Instructions for Co-amlessa tablets 8mg/2.5mg/10mg blister No. 30
Composition
active ingredients: perindopril tert-butylamine, indapamide, amlodipine;
1 tablet contains: 2 mg perindopril tert-butylamine, 0.625 mg indapamide and 5 mg amlodipine (as amlodipine besylate) or
4 mg perindopril tert-butylamine, 1.25 mg indapamide and 5 mg amlodipine (as amlodipine besylate), or
4 mg perindopril tert-butylamine, 1.25 mg indapamide and 10 mg amlodipine (as amlodipine besylate), or
8 mg perindopril tert-butylamine, 2.5 mg indapamide and 5 mg amlodipine (as amlodipine besylate), or
8 mg perindopril tert-butylamine, 2.5 mg indapamide and 10 mg amlodipine (as amlodipine besylate);
excipients:
microcrystalline cellulose; calcium chloride, hexahydrate; pregelatinized starch; sodium starch glycolate (type A); sodium bicarbonate; colloidal silicon dioxide; magnesium stearate.
Dosage form
Pills.
Main physicochemical properties:
2 mg/0.625 mg/5 mg: white to off-white, oval, biconvex tablets with a score on one side;
4 mg/1.25 mg/5 mg: white to off-white, round, slightly biconvex tablets with beveled edges;
4 mg/1.25 mg/10 mg: white to off-white, oval, biconvex tablets with a score on one side.
8 mg/2.5 mg/5 mg: white to off-white, round, biconvex tablets with beveled edges;
8 mg/2.5 mg/10 mg: white to off-white, round, biconvex tablets with beveled edges, scored on one side.
Pharmacotherapeutic group
Angiotensin-converting enzyme (ACE) inhibitors, other combinations. Perindopril, indapamide and amlodipine. ATC code C09B X01.
Pharmacological properties
Pharmacodynamics.
Co-Amlessa 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 antagonist.
The pharmacological action of Co-Amlessa is due to the properties of each component separately. In addition, the combination of perindopril/indapamide has an additive synergistic effect of the antihypertensive effects of the two components.
Mechanism of action
Perindopril
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, 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: vasodilatory effect on veins (possibly due to changes in prostaglandin metabolism) – reduction of preload on the heart; reduction of total peripheral vascular resistance – reduction of 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 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 antagonist and blocks the transmembrane influx 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 effectively reduces blood pressure in patients with any degree of arterial hypertension: mild, moderate and severe. The reduction in systolic and diastolic blood pressure is observed both in the supine and standing positions. The maximum antihypertensive effect develops 4–6 hours after taking a single dose and persists for more than a day. Perindopril has a high level of final ACE inhibitor 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 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 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 work 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 Prinzmetal's angina.
In patients with hypertension, once-daily administration of amlodipine provides clinically significant reductions in supine and standing blood pressure over 24 hours.
In patients with angina, once-daily administration of amlodipine prolongs total active time, time to angina onset, and time to 1 mm ST-segment depression. Amlodipine reduces the frequency of angina attacks and the need for nitroglycerin tablets.
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.
No studies of Co-Amlessa have been conducted on morbidity and mortality. Perindopril
The concomitant use of ACE inhibitors and angiotensin II receptor blockers has been investigated in two large-scale randomized controlled trials [ONTARGET (ONgoing Telmisartan Alone and Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)].
ONTARGET is a study in patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes mellitus with evidence of target organ damage. VA NEPHRON-D is a study in patients with type 2 diabetes mellitus and diabetic nephropathy.
The studies did not show a significant beneficial effect for patients with renal and/or cardiovascular diseases and on mortality from them, while compared with monotherapy there was an increased risk of developing hyperkalemia, acute kidney injury and/or hypotension. Given the similarity of pharmacodynamic properties, these results are also applicable to other ACE inhibitors and angiotensin II receptor blockers.
ALTITUDE (Aliskiren in Type 2 Diabetes with Cardiovascular Disease (CVD) and Renal Disease Endpoints) is a study of the treatment benefits of adding aliskiren to standard therapy with an ACE inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes and/or chronic kidney disease, CVD. The study was stopped early due to an increased risk of adverse events. CVD mortality, stroke, and reports of adverse events and serious complications (hyperkalemia, hypotension, or renal dysfunction) were more frequent in the aliskiren group compared with the placebo group.
Perindopril/indapamide
PICXEL is a multicenter, randomized, double-blind, controlled study that evaluated the effect of the combination of perindopril and indapamide on left ventricular hypertrophy compared with enalapril monotherapy (based on echocardiographic results).
In the PICXEL study, patients with arterial hypertension and left ventricular hypertrophy (with a left ventricular mass index > 120 g/m2 in men and > 100 g/m2 in women) were randomized into two groups: some patients received 2 mg perindopril tertbutylamine/0.625 mg indapamide, others - 10 mg enalapril 1 time per day for a year. The doses were adapted according to the BP indicators: the dose of perindopril tertbutylamine was increased to 8 mg, indapamide - to 2.5 mg, enalapril - to 40 mg 1 time per day. The drugs were continued to be taken at the starting dose by 34% of patients in the perindopril/indapamide group (2 mg perindopril and 0.625 mg indapamide) and 20% in the enalapril group (10 mg).
At the end of treatment, left ventricular mass index decreased significantly more in patients receiving perindopril/indapamide (-10.1 g/m²) than in the enalapril group (-1.1 g/m²). The difference between the two groups was -8.3 (95% confidence interval [CI] -11.5 to -5.0, p < 0.0001).
The best effect in reducing left ventricular mass index was achieved with perindopril/indapamide.
Blood pressure was reduced more effectively in the perindopril/indapamide group: the difference in mean BP reduction between the two groups of patients was -5.8 mmHg (95% CI -7.9 to -3.7, p < 0.0001) for systolic blood pressure and -2.3 mmHg (95% CI -3.6 to -0.9, p = 0.0004) for diastolic blood pressure, with an advantage for patients in the perindopril/indapamide group.
ADVANCE is an international multicenter randomized study with a bifactorial (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 death, 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 blood pressure lowering drugs (75%), lipid lowering drugs (35%, mainly statins – 28%), aspirin or other antiplatelet drugs (47%).
Treatment for 4.3 years with the combination of perindopril/indapamide resulted in a significant reduction of 9% in the relative risk of the primary endpoint (95% confidence interval (CI) [0.828; 0.996], p = 0.041). The benefits of treatment with perindopril/indapamide compared to placebo were due to: a significant reduction in the relative risk of all-cause mortality by 14% (95% CI [0.75; 0.98], p = 0.025); a significant reduction in the relative risk of cardiovascular mortality by 18% (95% CI [0.68; 0.98], p = 0.027); a significant reduction in the relative risk of all renal events by 21% (95% CI [0.74; 0.86], p < 0.001).
In the subgroup of patients with arterial hypertension who took perindopril/indapamide, there was a significant reduction in the relative risk of major macro- and microvascular events by 9% (95% CI [0.82; 1.00], p = 0.052) compared with the placebo group. In the subgroup of patients who took perindopril/indapamide, compared with the placebo group, there was also: 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).
The benefits of blood pressure-lowering treatment were independent of those seen with intensive glucose control.
Amlodipine
A total of 33,357 hypertensive patients aged 55 years or older were randomized and followed for a median of 4.9 years. Patients had at least one additional risk factor for coronary heart disease, including myocardial infarction or stroke (> 6 months before study entry) or other documented atherosclerotic cardiovascular disease (CVD) (overall 51.5%), type 2 diabetes (36.1%), HDL-cholesterol <35 mg/dL or <0.906 mmol/L (11.6%), left ventricular hypertrophy diagnosed by electrocardiogram or echocardiography (20.9%), and smoking (21.9%).
The primary endpoint was fatal coronary heart disease or nonfatal myocardial infarction. The primary endpoint did not differ significantly between amlodipine and chlorthalidone-based therapies: relative risk (RR) 0.98, 95% CI (0.90-1.07), p=0.65. Among the secondary endpoints, the incidence of heart failure (part of the composite cardiovascular outcome) was significantly higher in the amlodipine group compared with the chlorthalidone group (10.2% vs 7.7%, HR 1.38, 95% CI [1.25-1.52], <0.001). However, there was no significant difference between amlodipine and chlorthalidone in the treatment of any cause of death: HR 0.96, 95% CI [0.89 1.02], p=0.20.
Use in children
There are no data on the use of Co-Amlessa in children (see section “Method of administration and dosage”).
Pharmacokinetics.
Co-Amlessa
The administration of perindopril/indapamide and amlodipine in a fixed combination does not change their pharmacokinetic properties compared to the use of monodrugs.
Perindopril
After oral administration, perindopril is rapidly absorbed, with peak concentrations achieved within 1 hour. The plasma half-life of perindopril is 1 hour. Since food intake reduces the conversion to perindoprilat and therefore bioavailability, perindopril should be administered orally in a single daily dose in the morning before meals.
Distribution
The volume of distribution of free perindopril is approximately 0.2 l/kg. The protein binding of perindopril to plasma proteins is 20%, especially to ACE, but is concentration-dependent.
Metabolism
Perindopril is a prodrug. 27% of the total amount of perindopril absorbed is converted to the active metabolite perindoprilat. In addition, five more inactive metabolites are formed. The maximum concentration of perindoprilat in the blood plasma is reached within 3–4 hours.
Breeding
Perindoprilat is excreted in the urine, and the half-life of the unbound fraction is approximately 17 hours, resulting in a steady state within 4 days.
Linearity/nonlinearity
A linear relationship between the dose of perindopril and its plasma concentration has been demonstrated.
Special patient groups
Elderly patients
In the elderly and patients with heart or kidney failure, the excretion of perindoprilat is reduced.
Patients with renal impairment
In case of impaired renal function, it is recommended to change the dose depending on the degree of impairment (creatinine clearance).
Patients undergoing dialysis
Perindoprilat is removed from the circulation by dialysis, its clearance is 70 ml/min.
Patients with liver cirrhosis
In liver cirrhosis, the kinetics of perindopril change, with the hepatic clearance of the parent molecule being halved, but the amount of perindoprilat formed does not change, so the dose of the drug may not be changed in this disease (see sections “Method of administration and dosage” and “Special precautions for use”).
Indapamide
Absorption and distribution
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%.
Biotransformation and excretion
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%) in the form of inactive metabolites.
Special patient groups
Patients with renal impairment
In patients with renal insufficiency, pharmacokinetic parameters do not change.
Amlodipine
Absorption and bioavailability
When used in therapeutic doses orally, 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.
Biotransformation
Amlodipine is mainly metabolized in the liver to form inactive metabolites, 60% of the administered dose is excreted in the urine, and 10% is excreted unchanged.
Breeding
The half-life of amlodipine from blood plasma is approximately 35–50 hours, which allows the drug to be administered once a day.
Special patient groups
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.
Patients with renal impairment
The pharmacokinetics of amlodipine are not altered in patients with renal insufficiency.
Patients with liver dysfunction
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
Co-Amlessa 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
- Hypersensitivity to perindopril or to any other ACE inhibitor, to indapamide or any other sulfonamides, to amlodipine or dihydropyridine and to any of the excipients;
- 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);
- heart failure with unstable hemodynamics after acute myocardial infarction;
- untreated decompensated heart failure;
- simultaneous administration with drugs containing the active substance aliskiren to 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”);
- use in patients on hemodialysis;
- severe renal failure (creatinine clearance < 30 ml/min);
- moderate renal failure (creatinine clearance < 60 ml/min) when taking the drug Co-Amlessa, 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;
- pregnancy or pregnancy planning period;
- breastfeeding period;
- childhood;
- concomitant use with sacubitril/valsartan therapy - due to increased risk of angioedema. The drug should not be used within 36 hours after the last dose of sacubitril/valsartan or after switching from it to another drug containing a neprilysin inhibitor (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
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 (see section "Special warnings and precautions for use").
Extracorporeal treatments that result in contact of blood with negatively charged surfaces, such as high-flux membranes for dialysis or hemofiltration (e.g. polyacrylamide membranes) and for low-density lipoprotein apheresis with dextran sulfate, increase the risk of severe anaphylactoid reactions (see section 4.3). If such treatment is necessary, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive drug.
Sacubitril/Valsartan
Concomitant use of perindopril with sacubitril/valsartan is contraindicated as it increases the risk of angioedema. Sacubitril/valsartan should not be started earlier than 36 hours after the last dose of perindopril. Perindopril therapy should not be started earlier than 36 hours after the last dose of sacubitril/valsartan (see sections 4.3 and 4.4).
Concomitant 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 need for such a combination is proven, serum lithium concentrations should be carefully monitored (see section 4.4).
Perindopril
Concomitant use of ACE inhibitors and angiotensin receptor blockers
Clinical trial data suggest that dual blockade of the renin-angiotensin 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 to the use of a single RAAS-acting agent (see sections 5.1, 5.3 and 4.4).
Potassium-sparing diuretics, potassium supplements, or salt substitutes containing potassium
Although serum potassium usually remains within normal limits, hyperkalemia may occur in some patients treated with perindopril. Potassium-sparing diuretics (e.g. spironolactone, triamterene or amiloride), potassium supplements or potassium-containing salts may lead to significant increases in serum potassium. Caution should also be exercised when perindopril is administered concomitantly with other agents that increase serum potassium, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim is known to act as a potassium-sparing diuretic to amiloride. Therefore, these agents are not recommended for concomitant use with perindopril (see section 4.4). However, if concomitant administration of these agents is necessary, they should be used with caution and frequent monitoring of plasma potassium and electrocardiogram should be performed. Regarding the use of spironolactone in heart failure, see “Concomitant use requiring special attention”.
Cotrimoxazole (trimethoprim/sulfamethoxazole)
Patients receiving concomitant co-trimoxazole (trimethoprim/sulfamethoxazole) are at increased risk of hyperkalemia (see section 4.4).
Estramustine: increased risk of adverse reactions such as angioedema.
Concomitant use requiring special monitoring
Perindopril/indapamide/amlodipine
Baclofen enhances the antihypertensive effect. Blood pressure and renal function should be monitored and the dose adjusted if necessary.
Perindopril/indapamide
Nonsteroidal anti-inflammatory drugs (NSAIDs), including high doses of salicylates
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 is possible. The concomitant use of ACE inhibitors and NSAIDs increases the risk of worsening of renal function, including acute renal failure, and an increase 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
Antidiabetic agents (insulin, oral hypoglycemic agents)
Epidemiological studies suggest that the concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemic agents) may lead to an increased blood sugar-lowering effect with a risk of hypoglycemia. This phenomenon may occur most often during the first weeks of combined treatment and in the case of renal insufficiency.
Non-potassium-sparing diuretics or diuretics that do not conserve potassium
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 discontinuing the diuretic, increasing circulating blood volume (CV), and reducing salt intake before starting perindopril therapy, which should be started at a low dose and gradually increased.
In hypertension, when a previously prescribed diuretic may have caused water/electrolyte depletion, it should be discontinued before starting treatment with an ACE inhibitor (in such cases, the diuretic may be resumed over time) or an ACE inhibitor should be prescribed at a low dose with gradual titration.
In congestive heart failure on diuretic therapy, ACE inhibitors should be initiated at the lowest dose, possibly after reducing the dose of the non-potassium-sparing diuretic. In any case, renal function (creatinine levels) should be monitored during the first weeks of ACE inhibitor therapy.
Concomitant use of eplerenone or spironolactone at doses of 12.5 mg to 50 mg per day with low doses of an ACE inhibitor: If the recommendations for the use of this combination are not followed, there is a risk of hyperkalemia (possibly fatal) during the treatment of patients with heart failure class II-IV according to the NYHA classification (New York Heart Association) and an ejection fraction < 40%, who were previously treated with an ACE inhibitor and a loop diuretic. Before prescribing this combination, it is necessary to ensure that there is no hyperkalemia and renal insufficiency. Close monitoring of potassium and creatinine is recommended weekly during the first month of treatment and monthly thereafter.
Cyclosporine
The risk of hyperkalemia is increased when ACE inhibitors are used concomitantly with cyclosporine. Monitoring of serum potassium levels is recommended.
Heparin
The risk of hyperkalemia increases with the simultaneous use of ACE inhibitors with heparin. Monitoring of serum potassium levels is recommended.
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 plasma potassium levels should be prevented and, if necessary, corrected, and the QT interval monitored.
Drugs that lower potassium levels (amphotericin B (intravenously), gluco- and mineralocorticoids (systemic), tetracosactide, laxatives (stimulate peristalsis) increase the risk of a decrease in serum potassium (additive effect). It is necessary to monitor the potassium content in the blood plasma and adjust it if necessary, especially when used simultaneously with cardiac glycosides. It is recommended to use laxatives that do not stimulate peristalsis.
Cardiac glycosides
Low potassium levels increase the toxic effects of cardiac glycosides. Therefore, monitoring of plasma potassium levels and ECG monitoring is necessary, and if necessary, therapy should be reviewed.
Allopurinol
Concomitant use with indapamide increases the risk of hypersensitivity reactions to allopurinol.
Concomitant use for which there are reservations
Perindopril/indapamide/amlodipine
Imipramine-like (tricyclic) antidepressants and neuroleptics increase the antihypertensive effect and the risk of developing orthostatic hypotension (additive effect).
Other antihypertensive agents
The use of other antihypertensive drugs with Co-Amlessa may cause an additional decrease in blood pressure.
Corticosteroids, tetracosactide (systemic use)
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 medications
ACE inhibitors may enhance the hypotensive effect of some anesthetic drugs.
Diuretics
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 gliptin's inhibition of dipeptidyl peptidase-IV (DPP-IV) activity.
Sympathomimetics may weaken the antihypertensive effect of ACE inhibitors.
Gold preparations
Concomitant use of ACE inhibitors, including perindopril, and injectable gold preparations (sodium aurothiomalate) may occasionally cause reactions similar to those seen with nitrates (symptoms: flushing, nausea, vomiting and hypotension).
Racecadotril
ACE inhibitors (e.g. perindopril) are known to cause angioedema.
