Perindopres® trio: detailed information

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 edge.

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

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

Perindopres® Trio, tablets 8 mg/2.5 mg/10 mg – white or almost white, flat cylindrical tablets with a bevel edge 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 due to the properties of each individual component. In addition, the combination of perindopril and indapamide produces an additive synergistic antihypertensive effect of the two components.

Mechanism of action.

Perindopril is an ACE inhibitor that converts angiotensin I into angiotensin II (a vasoconstrictive substance), additionally stimulates aldosterone secretion by the adrenal cortex, and promotes bradykinin (a vasodilatory substance) breakdown into inactive heptapeptides. Inhibition of ACE leads to reduced aldosterone secretion; increased plasma renin activity without adverse effects of aldosterone; and decreased total peripheral vascular resistance due to predominant effects 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 vasodilatory effects on veins (possibly via changes in prostaglandin metabolism), thereby reducing cardiac preload, and due to decreased total peripheral resistance, which reduces 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; decreased total peripheral resistance; increased cardiac output and improved cardiac index; and increased regional blood flow in muscles.

In addition, 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, excretion of 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) that 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 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.

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 is achieved when a thiazide diuretic is added if necessary.

Combining an ACE inhibitor with 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, 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 relaxant action 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 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 areas of the myocardium; 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 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, on top of standard ongoing 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%, predominantly statins – 28%), and acetylsalicylic acid or other antiplatelet agents (47%).

Treatment with the perindopril/indapamide combination over 4.3 years led to a significant 9% reduction in the relative risk of the primary endpoint (95% CI [0.828; 0.996], p = 0.041). The benefits of perindopril/indapamide treatment versus placebo were due to a significant 14% reduction in relative risk of total mortality (95% CI [0.75; 0.98], p = 0.025); a significant 18% reduction in relative risk of cardiovascular mortality (95% CI [0.68; 0.98], p = 0.027); and a significant 21% reduction in relative risk of 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% reduction in relative risk of 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 versus placebo, there was also a significant 16% reduction in relative risk of total mortality (95% CI [0.73; 0.97], p = 0.019); a significant 20% reduction in relative risk of cardiovascular mortality (95% CI [0.66; 0.97], p = 0.023); and a significant 20% reduction in relative risk of all renal events (95% CI [0.73; 0.87], p < 0.001).

Pharmacokinetics.

Administration of perindopril/indapamide and amlodipine in 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 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.

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 plasma concentration of perindoprilat is reached within 3–4 hours.

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

Special patient populations

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

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

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

Hepatic cirrhosis. The pharmacokinetics of perindopril are altered in patients with hepatic cirrhosis: hepatic clearance of the parent compound is halved. However, the amount of perindoprilat formed 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. Protein binding in plasma is 79%.

Biotransformation and elimination. Elimination half-life ranges from 14 to 24 hours (average 18 hours). Repeated dosing does not lead to accumulation.

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

Amlodipine

Absorption and bioavailability. When administered orally at therapeutic doses, amlodipine is well absorbed and reaches peak blood concentration 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; 60% of metabolites are excreted in urine, and 10% are excreted unchanged.

Special patient populations

Elderly patients. 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 prolonged elimination 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 hepatic insufficiency, 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 requiring 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 dosage 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 dosage strengths;
Hypersensitivity to the active substances, other sulfonamide-derived drugs, dihydropyridine derivatives, any other 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 the active substance 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 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 treatment with 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 renal impairment, the risk of hyperkalemia, worsening renal function, and cardiovascular morbidity and mortality is increased.

Extracorporeal treatment methods: Treatment methods such as dialysis or hemofiltration using certain highly permeable 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 simultaneous inhibition of neprilysin and ACE may increase the risk of angioedema. Initiation of sacubitril/valsartan should not occur earlier than 36 hours after the last dose of perindopril. 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.

Increased serum lithium concentrations 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 combination is necessary, serum lithium concentrations should be closely monitored (see section "Special precautions").

Perindopril.

Aliskiren: In any 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").

Angiotensin receptor blockers: Published data show that in patients with established atherosclerosis, heart failure, or diabetes with target organ damage, concomitant use is associated with increased incidence of arterial hypotension, syncope, hyperkalemia, and renal impairment (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 with careful monitoring of renal function, potassium levels, and blood pressure (see section "Special precautions").

Estrogen: Increased risk of adverse reactions such as angioedema (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 potassium levels in serum 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 may be 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 established or suspected malignant hyperthermia.

Grapefruit or grapefruit juice: In some patients, bioavailability of amlodipine may be increased, 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.

NSAIDs, including high-dose acetylsalicylic acid: The antihypertensive effect may be attenuated when ACE inhibitors are 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 impaired renal function. This combination should be used with caution, especially in elderly patients. Patients should be adequately hydrated, and monitoring of renal function should be considered at the start and during continued therapy.

Perindopril.

Antidiabetic agents (insulin, oral hypoglycemic agents): Epidemiological studies suggest that concomitant use of ACE inhibitors with antidiabetic 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.

Diuretics: Excessive reduction in blood pressure may occur after initiation of ACE inhibitor therapy, especially in patients with fluid and electrolyte imbalance. The likelihood of hypotensive effects can be reduced by discontinuing diuretics, increasing circulating volume, and 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 (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 on diuretic therapy, ACE inhibitor therapy should be initiated at 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 (12.5 mg to 50 mg daily) is used concomitantly with low-dose ACE inhibitors in patients with NYHA class II–IV heart failure and ejection fraction < 40%, previously treated with ACE inhibitors and loop diuretics, there is a risk of hyperkalemia, potentially fatal, especially if recommendations for use of this combination are not followed. Before initiating such combination, absence of hyperkalemia and renal impairment should be confirmed. Careful monitoring of serum potassium and creatinine is recommended weekly during the first month of treatment 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 for treatment of acute diarrhea).

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

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:

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 vinca alkaloids, methadone, astemizole, terfenadine.

Serum potassium depletion should be avoided; potassium levels should be corrected and QT interval monitored if necessary.

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. Therefore, blood pressure should be monitored and dose adjustments made during and after concomitant use with CYP3A4 inducers, especially 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. 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. Such patients should be closely monitored.

Concomitant use requiring attention.

Perindopril/indapamide/amlodipine.

Tricyclic antidepressants (imipramine-like), neuroleptics: May enhance antihypertensive effect and increase the risk of orthostatic hypotension (additive effect).

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

Corticosteroids, tetracosactide: May reduce 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 reduction in blood pressure.

Allopurinol, cytostatic agents, 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 prescribed if plasma creatinine exceeds 15 mg/L (135 µmol/L) in men and 12 mg/L (110 µmol/L) in women.

In cases of dehydration due to diuretic use, the risk of acute renal failure increases, 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. To avoid toxicity, plasma tacrolimus levels should be monitored and the dose adjusted if necessary.

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

Cyclosporine: Interaction studies between cyclosporine and amlodipine in healthy volunteers or other populations, except kidney transplant recipients, have not been conducted. In kidney transplant recipients receiving amlodipine, cyclosporine blood levels should be monitored and the dose 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 monotherapy. Patients taking amlodipine should limit the simvastatin dose 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 and the combination of perindopril/indapamide is generally not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Dual blockade of the RAAS. Data indicate that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of hypotension, hyperkalaemia, and 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 blockade of the RAAS is considered absolutely necessary, it may be initiated 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 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, during 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. Additionally, patients should be informed of the need 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"). 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.

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

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

Perindopres® Trio with a dosage of 8 mg/2.5 mg/5 mg or 8 mg/2.5 mg/10 mg should not be prescribed to patients with known renal artery stenosis or suspected stenosis. In such cases, treatment should be initiated in a hospital setting with a 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 should be discontinued immediately, and appropriate patient monitoring should be maintained until symptoms completely resolve. If swelling is limited to the face and lips, the patient's condition usually improves without therapy, and antihistamines may be helpful in alleviating symptoms.

Angioedema involving swelling of the larynx may be fatal. If swelling extends to the tongue, glottis, or larynx with a risk of 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.

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 treated with ACE inhibitors. These patients presented with 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 on ACE inhibitor therapy.

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

Concomitant use of mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus). In patients receiving concomitant mTOR inhibitors, there may be an increased risk of angioedema (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").

Anaphylactoid reactions during desensitization therapy. Isolated cases of life-threatening, prolonged 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 may 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 with dextran sulfate. These reactions may be avoided by temporarily discontinuing ACE inhibitor therapy before each apheresis session.

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

Primary hyperaldosteronism. Patients with primary hyperaldosteronism generally do not respond to antihypertensive agents acting via inhibition of the RAAS. Therefore, this medicinal product is not recommended for such patients.

Hepatic encephalopathy. The use of thiazide and thiazide-like diuretics may precipitate hepatic encephalopathy in patients with impaired liver function. 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 should be discontinued. If diuretic therapy must be resumed, sensitive 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 Perindopres® Trio containing the perindopril/indapamide combination at 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 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 have been observed primarily in patients with severe heart failure or renal impairment, 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 has been observed primarily 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 drop in blood pressure and/or an increase in plasma creatinine levels, indicating functional renal failure. This may occasionally have an acute onset and very rarely occur at any time. In such cases, treatment should be initiated with a lower dose, gradually increasing it.

In patients with ischemic heart disease or cerebrovascular disease, significant lowering of 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 the impairment is mild (plasma 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 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. Such transient functional renal failure has no adverse consequences in patients with normal renal function but may exacerbate 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 Perindopres® Trio in patients with renal dysfunction have not been conducted. For patients with renal impairment, 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 sodium deficiency (particularly in patients with renal artery stenosis). Therefore, systematic monitoring for clinical signs of water 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 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. Concurrent loss of chloride ions may lead to secondary compensatory metabolic alkalosis; the frequency and severity of this effect are low.

Potassium levels. Treatment with the combination of indapamide, perindopril, and amlodipine does not eliminate the possibility of hypokalemia, particularly in patients with diabetes mellitus or renal failure. As with 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. Risk factors for hyperkalemia include renal failure, worsening renal function, age ≥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 causing increased serum potassium concentration (e.g., heparin, co-trimoxazole, also known as trimethoprim/sulfamethoxazole). Use of potassium-containing dietary supplements, potassium-sparing diuretics, or potassium-containing salt substitutes may also lead to significant increases in serum potassium concentration, especially in patients with impaired renal function. Hyperkalemia may cause serious, sometimes fatal, arrhythmias. If concomitant use of perindopril and any of the above-mentioned 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").

Reduced potassium levels in hypokalemia are the main risk associated with thiazide and thiazide-like diuretics. The risk of hypokalemia (< 3.4 mmol/l) should be prevented in high-risk patients (elderly patients and/or poorly nourished patients, patients taking multiple medications, patients with cirrhosis of the liver 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 determination of this parameter should be performed within the first week of treatment.

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

Magnesium levels. Thiazides and related diuretics, including indapamide, have been shown to increase urinary magnesium excretion, which may lead to hypomagnesemia (see sections "Interaction with other medicinal products and other forms of interaction" 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. Markedly elevated calcium levels may be a consequence of previously undiagnosed hyperparathyroidism. Treatment should be discontinued until parathyroid function is evaluated (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 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 tract obstruction.

Patients with diabetes mellitus. Treatment of patients with insulin-dependent diabetes mellitus (with a spontaneous tendency to increased blood potassium levels) should be initiated under medical supervision with a reduced initial dose.

In patients with diabetes mellitus 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 be 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 should 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 fulminant hepatic necrosis, sometimes with fatal outcome. The mechanism of this syndrome is unknown. Patients who develop jaundice or significant elevation of liver enzymes while taking 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 have been 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 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 impairment and should be used with caution in patients with mild to moderate liver impairment.

Uric acid. In patients with elevated uric acid levels, there may be a tendency toward 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 according to 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 (nearsightedness), and secondary angle-closure glaucoma. Medicinal products containing sulfonamide or sulfonamide derivatives may cause an idiosyncratic reaction leading to choroidal effusion with visual field defects, transient myopia, and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or eye pain and usually occur within hours or weeks of starting the drug. Untreated acute angle-closure glaucoma may lead to permanent vision loss. The primary treatment is to discontinue the drug as quickly as possible. If intraocular pressure remains uncontrolled, medical, pharmacological, or surgical interventions 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 ACE inhibitor therapy is considered necessary, women planning pregnancy should be switched to alternative antihypertensive agents with established safety data during pregnancy.

If pregnancy is confirmed during ACE inhibitor therapy, its use should be immediately discontinued and replaced with another alternative 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 kidney function, oligohydramnios, delayed formation of skull bones) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia).

If a woman has taken ACE inhibitors from the second trimester of pregnancy, ultrasound examination of kidney function and skull bones in the child is recommended. 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 thiazide diuretics in the third trimester of pregnancy may reduce 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 with high doses.

Period of breastfeeding. Perindopres® Trio is contraindicated during breastfeeding. A decision should be made to either discontinue breastfeeding during treatment or discontinue 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 breastfeeding newborns or premature infants, alternative treatment with a confirmed safety profile during breastfeeding should be prescribed.

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 received by the infant was estimated as interquartile range 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 or operating machinery.

Studies on the effect of Perindopres® Trio 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 or operate machinery. Impaired reaction may occur if the patient experiences dizziness, headache, weakness, fatigue, or nausea. As a result, the ability to drive or operate 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 meals.

The use of this fixed-dose 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 assessment 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 of 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 subsection "Pharmacokinetics").

Data on intentional overdose of amlodipine in humans are limited.

Based on available data, ingestion of very high doses is expected to result in 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 have been reported as a consequence of amlodipine overdose, which may have a delayed onset (24–48 hours after ingestion) and may require mechanical ventilation. Contributing factors to the development of non-cardiogenic pulmonary edema may include early resuscitation measures (including fluid overload) aimed at supporting perfusion and cardiac output.

Clinically evident 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 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 ingestion 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 dizziness, headache, paraesthesia, somnolence, dysgeusia, visual disturbances, diplopia, tinnitus, vertigo, palpitations, flushing, arterial hypotension (and associated symptoms), cough, dyspnoea, gastrointestinal disorders (abdominal pain, constipation, diarrhoea, dyspepsia, nausea, vomiting, changes in defecation rhythm), pruritus, skin rashes, maculopapular eruptions, muscle cramps, ankle swelling, asthenia, oedema, and fatigue, as well as hypokalaemia**.

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

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 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 anaemia: indapamide – very rare; pancytopenia: perindopril – very rare; leucopenia: perindopril, indapamide, amlodipine – very rare; neutropenia: perindopril – very rare; haemolytic anaemia: 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. Hypoglycaemia: perindopril – uncommon*; hyperkalaemia, which resolves after discontinuation of the drug: perindopril – uncommon*; hyponatraemia: perindopril and indapamide – uncommon*; hyperglycaemia: amlodipine – very rare; hypercalcaemia: indapamide – very rare; decreased blood potassium levels leading to hypokalaemia**, including severe cases in some high-risk patients: indapamide – common, hypochloraemia (indapamide – rare), hypomagnesaemia (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; paraesthesia: perindopril – common, indapamide – rare, amlodipine – uncommon; somnolence: perindopril – uncommon*, amlodipine – common; hypaesthesia: 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 hepatic 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), which may be potentially fatal: 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; dyspnoea: 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; diarrhoea: 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 eruptions: 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 oedema: amlodipine – very rare.

Musculoskeletal and connective tissue disorders. Muscle cramps: perindopril and amlodipine – common; ankle swelling: 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; pollakiuria: 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; gynaecomastia: amlodipine – uncommon.

General disorders. Asthenia: perindopril and amlodipine – common; increased fatigue: indapamide – rare, amlodipine – common; oedema: amlodipine – very common; chest pain: perindopril – uncommon*, amlodipine – uncommon; pain: amlodipine – uncommon; malaise: perindopril – uncommon*, amlodipine – uncommon; peripheral oedema: 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 enzymes: perindopril – rare, indapamide – frequency not known, amlodipine – very rare; decreased haemoglobin and haematocrit 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 from clinical trial data.

**During Phase II and III studies comparing 1.5 mg and 2.5 mg of indapamide, plasma potassium analysis revealed 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 levels 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 levels was 0.41 mmol/L.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after marketing authorization is an important procedure. It allows continued monitoring of the benefit-risk profile of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions via 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 in a 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 Borispilska Street, Kyiv, 02093, Ukraine.