Corderia Trio tablets 4 mg/1.25 mg/5 mg blister No. 30

Instructions for Corderia Trio tablets 4 mg/1.25 mg/5 mg blister No. 30

Composition

active ingredients: perindopril, indapamide, amlodipine;

1 tablet contains:

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

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

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

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

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

Dosage form

Pills.

Main physicochemical properties: round biconvex tablets from white to almost white in color.

Pharmacotherapeutic group

Drugs affecting the cardiovascular system. Drugs affecting the renin-angiotensin system. ACE inhibitors, combinations. ACE inhibitors and other combinations. Perindopril, amlodipine and indapamide.

ATX code C09B X01.

Pharmacological properties

Pharmacodynamics.

Corderia TRIO is a combination of three antihypertensive components, the mechanisms of action of which complement each other in controlling blood pressure in patients with arterial hypertension. Perindopril is an angiotensin-converting enzyme inhibitor, indapamide is a sulfonamide diuretic, amlodipine is a calcium ion flow inhibitor belonging to the dihydropyridine group.

The pharmacological action of Corderia TRIO is due to the properties of each component separately. In addition, the combination of perindopril/indapamide causes additive synergism of the antihypertensive effect of the two components.

Mechanism of action. Perindopril. Perindopril is an angiotensin-converting enzyme inhibitor (ACE inhibitor), ACE converts angiotensin I into angiotensin II (a vasoconstrictor substance), additionally stimulates the secretion of aldosterone by the adrenal cortex and the breakdown of bradykinin (a vasodilator substance) to inactive heptapeptides. As a result of ACE inhibition, there is a decrease in aldosterone secretion; an increase in renin activity in the blood plasma without the negative effect of aldosterone; a decrease in total peripheral vascular resistance due to the predominant effect on the vessels of the muscles and kidneys, while no water and salt retention or reflex tachycardia is observed, even with long-term treatment.

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

Perindopril acts through its active metabolite perindoprilat. Other metabolites are inactive.

Perindopril facilitates the work of the heart due to its vasodilatory effect on the veins (possibly due to changes in prostaglandin metabolism), which reduces preload on the heart and, by reducing total peripheral vascular resistance, reduces afterload on the heart.

Studies conducted in patients with heart failure have shown that the use of perindopril leads to a decrease in left and right ventricular filling pressure; a decrease in total peripheral vascular resistance; an increase in cardiac output and an improvement in cardiac index; and an increase in regional blood flow in the muscles.

In addition, the results of physical activity tests are significantly improved.

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

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

Pharmacodynamic effects. Perindopril/indapamide. The combination of perindopril/indapamide reduces systolic and diastolic blood pressure in patients of all ages with arterial hypertension, both in the supine and standing positions. The antihypertensive effect of the drug is dose-dependent. In clinical studies, it has been proven that the simultaneous administration of perindopril and indapamide causes a synergistic antihypertensive effect compared to the effect of each component of the drug, which were prescribed as separate drugs.

In patients who respond to treatment, normalization of blood pressure occurs within a month and is maintained without the occurrence of tachyphylaxis.

Discontinuation of therapy is not accompanied by a withdrawal effect.

Perindopril has vasodilating properties, restores the elasticity of large arteries, corrects histomorphometric changes in arterial resistance and reduces left ventricular hypertrophy. Additional synergism develops due to the addition of a thiazide diuretic, if necessary.

The combination of an ACE inhibitor and a thiazide diuretic reduces the risk of hypokalemia, which can occur when a diuretic is prescribed as monotherapy.

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

The antihypertensive effect of indapamide is associated with improved arterial elasticity and a decrease in 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 undesirable effects increases. If treatment is ineffective, the dose of the drug should not be increased.

Moreover, as shown in studies of various durations (short, medium and long) involving patients with arterial hypertension, 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 the antihypertensive effect of amlodipine is due to a direct relaxant effect on vascular smooth muscle. The exact mechanism by which amlodipine reduces the manifestations of angina is not fully defined, but it is known that the drug helps to reduce the overall ischemia of the load due to the following two actions:

· amlodipine dilates peripheral arterioles and thus reduces total peripheral resistance (afterload); since the heart rate does not change, the reduction in workload on the heart reduces myocardial energy consumption and its oxygen demand;

Amlodipine partially dilates the main coronary arteries and arterioles in both intact 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 hypertension, once-daily administration of amlodipine provides clinically significant reductions in supine and standing blood pressure over 24 hours. 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, so it can be used in patients with asthma, diabetes, and gout.

Pharmacokinetics: The administration of perindopril/indapamide and amlodipine in a fixed combination does not alter their pharmacokinetic properties compared to their use as monodrugs.

Perindopril. After oral administration, perindopril is rapidly absorbed, with peak plasma concentrations occurring within 1 hour (perindopril is the prodrug, and perindoprilat is the active metabolite). The plasma half-life of perindopril is 1 hour. 27% of the administered dose of perindopril enters the circulation as the active metabolite perindoprilat. In addition to active perindoprilat, perindopril forms 5 inactive metabolites. Peak plasma concentrations of perindoprilat are reached within 3–4 hours.

Since food intake reduces the conversion of perindopril to perindoprilat and, consequently, its bioavailability, it is recommended that perindopril be taken orally in a single daily dose in the morning before a meal. There is a linear relationship between the dose of perindopril and its plasma concentration.

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

The elimination of perindoprilat is reduced in elderly patients and in patients with heart or renal failure. In patients with renal failure, the dose should be adapted depending on the degree of renal impairment (creatinine clearance).

The dialysis clearance of perindoprilat is 70 ml/min.

The pharmacokinetics of perindopril are altered in patients with cirrhosis of the liver: the hepatic clearance of the parent molecule is halved. However, the amount of perindoprilat formed is not reduced. Therefore, no dose adjustment is required in such patients (see sections “Method of administration and dosage” and “Special warnings and precautions for use”).

Indapamide is excreted mainly in the urine (70% of the dose) and feces (22%) as inactive metabolites. In patients with renal insufficiency, pharmacokinetic parameters are not changed.

Amlodipine. When administered orally in therapeutic doses, amlodipine is well absorbed and reaches maximum blood concentrations 6–12 hours after administration. Absolute bioavailability is 64 to 80%. The volume of distribution is approximately 21 l/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins. Food intake does not affect the bioavailability of amlodipine. The plasma half-life of amlodipine is approximately 35–50 hours, which allows once-daily dosing. Amlodipine is primarily metabolized in the liver to inactive metabolites, 60% of metabolites are excreted in the urine, and 10% unchanged.

The time to reach maximum plasma concentrations of amlodipine is similar in elderly and younger patients. Elderly patients tend to have a decreased clearance of amlodipine, resulting in increased AUC and half-life. The increase in AUC and half-life in patients with congestive heart failure was consistent with the age of the patients studied.

There are very limited clinical data on the use of amlodipine in patients with hepatic impairment. In patients with hepatic impairment, the clearance of amlodipine is reduced, resulting in a prolonged half-life and an increase in AUC by approximately 40-60%.

Clinical characteristics.

Indication

Corderia TRIO is indicated for the treatment of arterial hypertension in patients who require treatment with perindopril, indapamide and amlodipine in doses available in a fixed combination.

Contraindication

· Being on hemodialysis;

· untreated decompensated heart failure;

Severe renal impairment (creatinine clearance below 30 ml/min);

· moderate renal impairment (creatinine clearance below 60 ml/min) (regarding the drug Corderia TRIO, containing a combination of active substances in doses of 8 mg/2.5 mg/5 mg or 8 mg/2.5 mg/10 mg);

· hypersensitivity to the active substances, other sulfonamide drugs, dihydropyridine derivatives, any other ACE inhibitor or to any of the excipients;

· pregnancy or planning a pregnancy (see section "Use during pregnancy or breastfeeding");

· a history of angioedema (Quincke's edema) associated with previous treatment with ACE inhibitors (see section "Special warnings and precautions for use");

· congenital or idiopathic angioedema;

· hepatic encephalopathy;

· severe liver dysfunction;

· hypokalemia;

· severe arterial hypotension;

· shock, including cardiogenic shock;

· obstruction of the outlet from the left ventricle (for example, severe aortic stenosis);

· heart failure with unstable hemodynamics after acute myocardial infarction;

· simultaneous use with drugs containing the active substance aliskiren, if the patient has diabetes mellitus or renal failure (glomerular filtration rate 2) (see sections "Special instructions" and "Interaction with other medicinal products and other types of interactions");

· simultaneous use with sacubitril/valsartan. The use of Corderia TRIO should not be started earlier than 36 hours after taking the last dose of sacubitril/valsartan (see sections “Special instructions for use” and “Interaction with other medicinal products and other types of interactions”);

· extracorporeal treatment methods that lead to contact of blood with negatively charged surfaces (see section "Interaction with other medicinal products and other types of interactions");

· significant bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney (see section "Special warnings and precautions for use").

Interaction with other medicinal products and other types of interactions

Clinical trial data suggest that dual blockade of the renin-angiotensin-aldosterone system (RAAS) through the use of a combination of ACE inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher incidence of adverse reactions, such as hypotension, hyperkalaemia and worsening renal function (including acute renal failure), compared with the use of a single RAAS-acting agent (see sections 4.3 and 4.4).

Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and gliptins (e.g. linagliptin, saxagliptin, sitagliptin, vildagliptin) may lead to an increased risk of angioedema (see section 4.4).

Drugs causing hyperkalemia. Serum potassium levels are usually within normal limits, but hyperkalemia may occur in some patients taking Corderia TRIO. Some drugs or therapeutic classes of drugs may cause hyperkalemia, such as: aliskiren, potassium salts, potassium-sparing diuretics (e.g. spironolactone, triamterene or amiloride), ACE inhibitors, angiotensin II receptor antagonists, non-steroidal anti-inflammatory drugs (NSAIDs), heparins, immunosuppressants such as ciclosporin or tacrolimus, trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim is known to act as a potassium-sparing diuretic, similar to amiloride. Concomitant use of these drugs increases the risk of hyperkalemia. Therefore, the concomitant use of Corderia TRIO with the above-mentioned drugs is not recommended. If such concomitant use is prescribed, they should be used with caution and serum potassium levels should be monitored frequently.

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

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

Extracorporeal therapies: Extracorporeal therapies that bring blood into contact with negatively charged surfaces, such as dialysis or hemofiltration using certain membranes with high hydraulic permeability (e.g. polyacrylonitrile) and low-density lipoprotein apheresis using dextran sulfate, due to an increased risk of severe anaphylactoid reactions (see section 4.3). If such treatments are necessary, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.

Concurrent use is not recommended.

Perindopril/Indapamide: Reversible increases in serum lithium concentrations and increased toxicity have been reported with concomitant use of lithium and ACE inhibitors. Concomitant use of perindopril with indapamide and lithium preparations is not recommended. However, if the combination proves necessary, serum lithium concentrations should be closely monitored (see section 4.4).

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

Published data indicate that in patients with established atherosclerosis, heart failure or diabetes mellitus with target organ damage, concomitant use of ACE inhibitors and angiotensin receptor blockers was associated with an increased incidence of hypotension, syncope, hyperkalemia and deterioration of renal function (including acute renal failure) compared with monotherapy with drugs that affect the renin-angiotensin-aldosterone system. The use of dual blockade (i.e. the combination of an ACE inhibitor with angiotensin II receptor antagonists) is possible only in exceptional cases, subject to careful monitoring of renal function, potassium levels and blood pressure (see section "Special instructions").

Estramustine: increased risk of adverse reactions such as angioedema.

Potassium-sparing drugs (e.g. triamterene, amiloride, etc.), potassium salts: hyperkalemia (potentially fatal), especially in patients with impaired renal function (additive hyperkalemic effect). These drugs are not recommended for concomitant use with perindopril (see section "Special warnings and precautions for use"). However, if concomitant use of these substances is necessary, they should be used with caution and serum potassium should be monitored frequently. For the use of spironolactone in heart failure, see below "Concomitant use requiring special attention".

Amlodipine. Dantrolene (infusion): In animal studies, fatal ventricular fibrillation and cardiovascular collapse in association with hyperkalemia have been observed after intravenous administration of verapamil and dantrolene. Because of the potential for hyperkalemia, it is recommended that concomitant administration of calcium channel blockers such as amlodipine be avoided in patients with known or suspected malignant hyperthermia.

Grapefruit or grapefruit juice: in some patients, the bioavailability of amlodipine may be increased, resulting in an increase in the hypotensive effect.

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

Perindopril/indapamide. Non-steroidal anti-inflammatory drugs (NSAIDs), including high doses of acetylsalicylic acid. When ACE inhibitors are administered concomitantly with NSAIDs, such as acetylsalicylic acid at anti-inflammatory doses, cyclooxygenase-2 inhibitors and non-selective NSAIDs, attenuation of the antihypertensive effect may occur. Concomitant use of ACE inhibitors and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with pre-existing impaired renal function. This combination should be administered with caution, especially in elderly patients. Patients should be rehydrated and renal function should be monitored after initiation of concomitant therapy and during subsequent treatment.

Perindopril: Epidemiological studies suggest that concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycaemic agents) may lead to an increased blood sugar lowering effect with a risk of hypoglycaemia. This phenomenon is more likely to occur during the first weeks of combined treatment and in cases of impaired renal function.

In patients taking diuretics, especially in patients with impaired water and electrolyte metabolism, an excessive decrease in blood pressure is possible after starting treatment with an ACE inhibitor. The likelihood of developing a hypotensive effect is reduced by canceling the diuretic, increasing the circulating blood volume, and salt intake before starting perindopril therapy, which should be started at low doses with a gradual increase. In arterial hypertension, when the previously prescribed diuretic could cause water/electrolyte depletion, it should be canceled before starting treatment with an ACE inhibitor (in such cases, the diuretic can be resumed over time) or an ACE inhibitor should be prescribed at a low dose with a gradual increase. In congestive heart failure on the background of taking a diuretic, the ACE inhibitor should be started with a minimum dose, possibly after reducing the dose of the diuretic. In any case, it is necessary to monitor renal function (creatinine level) during the first weeks of treatment with an ACE inhibitor.

Potassium-sparing diuretics (eplerenone, spironolactone). When eplerenone or spironolactone at doses of 12.5 mg to 50 mg per day are used concomitantly with low-dose ACE inhibitors in patients with heart failure of New York Heart Association (NYHA) functional classes II–IV and ejection fraction in case of non-compliance with the recommendations for the appointment of such a combination. Before starting the use of such a combination, it is necessary to ensure the absence of hyperkalemia and impaired renal function. It is recommended to carefully monitor potassium and creatinine levels weekly during the first month of treatment and monthly thereafter.

Indapamide: Due to the risk of hypokalemia, indapamide should be administered with caution in combination with drugs that may induce torsades de pointes, such as, but not limited to:

· class Ia antiarrhythmic drugs (e.g. quinidine, hydroquinidine, disopyramide);

· class III antiarrhythmic drugs (e.g. amiodarone, dofetilide, ibutilide, bretylium, sotalol);

· some antipsychotics: phenothiazines (e.g. chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine), benzamides (e.g. amisulpiride, sulpiride, sultopride, tiapride), butyrophenones (e.g. droperidol, haloperidol), other antipsychotics (e.g. pimozide);

· other drugs (e.g. bepridil, cisapride, diphemanil, erythromycin intravenously, halofantrine, mizolastine, moxifloxacin, pentamidine, sparfloxacin, vincamine intravenously, methadone, astemizole, terfenadine).

A decrease in serum potassium should be prevented, corrected if necessary, and the QT interval monitored.

Amphotericin B intravenously, gluco- and mineralocorticoids (systemic), tetracosactide, laxatives (stimulating peristalsis) increase the risk of a decrease in serum potassium (additive effect). It is necessary to monitor the content of potassium in the blood serum and correct it if necessary, especially when taken simultaneously with cardiac glycosides. It is recommended to use laxatives that do not stimulate peristalsis.

Cardiac glycosides. Hypokalemia and/or hypomagnesemia contribute to the toxic effects of digitalis. It is recommended to monitor the level of potassium, magnesium in the blood plasma and ECG control and, if necessary, adjust the treatment.

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

Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil or diltiazem) may result in significant increases in amlodipine concentrations. The clinical manifestation of the above pharmacokinetic changes may be more pronounced in elderly patients. In such cases, clinical monitoring of the patient's condition 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 in such patients.

Concurrent use requiring attention.

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

The use of other antihypertensive drugs may cause an additional decrease in blood pressure.

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

Perindopril. Antihypertensives and vasodilators: Concomitant use with nitroglycerin and other nitrates or with other vasodilators may contribute to an additional decrease in blood pressure.

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

ACE inhibitors may enhance the hypotensive effect of some anesthetic drugs.

Diuretics (thiazide and loop): previous treatment with high doses of diuretics may cause dehydration, which increases the risk of hypotension at the beginning of perindopril therapy.

Sympathomimetics may weaken the antihypertensive effect of ACE inhibitors.

With the simultaneous use of ACE inhibitors, including perindopril, and injectable gold preparations (sodium aurothiomalate), reactions similar to those occurring with the use of nitrates (symptoms: facial flushing (flushing), nausea, vomiting and hypotension) have been occasionally reported.

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

In case of dehydration associated with the use of diuretics, the risk of developing acute renal failure increases, especially when using large doses of iodocontrast agents. Before taking the latter, it is necessary to restore water balance.

Calcium salts: there is a risk of hypercalcemia due to decreased urinary calcium elimination.

Cyclosporine: There is a risk of increasing creatinine levels without affecting circulating cyclosporine levels, even in the absence of water and sodium depletion.

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

Tacrolimus: There is a risk of increased plasma concentrations of tacrolimus when co-administered with amlodipine. To avoid toxicity of tacrolimus when co-administered with amlodipine, plasma levels should be monitored and the dose adjusted if necessary.

Mechanistic target of rapamycin (mTOR) inhibitors. mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are substrates of CYP3A. Amlodipine is a weak CYP3A inhibitor. When used concomitantly with mTOR inhibitors, amlodipine may potentiate the effects of the latter.

Cyclosporine: No interaction studies have been conducted with cyclosporine and amlodipine in healthy volunteers or other populations, except in renal transplant patients, in whom an increase in the trough concentration of cyclosporine (on average from 0 to 40%) was observed. In renal transplant patients receiving amlodipine, cyclosporine blood levels should be monitored and, if necessary, the dose should be reduced.

Coadministration of amlodipine in multiples of 10 mg with simvastatin 80 mg resulted in a 77% increase in simvastatin concentrations compared to monotherapy. Patients taking amlodipine should limit the dose of simvastatin to 20 mg daily.

Application features

All the precautions listed below for each component of the drug also apply to the fixed combination Corderia TRIO.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS). There is evidence that the 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, the use of dual blockade of the RAAS through the combination of ACE inhibitors, angiotensin II receptor blockers or aliskiren is not recommended (see section 4.5). If treatment with two RAAS blockers is considered absolutely necessary, it should only be carried out under specialist supervision and with frequent and careful monitoring of renal function, electrolytes and blood pressure. ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Potassium-sparing medicinal products, potassium-containing food supplements or potassium-containing salt substitutes. The concomitant use of perindopril with potassium-sparing medicinal products or potassium-containing food supplements or potassium-containing salt substitutes is generally not recommended (see section 4.5).

Neutropenia/agranulocytosis/thrombocytopenia/anaemia. Neutropenia, agranulocytosis, thrombocytopenia and anaemia 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 great caution to patients with collagen vascular diseases, immunosuppressants, allopurinol, procainamide or a combination of these factors, especially if renal function is impaired. Some of these patients have developed serious infections, in several cases resistant to intensive antibiotic therapy. Periodic monitoring of white blood cell counts is recommended when perindopril is prescribed to such patients. In addition, patients should be advised to report any signs of infection (e.g. sore throat, fever) to their physician (see section 4.8).

Renovascular hypertension. Patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are at increased risk of hypotension and renal failure when treated with ACE inhibitors (see section 4.3). Diuretics may be a beneficial factor. Decreased renal function may be manifested by only minor changes in serum creatinine, even in patients with unilateral renal artery stenosis.

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

In such cases, it is necessary to urgently stop taking perindopril and establish the necessary monitoring of the patient's condition until the symptoms disappear completely. If the edema is limited to the face and lips, the patient's condition usually improves without therapy, and the appointment of antihistamines may be useful to relieve symptoms.

Angioedema with laryngeal edema can be fatal. If edema involves the tongue, glottis, or larynx and is likely to cause airway obstruction, emergency treatment is urgently required, which may include subcutaneous administration of epinephrine 1:1000 (0.3-0.5 mL) and/or airway management.

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

Patients with a history of angioedema unrelated to ACE inhibitors are at increased risk of developing angioedema while taking ACE inhibitors (see section 4.3).

In patients with