Perindopress® trio

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

Composition:

Active substances: perindopril, indapamide, amlodipine;

Perindopres® Trio, tablets 4 mg/1.25 mg/5 mg

Each tablet contains: perindopril tert-butylamine 4 mg (equivalent to 3.338 mg of perindopril), indapamide 1.25 mg, and amlodipine besilate 6.935 mg (equivalent to 5 mg of amlodipine);

Perindopres® Trio, tablets 4 mg/1.25 mg/10 mg

Each tablet contains: perindopril tert-butylamine 4 mg (equivalent to 3.338 mg of perindopril), indapamide 1.25 mg, and amlodipine besilate 13.87 mg (equivalent to 10 mg of amlodipine);

Perindopres® Trio, tablets 8 mg/2.5 mg/5 mg

Each tablet contains: perindopril tert-butylamine 8 mg (equivalent to 6.676 mg of perindopril), indapamide 2.5 mg, and amlodipine besilate 6.935 mg (equivalent to 5 mg of amlodipine);

Perindopres® Trio, tablets 8 mg/2.5 mg/10 mg

Each tablet contains: perindopril tert-butylamine 8 mg (equivalent to 6.676 mg of perindopril), indapamide 2.5 mg, and amlodipine besilate 13.87 mg (equivalent to 10 mg of amlodipine);

Excipients: pregelatinized starch, microcrystalline cellulose, sodium croscarmellose, colloidal anhydrous hydrophobic silicon dioxide, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

Perindopres® Trio, tablets 4 mg/1.25 mg/5 mg – white or almost white, flat cylindrical tablets with a bevel.

Perindopres® Trio, tablets 4 mg/1.25 mg/10 mg – white or almost white, flat cylindrical tablets with a bevel and a score line.

Perindopres® Trio, tablets 8 mg/2.5 mg/5 mg – white or almost white, flat cylindrical tablets with a bevel and a score line.

Perindopres® Trio, tablets 8 mg/2.5 mg/10 mg – white or almost white, flat cylindrical tablets with a bevel and a score line.

Pharmacotherapeutic group. Angiotensin-converting enzyme (ACE) inhibitors, other combinations. Perindopril, amlodipine and indapamide. ATC code C09BX01.

Pharmacological Properties.

Pharmacodynamics.

Perindopres® Trio is a combination of three antihypertensive components whose mechanisms of action complement each other in controlling blood pressure in patients with arterial hypertension. Perindopril tert-butylamine is an ACE inhibitor, indapamide is a sulfonamide diuretic, and amlodipine is a calcium channel blocker belonging to the dihydropyridine class.

The pharmacological effect of Perindopres® Trio is determined by the properties of each individual component. In addition, the combination of perindopril and indapamide results in an additive synergistic antihypertensive effect of the two components.

Mechanism of action.

Perindopril is an ACE inhibitor that converts angiotensin I to angiotensin II (a vasoconstrictor substance), additionally stimulates aldosterone secretion by the adrenal cortex, and promotes bradykinin (a vasodilator substance) breakdown into inactive heptapeptides. By inhibiting ACE, perindopril reduces aldosterone secretion; increases plasma renin activity without aldosterone's negative effects; and reduces total peripheral vascular resistance due to its predominant effect on muscle and renal vessels. Water and salt retention or reflex tachycardia are not observed, even during long-term treatment.

Perindopril reduces blood 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 its vasodilatory effect on veins (possibly via changes in prostaglandin metabolism), thereby reducing cardiac preload, and due to decreased total peripheral vascular resistance, thereby reducing cardiac afterload.

Studies conducted in patients with heart failure have demonstrated that perindopril use leads to reduced filling pressures 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.

Furthermore, physical exercise test results are significantly improved.

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 effect.

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

Pharmacodynamic effects.

Perindopril/indapamide. The combination of perindopril and 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 concomitant 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 the 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 large artery elasticity, corrects histomorphometric changes in arterial resistance, and reduces left ventricular hypertrophy. Additional synergism 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 observed 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, in studies of varying duration (short, medium, and long-term) involving patients with arterial hypertension, indapamide has been shown not to affect lipid metabolism (triglycerides, low- and high-density lipoproteins) and not to 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 action 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 ischemic load through two actions:

• Amlodipine dilates peripheral arterioles, thereby reducing total peripheral resistance (afterload); since heart rate remains unchanged, reduced cardiac load decreases myocardial energy consumption and oxygen demand;
• Amlodipine partially promotes dilation of major coronary arteries and arterioles in both unaffected and ischemic myocardial areas; 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.

Clinical efficacy and safety.

Perindopril/indapamide.

ADVANCE – an international multicenter randomized trial with a 2×2 factorial design aimed at evaluating the benefits of blood pressure reduction using the fixed combination of perindopril/indapamide versus placebo, against the background of standard therapy [double-blind comparison (prospective randomized open-label trial with blinded endpoint assessment)] regarding its impact on major macro- and microvascular events in patients with type 2 diabetes. The primary endpoint consisted of major macrovascular (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke) and microvascular events (new onset or worsening of nephropathy, eye disease). A total of 11,140 patients with type 2 diabetes were included in the study. Of these, 83% had arterial hypertension, 32% and 10% had a history of micro- and macrovascular disease, respectively, and 27% had microalbuminuria. Concomitant therapy included medications for blood pressure reduction (75%), lipid-lowering agents (35%, primarily statins – 28%), and acetylsalicylic acid or other antiplatelet agents (47%).

Treatment with the perindopril/indapamide combination over 4.3 years resulted in a significant 9% relative risk reduction in the primary endpoint (95% CI [0.828; 0.996], p = 0.041). The benefits of perindopril/indapamide treatment compared to placebo were due to a significant 14% relative risk reduction in total mortality (95% CI [0.75; 0.98], p = 0.025); a significant 18% relative risk reduction in cardiovascular mortality (95% CI [0.68; 0.98], p = 0.027); and a significant 21% relative risk reduction in all renal events (95% CI [0.74; 0.86], p < 0.001).

In the subgroup of hypertensive patients treated with perindopril/indapamide, a significant 9% relative risk reduction in major macro- and microvascular events was observed (95% CI [0.82; 1.00], p = 0.052) compared to the placebo group. In the subgroup receiving perindopril/indapamide compared to placebo, there was also a significant 16% relative risk reduction in total mortality (95% CI [0.73; 0.97], p = 0.019); a significant 20% relative risk reduction in cardiovascular mortality (95% CI [0.66; 0.97], p = 0.023); and a significant 20% relative risk reduction in all renal events (95% CI [0.73; 0.87], p < 0.001).

Pharmacokinetics.

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

Perindopril

Absorption and bioavailability. 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.

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

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

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

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

Special patient populations

Elderly patients. Perindoprilat elimination is reduced in elderly patients and in patients with heart or renal failure.

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

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

Liver cirrhosis. The pharmacokinetics of perindopril are altered in patients with liver cirrhosis: hepatic clearance of the parent compound is halved. However, the amount of formed perindoprilat is not reduced (see sections "Dosage and administration" and "Special precautions").

Indapamide

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

Distribution. Plasma protein binding is 79%.

Biotransformation and elimination. 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

Absorption and bioavailability. When administered orally at therapeutic doses, amlodipine is well absorbed and reaches maximum blood concentration within 6–12 hours after administration. Absolute bioavailability ranges from 64% to 80%. Food intake does not affect amlodipine bioavailability.

Distribution. Volume of distribution is approximately 21 L/kg. In vitro studies have shown that about 97.5% of circulating amlodipine in blood is bound to plasma proteins.

Elimination. The elimination half-life of amlodipine in plasma is approximately 35–50 hours, allowing once-daily dosing. Amlodipine is predominantly metabolized in the liver into inactive metabolites, with 60% of metabolites excreted in urine and 10% excreted unchanged.

Special patient populations

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

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

Clinical characteristics.

Indications.

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

Contraindications.

• Hemodialysis;
• Untreated decompensated heart failure;
• Severe renal impairment (creatinine clearance < 30 mL/min) for the 4 mg/1.25 mg/5 mg and 4 mg/1.25 mg/10 mg strengths;
• Moderate renal impairment (creatinine clearance < 60 mL/min) for the 8 mg/2.5 mg/5 mg or 8 mg/2.5 mg/10 mg strengths;
• Hypersensitivity to the active substances, other sulfonamide-derived drugs, dihydropyridine derivatives, any other angiotensin-converting enzyme (ACE) inhibitor, or to any of the excipients listed in the section "Composition";
• Pregnancy or planned pregnancy (see section "Use in pregnancy or breastfeeding");
• Breastfeeding (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);
• Hemodynamically unstable heart failure 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" and "Interaction with other medicinal products and other forms of interaction");
• Concomitant use with sacubitril/valsartan (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction");
• Extracorporeal treatment methods leading to blood contact with negatively charged surfaces (see section "Interaction with other medicinal products and other forms of interaction");
• Significant bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney (see section "Special precautions").

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 using a single RAAS-acting agent (see sections "Contraindications" and "Special precautions").

Medicinal products causing hyperkalemia.

Some drugs or therapeutic classes may cause hyperkalemia: aliskiren, potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, nonsteroidal anti-inflammatory drugs (NSAIDs), heparins, immunosuppressants such as cyclosporine or tacrolimus, and trimethoprim. Concomitant use of these medicinal products increases the risk of hyperkalemia.

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

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

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

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

Concomitant use not recommended.

Perindopril/indapamide.

Reversible increases in serum lithium concentration and 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").

Perindopril.

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

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

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"). However, if concomitant use is necessary, they should be used with caution and serum potassium levels should be monitored frequently. For spironolactone use in heart failure, see below "Concomitant use requiring special attention".

Co-trimoxazole (trimethoprim/sulfamethoxazole): In patients receiving co-trimoxazole, there is an increased risk of hyperkalemia (see section "Special precautions").

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, concomitant use of calcium channel blockers such as amlodipine should be avoided in patients with diagnosed 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: Enhances antihypertensive effect. Blood pressure should be monitored and antihypertensive dosage adjusted if necessary.

Perindopril/indapamide.

NSAIDs, including high-dose acetylsalicylic acid: The antihypertensive effect of ACE inhibitors may be attenuated when used concomitantly with NSAIDs such as acetylsalicylic acid at anti-inflammatory doses, COX-2 inhibitors, and nonselective NSAIDs. This combination may also 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 renal impairment. This combination should be used with caution, especially in elderly patients. Patients should be adequately hydrated, and renal function should be monitored after initiation and during ongoing concomitant therapy.

Perindopril.

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

Diuretics: Excessive reduction in blood pressure may occur after initiation of ACE inhibitor therapy, particularly in patients with fluid and electrolyte imbalance. The likelihood of hypotensive effects can be reduced by discontinuing diuretics, increasing circulating 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, the diuretic should be discontinued before starting ACE inhibitor therapy (diuretic therapy may be resumed later) or the ACE inhibitor should be initiated at a low dose with gradual titration. In congestive heart failure on diuretic therapy, ACE inhibitor therapy should be initiated at the lowest dose, possibly after reducing the diuretic dose. In all cases, renal function (creatinine levels) should be monitored during the first weeks of ACE inhibitor therapy.

Potassium-sparing diuretics (eplerenone, spironolactone): When eplerenone or spironolactone is used concomitantly with low-dose ACE inhibitors in patients with NYHA class II–IV heart failure and ejection fraction < 40%, previously treated with ACE inhibitors and loop diuretics, there is a risk of potentially fatal hyperkalemia, especially if recommendations for use are not followed. Hyperkalemia and renal impairment should be excluded before initiating such combination therapy. Close monitoring of serum potassium and creatinine is recommended weekly during the first month and monthly thereafter.

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

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

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:

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

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

Intravenous amphotericin B, glucocorticoids and mineralocorticoids (systemic), tetracosactide, stimulant laxatives: Increased 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 may increase the toxic effects of cardiac glycosides. Serum potassium and magnesium levels and ECG should be monitored, and therapy reviewed if necessary.

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

Amlodipine.

CYP3A4 inhibitors: Plasma concentrations of amlodipine may be altered when used concomitantly with known CYP3A4 inducers. Blood pressure should be monitored and dosage adjusted during and after concomitant use with CYP3A4 inducers, particularly strong CYP3A4 inducers (e.g., St. John's wort (Hypericum perforatum), rifampicin).

Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil, or diltiazem) may cause a significant increase 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: Enhanced antihypertensive effect and increased risk of orthostatic hypotension (additive effect).

Other antihypertensive agents: May cause additional reduction in blood pressure.

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

Perindopril.

Antihypertensives 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.

Gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin): In patients receiving a combination of a gliptin and an ACE inhibitor, the risk of angioedema is increased because gliptins reduce dipeptidyl peptidase-IV (DPP-IV) activity.

Sympathomimetics: May reduce the antihypertensive effect of ACE inhibitors.

Gold compounds: Rarely, when ACE inhibitors including perindopril are used concomitantly with injectable gold compounds (sodium aurothiomalate), reactions similar to those seen with nitrates (flushing, nausea, vomiting, hypotension) have been reported.

Indapamide.

Metformin: Risk of lactic acidosis due to possible development of functional renal impairment associated with diuretic use, especially loop diuretics. Metformin should not be used if plasma creatinine exceeds 15 mg/L (135 µmol/L) in men 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. Therefore, hydration should be restored before administration.

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

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

Amlodipine.

Atorvastatin, digoxin, or warfarin: Clinical interaction studies have shown that amlodipine does not affect their pharmacokinetics.

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

mTOR inhibitors (mechanistic target of rapamycin inhibitors): mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are CYP3A substrates. Amlodipine is a weak CYP3A inhibitor. Concomitant use 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 kidney transplant recipients, in whom increases in cyclosporine trough concentrations (on average 0 to 40%) were observed. In kidney transplant recipients receiving amlodipine, cyclosporine blood levels should be monitored and dosage reduced if necessary.

Simvastatin: The use of amlodipine at doses ≥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 simvastatin dosage to 20 mg daily.

Special precautions for use.

All the warnings listed below for each component of the medicinal product also apply to the fixed combination Perindopres® Trio.

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

Double blockade of the RAAS. Data indicate that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of hypotension, hyperkalemia, 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 types of interactions"). If dual RAAS blockade therapy is considered absolutely necessary, it may be administered 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 or potassium-containing dietary supplements is generally not recommended (see section "Interaction with other medicinal products and other types of interactions").

Neutropenia/Agranulocytosis/Thrombocytopenia/Anemia. Cases of neutropenia, agranulocytosis, thrombocytopenia, and anemia have been reported in patients treated with ACE inhibitors. Neutropenia is rare in patients with normal renal function and no risk factors. Perindopril should be used with extreme caution in patients with collagen diseases, during immunosuppressive therapy, treatment with allopurinol, procainamide, or in combination with these factors, especially if renal function is impaired. In some of these patients, serious infectious diseases have been observed, in several cases resistant to intensive antibiotic therapy. If perindopril is prescribed to such patients, periodic monitoring of white blood cell count is recommended. Additionally, patients should be informed about the need to report any signs of infection (e.g., sore throat, elevated body temperature) (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 favorable factor. Impaired renal function may manifest only as slight changes in serum creatinine levels, even in patients with unilateral renal artery stenosis.

The treatment of renovascular hypertension is revascularization. However, ACE inhibitors may be beneficial for patients with renovascular hypertension awaiting surgery or if such surgery is impossible.

If the medicinal product Perindopres® Trio with dosages of 4 mg/1.25 mg/5 mg and 4 mg/1.25 mg/10 mg is prescribed to patients with existing renal artery stenosis or suspected stenosis, treatment should be initiated in a hospital setting with a low dose, monitoring renal function and blood potassium levels, as functional renal failure has been observed in some patients, which was reversible upon discontinuation of treatment.

The medicinal product Perindopres® Trio with dosages of 8 mg/2.5 mg/5 mg or 8 mg/2.5 mg/10 mg should not be prescribed to patients with existing renal artery stenosis or suspected stenosis. In such cases, treatment should be initiated in a hospital setting with a lower dose than the recommended dose of the drug.

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. This may occur at any time during treatment.

In such cases, the medicinal product must be discontinued immediately, and appropriate patient monitoring should be established until symptoms completely resolve. If swelling is limited to the face and lips, the patient's condition usually improves without therapy, and antihistamine drugs may be helpful in alleviating symptoms.

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

It has been reported that ACE inhibitors more frequently cause angioedema 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 during treatment with ACE inhibitors. These patients experienced abdominal pain (with or without nausea and vomiting); in some cases, prior angioedema of the face 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 treated with ACE inhibitors.

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

Initiation of sacubitril/valsartan should not occur earlier than 36 hours after the last dose of perindopril. If treatment with sacubitril/valsartan is discontinued, therapy with perindopril 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 types of interactions"). Concomitant use of other neutral endopeptidase (NEP) inhibitors (e.g., racecadotril) and ACE inhibitors may also increase the risk of angioedema (see section "Interaction with other medicinal products and other types of interactions"). Therefore, a careful benefit-risk assessment should be conducted before initiating NEP inhibitors (e.g., racecadotril) in patients receiving perindopril.

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

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 (bees, wasps). ACE inhibitors should be used with caution in patients with allergies after desensitization and should be avoided during immunotherapy with animal-derived venomous substances.

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

Anaphylactoid reactions during 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 with high-flux polyacrylonitrile membranes (e.g., AN 69®). Such patients should use another type of dialysis membrane or be prescribed another class of antihypertensive drugs.

Primary hyperaldosteronism. Patients with primary hyperaldosteronism generally do not respond to antihypertensive drugs acting by suppressing the RAAS. Therefore, this medicinal product is not recommended for such patients.

Hepatic encephalopathy. In patients with impaired liver function, the use of thiazide and thiazide-like diuretics may trigger hepatic encephalopathy. Hepatic encephalopathy is a contraindication for the use of this medicinal product.

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 needs to be resumed, sensitive skin areas should be protected from sunlight or artificial UV sources.

Renal function. The use of the drug is contraindicated in patients with severe renal impairment (creatinine clearance < 30 ml/min). Therapy with the medicinal product Perindopres® Trio containing the perindopril/indapamide combination in doses of 8 mg/2.5 mg (i.e., Perindopres® Trio 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 without signs of kidney damage show signs of functional renal failure, treatment with the drug should be discontinued; therapy may be resumed at a lower dose or with one of the monocomponents. Such 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 were predominantly observed 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 RAAS was predominantly observed in connection with 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 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 failure. Sometimes this may have an acute onset and very rarely occur at any time. In such cases, treatment should be initiated with a lower dose with gradual dose escalation.

In patients with ischemic heart disease or cerebrovascular diseases, a significant drop in blood pressure may lead to myocardial infarction or stroke.

Thiazide and thiazide-like diuretics show the greatest efficacy when there is no renal impairment or the impairment is insignificant (creatinine level 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. Such transient functional renal failure has no adverse consequences in patients with normal renal function but may exacerbate existing renal impairment.

Amlodipine can be used in patients with renal insufficiency 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 Perindopres® Trio in patients with renal dysfunction have not been conducted. For patients with impaired renal function, the dosage of the fixed combination Perindopres® Trio should correspond to individually adjusted doses of the monocomponents.

Hypotension, water 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 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 medicinal product. After restoration of circulating blood volume and normalization of blood pressure, treatment may be resumed at a lower dose or with one of the drug components.

Initially, decreased 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 insignificant.

Potassium levels. Treatment with the combination of indapamide, perindopril, and amlodipine does not eliminate the possibility of hypokalemia, particularly in patients with diabetes or renal insufficiency. As with any antihypertensive drug combined with a diuretic, regular monitoring of plasma potassium levels should be performed.

In some patients during treatment with ACE inhibitors, including perindopril, increased plasma potassium concentration has been observed. Risk factors for hyperkalemia include renal failure, worsening renal function, age over 70 years, diabetes, 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 causing increased potassium concentration in serum (e.g., heparin, co-trimoxazole, also known as trimethoprim/sulfamethoxazole). The use of potassium-containing dietary supplements, potassium-sparing diuretics, or potassium-containing salt substitutes may also lead to significant increases in serum potassium levels, especially in patients with impaired renal function. Hyperkalemia may cause serious, sometimes fatal arrhythmias. If concomitant use of perindopril with any of these 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 types of interactions").

Reduced potassium levels in hypokalemia are the main risk associated with the use of thiazide and thiazide-like diuretics. The risk of hypokalemia (< 3.4 mmol/l) should be prevented in patients at high risk (elderly patients and/or poorly nourished patients, patients 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, the 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 rhythm disturbances, 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 reduced, correction is necessary. Hypokalemia detected in association with low serum magnesium concentration may be refractory to treatment unless serum magnesium levels are corrected.

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

Calcium levels. Thiazide and thiazide-like diuretics may reduce urinary calcium excretion and lead to slight and transient increases in plasma calcium levels. Significantly elevated calcium levels may be a consequence of previously undiagnosed hyperparathyroidism. Treatment should be discontinued until parathyroid function is examined (see section "Side effects").

Cough. Dry cough has been reported during treatment with ACE inhibitors. This cough is persistent and resolves after discontinuation of the drug. If this symptom occurs, iatrogenic etiology of cough should be considered. If ACE inhibitor therapy is still preferred, continuation of therapy 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 (IV degree), 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. Treatment of patients with insulin-dependent diabetes (spontaneous tendency to increased blood potassium levels) should be initiated under medical supervision with a reduced initial dose.

In patients with diabetes 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, it is important to monitor blood glucose levels, especially when potassium levels are low.

Racial characteristics. Perindopril, like other ACE inhibitors, is likely less effective in lowering blood pressure 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 anesthetics that lower blood pressure are used. Therefore, when treating 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 beginning with cholestatic jaundice and progressing to rapid hepatic necrosis, sometimes with a fatal outcome. The mechanism of this syndrome is unknown. Patients who develop jaundice or significant increases in liver enzymes during ACE inhibitor use 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 therapy should be initiated with the lowest doses, with caution at the beginning of therapy and during dose escalation. Patients with severe liver function impairment may require gradual dose titration and careful monitoring.

Studies on the use of the fixed combination Perindopres® Trio in patients with liver dysfunction have not been conducted. Since the effects of individual components of the fixed combination Perindopres® Trio are known, the drug is contraindicated in patients with severe liver function impairment and should be used with caution in mild to moderate liver function 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 water or electrolyte deficiency, the initial dose should be adjusted based on the blood pressure response to treatment. Dose escalation in elderly patients should be done cautiously (see sections "Method of administration and dosage" and subsection "Pharmacokinetics").

Choroidal effusion, acute myopia, and secondary angle-closure glaucoma. Medicinal products containing sulfonamide or sulfonamide derivatives may cause an idiosyncratic reaction leading to choroidal effusion with visual field defects, transient myopia, and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or eye pain and usually occur within hours or weeks of starting the medicinal product. Untreated acute angle-closure glaucoma may lead to permanent vision loss. The primary treatment is to discontinue the drug as quickly as possible. If intraocular pressure remains uncontrolled, medical or surgical treatment may be necessary. Risk factors for developing acute angle-closure glaucoma may include a history of allergy to sulfonamides or penicillin.

Important information about excipients.

This medicinal product contains less than 23 mg/dose of sodium, i.e., practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy. Perindopres® Trio 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 in the first trimester of pregnancy are inconclusive, so a slight increase in risk cannot be excluded. The drug should not be used 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 drugs with confirmed safety data during pregnancy.

If pregnancy is confirmed during ACE inhibitor treatment, its use must be immediately discontinued and replaced with another alternative medicinal product permitted 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 skull bone formation) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia).

If a woman has taken ACE inhibitors from the second trimester of pregnancy, the child is recommended to undergo ultrasound examination of kidney function and skull bones. 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 in 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.

Period of breastfeeding. Perindopres® Trio is contraindicated during breastfeeding. A decision should be made regarding discontinuation of breastfeeding during treatment or discontinuation of the drug during breastfeeding, considering the importance of therapy for the mother.

Perindopril. The use of perindopril during breastfeeding is not recommended due to lack of data. Particularly in the breastfeeding period, an alternative treatment with a confirmed safety profile during breastfeeding should be prescribed to newborns or premature infants.

Indapamide. Available information on the penetration 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, whose use during breastfeeding has been associated with reduced and suppressed lactation.

Amlodipine. Amlodipine passes into breast milk. The fraction of the initial dose taken by the mother that the infant receives was 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 amlodipine on male fertility.

Ability to influence reaction speed when driving vehicles or operating other machinery.

Studies on the effect of the Perindopres® Trio drug on the ability to drive vehicles or operate other automated systems have not been conducted.

Perindopril and indapamide do not affect the ability to drive vehicles and operate other 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 vehicles and operate other machinery. Reaction impairment may occur if the patient experiences dizziness, headache, weakness, fatigue, or nausea. As a result, the ability to drive vehicles and operate other automated systems may be impaired. Caution is recommended, especially at the beginning of treatment.

Method of Administration and Dosage

For oral use.

Take 1 tablet of Perindopres® Trio once daily, preferably in the morning before food.

The use of this fixed combination is not intended for initial therapy.

If necessary, the dose of the fixed combination Perindopres® Trio may be adjusted or individual dose titration of each component may be recommended.

Special patient groups

Patients with renal impairment (see sections "Contraindications" and "Special warnings and precautions for use"). Perindopres® Trio is contraindicated in patients with severe renal impairment (creatinine clearance below 30 mL/min). The use of Perindopres® Trio 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). Routine medical monitoring should include frequent checks of serum creatinine and potassium levels.

Elderly patients (see section "Special warnings and precautions for use"). It should be noted that the elimination of perindoprilat is reduced in elderly patients (see subsection "Pharmacokinetics"). Perindopres® Trio may be prescribed to elderly patients taking into account renal function (see section "Contraindications").

Patients with hepatic impairment (see sections "Contraindications", "Special warnings and precautions for use" and subsection "Pharmacokinetics"). Perindopres® Trio is contraindicated in patients with severe hepatic impairment. Perindopres® Trio should be used with caution in patients with mild to moderate hepatic impairment due to the lack of dosing recommendations for amlodipine.

Children

There are no data on the safety and efficacy of Perindopres® Trio in children; therefore, it should not be used in this age group.

Overdose

There are no data on overdose with Perindopres® Trio in humans.

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 fluid and 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 fluid and 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 subsection "Pharmacokinetics").

Data on intentional amlodipine overdose in humans are limited.

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

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 legs elevated, and monitoring circulating blood volume and urine output.

Administration of a vasoconstrictor may be beneficial to restore vascular tone and blood 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 treatment with perindopril, indapamide, and amlodipine used separately include 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 edema, asthenia, edema, and fatigue, as well as hypokalemia**.

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

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 (> 1/1,000, < 1/100); rare (> 1/10,000, < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data).

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

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.

Endocrine system disorders. SIADH: perindopril – rare.

Metabolism and nutrition disorders. Hypoglycemia: perindopril – uncommon*; hyperkalemia, resolving after discontinuation of the drug: perindopril – uncommon*; hyponatremia: perindopril and indapamide – uncommon*; hyperglycemia: amlodipine – very rare; hypercalcemia: indapamide – very rare; decreased blood potassium levels leading to hypokalemia**, including severe cases in some high-risk patients: indapamide – common; hypochloremia (indapamide – rare), hypomagnesemia (indapamide – rare).

Psychiatric disorders. Insomnia: amlodipine – uncommon; mood changes (including anxiety): amlodipine, perindopril – uncommon; depression: perindopril and amlodipine – 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; hepatic encephalopathy may occur in patients with liver insufficiency: indapamide – frequency not known.

Eye disorders. Visual disturbances: perindopril and amlodipine – common, indapamide – frequency not known; diplopia: amlodipine – common; myopia: indapamide – frequency not known; blurred vision: indapamide – frequency not known; choroidal effusion: 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; ankle edema: amlodipine – common; arthralgia: perindopril – uncommon*, amlodipine – uncommon; myalgia: perindopril – uncommon*, amlodipine – uncommon; 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; acute renal failure: perindopril – rare, indapamide – very rare; renal failure: perindopril – uncommon, indapamide – very rare; anuria/oliguria (rare – perindopril).

Reproductive system and breast disorders. Erectile dysfunction: perindopril, amlodipine, and 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 increase: amlodipine – uncommon; weight decrease: amlodipine – uncommon; increased blood urea levels: perindopril – uncommon*; increased blood 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 blood uric acid levels: indapamide – frequency not known.

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

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

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

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

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

Reporting suspected adverse reactions.

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

Shelf life. 2 years.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

10 tablets per blister; 3 or 9 blisters per carton.

Prescription status. Prescription only.

Manufacturer. JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's address and location of business activity.

13, Boryspilska Street, Kyiv, 02093, Ukraine.