss of chloride ions may lead to secondary compensatory metabolic alkalosis; the frequency and severity of this effect are insignificant.

Potassium levels. Treatment with the combination of indapamide, perindopril, and amlodipine does not exclude the possibility of hypokalemia, particularly in patients with diabetes mellitus or renal failure. As with the use of any antihypertensive agent combined with a diuretic, plasma potassium levels should be regularly monitored.

In some patients receiving ACE inhibitors, including perindopril, increased plasma potassium concentration has been observed. ACE inhibitors may cause hyperkalemia as they inhibit aldosterone release. In patients with normal renal function, this effect is usually insignificant. Risk factors for hyperkalemia include renal failure, worsening renal function, age over 70 years, diabetes mellitus, intercurrent conditions such as dehydration, acute heart decompensation, metabolic acidosis, and concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium-containing dietary supplements, or potassium-containing salt substitutes; use of other drugs that increase serum potassium concentration (e.g., heparin, co-trimoxazole, also known as trimethoprim/sulfamethoxazole), and especially aldosterone antagonists or angiotensin receptor blockers. The use of potassium-containing dietary supplements, potassium-sparing diuretics, or potassium-containing salt substitutes may also lead to significant increases in serum potassium, especially in patients with impaired renal function. Hyperkalemia may cause serious, sometimes fatal, arrhythmias. Patients receiving ACE inhibitors should use potassium-sparing diuretics and angiotensin receptor blockers with caution, and serum potassium levels and renal function should be monitored. If concomitant use of perindopril and any of the above substances is considered appropriate, they should be used with caution, with frequent monitoring of serum potassium levels (see section "Interaction with other medicinal products and other forms of interaction").

Decreased potassium levels in hypokalemia are the main risk associated with thiazide and thiazide-like diuretics. Hypokalemia may cause muscle disorders. Cases of rhabdomyolysis have been reported, mainly associated with severe hypokalemia. The risk of low potassium levels (< 3.4 mmol/L) should be prevented in patients at high risk (elderly patients and/or poorly nourished patients, regardless of whether they are taking multiple medications, patients with liver cirrhosis accompanied by edema and ascites, patients with ischemic heart disease, and patients with heart failure). In case of hypokalemia, cardiotoxicity of cardiac glycosides and the risk of arrhythmias increase. Patients with congenital or iatrogenic prolonged QT interval also belong to the risk group. Hypokalemia, as well as bradycardia, may promote the development of severe cardiac arrhythmias, including paroxysmal ventricular tachycardia of the "torsades de pointes" type, which may be fatal.

In all these cases, more frequent monitoring of serum potassium levels is necessary. The first determination of this parameter should be performed within the first week of treatment.

If serum potassium levels are decreased, correction is required. Hypokalemia detected in association with low serum magnesium concentration may be refractory to treatment unless serum magnesium levels are corrected.

Calcium levels. Thiazide and thiazide-like diuretics may reduce calcium excretion in urine and lead to slight and transient increases in plasma calcium levels. Significantly elevated calcium levels may be due to previously undiagnosed hyperparathyroidism. In such cases, treatment should be discontinued until parathyroid function is examined (see section "Side effects").

Plasma magnesium. 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 "Side effects").

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

If TRI-ALITRE® is prescribed to patients with diagnosed or suspected renal artery stenosis, therapy should be initiated in a hospital setting with low doses, monitoring renal function and potassium levels. In some patients, functional renal failure developed, which was reversible after discontinuation of treatment.

Cough. Dry cough has been reported during treatment with ACE inhibitors. This cough is persistent and resolves after discontinuation of the drug. When this symptom occurs, iatrogenic etiology of cough should be considered. If ACE inhibitor therapy is still preferred, continuation of treatment may be considered.

Atherosclerosis. The risk of hypotension exists in all patients, but perindopril should be prescribed with particular caution to patients with ischemic heart disease or cerebral circulation insufficiency. In such cases, treatment should be initiated with a low dose.

Hypertensive crisis. The safety and efficacy of amlodipine use in patients with hypertensive crisis have not been studied.

Heart failure / severe heart failure. Amlodipine should be prescribed with caution to patients with heart failure. In a long-term placebo-controlled study involving patients with severe heart failure (NYHA class III, IV), the incidence of pulmonary angioedema with amlodipine was higher compared to placebo. Calcium channel blockers, including amlodipine, should be prescribed with caution to patients with congestive heart failure, as they increase the risk of cardiovascular events and fatal outcomes.

In patients with severe heart failure (NYHA class IV), treatment 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: the ACE inhibitor is added to the β-blocker.

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

Patients with diabetes mellitus. Treatment should be initiated under medical supervision with a reduced initial dose in patients with insulin-dependent diabetes mellitus (due to the tendency to spontaneous increase in potassium levels).

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

In patients with diabetes mellitus, blood glucose levels should be monitored carefully, particularly when potassium levels are low.

Racial characteristics. Perindopril, like other ACE inhibitors, is likely to reduce blood pressure less effectively in hypertensive patients of non-Caucasian race compared to patients of other races, possibly due to low plasma renin levels in these patients.

Surgery / anesthesia. ACE inhibitors may cause hypotension during anesthesia, especially when using anesthetics that lower blood pressure. Therefore, with long-acting ACE inhibitors such as perindopril, the drug is recommended to be discontinued, if possible, one day before surgery.

Liver function impairment. Rarely, ACE inhibitor use has been associated with a syndrome starting with cholestatic jaundice and progressing to rapid liver necrosis, sometimes with fatal outcomes. The mechanism of this syndrome is unknown. Patients who develop jaundice or significant elevation of liver enzymes while receiving an ACE inhibitor should discontinue the ACE inhibitor and undergo appropriate medical evaluation and treatment (see section "Side effects").

In patients with impaired liver function, prolonged elimination half-life and higher AUC values for amlodipine are observed; dosage recommendations are lacking. Amlodipine treatment should be initiated with the lowest doses, with caution at the beginning of therapy and during dose escalation. Patients with severe liver impairment may require gradual dose titration and careful monitoring.

Studies on the use of the fixed combination TRI-ALITRE® in patients with liver dysfunction have not been conducted. Since the effects of the individual components of the fixed combination TRI-ALITRE® are known, the medicinal product is contraindicated in patients with severe liver impairment and should be used with caution in mild to moderate liver impairment.

Uric acid. In patients with elevated uric acid levels, there may be a tendency to increased frequency of gout attacks.

Elderly patients. Renal function and potassium levels should be checked before starting treatment. To reduce the risk of sudden hypotension, especially in the presence of water or electrolyte deficiency, the initial dose should be adjusted according to the blood pressure response to treatment. Dose escalation in elderly patients should be done cautiously (see section "Dosage and administration" and section "Pharmacokinetics").

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 defect, 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 to discontinue the medicinal product as quickly as possible. If intraocular pressure remains uncontrolled, medical or surgical treatment may be necessary. Risk factors for acute angle-closure glaucoma may include a history of allergy to sulfonamides or penicillin.

Athletes. Athletes should be aware that this medicinal product contains an active substance that may result in a positive doping test.

Excipients. If you have been diagnosed with intolerance to certain sugars, consult your doctor before taking this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy. TRI-ALITRE® is contraindicated during pregnancy (see section "Contraindications").

Perindopril. The use of ACE inhibitors is contraindicated during pregnancy. Epidemiological data on the risk of teratogenic effects from ACE inhibitor use during the first trimester of pregnancy are insufficient, so a slight increase in risk cannot be excluded. The medicinal product is contraindicated in pregnant women or women planning pregnancy. If continued treatment with ACE inhibitors is considered mandatory, patients planning pregnancy should be switched to alternative antihypertensive agents with confirmed safety data during pregnancy. If pregnancy is confirmed during ACE inhibitor treatment, its use should be immediately discontinued and replaced with another alternative medicinal product approved for use in pregnant women.

It is known that ACE inhibitor use during the second and third trimesters of pregnancy leads to fetotoxicity (reduced kidney function, oligohydramnios, delayed skull bone formation) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia).

If a woman has taken ACE inhibitors from the second trimester of pregnancy, ultrasound examination of fetal kidney function and skull bones is recommended for the child. Newborns whose mothers took ACE inhibitors during pregnancy should be closely monitored for timely detection and correction of arterial hypotension (see sections "Contraindications" and "Special precautions for use").

Indapamide. Data on indapamide use during pregnancy are limited (less than 300 cases). Prolonged use of a thiazide diuretic during the third trimester of pregnancy may lead to reduced circulating blood volume and uteroplacental perfusion, potentially causing fetoplacental ischemia and delayed fetal development. Additionally, hypoglycemia and thrombocytopenia have been rarely observed in newborns. Animal studies did not reveal direct or indirect toxic effects on reproductive function.

Amlodipine. The safety of amlodipine use in pregnant women has not been established. Animal studies revealed toxic effects on reproductive function when high doses were administered.

Breastfeeding. TRI-ALITRE® is not recommended during breastfeeding.

Perindopril. Perindopril use during breastfeeding is not recommended due to lack of data. In particular, during breastfeeding of a newborn or premature infant, alternative treatment with a confirmed safety profile during breastfeeding should be prescribed.

Indapamide. Available information on indapamide/metabolite penetration into breast milk is 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 has been associated with reduced and suppressed lactation.

Amlodipine. Amlodipine passes into breast milk. The fraction of the maternal dose received by the infant is estimated as an interquartile range of 3–7% with a maximum of 15%. The effect of amlodipine on infants is unknown.

Fertility.

Perindopril and indapamide. Reproductive toxicity studies did not reveal effects on fertility in male and female animals. Effects on human fertility are not expected.

Amlodipine. Reversible biochemical changes in the sperm head have been reported in some patients treated with calcium channel blockers. Clinical data on the potential effect of amlodipine on fertility are insufficient. It is known that animal studies revealed a negative effect of the drug on male fertility.

Ability to affect reaction speed when driving or operating machinery.

Studies on the effect of the medicinal product TRI-ALITRE® on the ability to drive or operate machinery have not been conducted.

Perindopril and indapamide do not affect the ability to drive or operate machinery. However, individual reactions related to decreased blood pressure may occur in some patients.

Amlodipine may have a slight or moderate effect on the ability to drive and operate machinery. Impaired reaction may occur if the patient experiences dizziness, headache, weakness, fatigue, or nausea. As a result, the ability to drive and operate machinery may be impaired. Caution is recommended, especially at the beginning of treatment.

Method of Administration and Dosage.

For oral use.

1 tablet of the medicinal product TRI-ALITER® once daily, preferably in the morning before food.

The fixed-dose combination is not intended for initial therapy.

If necessary, the dose of the fixed combination TRI-ALITER® may be adjusted or individual dose titration of each component separately may be recommended.

Special patient groups.

Patients with renal impairment (see sections "Contraindications" and "Special precautions for use").

Treatment with the medicinal product is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min). Administration of TRI-ALITER® in doses of 8 mg / 2.5 mg / 5 mg and 8 mg / 2.5 mg / 10 mg is contraindicated in patients with moderate renal impairment (creatinine clearance 30–60 mL/min). Regular medical monitoring should include frequent checks of serum creatinine and potassium levels.

Elderly patients (see section "Special precautions for use").

It should be considered that elimination of perindoprilat is reduced in elderly patients (see section "Pharmacokinetics"). Administration of the medicinal product TRI-ALITER® to elderly patients is possible with consideration of renal function (see section "Contraindications").

Patients with hepatic impairment (see sections "Contraindications", "Special precautions for use", and "Pharmacokinetics").

Treatment with TRI-ALITER® is contraindicated in patients with severe hepatic impairment. TRI-ALITER® should be administered with caution to patients with mild to moderate hepatic impairment due to the lack of dosing recommendations for amlodipine.

Children.

Data on safety and efficacy of TRI-ALITER® in children are lacking; therefore, it is not used in this age group.

Overdose.

Data regarding overdose with the medicinal product TRI-ALITER® are lacking.

For the combination perindopril/indapamide, the most common adverse reaction in case of overdose is arterial hypotension, which may sometimes be accompanied by nausea, vomiting, seizures, dizziness, somnolence, confusion, oliguria, which may progress to anuria (due to hypovolemia). Disturbances in water-electrolyte balance may occur (decreased serum sodium and potassium levels).

First aid measures include rapid elimination of the drug from the body: gastric lavage and/or administration of activated charcoal, followed by restoration of water-electrolyte balance under hospital conditions until these parameters return to normal.

In case of significant hypotension, the patient should be placed in a supine position with low head elevation. If necessary, isotonic sodium chloride solution should be administered intravenously or any other method used to restore blood volume.

Perindoprilat, the active form of perindopril, can be removed from the body by hemodialysis (see section "Pharmacokinetics").

Data on intentional overdose with amlodipine in humans are limited.

Based on available data, it can be assumed that ingestion of very large doses will lead to excessive peripheral vasodilation and reflex tachycardia. Severe, possibly prolonged systemic hypotension and shock with fatal outcome have been reported.

Rarely, non-cardiogenic pulmonary edema has been reported as a consequence of amlodipine overdose, which may manifest with delayed onset (within 24–48 hours after administration) and may require mechanical ventilation. Early resuscitation measures (including fluid overload) to support perfusion and cardiac output may act as triggering factors.

Clinically significant hypotension caused by amlodipine overdose requires active cardiovascular support, including continuous monitoring of cardiac and respiratory function, placing the patient in a supine position with elevated lower limbs, and monitoring of circulating blood volume and urine output.

Administration of a vasoconstrictor may be beneficial to restore vascular tone and arterial pressure, provided there are no contraindications. Intravenous calcium gluconate may help reverse the effects of calcium channel blockade.

In some cases, gastric lavage may be appropriate. Studies in healthy volunteers have shown that administration of activated charcoal 2 hours after intake of 10 mg amlodipine reduces the rate of amlodipine absorption. Since amlodipine is highly protein-bound, hemodialysis is considered ineffective.

Adverse Reactions.

The most commonly observed adverse reactions during treatment with perindopril, indapamide, and amlodipine used separately include: hypokalemia, dizziness, headache, paresthesia, somnolence, dysgeusia, visual disturbances, diplopia, tinnitus, vertigo, palpitations, flushing, arterial hypotension (and associated symptoms), cough, dyspnea, gastrointestinal disorders (abdominal pain, constipation, diarrhea, dyspepsia, nausea, vomiting, changes in defecation rhythm), pruritus, skin rash, maculopapular rash, muscle cramps, ankle swelling, asthenia, edema, and fatigue.

The following adverse reactions have been reported during treatment with perindopril, indapamide, or amlodipine, categorized by frequency as follows: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (> 1/1000, < 1/100); rare (> 1/10,000, < 1/1000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data).

Infections and infestations. Rhinitis: perindopril — very rare, amlodipine — uncommon.

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

Blood and lymphatic system disorders. Eosinophilia: perindopril — uncommon*; agranulocytosis: perindopril and indapamide — very rare; aplastic anemia: indapamide — very rare; pancytopenia: perindopril — very rare; leukopenia: perindopril, indapamide, amlodipine — very rare; neutropenia: perindopril — very rare; hemolytic anemia: perindopril, indapamide — very rare; thrombocytopenia: perindopril, indapamide, amlodipine — very rare.

Immune system disorders. Hypersensitivity reactions: amlodipine — very rare, indapamide — uncommon.

Metabolism and nutrition disorders. Hypokalemia: indapamide — common; hypoglycemia: perindopril — uncommon*; hyperkalemia, reversible upon discontinuation of the drug: perindopril — uncommon*; hyponatremia: perindopril — uncommon*, indapamide — uncommon; hypochloremia: indapamide — rare; hypomagnesemia: indapamide — rare; hyperglycemia: amlodipine — very rare; hypercalcemia: indapamide — very rare.

Psychiatric disorders. Insomnia: amlodipine — uncommon; mood changes (including anxiety): amlodipine, perindopril — uncommon; depression: amlodipine — uncommon, perindopril — uncommon*; sleep disturbances: perindopril — uncommon; confusion: perindopril — very rare, amlodipine — rare.

Nervous system disorders. Dizziness: perindopril and amlodipine — common; headache: perindopril and amlodipine — common, indapamide — rare; paresthesia: perindopril — common, indapamide — rare, amlodipine — uncommon; somnolence: perindopril — uncommon*, amlodipine — common; hypesthesia: amlodipine — uncommon; dysgeusia: perindopril — common, amlodipine — uncommon; tremor: amlodipine — uncommon; syncope: perindopril — uncommon*, indapamide — frequency not known, amlodipine — uncommon; hypertension: amlodipine — very rare; peripheral neuropathy: amlodipine — very rare; extrapyramidal disorders (extrapyramidal syndrome): amlodipine — frequency not known; stroke, potentially due to excessive reduction in blood pressure in high-risk patients: perindopril — very rare; in case of hepatic insufficiency, hepatic encephalopathy may occur: indapamide — frequency not known.

Eye disorders. Visual disturbances: perindopril and amlodipine — common, indapamide — frequency not known; acute angle-closure glaucoma: indapamide — frequency not known; choroidal effusion: indapamide — frequency not known; diplopia: amlodipine — common; myopia: indapamide — frequency not known; blurred vision: indapamide — frequency not known.

Ear and labyrinth disorders. Tinnitus: perindopril — common, amlodipine — uncommon; vertigo: perindopril — common, indapamide — rare.

Cardiac disorders. Palpitations: perindopril — uncommon*, amlodipine — common; tachycardia: perindopril — uncommon*; angina pectoris: perindopril — very rare; arrhythmia (including bradycardia, ventricular tachycardia, and atrial fibrillation): perindopril and indapamide — very rare, amlodipine — uncommon; myocardial infarction may occur due to excessive reduction in blood pressure in high-risk patients: perindopril and amlodipine — very rare; torsade de pointes (paroxysmal ventricular tachycardia), potentially life-threatening: indapamide — frequency not known.

Vascular disorders. Flushing: amlodipine — common, perindopril — rare*; hypotension (and associated symptoms): perindopril — common, indapamide — very rare, amlodipine — uncommon; vasculitis: perindopril — uncommon*, amlodipine — very rare; Raynaud's phenomenon: perindopril — frequency not known.

Respiratory, thoracic and mediastinal disorders. Cough: perindopril — common, amlodipine — uncommon; dyspnea: perindopril and amlodipine — common; bronchospasm: perindopril — uncommon; eosinophilic pneumonia: perindopril — very rare.

Gastrointestinal disorders. Abdominal pain: perindopril and amlodipine — common; constipation: perindopril and amlodipine — common, indapamide — rare; diarrhea: perindopril and amlodipine — common; dyspepsia: perindopril and amlodipine — common; nausea: perindopril and amlodipine — common, indapamide — rare; vomiting: perindopril — common, indapamide and amlodipine — uncommon; dry mouth: perindopril and amlodipine — uncommon, indapamide — rare; changes in defecation rhythm: amlodipine — common; gingival hyperplasia: amlodipine — very rare; pancreatitis: perindopril, indapamide, and amlodipine — very rare; gastritis: amlodipine — very rare.

Hepatobiliary disorders. Hepatitis: perindopril and amlodipine — very rare, indapamide — frequency not known; jaundice: amlodipine — very rare; liver function abnormalities: indapamide — very rare.

Skin and subcutaneous tissue disorders. Pruritus: perindopril — common, amlodipine — uncommon; rash: perindopril — common, amlodipine — uncommon; maculopapular rash: indapamide — common; urticaria: perindopril and amlodipine — uncommon, indapamide — very rare; angioedema: perindopril — uncommon, indapamide and amlodipine — very rare; alopecia: amlodipine — uncommon; purpura: indapamide and amlodipine — uncommon; skin discoloration: amlodipine — uncommon; hyperhidrosis: perindopril and amlodipine — uncommon; exanthema: amlodipine — uncommon; photosensitivity reaction: perindopril — uncommon*, indapamide — frequency not known, amlodipine — very rare; exacerbation of psoriasis symptoms: perindopril — rare; pemphigoid: perindopril — uncommon*; erythema multiforme: perindopril and amlodipine — very rare; Stevens-Johnson syndrome: indapamide and amlodipine — very rare; exfoliative dermatitis: amlodipine — very rare; toxic epidermal necrolysis: indapamide — very rare, amlodipine — frequency not known; Quincke's edema: amlodipine — very rare.

Musculoskeletal and connective tissue disorders. Muscle cramps: perindopril and amlodipine — common, indapamide — frequency not known; ankle swelling: amlodipine — common; arthralgia: perindopril — uncommon*, amlodipine — uncommon; muscle weakness: indapamide — frequency not known; myalgia: perindopril — uncommon*, indapamide — frequency not known, amlodipine — uncommon; rhabdomyolysis: indapamide — frequency not known; back pain: amlodipine — uncommon; possible exacerbation of existing systemic lupus erythematosus: indapamide — frequency not known.

Renal and urinary disorders. Micturition disorders: amlodipine — uncommon; nocturia: amlodipine — uncommon; polyuria: amlodipine — uncommon; anuria/oliguria: perindopril — rare*; acute renal failure: perindopril — rare; renal failure: perindopril — uncommon, indapamide — very rare.

Reproductive system and breast disorders. Erectile dysfunction: perindopril and amlodipine — uncommon, indapamide — uncommon; gynecomastia: amlodipine — uncommon.

General disorders. Asthenia: perindopril and amlodipine — common; increased fatigue: indapamide — rare, amlodipine — common; edema: amlodipine — very common; chest pain: perindopril — uncommon*, amlodipine — uncommon; pain: amlodipine — uncommon; malaise: perindopril — uncommon*, amlodipine — uncommon; peripheral edema: perindopril — uncommon*; hyperthermia: perindopril — uncommon*.

Investigations. Weight gain: amlodipine — uncommon; weight loss: amlodipine — uncommon; increased blood urea nitrogen: perindopril — uncommon*; increased serum creatinine: perindopril — uncommon*; increased serum bilirubin: perindopril — rare; elevated liver enzymes: perindopril — rare, indapamide — frequency not known, amlodipine — very rare; decreased hemoglobin and hematocrit: perindopril — very rare; QT interval prolongation on electrocardiogram: indapamide — frequency not known; increased blood glucose: indapamide — frequency not known; increased serum uric acid: indapamide — frequency not known.

Injury, poisoning and procedural complications. Falls: perindopril — uncommon*.

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

Reporting suspected adverse reactions. Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives should report any suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua

Shelf life.

2 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

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

Prescription status.

Prescription only.

Manufacturer.

TOV NVF "MIKROKHIM" (responsible for batch release excluding batch control/testing)

JSC "FARMAC" (full-cycle manufacturing)

Manufacturer's address and place of business.

Ukraine, 01013, Kyiv, Budynsturiyi St., 5

Ukraine, 04080, Kyiv, Kyrylivska St., 74

Marketing Authorization Holder.

TOV NVF "MIKROKHIM".

Address of Marketing Authorization Holder.

Ukraine, 01013, Kyiv, Budynsturiyi St., 5.

To report an adverse event related to the use of the medicinal product, please contact the pharmacovigilance system of TOV NVF "MIKROKHIM"

by phone: +38 (050) 309-83-54 (24/7)

or via https://microkhim.com.ua/farmakonaglyad/

INSTRUCTION

for medical use of the medicinal product

TRI-ALITER®

(TRI-ALITER)

Composition:

Active substances: perindopril, indapamide, amlodipine;

1 tablet contains:

perindopril tert-butylamine 4 mg (equivalent to 3.338 mg of perindopril), indapamide 1.25 mg and amlodipine besylate 6.935 mg (equivalent to 5 mg of amlodipine)

or perindopril tert-butylamine 4 mg (equivalent to 3.338 mg of perindopril), indapamide 1.25 mg and amlodipine besylate 13.870 mg (equivalent to 10 mg of amlodipine),

or perindopril tert-butylamine 8 mg (equivalent to 6.676 mg of perindopril), indapamide 2.5 mg and amlodipine besylate 6.935 mg (equivalent to 5 mg of amlodipine),

or perindopril tert-butylamine 8 mg (equivalent to 6.676 mg of perindopril), indapamide 2.5 mg and amlodipine besylate 13.870 mg (equivalent to 10 mg of amlodipine);

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

Pharmaceutical form. Tablets.

Main physical and chemical properties: round, biconvex tablets, white to almost white in colour.

Pharmacotherapeutic group.

Agents acting on the renin-angiotensin system. ACE inhibitors, combinations. ACE inhibitors and other combinations. Perindopril, amlodipine and indapamide.

ATC code C09B X01.

Pharmacological properties.

Pharmacodynamics.

TRI-ALITRE® is a combination of three antihypertensive components whose mechanisms of action complement each other in controlling blood pressure in patients with arterial hypertension. Perindopril is an angiotensin-converting enzyme (ACE) inhibitor, indapamide is a sulfonamide diuretic, and amlodipine is a calcium channel blocker belonging to the dihydropyridine group.

The pharmacological effect of the medicinal product TRI-ALITRE® is determined by the properties of each individual component. In addition, the combination of perindopril/indapamide produces an additive synergistic antihypertensive effect of these components.

Mechanism of action.

Perindopril. Perindopril is an angiotensin-converting enzyme inhibitor (ACE inhibitor). ACE converts angiotensin I into angiotensin II (a vasoconstrictor substance), additionally stimulates aldosterone secretion by the adrenal cortex, and promotes bradykinin (a vasodilator substance) breakdown into inactive heptapeptides. As a result of ACE inhibition, aldosterone secretion is reduced; plasma renin activity increases without negative influence from aldosterone; total peripheral vascular resistance decreases due to predominant effects on muscle and renal vessels, while water and salt retention or reflex tachycardia are not observed, even during prolonged treatment.

Perindopril reduces blood pressure in patients with normal and low plasma renin levels as well.

Perindopril acts via its active metabolite, perindoprilat. Other metabolites are inactive.

Perindopril reduces cardiac workload due to vasodilatory effects on veins (possibly through changes in prostaglandin metabolism), thereby decreasing cardiac preload, and by reducing total peripheral resistance, it decreases cardiac afterload.

Studies conducted in patients with heart failure have demonstrated that perindopril use leads to reduced filling pressure in the left and right ventricles; reduced total peripheral vascular resistance; increased cardiac output and improved cardiac index; and increased regional blood flow in muscles.

In addition, results of exercise tests significantly improve.

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

Amlodipine. Amlodipine is a calcium ion influx inhibitor belonging to the dihydropyridine group (a slow calcium channel blocker or calcium antagonist) that blocks transmembrane calcium ion influx into myocardial and vascular smooth muscle cells.

Pharmacodynamic effects.

Perindopril/indapamide. The combination of perindopril/indapamide reduces systolic and diastolic blood pressure in hypertensive patients of any age, both in supine and standing positions. The antihypertensive effect of the drug is dose-dependent. Clinical studies have demonstrated that simultaneous administration of perindopril and indapamide results in a synergistic antihypertensive effect compared to the effect of each component administered separately.

Perindopril. Perindopril effectively reduces blood pressure in patients with mild, moderate, and severe arterial hypertension. Reduction in systolic and diastolic blood pressure is observed both in supine and standing positions. The maximum antihypertensive effect develops 4–6 hours after a single dose and lasts for more than 24 hours. Perindopril achieves a high level of sustained ACE inhibition (approximately 80%) 24 hours after administration.

In patients who respond to treatment, blood pressure normalization occurs within one month and is maintained without tachyphylaxis development.

Discontinuation of therapy is not associated with a rebound effect.

Perindopril has vasodilatory properties, restores elasticity of large arteries, corrects histomorphometric changes in arterial resistance, and reduces left ventricular hypertrophy. Additional synergy develops when a thiazide diuretic is added if necessary.

The combination of an ACE inhibitor and a thiazide diuretic reduces the risk of hypokalemia that may occur when a diuretic is used as monotherapy.

Indapamide. The antihypertensive effect of indapamide, when used as monotherapy, lasts for 24 hours. This effect is evident at doses where diuretic properties are minimal.

The antihypertensive effect of indapamide is associated with improved arterial elasticity and reduced arteriolar resistance and total peripheral vascular resistance.

Indapamide reduces left ventricular hypertrophy.

When the recommended dose is exceeded, the antihypertensive effect of thiazide and thiazide-like diuretics reaches a plateau, while the number of adverse effects increases. If treatment is ineffective, the dose should not be increased.

Moreover, studies of various durations (short, medium, and long-term) involving 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.

Amlodipine. The mechanism of amlodipine’s antihypertensive effect is due to its direct relaxant effect on vascular smooth muscle. The exact mechanism by which amlodipine reduces angina symptoms is not fully defined, but it is known that the drug reduces total ischemic load through two actions:

• amlodipine dilates peripheral arterioles, thereby reducing total peripheral resistance (afterload); since heart rate does not change, reduced cardiac workload decreases myocardial energy consumption and oxygen demand;
• amlodipine partially promotes dilation of major coronary arteries and arterioles in both unaffected and ischemic areas of the myocardium; this dilation increases oxygen supply to the myocardium in patients with vasospastic angina (Prinzmetal's angina or variant angina).

In patients with arterial hypertension, once-daily administration of amlodipine provides clinically significant blood pressure reduction over 24 hours, both in supine and standing positions. Due to its slow onset of action, amlodipine does not cause acute hypotension.

Amlodipine is not associated with negative metabolic effects or changes in plasma lipid levels; therefore, it can be used in patients with asthma, diabetes mellitus, and gout.

Pharmacokinetics.

Administration of perindopril/indapamide and amlodipine in a fixed combination does not alter their pharmacokinetic properties compared to their use as monotherapies.

Perindopril. After oral administration, perindopril is rapidly absorbed, with maximum concentration reached within 1 hour (perindopril is a prodrug, and perindoprilat is the active metabolite). The elimination half-life of perindopril in plasma is 1 hour. Approximately 27% of the administered dose of perindopril reaches 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.

Since food intake reduces the conversion of perindopril to perindoprilat, thereby decreasing its bioavailability, perindopril is recommended to be taken orally as a single daily dose in the morning before meals. A linear relationship exists between perindopril dose and its plasma concentration.

The volume of distribution of unbound perindoprilat is approximately 0.2 L/kg. Perindoprilat binding to plasma proteins is 20%, primarily to angiotensin-converting enzyme, and is dose-dependent. Perindoprilat is excreted in urine, with the terminal elimination half-life of the unbound fraction being approximately 17 hours. Steady state is achieved within 4 days.

Perindoprilat elimination is reduced in elderly patients and in patients with cardiac or renal impairment. Dose adjustment is required in patients with renal impairment depending on the degree of renal function (creatinine clearance).

Dialysis clearance of perindoprilat is 70 mL/min.

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

Indapamide. Indapamide is rapidly and completely absorbed in the gastrointestinal tract. Maximum plasma concentration is reached approximately 1 hour after oral administration. Protein binding in plasma is 79%. Elimination half-life ranges from 14 to 24 hours (on average, 18 hours). Repeated dosing does not lead to accumulation.

Indapamide is primarily excreted in urine (70% of the dose) and feces (22%) as inactive metabolites. Pharmacokinetic parameters do not change in patients with renal impairment.

Amlodipine. When administered orally at therapeutic doses, amlodipine is well absorbed and reaches maximum blood concentration 6–12 hours after administration. Absolute bioavailability ranges from 64% to 80%. Volume of distribution is approximately 21 L/kg. In vitro studies have shown that about 97.5% of circulating amlodipine in blood is protein-bound. Food intake does not affect amlodipine bioavailability. The elimination half-life of amlodipine from plasma is approximately 35–50 hours, allowing once-daily dosing. Amlodipine is primarily metabolized in the liver into inactive metabolites, with 60% of metabolites excreted in urine and 10% excreted unchanged.

Time to reach maximum plasma concentration of amlodipine is similar in elderly and younger patients. In elderly patients, there is a tendency toward reduced amlodipine clearance, leading to increased AUC and elimination half-life. Increased AUC and elimination half-life in patients with congestive heart failure corresponded to the age characteristics of the studied patients.

Clinical data on amlodipine use in patients with hepatic impairment are very limited. In patients with hepatic impairment, amlodipine clearance is reduced—this leads to prolonged elimination half-life and increased AUC by approximately 40–60%.

Clinical characteristics.

Indications.

TRI-ALITER® is indicated for the treatment of arterial hypertension in patients who require therapy with perindopril, indapamide, and amlodipine in the doses available in the fixed combination.

Contraindications.

• Hemodialysis;
• Untreated decompensated heart failure;
• Severe renal impairment (creatinine clearance below 30 mL/min);
• Moderate renal impairment (creatinine clearance below 60 mL/min) (applies to the medicinal product TRI-ALITER® containing the combination of active substances in doses of 8 mg / 2.5 mg / 5 mg or 8 mg / 2.5 mg / 10 mg);
• Hypersensitivity to the active substances, other sulfonamide drugs, dihydropyridine derivatives, any other ACE inhibitor, or to any of the excipients;
• Pregnancy or planning pregnancy (see section "Use in pregnancy or lactation");
• History of angioedema (Quincke's edema) associated with previous treatment with ACE inhibitors (see section "Special precautions for use");
• Hereditary or idiopathic angioedema;
• Hepatic encephalopathy;
• Severe hepatic impairment;
• Hypokalemia;
• Severe arterial hypotension;
• Shock, including cardiogenic shock;
• Obstruction of the left ventricular outflow tract (e.g., severe aortic stenosis);
• Heart failure with unstable hemodynamics following acute myocardial infarction;
• 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 "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction");
• Concomitant use with sacubitril/valsartan. Initiation of treatment with the medicinal product TRI-ALITER® must not occur earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction");
• Extracorporeal treatment methods leading to blood contact with negatively charged surfaces (see section "Interaction with other medicinal products and other forms of interaction");
• Significant bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney (see section "Special precautions for use").

Interaction with other medicinal products and other forms of interaction.

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

Medicinal products increasing the risk of angioedema. Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to an increased risk of angioedema (see sections "Contraindications" and "Special precautions for use"). Initiation of sacubitril/valsartan therapy 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 for use").

Concomitant use of ACE inhibitors with racécadotril, 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 for use").

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

Concomitant use is contraindicated (see section "Contraindications").

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

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

Concomitant use is not recommended.

Perindopril/indapamide. Reversible increases in serum lithium concentration and increased lithium toxicity have been reported with concomitant use of lithium and ACE inhibitors. Concomitant use of perindopril with indapamide and lithium-containing products is not recommended. However, if such a combination is necessary, serum lithium concentrations should be closely monitored (see section "Special precautions for use").

Perindopril.Aliskiren: in any other patients, as in those with diabetes mellitus or renal impairment, the risk of hyperkalemia, worsening of renal function, and cardiovascular morbidity and mortality is increased (see section "Special precautions for use").

Published data show that in patients with established atherosclerosis, heart failure, or diabetes with target organ damage, concomitant use of ACE inhibitors and angiotensin receptor blockers was associated with increased incidence of arterial hypotension, syncope, hyperkalemia, and worsening of renal function (including acute renal failure) compared to monotherapy with agents affecting the renin-angiotensin-aldosterone system. Dual blockade (i.e., combination of an ACE inhibitor with angiotensin II receptor antagonists) may be considered only in exceptional cases with careful monitoring of renal function, potassium levels, and blood pressure (see section "Special precautions for use").

Estramustine: increased risk of adverse reactions such as angioedema.

Potassium-sparing agents (e.g., triamterene, amiloride, etc.), potassium salts: risk of hyperkalemia (potentially fatal), especially in patients with renal impairment (additive hyperkalemic effect). These agents are not recommended for concomitant use with perindopril (see section "Special precautions for use"). However, if concomitant use is necessary, they should be used with caution and frequent monitoring of serum potassium levels is required. For use of spironolactone in heart failure, see below "Concomitant use requiring special attention".

Amlodipine.Dantrolene (infusion): in animal studies, ventricular fibrillation with fatal outcome and cardiovascular collapse associated with hyperkalemia were observed after intravenous administration of verapamil and dantrolene. Due to the potential for hyperkalemia, it is recommended to avoid concomitant administration of calcium channel blockers such as amlodipine to patients with established or suspected malignant hyperthermia.

Grapefruit or grapefruit juice: in some patients, increased bioavailability of amlodipine may occur, resulting in enhanced hypotensive effect.

Concomitant use requiring special attention.

Perindopril/indapamide. Baclofen enhances the antihypertensive effect. Blood pressure should be monitored and the dose of antihypertensive agent adjusted if necessary.

Perindopril/indapamide.Nonsteroidal anti-inflammatory drugs (NSAIDs), including high doses of acetylsalicylic acid. When ACE inhibitors are used concomitantly with NSAIDs, such as acetylsalicylic acid at anti-inflammatory doses, COX-2 inhibitors, and nonselective NSAIDs, the antihypertensive effect may be attenuated. Concomitant use of ACE inhibitors and NSAIDs may increase the risk of worsening renal function, including possible development of acute renal failure, and increased serum potassium levels, particularly in patients with pre-existing impaired renal function. Such combinations should be used with caution, especially in elderly patients. Patients should be adequately hydrated, and renal function should be monitored after initiation of concomitant therapy and during ongoing treatment.

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

In patients taking diuretics, particularly those with fluid and electrolyte imbalance, excessive reduction in blood pressure may occur after initiation of ACE inhibitor therapy. The risk of hypotensive effects can be reduced by discontinuing the diuretic, increasing circulating blood volume, and increasing salt intake before starting perindopril therapy, which should begin with low doses and be gradually increased. In arterial hypertension, if a previously prescribed diuretic may have caused fluid/electrolyte deficiency, it should be discontinued before starting ACE inhibitor therapy (in such cases, diuretic therapy may be resumed later) or the ACE inhibitor should be initiated at a low dose with gradual dose escalation. In congestive heart failure, when diuretic therapy is ongoing, initiation of ACE inhibitor therapy should begin with the lowest dose, possibly after reducing the diuretic dose. In any case, renal function (creatinine level) should be monitored during the first weeks of ACE inhibitor therapy.

Potassium-sparing diuretics (eplerenone, spironolactone). When eplerenone or spironolactone is used concomitantly with low doses of ACE inhibitors in patients with NYHA class II–IV heart failure and ejection fraction < 40%, who have previously received ACE inhibitors and loop diuretics, there is a risk of hyperkalemia, potentially fatal, especially if recommendations for use of this combination are not followed. Before initiating such a combination, ensure absence of hyperkalemia and renal impairment. Careful monitoring of serum potassium and creatinine is recommended weekly during the first month of treatment and monthly thereafter.

Indapamide. Due to the risk of hypokalemia, indapamide should be used with caution in combination with medicinal products that may induce torsades de pointes-type ventricular tachycardia, such as, but not limited to:

• 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, sulthiame, tiapride), butyrophenones (e.g., droperidol, haloperidol), other antipsychotics (e.g., pimozide);
• Other agents (e.g., bepridil, cisapride, difemanel, intravenous erythromycin, halofantrine, mizolastine, moxifloxacin, pentamidine, sparfloxacin, intravenous vincamine, methadone, astemizole, terfenadine).

Serum potassium levels should be maintained, corrected if necessary, and QT interval monitored.

Intravenous amphotericin B, glucocorticoids and mineralocorticoids (systemic action), tetracosactide, stimulant laxatives increase the risk of serum potassium reduction (additive effect). Serum potassium levels should be monitored and corrected as needed, especially when used concomitantly with cardiac glycosides. It is recommended to use laxatives that do not stimulate peristalsis.

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

Allopurinol. Concomitant use with indapamide increases the risk of hypersensitivity reactions to allopurinol.

*Amlodipine. When used concomitantly with known CYP3A4 inducers, plasma concentrations of amlodipine may change. Therefore, blood pressure should be monitored and dose adjustments made during and after concomitant use with CYP3A4 inducers, particularly strong CYP3A4 inducers (e.g., rifampicin, St. John's wort [Hypericum perforatum]).

Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin and clarithromycin, verapamil, or diltiazem) may cause significant increases in amlodipine concentration. The clinical manifestation of these pharmacokinetic changes may be more pronounced in elderly patients. In such cases, clinical monitoring and dose adjustment may be necessary.

There is an increased risk of hypotension in patients taking clarithromycin in combination with amlodipine. Close monitoring is recommended for such patients.

Concomitant use requiring attention.

Perindopril/indapamide/amlodipine.Imipramine-like (tricyclic) antidepressants, neuroleptics enhance antihypertensive effects and increase the risk of orthostatic hypotension (additive effect).

Concomitant use of other antihypertensive agents may cause additional blood pressure reduction.

Corticosteroids, tetracosactide. Weakening of antihypertensive effect (due to water and salt retention by corticosteroids).

Perindopril. Antihypertensive agents and vasodilators: concomitant use with nitroglycerin and other nitrates or other vasodilators may lead to additional blood pressure reduction.

Allopurinol, cytostatics, immunosuppressants, systemic corticosteroids, or procainamide: concomitant use with ACE inhibitors increases the risk of leukopenia.

ACE inhibitors may enhance the hypotensive effect of certain anesthetic agents.

Diuretics (thiazide and loop diuretics): prior treatment with high doses of diuretics may cause dehydration, increasing the risk of hypotension at the start of perindopril therapy.

Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.

Rarely, concomitant use of ACE inhibitors, including perindopril, and injectable gold (sodium aurothiomalate) has been associated with reactions similar to those seen with nitrates (symptoms: facial flushing, nausea, vomiting, and hypotension).

Indapamide. Metformin may cause lactic acidosis due to possible development of functional renal impairment associated with diuretic use, especially loop diuretics. Metformin should not be prescribed if plasma creatinine levels exceed 15 mg/L (135 µmol/L) in men and 12 mg/L (110 µmol/L) in women.

In cases of dehydration associated with diuretic use, the risk of acute renal failure increases, especially with large doses of iodinated contrast agents. Fluid balance should be restored before administration of such agents.

Calcium salts: risk of hypercalcemia due to reduced urinary calcium excretion.

Cyclosporine: risk of increased creatinine levels without affecting circulating cyclosporine levels, even in the absence of water and sodium deficiency.

Amlodipine: clinical interaction studies have shown that amlodipine does not affect the pharmacokinetics of atorvastatin, digoxin, or warfarin.

Tacrolimus: risk of increased plasma tacrolimus concentration with concomitant use of amlodipine. To avoid tacrolimus toxicity when used concomitantly with amlodipine, plasma levels should be monitored and the dose adjusted if necessary.

mTOR (mechanistic target of rapamycin) inhibitors. mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are CYP3A substrates. Amlodipine is a weak CYP3A inhibitor. Concomitant use of amlodipine with mTOR inhibitors may enhance their effects.

Cyclosporine: interaction studies between cyclosporine and amlodipine have not been conducted in healthy volunteers or other populations, except in kidney transplant patients, where increased fluctuations in cyclosporine trough concentrations (on average from 0 to 40%) have been observed. In kidney transplant patients receiving amlodipine, cyclosporine blood levels should be monitored and the dose reduced if necessary.

Use of amlodipine at doses greater than 10 mg in combination with 80 mg simvastatin resulted in a 77% increase in simvastatin concentration compared to simvastatin monotherapy. Patients taking amlodipine should limit the dose of simvastatin to 20 mg daily.

Special precautions for use.

All the following warnings regarding the use of individual components of the medicinal product also apply to the fixed combination TRI-ALITRE®.

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

Double blockade of the renin-angiotensin-aldosterone system (RAAS). Data indicate that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of hypotension, hyperkalaemia, and impaired renal function (including acute renal failure). Therefore, dual blockade of the RAAS by combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see section "Interaction with other medicinal products and other forms of interactions"). If dual RAAS blockade therapy is considered absolutely necessary, it should only be administered under specialist supervision with frequent and careful monitoring of renal function, electrolyte levels, and blood pressure. ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Potassium-sparing agents, potassium-containing dietary supplements, or potassium-containing salt substitutes. Concomitant use of perindopril with potassium-sparing agents, potassium-containing dietary 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 receiving ACE inhibitors. Neutropenia is rare in patients with normal renal function and no risk factors. Perindopril should be administered with extreme caution to patients with collagen vascular diseases, those receiving immunosuppressive therapy, allopurinol, procainamide, or a combination of these factors, especially if renal function is impaired. Some of these patients have developed severe infections, in several cases resistant to intensive antibiotic therapy. In such patients, periodic monitoring of white blood cell counts is recommended. Patients should also be informed to report any signs of infection (e.g., sore throat, fever) to their physician (see section "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 renal function may manifest only as slight changes in serum creatinine levels, even in patients with unilateral renal artery stenosis.

Hypersensitivity/angioedema. Rare cases of angioedema of the face, extremities, lips, tongue, glottis, and/or larynx have been reported during treatment with ACE inhibitors, including perindopril. Angioedema may occur at any time during treatment.

In such cases, perindopril must be discontinued immediately, and appropriate monitoring should be instituted until symptoms completely resolve. If swelling is limited to the face and lips, the condition usually resolves spontaneously, and antihistamines may help relieve symptoms.

Angioedema involving swelling of the larynx may be fatal. If swelling involves the tongue, glottis, or larynx with potential airway obstruction, emergency treatment is required, which may include subcutaneous administration of 1:1000 epinephrine solution (0.3–0.5 mL) and/or securing airway patency.

ACE inhibitors have been reported to cause angioedema more frequently in black patients compared to patients of other races.

Patients with a history of angioedema unrelated to ACE inhibitor use have an increased risk of developing angioedema during ACE inhibitor therapy (see section "Contraindications").

Rare cases of intestinal angioedema have been reported in patients receiving ACE inhibitors. These patients presented with abdominal pain (with or without nausea and vomiting); in some cases, prior facial angioedema was not observed, and C-1 esterase levels were within normal limits. Diagnosis of intestinal angioedema was confirmed by computed tomography, ultrasound, or surgical intervention. Symptoms resolved after discontinuation of the ACE inhibitor. Intestinal angioedema should be considered in the differential diagnosis of abdominal pain in patients receiving ACE inhibitors.

Concomitant use of perindopril with sacubitril/valsartan is contraindicated due to an increased risk of angioedema (see section "Contraindications").

Sacubitril/valsartan should not be initiated earlier than 36 hours after the last dose of perindopril. If treatment with sacubitril/valsartan is discontinued, perindopril therapy should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Concomitant use of ACE inhibitors with neutral endopeptidase (NEP) inhibitors (e.g., racecadotril), mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) may increase the risk of angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) (see section "Interaction with other medicinal products and other forms of interaction"). Caution is advised when initiating treatment with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) in patients already receiving ACE inhibitors.

Anaphylactoid reactions during desensitization therapy. Isolated cases of prolonged, life-threatening anaphylactoid reactions have been reported in patients receiving ACE inhibitors during desensitization therapy with insect venom preparations (bees, wasps). ACE inhibitors should be used with caution in patients undergoing allergen desensitization and avoided during immunotherapy with animal-derived venomous substances.

However, in patients requiring both ACE inhibitors and desensitization therapy, such reactions may be avoided by temporarily discontinuing the ACE inhibitor at least 24 hours before desensitization.

Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis. Rarely, life-threatening anaphylactoid reactions have occurred in patients receiving ACE inhibitors during LDL apheresis using dextran sulfate. These reactions can be avoided by temporarily discontinuing ACE inhibitor therapy before each apheresis session.

Patients undergoing hemodialysis. Cases of anaphylactoid reactions have been reported in patients receiving ACE inhibitors during hemodialysis using high-flux polyacrylonitrile membranes (e.g., AN 69®). These 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 therapy acting via suppression of the renin-angiotensin system. Therefore, this medicinal product is not recommended for such patients.

Pregnancy. ACE inhibitors should not be prescribed during pregnancy. Women planning pregnancy who require continued ACE inhibitor therapy should be switched to alternative antihypertensive agents with established safety profiles during pregnancy. If pregnancy is diagnosed, ACE inhibitor therapy should be discontinued immediately and, if necessary, replaced with another medicinal product approved for use in pregnant women (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

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

Photosensitization. Cases of photosensitization reactions have been reported in patients receiving thiazide and thiazide-like diuretics (see section "Side effects"). If such reactions occur, diuretic therapy is recommended to be discontinued. If diuretic therapy must be resumed, vulnerable skin areas should be protected from sunlight or artificial ultraviolet sources.

Renal function. The use of the medicinal product is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min). Therapy with the fixed combination TRI-ALITRE® containing perindopril/indapamide in doses of 8 mg / 2.5 mg (i.e., TRI-ALITRE® 8 mg / 2.5 mg / 5 mg and 8 mg / 2.5 mg / 10 mg) is contraindicated in patients with moderate renal impairment (creatinine clearance < 60 mL/min). If laboratory blood tests in some patients with arterial hypertension and no signs of kidney damage show signs of functional renal impairment, treatment should be discontinued; resumption of therapy at a lower dose or with one of its components may be considered. These patients require frequent monitoring of potassium and creatinine: 2 weeks after initiation of treatment and subsequently every two months during therapeutic stabilization. Cases of renal failure have primarily occurred in patients with severe heart failure or impaired renal function, including renal artery stenosis.

This combination is not recommended for patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney.

Risk of arterial hypotension and/or renal failure (in heart failure, fluid and electrolyte deficiency, etc.): marked stimulation of the renin-angiotensin-aldosterone system was observed primarily due to perindopril in cases of pronounced fluid and electrolyte deficiency (strict salt-free diet or prolonged diuretic therapy), in patients with initially low blood pressure, renal artery stenosis, congestive heart failure, or patients with liver cirrhosis with edema and ascites.

Blocking this system with an ACE inhibitor, especially during the first dose and the first two weeks of treatment, may cause a sharp drop in blood pressure and/or an increase in plasma creatinine levels, indicating functional renal impairment. This may occasionally have an acute onset and very rarely may occur at any time during treatment. In such cases, treatment should be initiated with a lower dose, gradually increasing it. In patients with ischemic heart disease or cerebrovascular disease, a significant drop in blood pressure may lead to myocardial infarction or stroke.

Thiazide and thiazide-like diuretics show the greatest efficacy when renal function is normal or only slightly impaired (serum creatinine approximately below 25 mg/L, i.e., 220 μmol/L, in adults).

In elderly patients, plasma creatinine levels should correspond to age, body weight, and sex. Hypovolemia caused by loss of water and sodium due to diuretic use at the beginning of treatment leads to decreased glomerular filtration. This may result in increased blood urea and creatinine levels. This transient functional renal impairment has no adverse consequences in patients with normal renal function but may exacerbate pre-existing renal impairment.

Amlodipine may be used in patients with renal impairment at usual doses. Plasma amlodipine concentrations do not correlate with the degree of renal impairment.

Studies on the use of the fixed combination TRI-ALITRE® in patients with renal dysfunction have not been conducted. For patients with impaired renal function, dosing of the fixed combination TRI-ALITRE® should correspond to individually adjusted doses of its monocomponents.

Hypotension, fluid and electrolyte deficiency. There is a risk of sudden drop in blood pressure in patients with existing sodium deficiency (particularly in patients with renal artery stenosis). Therefore, systematic monitoring for clinical signs of fluid and electrolyte deficiency, which may occur during intercurrent vomiting or diarrhea, is necessary. In such patients, serum electrolyte levels should be regularly monitored.

In cases of pronounced hypotension, intravenous administration of isotonic sodium chloride solution may be required. Transient hypotension is not a contraindication for further use of the medicinal product. After restoration of circulating blood volume (CBV) and normalization of blood pressure, treatment may be resumed at a lower dose or with one of the components.

Initial decrease in sodium concentration may be asymptomatic, so regular laboratory monitoring of this parameter is very important. More frequent monitoring is necessary for 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 arterial hypotension. Concomitant loss of chloride ions may lead to secondary compensatory metabolic alkalosis; the frequency and severity of this effect are minor.

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

In some patients receiving ACE inhibitors, including perindopril, increased plasma potassium concentration has been observed. ACE inhibitors may cause hyperkalemia as they suppress aldosterone release. In patients with normal renal function, this effect is usually insignificant. Risk factors for hyperkalemia include renal impairment, worsening renal function, age over 70 years, diabetes, intercurrent conditions such as dehydration, acute heart failure, metabolic acidosis, and concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium-containing dietary supplements, or potassium-containing salt substitutes; use of other agents that increase serum potassium concentration (e.g., heparin, co-trimoxazole, also known as trimethoprim/sulfamethoxazole), and particularly aldosterone antagonists or angiotensin receptor blockers. Use of potassium-containing dietary supplements, potassium-sparing diuretics, or potassium-containing salt substitutes may also lead to significant increases in serum potassium, especially in patients with impaired renal function. Hyperkalemia may cause serious, sometimes fatal, arrhythmias. Patients receiving ACE inhibitors should use potassium-sparing diuretics and angiotensin receptor blockers cautiously and require monitoring of serum potassium levels and renal function. If concomitant use of perindopril and any of the above-mentioned substances is considered appropriate, they should be used with caution and serum potassium levels should be monitored frequently (see section "Interaction with other medicinal products and other forms of interaction").

Reduced potassium levels in hypokalemia are the main risk associated with thiazide and thiazide-like diuretics. Hypokalemia may cause muscle disorders. Cases of rhabdomyolysis have been reported, predominantly associated with severe hypokalemia. The risk of low potassium levels (< 3.4 mmol/L) should be prevented in high-risk patients (elderly patients and/or poorly nourished patients, regardless of polypharmacy, patients with liver cirrhosis associated with edema and ascites, patients with ischemic heart disease, and patients with heart failure). In cases of hypokalemia, cardiotoxicity of cardiac glycosides and the risk of arrhythmias increase. Patients with congenital or iatrogenic prolonged QT interval also belong to the risk group. Hypokalemia, as well as bradycardia, may promote the development of severe cardiac arrhythmias, including paroxysmal ventricular tachycardia of the "torsades de pointes" type, which may be fatal.

In all these cases, more frequent monitoring of serum potassium levels is necessary. The first measurement should be performed within the first week of treatment.

If serum potassium levels are reduced, correction is required. Hypokalemia associated with low serum magnesium levels may be refractory to treatment unless serum magnesium levels are corrected.

Calcium levels. Thiazide and thiazide-like diuretics may reduce urinary calcium excretion and cause slight and transient elevation of plasma calcium levels. Markedly elevated calcium levels may be due to previously undiagnosed hyperparathyroidism. In such cases, treatment should be discontinued until parathyroid function is evaluated (see section "Side effects").

Plasma magnesium. Thiazides and related diuretics, including indapamide, have been shown to increase urinary magnesium excretion, which may lead to hypomagnesemia (see sections "Interaction with other medicinal products and other forms of interaction" and "Side effects").

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

If TRI-ALITRE® is prescribed to patients with diagnosed or suspected renal artery stenosis, therapy should be initiated in a hospital setting with low doses, monitoring renal function and potassium levels. Functional renal impairment, reversible after discontinuation of treatment, has been observed in some patients.

Cough. Dry cough has been reported during treatment with ACE inhibitors. This cough is persistent and resolves after discontinuation of the drug. Iatrogenic etiology of cough should be considered if this symptom occurs. If ACE inhibitor therapy is still preferred, continuation of treatment may be considered.

Atherosclerosis. The risk of hypotension exists in all patients, but perindopril should be prescribed with particular caution to patients with ischemic heart disease or cerebral circulation insufficiency. In such cases, treatment should be initiated with a low dose.

Hypertensive crisis. The safety and efficacy of amlodipine use in patients with hypertensive crisis have not been studied.

Heart failure/severe heart failure. Amlodipine should be administered with caution in patients with heart failure. In a long-term placebo-controlled study involving patients with severe heart failure (NYHA class III, IV), the incidence of pulmonary angioedema was higher with amlodipine compared to placebo. Calcium channel blockers, including amlodipine, should be administered with caution in patients with congestive heart failure, as they increase the risk of cardiovascular events and mortality.

In patients with severe heart failure (NYHA class IV), treatment 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: the ACE inhibitor is added to the β-blocker.

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

Patients with diabetes mellitus. Treatment should be initiated under medical supervision with a reduced initial dose in patients with insulin-dependent diabetes mellitus (due to the tendency to spontaneous increase in potassium levels).

In patients with diabetes mellitus receiving oral hypoglycemic agents or insulin, blood glucose levels should be closely monitored, especially during the first month of ACE inhibitor therapy.

In patients with diabetes mellitus, blood glucose levels should be carefully monitored, particularly when potassium levels are low.

Racial characteristics. Perindopril, like other ACE inhibitors, is likely to be less effective in lowering blood pressure in black hypertensive patients compared to patients of other races, possibly due to lower plasma renin levels in these patients.

Surgery/anesthesia. ACE inhibitors may cause hypotension during anesthesia, especially when using anesthetics that lower blood pressure. Therefore, when treating with long-acting ACE inhibitors such as perindopril, the drug should be discontinued, if possible, one day before surgery.

Hepatic impairment. Rarely, ACE inhibitor use has been associated with a syndrome beginning with cholestatic jaundice and progressing to fulminant hepatic necrosis, sometimes fatal. The mechanism of this syndrome is unknown. Patients who develop jaundice or marked elevation of liver enzymes while receiving an ACE inhibitor should discontinue the ACE inhibitor and undergo appropriate medical evaluation and treatment (see section "Side effects").

In patients with hepatic impairment, prolonged elimination half-life and higher AUC values for amlodipine have been observed; dosing recommendations are lacking. Amlodipine therapy should be initiated at the lowest doses, with caution at the beginning of treatment and during dose escalation. Patients with severe hepatic impairment may require gradual dose titration and careful monitoring.

Studies on the use of the fixed combination TRI-ALITRE® in patients with hepatic dysfunction have not been conducted. Since the effects of individual components of the fixed combination TRI-ALITRE® are known, the medicinal product is contraindicated in patients with severe hepatic impairment and should be used with caution in mild to moderate hepatic impairment.

Uric acid. In patients with elevated uric acid levels, there may be a tendency to increased frequency of gout attacks.

Elderly patients. Renal function and potassium levels should be checked before initiating treatment. To reduce the risk of sudden hypotension, especially in the presence of fluid or electrolyte deficiency, the initial dose should be adjusted according to the blood pressure response to treatment. Dose escalation in elderly patients should be done cautiously (see section "Dosage and administration" and section "Pharmacokinetics").

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 defect, 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 after starting the drug. Untreated acute angle-closure glaucoma may lead to permanent vision loss. The primary treatment is to discontinue the medicinal product as quickly as possible. If intraocular pressure remains uncontrolled, medical or surgical treatment may be necessary. Risk factors for acute angle-closure glaucoma may include a history of allergy to sulfonamides or penicillin.

Athletes. Athletes should be aware that this medicinal product contains an active substance that may lead to a positive anti-doping test.

Excipients. If you have been diagnosed with intolerance to certain sugars, consult your physician before taking this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy. TRI-ALITRE® is contraindicated during pregnancy (see section "Contraindications").

Perindopril. The use of ACE inhibitors is contraindicated during pregnancy. Epidemiological data on the risk of teratogenic effects from ACE inhibitor use during the first trimester of pregnancy are insufficient, so a slight increase in risk cannot be excluded. The medicinal product is contraindicated in pregnant women or women planning pregnancy. If continued ACE inhibitor therapy is considered mandatory, women planning pregnancy should be switched to alternative antihypertensive agents with established safety data during pregnancy. If pregnancy is confirmed during ACE inhibitor therapy, treatment must be discontinued immediately and replaced with another medicinal product approved for use during pregnancy.

It is known that ACE inhibitor use during the second and third trimesters of pregnancy leads to fetotoxicity (impaired renal function, oligohydramnios, delayed ossification of skull bones) and neonatal toxicity (renal failure, arterial hypotension, hyperkalaemia).

If a woman has taken ACE inhibitors from the second trimester of pregnancy, ultrasound evaluation of fetal renal and skull bone development is recommended. Newborns whose mothers received ACE inhibitors during pregnancy should be closely monitored for timely detection and correction of arterial hypotension (see sections "Contraindications" and "Special precautions for use").

Indapamide. Data on indapamide use during pregnancy are limited (fewer than 300 cases). Prolonged use of thiazide diuretics during the third trimester of pregnancy may reduce circulating blood volume and uteroplacental perfusion, potentially leading to fetoplacental ischemia and delayed fetal development. Additionally, hypoglycemia and thrombocytopenia have been rarely observed in newborns. Animal studies did not reveal direct or indirect toxic effects on reproductive function.

Amlodipine. The safety of amlodipine use in pregnant women has not been established. Animal studies revealed toxic effects on reproductive function when high doses were administered.

Breastfeeding. TRI-ALITRE® is not recommended during breastfeeding.

Perindopril. The use of perindopril during breastfeeding is not recommended due to lack of data. Particularly during breastfeeding of a newborn or premature infant, alternative treatment with a confirmed safety profile during breastfeeding should be prescribed.

Indapamide. Available information on the passage of indapamide/metabolites into breast milk is insufficient. Hypersensitivity to sulfonamide derivatives and hypokalemia may develop. Risk to newborns/infants cannot be excluded.

Indapamide belongs to thiazide-like diuretics, the use of which during breastfeeding has been associated with reduced and suppressed lactation.

Amlodipine. Amlodipine passes into breast milk. The fraction of the maternal dose received by the infant has been estimated as an interquartile range of 3–7% with a maximum of 15%. The effect of amlodipine on infants is unknown.

Fertility.

Perindopril and indapamide. Reproductive toxicity studies did not reveal effects on fertility in male and female animals. Effects on human fertility are not expected.

Amlodipine. Reversible biochemical changes in the head of spermatozoa have been reported in some patients treated with calcium channel blockers. Clinical data on the potential effect of amlodipine on fertility are insufficient. It is known that animal studies revealed a negative effect of the drug on male fertility.

Ability to affect reaction speed when driving or operating machinery.

Studies on the effect of the medicinal product TRI-ALITRE® on the ability to drive or operate machinery have not been conducted.

Perindopril and indapamide do not affect the ability to drive or operate machinery. However, individual reactions related to decreased blood pressure may occur in some patients.

Amlodipin may have a slight or moderate effect on the ability to drive and operate machinery. Impaired reaction may occur if the patient experiences dizziness, headache, weakness, fatigue, or nausea. This may impair the ability to drive and operate machinery. Caution is recommended, especially at the beginning of treatment.

Method of Administration and Dosage.

For oral use.

1 tablet of the medicinal product TRI-ALITER® once daily, preferably in the morning before food.

The fixed-dose combination is not intended for initial therapy.

If necessary, the dose of the fixed-dose combination TRI-ALITER® may be adjusted or individual dose titration of each component separately may be recommended.

Special patient groups.

Patients with renal impairment (see sections “Contraindications” and “Special precautions for use”).

Treatment with the medicinal product is contraindicated in patients with severe renal impairment (creatinine clearance ˂ 30 mL/min). The use of TRI-ALITER® at doses of 8 mg / 2.5 mg / 5 mg and 8 mg / 2.5 mg / 10 mg is contraindicated in patients with moderate renal impairment (creatinine clearance 30–60 mL/min). Regular medical monitoring should include frequent assessment of serum creatinine and potassium levels.

Elderly patients (see section “Special precautions for use”).

It should be taken into account that the elimination of perindoprilat is reduced in elderly patients (see section “Pharmacokinetics”). The use of the medicinal product TRI-ALITER® in elderly patients is possible with consideration of renal function (see section “Contraindications”).

Patients with hepatic impairment (see sections “Contraindications”, “Special precautions for use”, and “Pharmacokinetics”).

Treatment with TRI-ALITER® is contraindicated in patients with severe hepatic impairment. TRI-ALITER® should be administered with caution to patients with mild to moderate hepatic impairment due to the lack of dosage recommendations for amlodipine.

Children.

Safety and efficacy data for the use of the medicinal product TRI-ALITER® in children are lacking; therefore, it is not used in this age group.

Overdose.

Data on overdose with the medicinal product TRI-ALITER® are lacking.

For the combination perindopril/indapamide, the most common adverse reaction in case of overdose is arterial hypotension, which may sometimes be accompanied by nausea, vomiting, seizures, dizziness, drowsiness, confusion, oliguria, which may progress to anuria (due to hypovolemia). Disturbances in water-electrolyte balance may occur (decreased serum sodium and potassium levels).

First aid measures include rapid elimination of the drug from the body: gastric lavage and/or administration of activated charcoal, followed by restoration of water-electrolyte balance under hospital conditions until these parameters return to normal.

In case of significant hypotension, the patient should be placed in a supine position with low head elevation. If necessary, isotonic sodium chloride solution should be administered intravenously or any other method used to restore blood volume.

Perindoprilat, the active form of perindopril, can be removed from the body by hemodialysis (see section “Pharmacokinetics”).

Data on intentional overdose of amlodipine in humans are limited.

Based on available data, it can be assumed that ingestion of very large doses will lead to excessive peripheral vasodilation and reflex tachycardia. Severe, possibly prolonged systemic hypotension and shock with fatal outcome have been reported.

Rare cases of non-cardiogenic pulmonary edema as a result of amlodipine overdose have been reported, which may present with delayed onset (24–48 hours after administration) and may require mechanical ventilation. Early resuscitation measures (including fluid overload) to support perfusion and cardiac output may act as triggering factors.

Clinically significant hypotension caused by amlodipine overdose requires active cardiovascular support, including continuous monitoring of cardiac and respiratory function, placing the patient in a supine position with elevated legs, and monitoring of circulating blood volume and urine output.

Administration of a vasoconstrictor may be beneficial to restore vascular tone and arterial pressure, provided there are no contraindications. Intravenous administration of calcium gluconate may help counteract the effects of calcium channel blockade.

In some cases, gastric lavage may be appropriate. Studies in healthy volunteers have shown that administration of activated charcoal 2 hours after intake of 10 mg amlodipine reduces the rate of amlodipine absorption. Since amlodipine is highly protein-bound, hemodialysis is considered ineffective.

Adverse Reactions.

The most commonly observed adverse reactions during the use of perindopril, indapamide, and amlodipine administered separately include: hypokalemia, dizziness, headache, paresthesia, somnolence, dysgeusia, visual disturbances, diplopia, tinnitus, vertigo, palpitations, flushing, arterial hypotension (and associated symptoms), cough, dyspnea, gastrointestinal disorders (abdominal pain, constipation, diarrhea, dyspepsia, nausea, vomiting, changes in defecation rhythm), pruritus, skin rashes, maculopapular rash, muscle cramps, ankle swelling, asthenia, edema, and fatigue.

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

Infections and infestations. Rhinitis: perindopril — very rare, amlodipine — uncommon.

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

Blood and lymphatic system disorders. Eosinophilia: perindopril — uncommon*; agranulocytosis: perindopril and indapamide — very rare; aplastic anemia: indapamide — very rare; pancytopenia: perindopril — very rare; leukopenia: perindopril, indapamide, amlodipine — very rare; neutropenia: perindopril — very rare; hemolytic anemia: perindopril, indapamide — very rare; thrombocytopenia: perindopril, indapamide, amlodipine — very rare.

Immune system disorders. Hypersensitivity reactions: amlodipine — very rare, indapamide — uncommon.

Metabolism and nutrition disorders. Hypokalemia: indapamide — common; hypoglycemia: perindopril — uncommon*; hyperkalemia, reversible upon discontinuation of the drug: perindopril — uncommon*; hyponatremia: perindopril — uncommon*, indapamide — uncommon; hypochloremia: indapamide — rare; hypomagnesemia: indapamide — rare; hyperglycemia: amlodipine — very rare; hypercalcemia: indapamide — very rare.

Psychiatric disorders. Insomnia: amlodipine — uncommon; mood changes (including anxiety): amlodipine, perindopril — uncommon; depression: amlodipine — uncommon, perindopril — uncommon*; sleep disturbances: perindopril — uncommon; confusion: perindopril — very rare, amlodipine — rare.

Nervous system disorders. Dizziness: perindopril and amlodipine — common; headache: perindopril and amlodipine — common, indapamide — rare; paresthesia: perindopril — common, indapamide — rare, amlodipine — uncommon; somnolence: perindopril — uncommon*, amlodipine — common; hypesthesia: amlodipine — uncommon; dysgeusia: perindopril — common, amlodipine — uncommon; tremor: amlodipine — uncommon; syncope: perindopril — uncommon*, indapamide — frequency not known, amlodipine — uncommon; hypertension: amlodipine — very rare; peripheral neuropathy: amlodipine — very rare; extrapyramidal disorders (extrapyramidal syndrome): amlodipine — frequency not known; stroke, potentially due to excessive reduction in blood pressure in high-risk patients: perindopril — very rare; in case of hepatic insufficiency, hepatic encephalopathy may occur: indapamide — frequency not known.

Eye disorders. Visual disturbances: perindopril and amlodipine — common, indapamide — frequency not known; acute angle-closure glaucoma: indapamide — frequency not known; choroidal effusion: indapamide — frequency not known; diplopia: amlodipine — common; myopia: indapamide — frequency not known; blurred vision: indapamide — frequency not known.

Ear and labyrinth disorders. Tinnitus: perindopril — common, amlodipine — uncommon; vertigo: perindopril — common, indapamide — rare.

Cardiac disorders. Palpitations: perindopril — uncommon*, amlodipine — common; tachycardia: perindopril — uncommon*; angina pectoris: perindopril — very rare; arrhythmia (including bradycardia, ventricular tachycardia, and atrial fibrillation): perindopril and indapamide — very rare, amlodipine — uncommon; myocardial infarction, potentially due to excessive reduction in blood pressure in high-risk patients: perindopril and amlodipine — very rare; torsade de pointes (paroxysmal ventricular tachycardia), potentially life-threatening: indapamide — frequency not known.

Vascular disorders. Flushing: amlodipine — common, perindopril — rare*; hypotension (and associated symptoms): perindopril — common, indapamide — very rare, amlodipine — uncommon; vasculitis: perindopril — uncommon*, amlodipine — very rare; Raynaud's phenomenon: perindopril — frequency not known.

Respiratory, thoracic and mediastinal disorders. Cough: perindopril — common, amlodipine — uncommon; dyspnea: perindopril and amlodipine — common; bronchospasm: perindopril — uncommon; eosinophilic pneumonia: perindopril — very rare.

Gastrointestinal disorders. Abdominal pain: perindopril and amlodipine — common; constipation: perindopril and amlodipine — common, indapamide — rare; diarrhea: perindopril and amlodipine — common; dyspepsia: perindopril and amlodipine — common; nausea: perindopril and amlodipine — common, indapamide — rare; vomiting: perindopril — common, indapamide and amlodipine — uncommon; dry mouth: perindopril and amlodipine — uncommon, indapamide — rare; changes in defecation rhythm: amlodipine — common; gingival hyperplasia: amlodipine — very rare; pancreatitis: perindopril, indapamide, and amlodipine — very rare; gastritis: amlodipine — very rare.

Hepatobiliary disorders. Hepatitis: perindopril and amlodipine — very rare, indapamide — frequency not known; jaundice: amlodipine — very rare; hepatic function abnormalities: indapamide — very rare.

Skin and subcutaneous tissue disorders. Pruritus: perindopril — common, amlodipine — uncommon; rash: perindopril — common, amlodipine — uncommon; maculopapular rash: indapamide — common; urticaria: perindopril and amlodipine — uncommon, indapamide — very rare; angioedema: perindopril — uncommon, indapamide and amlodipine — very rare; alopecia: amlodipine — uncommon; purpura: indapamide and amlodipine — uncommon; skin discoloration: amlodipine — uncommon; hyperhidrosis: perindopril and amlodipine — uncommon; exanthema: amlodipine — uncommon; photosensitivity reaction: perindopril — uncommon*, indapamide — frequency not known, amlodipine — very rare; exacerbation of psoriasis symptoms: perindopril — rare; pemphigoid: perindopril — uncommon*; erythema multiforme: perindopril and amlodipine — very rare; Stevens-Johnson syndrome: indapamide and amlodipine — very rare; exfoliative dermatitis: amlodipine — very rare; toxic epidermal necrolysis: indapamide — very rare, amlodipine — frequency not known; Quincke's edema: amlodipine — very rare.

Musculoskeletal and connective tissue disorders. Muscle cramps: perindopril and amlodipine — common, indapamide — frequency not known; ankle swelling: amlodipine — common; arthralgia: perindopril — uncommon*, amlodipine — uncommon; muscle weakness: indapamide — frequency not known; myalgia: perindopril — uncommon*, indapamide — frequency not known, amlodipine — uncommon; rhabdomyolysis: indapamide — frequency not known; back pain: amlodipine — uncommon; possible exacerbation of existing systemic lupus erythematosus: indapamide — frequency not known.

Renal and urinary system disorders. Micturition disorders: amlodipine — uncommon; nocturia: amlodipine — uncommon; pollakiuria: amlodipine — uncommon; anuria/oliguria: perindopril — rare*; acute renal failure: perindopril — rare; renal failure: perindopril — uncommon, indapamide — very rare.

Reproductive system and breast disorders. Erectile dysfunction: perindopril and amlodipine — uncommon, indapamide — uncommon; gynecomastia: amlodipine — uncommon.

General disorders. Asthenia: perindopril and amlodipine — common; increased fatigue: indapamide — rare, amlodipine — common; edema: amlodipine — very common; chest pain: perindopril — uncommon*, amlodipine — uncommon; pain: amlodipine — uncommon; malaise: perindopril — uncommon*, amlodipine — uncommon; peripheral edema: perindopril — uncommon*; hyperthermia: perindopril — uncommon*.

Investigations. Weight gain: amlodipine — uncommon; weight loss: amlodipine — uncommon; increased blood urea levels: perindopril — uncommon*; increased serum creatinine levels: perindopril — uncommon*; increased blood bilirubin levels: perindopril — rare; increased liver enzyme levels: perindopril — rare, indapamide — frequency not known, amlodipine — very rare; decreased hemoglobin and hematocrit levels: perindopril — very rare; QT interval prolongation on electrocardiogram: indapamide — frequency not known; increased blood glucose levels: indapamide — frequency not known; increased serum uric acid levels: indapamide — frequency not known.

Injury, poisoning and procedural complications. Falls: perindopril — uncommon*.

*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 continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua

Shelf life.

2 years.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

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

Prescription category.

Prescription only.

Manufacturer.

LLC NPF "MIKROKHIM" (production unit (all stages of manufacturing process)).

Manufacturer's address and location of operations.

Ukraine, 93400, Luhansk region, Severodonetsk, Promyslova St., 24-v.

Marketing Authorization Holder.

LLC NPF "MIKROKHIM".

Address of Marketing Authorization Holder.

Ukraine, 01013, Kyiv, Budyndustrії St., 5.

To report an adverse event related to the use of the medicinal product, please contact the pharmacovigilance system of LLC NPF "MIKROKHIM"

by phone: +38 (050) 309-83-54 (24/7)

or via the link: https://microkhim.com.ua/farmakonaglyad/