Instructions for Tri-Aliter tablets 8 mg/ 2.5 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 renin-angiotensin system. ACE inhibitors, combinations. ACE inhibitors and other combinations. Perindopril, amlodipine and indapamide.
ATX code C09B X01.
Pharmacological properties
Pharmacodynamics
TRI-ALITER® is a combination of three antihypertensive components, the mechanism of action of which complements each other to control blood pressure in patients with arterial hypertension. Perindopril tert-butylamine 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 TRI-ALITER® is due to the properties of each component separately. In addition, the combination of perindopril/indapamide has an additive, synergistic effect of the two antihypertensive 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, while aldosterone does not have a negative effect; a decrease in total peripheral vascular resistance due to the predominant effect on the vessels of the muscles and kidneys, while there is no water and salt retention or reflex tachycardia, 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 reduces cardiac work due to: a vasodilatory effect on the veins (possibly due to changes in prostaglandin metabolism) - reducing preload on the heart; a decrease in total peripheral vascular resistance - reducing 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; an increase in regional blood circulation in the muscles.
In addition, performance on exercise tests improves significantly.
Indapamide.
Indapamide is a sulfonamide derivative with an indole ring, pharmacologically related to thiazide diuretics. Indapamide inhibits sodium reabsorption in the cortical segment of the kidney. 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 and vascular smooth muscle cells.
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. Clinical studies have shown that the simultaneous administration of perindopril and indapamide causes an antihypertensive effect of synergistic origin, which is the result of the individual effects of the components of the drug.
Perindopril.
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, if necessary, of a thiazide diuretic.
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 in 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 therapeutic effect of thiazide and thiazide-like diuretics does not increase, while the number of undesirable effects increases. If the treatment is not effective enough, increasing the dose is not recommended.
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); 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 relaxing 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 actions:
- amlodipine dilates peripheral arterioles and thus reduces total peripheral resistance (afterload); since the heart rate does not change, the reduction in the load on the heart reduces myocardial energy consumption and its oxygen demand;
- amlodipine partially contributes to the expansion of the main coronary arteries and arterioles in both intact and ischemic areas of the myocardium; such dilation increases the supply of oxygen 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.
Clinical efficacy and safety.
Perindopril/indapamide.
ADVANCE is an international multicenter randomized study with a bi-factorial (2×2) 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 mortality, non-fatal myocardial infarction, non-fatal stroke) and microvascular events (new cases or worsening of nephropathy, retinopathy). The study included 11,140 patients with type 2 diabetes. Among them, 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 drugs to reduce blood pressure (75%), to lower lipids (35%, mainly statins 28%), aspirin or other antiplatelet drugs (47%).
Treatment for 4.3 years with the perindopril/indapamide combination resulted in a significant 9% reduction in the relative risk of the primary endpoint. The benefits of treatment with the perindopril/indapamide combination compared to placebo were due to: a significant reduction in the relative risk of all-cause mortality by 14%; a significant reduction in the relative risk of cardiovascular mortality by 18%; a significant reduction in the relative risk of all renal complications by 21%.
In the subgroup of patients with arterial hypertension treated with the combination of perindopril/indapamide, a significant reduction in the relative risk of major macro- and microvascular events by 9% compared to the placebo group was observed. In the subgroup of patients taking the combination of perindopril/indapamide, compared to the placebo group, there was also a significant reduction in the relative risk of all-cause mortality by 16%; a significant reduction in the relative risk of cardiovascular mortality by 20%; a significant reduction in the relative risk of all renal complications by 20%.
Pharmacokinetics
The administration of perindopril, indapamide, and amlodipine in a fixed combination does not change their pharmacokinetic properties compared to the use of monodrugs.
After oral administration, perindopril is rapidly absorbed, with peak plasma concentrations occurring within 1 hour. The half-life of perindopril from plasma is 1 hour. Perindopril is a prodrug. 27% of the administered dose of perindopril enters the bloodstream 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 tert-butylamine be taken orally in a single daily dose in the morning before meals. 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 cardiac or renal insufficiency. In patients with renal insufficiency, 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.
Indapamide is rapidly and completely absorbed from the gastrointestinal tract. Peak plasma concentrations are reached approximately 1 hour after oral administration. Plasma protein binding is 79%. 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.
When used in therapeutic doses orally, amlodipine is well absorbed and reaches maximum blood concentrations 6–12 hours after administration. Absolute bioavailability is from 64% to 80%. The volume of distribution is approximately 21 l/kg. In vitro studies have shown that about 97.5% of amlodipine circulating in the blood binds to plasma proteins. Food intake does not affect the bioavailability of amlodipine. The half-life of amlodipine from blood plasma is approximately 35–50 hours, which allows the drug to be administered once a day. Amlodipine is mainly metabolized in the liver with the formation of 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%.
Indication
TRI-ALITER® 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
- Use in patients on hemodialysis;
- use in patients with untreated decompensated heart failure;
- severe renal impairment (creatinine clearance < 30 ml/min);
- moderate renal impairment (creatinine clearance < 60 ml/min) when taking the drug TRI-ALITER®, which contains 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;
- pregnant women or women planning to become pregnant (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;
- 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);
- simultaneous use with drugs containing the active substance aliskiren in patients with diabetes mellitus or renal insufficiency (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", "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
Dual blockade of the renin-angiotensin-aldosterone system (RAAS).
Clinical trial data suggest that dual blockade of the renin-angiotensin-aldosterone system (RAAS) through the concomitant use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher incidence of adverse reactions such as hypotension, hyperkalaemia and decreased 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 medicinal products or therapeutic classes of medicinal products may cause hyperkalaemia, such as: aliskiren, potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, non-steroidal anti-inflammatory drugs (NSAIDs), heparins, immunosuppressants such as ciclosporin or tacrolimus, trimethoprim. Concomitant use of these medicinal products increases the risk of hyperkalaemia.
Concomitant use is contraindicated (see section "Contraindications").
Aliskiren.
In patients with diabetes mellitus or patients with impaired renal function, the risk of hyperkalemia, deterioration of renal function and cardiovascular morbidity and mortality is increased.
Extracorporeal treatment methods.
Extracorporeal treatments that result in contact of blood with negatively charged surfaces, such as dialysis or haemofiltration using certain membranes with high hydraulic permeability (e.g. polyacrylonitrile) and low-density lipoprotein apheresis using dextran sulphate, 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 inhibition of neprilysin and ACE may increase the risk of angioedema. Sacubitril/valsartan should not be initiated 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 4.3 and 4.4).
Concurrent use is not recommended.
Perindopril/indapamide.
Lithium.
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 need for such a combination is proven, serum lithium concentrations should be carefully 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, deterioration of renal function and cardiovascular morbidity and mortality is increased (see section "Special warnings and precautions for use").
Concomitant use of ACE inhibitors and angiotensin receptor blockers.
According to the literature, in patients with established atherosclerosis, heart failure or diabetes mellitus with target organ damage, the simultaneous 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 (RAAS). Dual blockade (i.e. the combination of an ACE inhibitor with angiotensin II receptor antagonists) may be used in individual cases with careful monitoring of renal function, potassium levels and blood pressure (see section "Special instructions").
Estramustine.
Increased risk of adverse reactions such as angioedema.
Hyperkalemia (possibly fatal) may occur, especially in patients with renal insufficiency (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 is necessary, they should be used with caution and with frequent monitoring of plasma potassium. For the use of spironolactone in heart failure, see section "Concomitant use requiring special attention".
Co-trimoxazole (trimethoprim/sulfamethoxazole).
In patients concomitantly using co-trimoxazole, there may be an increased risk of developing hyperkalemia (see section "Special warnings and precautions for use").
Amlodipine.
Dantrolene (infusion).
In experimental 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 antagonists such as amlodipine be avoided in patients with known or suspected malignant hyperthermia.
Grapefruits or grapefruit juice.
In some patients, the bioavailability of amlodipine may increase, resulting in an increased hypotensive effect.
Concomitant use requiring special attention.
Perindopril/indapamide.
Baclofen.
Enhances antihypertensive effect. Blood pressure should be monitored and dose adjusted if necessary.
Perindopril/indapamide.
Nonsteroidal anti-inflammatory drugs (NSAIDs), including high doses of salicylates.
If 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. The concomitant use of ACE inhibitors and NSAIDs increases the risk of worsening of renal function, including acute renal failure, and increases in serum potassium, especially in patients with pre-existing renal impairment. This combination should be administered with caution, especially in elderly patients. In the latter, fluid balance should be restored and renal function should be monitored after initiation of combination therapy and during subsequent treatment.
Perindopril.
Diabetes medications (insulin, oral diabetes medications).
Epidemiological studies suggest that the concomitant use of ACE inhibitors and hypoglycemic agents (insulin, oral hypoglycemic agents) may lead to an increased hypoglycemic effect with a risk of hypoglycemia. This phenomenon may occur most often during the first weeks of combined treatment and in patients with impaired renal function.
Diuretics.
In patients taking diuretics, and especially in those 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 volume of circulating blood, and reducing 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 at the minimum dose, possibly after reducing the dose of the diuretic. In any case, it is necessary to monitor kidney function (creatinine level) during the first weeks of treatment with an ACE inhibitor.
Potassium-sparing diuretics (eplerenone, spironolactone).
In the case of simultaneous use of eplerenone or spironolactone in doses from 12.5 mg to 50 mg per day with low doses of an ACE inhibitor, there is a risk of hyperkalemia (possibly fatal) when treating patients with NYHA class II-IV heart failure and an ejection fraction < 40%, who were previously treated with an ACE inhibitor and a loop diuretic, if the recommendations for the appointment of such a combination are not followed. Before prescribing 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) are known to cause angioedema. This risk may be increased when used concomitantly with racecadotril (a medicine used to treat acute diarrhoea).
mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus).
Patients taking 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, sotalol, dofetilide, ibutilide, bretylium);
- 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, pentamidine, moxifloxacin, sparfloxacin, vincamine intravenously, methadone, astemizole, terfenadine.
A decrease in potassium in the blood plasma should be prevented and, if necessary, corrected, and the QT interval should be monitored.
Amphotericin B intravenously, gluco- and mineralocorticoids (systemic), tetracosactide, laxatives (stimulate peristalsis).
Increases the risk of decreased serum potassium (additive effect). It is necessary to monitor the potassium content in the blood plasma and adjust it if necessary, especially when taken simultaneously with cardiac glycosides. It is recommended to use laxatives that do not stimulate peristalsis.
Cardiac glycosides.
Hypokalemia increases the toxic effects of cardiac glycosides. Therefore, it is necessary to monitor plasma potassium and ECG, and, if necessary, review therapy.
Allopurinol.
Concomitant use with indapamide may increase the risk of hypersensitivity reactions to allopurinol.
Amlodipine.
CYP3A4 inducers.
When used concomitantly with known CYP3A4 inducers, amlodipine plasma concentrations may be altered. Therefore, blood pressure should be monitored and dose adjustments should be made during and after concomitant use with CYP3A4 inducers, particularly strong CYP3A4 inducers (e.g. rifampicin, St. John's wort (hypericum perforatum)).
CYP3A4 inhibitors.
Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, imidazole and triazole antifungals, macrolides such as erythromycin or clarithromycin, verapamil or diltiazem) may result in significant increases in amlodipine concentrations. The clinical manifestations of the above pharmacokinetic changes may be more pronounced in elderly patients. In such cases, clinical monitoring and dose adjustment are necessary. There is an increased risk of hypotension in patients taking clarithromycin in combination with amlodipine. Close supervision is recommended in such patients.
Concurrent use requiring attention.
Perindopril/indapamide/amlodipine.
Imipramine-like (tricyclic) antidepressants, neuroleptics.
Increases antihypertensive effect and the risk of orthostatic hypotension (additive effect).
Other antihypertensive drugs.
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.
Anesthesia drugs.
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.
Gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin).
Patients prescribed a combination of a gliptin and an ACE inhibitor are at increased risk of angioedema due to the fact that the gliptin reduces the activity of dipeptidyl peptidase-IV (DPP-IV).
Sympathomimetics.
Sympathomimetics may weaken the antihypertensive effect of ACE inhibitors.
Gold.
Concomitant use of ACE inhibitors, including perindopril, and injectable gold preparations (sodium aurothiomalate) may occasionally cause reactions similar to those seen with nitrates (facial flushing (flushing), nausea, vomiting and hypotension).
Indapamide.
Metformin.
May cause lactic acidosis due to the development of functional renal failure associated with diuretics, especially loop diuretics. Metformin should not be prescribed if the level of creatinine in the blood plasma exceeds 15 mg / l (135 μmol / l) in men and 12 mg / l (110 μmol / l) in women.
Iodine contrast agents.
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. 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.
There is a 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 the pharmacokinetics of atorvastatin, digoxin, or warfarin.
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.
Tacrolimus.
There is a risk of increased blood levels of tacrolimus when used concomitantly with amlodipine. To avoid toxicity of tacrolimus when used concomitantly with amlodipine, blood 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 fluctuation of cyclosporine trough concentrations (on average from 0% to 40%) was observed. In renal transplant patients receiving amlodipine, cyclosporine blood levels should be monitored and the dose reduced if necessary.
Application features
All the precautions listed below for each component of the drug also apply to the fixed combination TRI-ALITER®.
Lithium.
The concomitant use of lithium and the combination of perindopril/indapamide is generally not recommended (see section "Interaction with other medicinal products and other types of interactions").
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, dual blockade of the RAAS by concomitant use 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 not recommended (see section "Interaction with other medicinal products and other types of interactions").
Neutropenia/agranulocytosis/thrombocytopenia/anemia.
Neutropenia/agranulocytosis, thrombocytopenia and anemia have been reported in patients receiving ACE inhibitors. Neutropenia is rare in patients with normal renal function and in the absence of other risk factors. Perindopril should be administered with extreme caution to patients with collagen vascular diseases, during therapy with immunosuppressants, allopurinol,
