Perindopress trio tablets 8mg/2.5mg/5mg No. 30

Instructions for Perindopress trio tablets 8mg/2.5mg/5mg No. 30

Composition

active ingredients: perindopril, indapamide, amlodipine;

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

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);

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

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

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

1 tablet contains: 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);

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

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

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

Dosage form

Pills.

Main physicochemical properties:

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

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

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

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

Pharmacotherapeutic group

Angiotensin-converting enzyme (ACE) inhibitors, other combinations. Perindopril, amlodipine and indapamide. ATC code C09B X01.

Pharmacological properties

Pharmacodynamics.

Perindopres® 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 tert-butylamine is an ACE inhibitor, indapamide is a sulfonamide diuretic, amlodipine is a calcium ion flow inhibitor belonging to the dihydropyridine group.

The pharmacological action of Perindopril/Indapamide 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 is an ACE inhibitor that converts angiotensin I to 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. At the same time, there is no water and salt retention or reflex tachycardia, even with prolonged 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 a vasodilatory effect on the veins (possibly due to changes in prostaglandin metabolism), which reduces preload on the heart and a decrease in total peripheral vascular resistance, which 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 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 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. Perindopril effectively lowers blood pressure in patients with any degree of arterial hypertension: mild, moderate and severe. A decrease in systolic and diastolic blood pressure is observed both in the supine and standing positions. The maximum antihypertensive effect develops 4–6 hours after taking a single dose and persists for more than 24 hours. Perindopril has a high level of final ACE blockade (approximately 80%) 24 hours after administration.

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 manifested 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 different durations (short, medium and long) in 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, thereby reducing total peripheral resistance (afterload); since the heart rate does not change, reducing the load 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 adverse metabolic effects or changes in plasma lipid levels, so it can be used in patients with asthma, diabetes, and gout.

Clinical efficacy and safety.

Perindopril/indapamide.

ADVANCE is an international multicenter randomized study with a bifactorial (2x2) design aimed at determining the benefits of lowering blood pressure with a fixed combination of perindopril/indapamide compared with placebo against the background of current standard therapy [double-blind comparison (prospective randomized open-label study with blinded determination)] in terms of the effect 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 cases or worsening of nephropathy, eye disease). The study included 11,140 patients with type 2 diabetes. Of these, 83% of patients had arterial hypertension, 32% and 10% of patients had a history of micro- and macrovascular diseases, respectively, 27% had microalbuminuria. Concomitant therapy included medications: to lower blood pressure (75%), to lower lipid levels (35%, mainly statins – 28%), acetylsalicylic acid or other antiplatelet drugs (47%).

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

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

Absorption and bioavailability: After oral administration, perindopril is rapidly absorbed, with peak concentrations occurring within 1 hour (perindopril is the prodrug and perindoprilat is the active metabolite). The plasma half-life of perindopril is 1 hour.

Since food intake reduces the conversion of perindopril to perindoprilat and, consequently, its bioavailability, it is recommended that perindopril tert-butylamine 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.

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

Biotransformation. 27% of the administered dose of perindopril enters the bloodstream as the active metabolite perindoprilat. In addition to the active perindoprilat, perindopril forms 5 more inactive metabolites. The maximum concentration of perindoprilat in the blood plasma is reached after 3–4 hours.

Excretion: Perindoprilat is excreted in the urine, with a terminal half-life of the unbound fraction of approximately 17 hours. Steady state is reached after 4 days.

Special categories of patients

Elderly patients: The elimination of perindoprilat is reduced in elderly patients and in patients with cardiac or renal insufficiency.

Renal impairment: In patients with renal insufficiency, the dose should be adapted depending on the degree of renal impairment (creatinine clearance).

Need for dialysis. The dialysis clearance of perindoprilat is 70 ml/min.

Cirrhosis of the liver. 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 (see sections "Method of administration and dosage" and "Special warnings and precautions for use").

Indapamide

Absorption: Indapamide is rapidly and completely absorbed from the gastrointestinal tract. Peak plasma concentrations are reached approximately 1 hour after oral administration.

Distribution: Plasma protein binding is 79%.

Biotransformation and elimination: The elimination half-life is 14 to 24 hours (average 18 hours). Repeated administration does not cause accumulation.

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

Absorption and bioavailability. 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%. Food intake does not affect the bioavailability of amlodipine.

Distribution: 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.

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

Special categories of patients

Elderly patients. The time to reach maximum plasma concentrations of amlodipine is similar in elderly and young 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.

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

Indication

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

Contraindication

• Being on hemodialysis;
• severe renal impairment (creatinine clearance < 30 ml/min) for dosages 4 mg/1.25 mg/5 mg and 4 mg/1.25 mg/10 mg;
• moderate renal impairment (creatinine clearance < 60 ml/min) for dosages 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 listed in the "Composition" section;
• pregnancy or planning a pregnancy (see section "Use during pregnancy or breastfeeding");
• breastfeeding period (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;
• Left ventricular outflow obstruction (e.g., 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 < 60 ml/min/1.73 m2) (see sections "Special instructions" and "Interaction with other medicinal products and other types of interactions");
• simultaneous use with sacubitril/valsartan (see sections “Special instructions for use” and “Interaction with other medicinal products and other types of interactions”);
• extracorporeal treatments that result in blood coming into contact 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).

Drugs that cause hyperkalemia.

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

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: therapies such as dialysis or hemofiltration using certain membranes with high hydraulic permeability (e.g. polyacrylonitrile) and low-density lipoprotein (LDL) apheresis using dextran sulfate, which result in contact of blood with negatively charged surfaces, 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.

Sacubitril/valsartan: Concomitant use of perindopril with sacubitril/valsartan is contraindicated as concomitant neprilysin and ACE inhibition may increase the risk of angioedema. Sacubitril/valsartan should not be initiated earlier than 36 hours after the last dose of perindopril. Perindopril should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections 4.3 and 4.4).

Concurrent use is not recommended.

Perindopril/indapamide.

Reversible increases in serum lithium concentrations and increased toxicity have been reported during concomitant use of lithium and ACE inhibitors. Concomitant administration 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.

Angiotensin receptor blockers: published data indicate that in patients with established atherosclerosis, heart failure or diabetes mellitus with target organ damage, concomitant use was associated with an increased incidence of hypotension, syncope, hyperkalaemia and renal impairment (including acute renal failure) compared with monotherapy with drugs affecting the RAAS. Dual blockade (i.e. the combination of an ACE inhibitor with an angiotensin II receptor antagonist) should only be considered in selected cases with careful monitoring of renal function, potassium levels and blood pressure (see section 4.4).

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".

Co-trimoxazole (trimethoprim/sulfamethoxazole): Patients receiving co-trimoxazole may be at increased risk of developing hyperkalemia (see section 4.4).

Amlodipine.

Dantrolene (infusion): In animal studies, fatal ventricular fibrillation and cardiovascular collapse have been observed in association with hyperkalemia following 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 increase, resulting in an increase in the hypotensive effect.

Concomitant use requiring special attention.

Perindopril/indapamide.

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

Perindopril/indapamide.

NSAIDs, in particular high doses of acetylsalicylic acid: a possible weakening of the antihypertensive effect when ACE inhibitors and NSAIDs, such as acetylsalicylic acid in anti-inflammatory doses, cyclooxygenase COX-2 inhibitors and non-selective NSAIDs, are administered concomitantly. This combination may also lead to an increased risk of worsening renal function, including the possible development of 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.

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

Potassium-sparing diuretics (eplerenone, spironolactone): When eplerenone or spironolactone at doses of 12.5 mg to 50 mg per day is co-administered with low-dose ACE inhibitors in patients with heart failure of New York Heart Association (NYHA) functional classes II–IV and an ejection fraction < 40%, who have previously received ACE inhibitors and loop diuretics, there is a risk of hyperkalemia, potentially fatal, especially if the recommendations for the appointment of such a combination are not followed. 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 weekly during the first month of treatment and monthly thereafter.

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

mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus): Patients receiving concomitant mTOR inhibitors may be at increased risk of developing angioedema (see section 4.4).

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:

• class IA antiarrhythmic drugs (quinidine, hydroquinidine, disopyramide);
• class III antiarrhythmic drugs (amiodarone, dofetilide, ibutilide, bretylium, sotalol);
• some neuroleptics (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine), benzamides (amisulpiride, sulpiride, sultopride, tiapride), butyrophenones (droperidol, haloperidol), other neuroleptics (pimozide);
• other drugs such as 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). Serum potassium should be monitored and adjusted if necessary, particularly when administered concomitantly with cardiac glycosides. It is recommended to use laxatives that do not stimulate peristalsis.

Digitalis preparations. Hypokalemia and/or hypomagnesemia increase the toxic effects of digitalis preparations. It is necessary to monitor the level of potassium, magnesium in the blood plasma and ECG, and, if necessary, review the therapy.

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 co-administered with known CYP3A4 inducers. Therefore, blood pressure should be monitored and dose adjustments should be made during and after co-administration with CYP3A4 inducers, particularly strong CYP3A4 inducers (e.g. St. John's wort (Hypericum perforatum), rifampicin).

Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil or diltiazem) may result in significant increases in amlodipine concentrations. The clinical manifestation of these 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 developing orthostatic hypotension (additive effect).

Other antihypertensive drugs: may cause additional reduction 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: possible weakening of the antihypertensive effect of ACE inhibitors.

Gold preparations: 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: risk of lactic acidosis due to possible development of functional renal failure associated with diuretics, especially loop diuretics. Metformin should not be prescribed if plasma creatinine levels exceed 15 mg/L (135 μmol/L) in men and 12 mg/L (110 μmol/L) in women.

In case of dehydration associated with the use of diuretics, the risk of developing acute renal failure increases, especially when using large doses of iodinated contrast agents. Therefore, it is necessary to restore water balance before their administration.

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

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

Amlodipine.

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

Tacrolimus: Risk of increased plasma concentrations of tacrolimus when co-administered with amlodipine. Tacrolimus plasma levels should be monitored and the dose adjusted if necessary to avoid toxicity.

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 their effects.

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 reduced.

Simvastatin: 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 medicinal product also apply to the fixed combination Perindopril/Indapamide Trio.

Lithium: The concomitant use of lithium and the combination of perindopril/indapamide is generally not recommended (see section 4.5).

Dual blockade of the 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 by 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 drugs, dietary supplements containing potassium, or salt substitutes containing potassium.

The concomitant use of perindopril with potassium-sparing medicinal products or potassium-containing food supplements is generally not recommended (see section “Contraindications”).