Co-amlessa

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CO-AMLESSA® (CO-AMLESSA)

Composition:

Active substances: perindopril tert-butylamine, indapamide, amlodipine;

One tablet contains: 2 mg perindopril tert-butylamine, 0.625 mg indapamide, and 5 mg amlodipine (as amlodipine besilate), or

4 mg perindopril tert-butylamine, 1.25 mg indapamide, and 5 mg amlodipine (as amlodipine besilate), or

4 mg perindopril tert-butylamine, 1.25 mg indapamide, and 10 mg amlodipine (as amlodipine besilate), or

8 mg perindopril tert-butylamine, 2.5 mg indapamide, and 5 mg amlodipine (as amlodipine besilate), or

8 mg perindopril tert-butylamine, 2.5 mg indapamide, and 10 mg amlodipine (as amlodipine besilate);

Excipients:

microcrystalline cellulose; calcium chloride hexahydrate; pregelatinized starch; sodium starch glycolate (type A); sodium hydrogencarbonate; colloidal anhydrous silicon dioxide; magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

2 mg/0.625 mg/5 mg: white to almost white, oval, biconvex tablets with a score on one side;

4 mg/1.25 mg/5 mg: white to almost white, round, slightly biconvex tablets with beveled edges;

4 mg/1.25 mg/10 mg: white to almost white, oval, biconvex tablets with a score on one side.

8 mg/2.5 mg/5 mg: white to almost white, round, biconvex tablets with beveled edges;

8 mg/2.5 mg/10 mg: white to almost white, round, biconvex tablets with beveled edges, with a score on one side.

Pharmacotherapeutic group. Angiotensin-converting enzyme (ACE) inhibitors, other combinations. Perindopril, indapamide, and amlodipine. ATC code: C09BX01.

Pharmacological Properties.

Pharmacodynamics.

Co-Amlessa is a combination of three antihypertensive components whose mechanisms of action complement each other in controlling arterial pressure in patients with arterial hypertension. Perindopril tert-butylamine is an angiotensin-converting enzyme (ACE) inhibitor, indapamide is a sulfonamide diuretic, and amlodipine is a calcium ion antagonist.

The pharmacological effect of Co-Amlessa is determined by the properties of each individual component. Furthermore, the combination of perindopril/indapamide has additive synergistic 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 aldosterone secretion by the adrenal cortex, and promotes bradykinin (a vasodilator substance) breakdown into inactive heptapeptides. As a result of ACE inhibition, the following occur: reduction in aldosterone secretion; increased plasma renin activity, while aldosterone has no negative effect; reduction in total peripheral vascular resistance due to predominant action on muscle and renal vessels, without water and salt retention or reflex tachycardia, even during long-term treatment.

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

Perindopril acts via its active metabolite, perindoprilat. Other metabolites are inactive.

Perindopril reduces cardiac workload through: vasodilatory effects on veins (possibly due to changes in prostaglandin metabolism) – reduction in preload; reduction in total peripheral vascular resistance – reduction in afterload.

Studies conducted in patients with heart failure have demonstrated that perindopril use leads to: reduction in filling pressures of the left and right ventricles; reduction in total peripheral vascular resistance; increased cardiac output and improved cardiac index; increased regional blood flow in muscles.

Moreover, physical exercise test parameters significantly improve.

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 urinary excretion of sodium and chloride, and to a lesser extent, excretion of potassium and magnesium, thereby increasing diuresis. This mechanism provides antihypertensive action.

Amlodipine

Amlodipine is a calcium ion antagonist that blocks transmembrane calcium ion influx into smooth muscle cells of the myocardium and blood vessels.

Pharmacodynamic Effects

Perindopril/Indapamide

The combination of perindopril/indapamide reduces systolic and diastolic blood pressure in hypertensive patients of any age, both in supine and standing positions. The antihypertensive effect of the drug is dose-dependent. Clinical studies have demonstrated that concomitant administration of perindopril and indapamide results in synergistic antihypertensive action, resulting from the individual effects of the drug components.

Perindopril

Perindopril effectively reduces arterial pressure in arterial hypertension of any severity: mild, moderate, and severe. Reduction in systolic and diastolic arterial pressure is observed both in supine and standing positions. Maximum antihypertensive effect develops within 4–6 hours after a single dose and persists for more than 24 hours. Perindopril achieves a high level of sustained ACE inhibition (approximately 80%) 24 hours after administration.

In patients who respond to treatment, normalization of arterial pressure occurs within one month and is maintained without tachyphylaxis.

Discontinuation of therapy is not associated with a rebound effect.

Perindopril has vasodilatory properties, restores elasticity of large arteries, corrects histomorphometric changes in resistance arteries, and reduces left ventricular hypertrophy. Additional synergy develops when a thiazide diuretic is added, if necessary.

The combination of an ACE inhibitor and a thiazide diuretic reduces the risk of hypokalemia that may occur when a diuretic is used as monotherapy.

Indapamide

The antihypertensive effect of indapamide as monotherapy lasts 24 hours. This effect is evident at doses where diuretic properties are minimal.

The antihypertensive effect of indapamide is associated with improved arterial elasticity and reduced arteriolar resistance and total peripheral vascular resistance.

Indapamide reduces left ventricular hypertrophy.

When the recommended dose is exceeded, the therapeutic effect of thiazide and thiazide-like diuretics does not increase, while the number of adverse effects increases. If treatment is insufficiently effective, dose escalation is not recommended.

Moreover, studies of varying duration (short, medium, and long-term) in patients with arterial hypertension have shown that indapamide: does not affect lipid metabolism (triglycerides, low- and high-density lipoproteins); does not affect carbohydrate metabolism, even in patients with arterial hypertension and diabetes mellitus.

Amlodipine

The mechanism of amlodipine’s antihypertensive effect is due to direct relaxation of vascular smooth muscle. The exact mechanism by which amlodipine reduces angina symptoms is not fully defined, but it is known that the drug reduces total ischemic load through the following actions:

• amlodipine dilates peripheral arterioles, thereby reducing total peripheral resistance (afterload); since heart rate does not change, reduced cardiac load decreases myocardial energy consumption and oxygen demand;
• amlodipine partially promotes dilation of major coronary arteries and arterioles in both unaffected and ischemic myocardial zones; this dilation increases oxygen delivery to the myocardium in patients with Prinzmetal’s angina.

In patients with arterial hypertension, once-daily administration of amlodipine provides clinically significant reduction in arterial pressure over 24 hours, both in supine and standing positions.

In patients with angina, once-daily administration of amlodipine prolongs total exercise duration, time to onset of angina, and time to 1 mm ST-segment depression. Amlodipine reduces the frequency of angina attacks and decreases the need for nitroglycerin tablets.

Amlodipine is not associated with negative metabolic effects or changes in plasma lipid levels, making it suitable for use in patients with asthma, diabetes mellitus, and gout.

Clinical Efficacy and Safety.

No morbidity and mortality studies have been conducted with Co-Amlessa. Perindopril

Concomitant use of ACE inhibitors and angiotensin II receptor blockers was 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 was a study involving patients with prior cardiovascular or cerebrovascular disease or type 2 diabetes with target organ damage. VA NEPHRON-D was a study involving patients with type 2 diabetes and diabetic nephropathy.

The studies did not demonstrate significant beneficial effects on renal and/or cardiovascular disease outcomes or mortality, while an increased risk of hyperkalemia, acute kidney injury, and/or hypotension was observed compared to monotherapy. Given the similar pharmacodynamic properties, these results are also applicable to other ACE inhibitors and angiotensin II receptor blockers.

Concomitant use of ACE inhibitors and angiotensin II receptor blockers is contraindicated in patients with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes with Cardiovascular and Renal Disease Endpoints) was a study evaluating the benefits of adding aliskiren to standard therapy with an ACE inhibitor or angiotensin II receptor blocker in patients with type 2 diabetes and/or chronic kidney disease, cardiovascular disease. The study was terminated prematurely due to increased risk of adverse outcomes. Cardiovascular mortality, incidence of stroke, and reports of adverse events and serious complications (hyperkalemia, arterial hypotension, or renal function impairment) were more frequent in the group receiving aliskiren compared to the placebo group.

Perindopril/Indapamide

PICXEL was a multicenter, randomized, double-blind, controlled study evaluating the effect of perindopril/indapamide combination on left ventricular hypertrophy compared to enalapril monotherapy (based on echocardiographic results).

In the PICXEL study, hypertensive patients with left ventricular hypertrophy (left ventricular mass index >120 g/m² in men and >100 g/m² in women) were randomized into two groups: one group received 2 mg perindopril tert-butylamine/0.625 mg indapamide, and the other received 10 mg enalapril once daily for one year. Doses were adjusted according to blood pressure: perindopril tert-butylamine dose was increased up to 8 mg, indapamide up to 2.5 mg, enalapril up to 40 mg once daily. Starting doses were maintained in 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] from -11.5 to -5.0, p < 0.0001).

The best effect on reducing left ventricular mass index was achieved with perindopril/indapamide.

Arterial pressure reduction was more effective in the perindopril/indapamide group: the difference in mean blood pressure reduction between the two patient groups was -5.8 mm Hg (95% CI from -7.9 to -3.7, p < 0.0001) for systolic blood pressure and -2.3 mm Hg (95% CI from -3.6 to -0.9, p = 0.0004) for diastolic blood pressure, favoring the perindopril/indapamide group.

ADVANCE was an international multicenter randomized study with a 2×2 factorial design aimed at determining the benefits of blood pressure reduction with fixed combination perindopril/indapamide compared to placebo on background standard therapy [double-blind comparison (prospective randomized open-label blinded endpoint evaluation)] regarding impact on major macro- and microvascular events in patients with type 2 diabetes. The primary endpoint consisted of major macrovascular (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke) and microvascular events (new onset or worsening nephropathy, retinopathy). A total of 11,140 patients with type 2 diabetes were included. Among them, 83% had arterial hypertension, 32% and 10% had prior micro- and macrovascular disease, respectively, and 27% had microalbuminuria. Concomitant therapy included antihypertensive agents (75%), lipid-lowering agents (35%, primarily statins – 28%), aspirin or other antiplatelet agents (47%).

Treatment with perindopril/indapamide combination for 4.3 years led to a significant 9% relative risk reduction in the primary endpoint (95% confidence interval [CI] [0.828; 0.996], p = 0.041). The benefits of perindopril/indapamide treatment compared to placebo group were due to: significant 14% relative risk reduction in all-cause mortality (95% CI [0.75; 0.98], p = 0.025); significant 18% relative risk reduction in cardiovascular mortality (95% CI [0.68; 0.98], p = 0.027); significant 21% relative risk reduction in all renal events (95% CI [0.74; 0.86], p < 0.001).

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

The benefits of blood pressure-lowering treatment were independent of those observed with intensive glucose control.

Amlodipine

A randomized, double-blind, clinical trial on morbidity and mortality, "Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial" (ALLHAT), compared newer treatment approaches: amlodipine 2.5–10 mg/day (calcium channel blocker) or lisinopril 10–40 mg/day (ACE inhibitor) as first-line therapy versus treatment with the thiazide diuretic chlorthalidone 12.5–25 mg/day in mild to moderate hypertension.

A total of 33,357 hypertensive patients aged 55 years and older were randomized and followed for a median of 4.9 years. Patients had at least one additional risk factor for ischemic heart disease, including prior myocardial infarction or stroke (>6 months before enrollment) or confirmed other atherosclerotic cardiovascular disease (CVD) (overall 51.5%), type 2 diabetes (36.1%), LDL cholesterol <35 mg/dL or <0.906 mmol/L (11.6%), left ventricular hypertrophy diagnosed by ECG or echocardiography (20.9%), smoking (21.9%).

The primary endpoint consisted of fatal ischemic heart disease or non-fatal myocardial infarction. The primary endpoint did not significantly differ between amlodipine-based and chlorthalidone-based therapies: relative risk (RR) 0.98, 95% CI (0.90–1.07), p=0.65. Among secondary endpoints, the incidence of heart failure (a component of the composite cardiovascular endpoint) was significantly higher in the amlodipine group compared to the chlorthalidone group (10.2% vs. 7.7%, RR 1.38, 95% CI [1.25–1.52], <0.001). However, there was no significant difference between amlodipine and chlorthalidone in all-cause mortality: RR 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 "Dosage and Administration").

Pharmacokinetics.

Co-Amlessa

Administration of perindopril/indapamide and amlodipine in fixed combination does not alter their pharmacokinetic properties compared to monotherapy.

Perindopril

After oral administration, perindopril is rapidly absorbed, and peak concentration is reached within 1 hour. The elimination half-life of perindopril in plasma is 1 hour. Since food intake reduces conversion to perindoprilat and thus bioavailability, perindopril should be administered orally as a single daily dose in the morning before meals.

Distribution

The volume of distribution of free perindopril is approximately 0.2 L/kg. Protein binding of perindopril to plasma proteins is 20%, particularly to ACE, but depends on concentration.

Metabolism

Perindopril is a prodrug. 27% of the total absorbed perindopril is converted into the active metabolite perindoprilat. Additionally, five inactive metabolites are formed. Maximum plasma concentration of perindoprilat is reached within 3–4 hours.

Excretion

Perindoprilat is excreted in urine, and the half-life of the unbound fraction is approximately 17 hours, leading to steady-state levels within 4 days.

Linearity/Non-linearity

A linear relationship between perindopril dose and plasma concentration has been demonstrated.

Special Patient Populations

Elderly Patients

In elderly individuals and patients with cardiac or renal insufficiency, perindoprilat elimination is reduced.

Patients with Renal Impairment

In renal impairment, dose adjustment is recommended depending on the degree of impairment (creatinine clearance).

Patients Undergoing Dialysis

Perindoprilat is removed from circulation by dialysis, with a clearance of 70 mL/min.

Patients with Liver Cirrhosis

In liver cirrhosis, perindopril kinetics are altered, with hepatic clearance of the parent molecule reduced by half, but the amount of formed perindoprilat remains unchanged; therefore, the dose of the drug does not need to be adjusted in this condition (see sections "Dosage and Administration" and "Special Warnings and Precautions for Use").

Indapamide

Absorption and Distribution

Indapamide is rapidly and completely absorbed in the gastrointestinal tract. Maximum plasma concentration is reached approximately 1 hour after oral administration. Protein binding to plasma proteins is 79%.

Biotransformation and Excretion

The elimination half-life ranges from 14 to 24 hours (average 18 hours). Repeated administration does not lead to accumulation.

Indapamide is primarily excreted in urine (70% of dose) and feces (22%) as inactive metabolites.

Special Patient Populations

Patients with Renal Impairment

In patients with renal insufficiency, pharmacokinetic parameters do not change.

Amlodipine

Absorption and Bioavailability

After oral administration of therapeutic doses, amlodipine is well absorbed and reaches maximum blood concentration 6–12 hours after administration. Absolute bioavailability ranges from 64% to 80%. Food intake does not affect amlodipine bioavailability.

Distribution

The volume of distribution is approximately 21 L/kg. In vitro studies have shown that about 97.5% of circulating amlodipine in blood is protein-bound.

Biotransformation

Amlodipine is primarily metabolized in the liver into inactive metabolites; 60% of the administered dose is excreted in urine, and 10% is excreted unchanged.

Excretion

The elimination half-life of amlodipine from plasma is approximately 35–50 hours, allowing once-daily dosing.

Special Patient Populations

Elderly Patients

Time to reach maximum plasma concentration of amlodipine is similar in elderly and younger patients. In elderly patients, there is a tendency toward reduced amlodipine clearance, leading to increased AUC and elimination half-life. Increased AUC and half-life in patients with congestive heart failure corresponded to age-related characteristics.

Patients with Renal Impairment

Pharmacokinetics of amlodipine are not altered in patients with renal insufficiency.

Patients with Hepatic Impairment

There is very limited clinical data on amlodipine use in patients with hepatic impairment. In patients with hepatic insufficiency, amlodipine clearance is reduced, leading to prolonged elimination half-life and increased AUC by approximately 40–60%.

Clinical characteristics.

Indications.

Co-Amalessa is indicated for the treatment of arterial hypertension in patients who require treatment with perindopril, indapamide, and amlodipine in doses available in fixed combination.

Contraindications.

• Hypersensitivity to perindopril or any other angiotensin-converting enzyme (ACE) inhibitor, to indapamide or any other sulfonamides, to amlodipine or dihydropyridines, or to any of the excipients;
• History of angioedema (Quincke's edema) associated with previous ACE inhibitor therapy (see section "Special precautions for use");
• Hereditary or idiopathic angioedema;
• Hepatic encephalopathy;
• Severe hepatic impairment;
• Hypokalemia;
• Severe arterial hypotension;
• Shock, including cardiogenic shock;
• Left ventricular outflow tract obstruction (e.g., severe aortic stenosis);
• Heart failure with unstable hemodynamics following acute myocardial infarction;
• Untreated decompensated heart failure;
• Concomitant administration with medicinal products containing the active substance aliskiren in patients with diabetes mellitus or renal impairment (glomerular filtration rate < 60 mL/min/1.73 m²) (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction");
• Use in patients undergoing hemodialysis;
• Severe renal impairment (creatinine clearance < 30 mL/min);
• Moderate renal impairment (creatinine clearance < 60 mL/min) when using Co-Amalessa containing active substances in doses of 8 mg/2.5 mg/5 mg or 8 mg/2.5 mg/10 mg;
• Pregnancy or planned pregnancy;
• Pediatric age;
• Concomitant use with sacubitril/valsartan therapy – due to increased risk of angioedema. The medicinal product should not be used within 36 hours after the last dose of sacubitril/valsartan or after switching from sacubitril/valsartan to another drug containing a neprilysin inhibitor (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction");
• Extracorporeal treatment methods leading to blood contact with negatively charged surfaces (see section "Interaction with other medicinal products and other forms of interaction");
• Significant bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney (see section "Special precautions for use").

Interaction with other medicinal products and other forms of interaction.

Medicinal products causing hyperkalemia

Some medicinal products or therapeutic classes may cause hyperkalemia, namely: 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 medicinal products increases the risk of hyperkalemia.

Concomitant use is contraindicated (see section "Contraindications")

Aliskiren

In patients with diabetes mellitus or impaired renal function, the risk of hyperkalemia, worsening renal function, and cardiovascular morbidity and mortality increases (see section "Special precautions for use").

Extracorporeal treatment methods leading to blood contact with negatively charged surfaces, such as high-flux dialysis or hemofiltration membranes (e.g., polyacrylonitrile membranes) or for low-density lipoprotein apheresis with dextran sulfate – increases the risk of severe anaphylactoid reactions (see section "Contraindications"). If such treatment is necessary, consider using a different type of dialysis membrane or another class of antihypertensive agents.

Sacubitril/valsartan

Concomitant use of perindopril with sacubitril/valsartan is contraindicated due to increased risk of angioedema. Initiation of sacubitril/valsartan should not occur earlier than 36 hours after the last dose of perindopril. Therapy with perindopril should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Special precautions for use").

Concomitant use not recommended

Perindopril/indapamide

Lithium

Reversible increases in serum lithium concentration and lithium toxicity have been reported with concomitant use of lithium and ACE inhibitors. However, if such combination is necessary, serum lithium levels should be closely monitored (see section "Special precautions for use").

Perindopril

Concomitant use of ACE inhibitors and angiotensin receptor blockers

Clinical trial data indicate that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with a higher incidence of adverse reactions such as hypotension, hyperkalemia, and reduced renal function (including acute renal failure), compared to use of a single RAAS-acting agent (see sections "Pharmacodynamics", "Contraindications", and "Special precautions for use").

Potassium-sparing diuretics (e.g., triamterene, amiloride, etc.), potassium-containing compounds

Combining perindopril with the above-mentioned agents is not recommended due to the risk of hyperkalemia (potentially fatal), especially in patients with impaired renal function (additive hyperkalemic effect) (see section "Special precautions for use"). If concomitant use is indicated, it should be done with caution and regular monitoring of serum potassium levels. For spironolactone use in heart failure, see "Concomitant use requiring special monitoring" below.

Co-trimoxazole (trimethoprim/sulfamethoxazole)

In patients receiving co-trimoxazole (trimethoprim/sulfamethoxazole), the risk of hyperkalemia is increased (see section "Special precautions for use").

Estramustine: increased risk of adverse reactions such as angioedema.

Concomitant use requiring special monitoring

Perindopril/indapamide/amlodipine

Baclofen potentiates the antihypertensive effect. Blood pressure and renal function should be monitored, and dose adjustment may be necessary.

Perindopril/indapamide

Nonsteroidal anti-inflammatory drugs (NSAIDs), including salicylates at doses > 3 g/day

When ACE inhibitors are administered concomitantly with NSAIDs such as acetylsalicylic acid at anti-inflammatory doses, COX-2 inhibitors, or non-selective NSAIDs, the antihypertensive effect may be attenuated. Concomitant use of ACE inhibitors and NSAIDs increases the risk of worsening renal function, including acute renal failure, and elevated blood potassium levels, particularly in patients with pre-existing renal impairment. This combination should be used with caution, especially in elderly patients. In such patients, fluid balance should be restored and renal function monitoring considered after initiation of combination therapy and during continued treatment.

Perindopril

Antidiabetic agents (insulin, oral hypoglycemic agents)

Epidemiological studies suggest that concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemic agents) may enhance the hypoglycemic effect, increasing the risk of hypoglycemia. This phenomenon most commonly occurs during the first weeks of combination therapy and in patients with renal impairment.

Non-potassium-sparing diuretics or diuretics that do not conserve potassium

In patients taking diuretics, especially those with disturbed water-electrolyte balance, excessive reduction in blood pressure may occur after initiation of ACE inhibitor therapy. The likelihood of hypotensive effects can be reduced by discontinuing the diuretic, increasing circulating blood volume (CBV), and increasing salt intake before starting perindopril therapy, which should begin with low doses and gradually increase.

In arterial hypertension, if a previously prescribed diuretic may have caused fluid/electrolyte deficiency, it should be discontinued before starting ACE inhibitor therapy (diuretic use may be resumed later), or the ACE inhibitor should be initiated at a low dose with gradual dose escalation.

In congestive heart failure, when diuretics are used, ACE inhibitor therapy should be initiated at the lowest dose, possibly after reducing the dose of non-potassium-sparing diuretics. In any case, renal function (creatinine levels) should be monitored during the first weeks of ACE inhibitor therapy.

Potassium-sparing diuretics (eplerenone, spironolactone)

Concomitant use of eplerenone or spironolactone at doses from 12.5 mg to 50 mg daily with low doses of ACE inhibitors: if recommendations for such combination are not followed, there is a risk of hyperkalemia (possibly fatal) during treatment of patients with NYHA class II–IV heart failure and ejection fraction < 40%, previously treated with an ACE inhibitor and a loop diuretic. Before prescribing such combination, ensure absence of hyperkalemia and renal impairment. Close monitoring of serum potassium and creatinine is recommended weekly during the first month of treatment and monthly thereafter.

Cyclosporine

Concomitant use of ACE inhibitors with cyclosporine increases the risk of hyperkalemia. Monitoring of serum potassium levels is recommended.

Heparin

Concomitant use of ACE inhibitors with heparin increases the risk of hyperkalemia. Monitoring of serum potassium levels is recommended.

Indapamide

Due to the risk of hypokalemia, indapamide should be used cautiously in combination with medicinal products that may cause torsades de pointes-type ventricular tachycardia, such as:

• Class IA antiarrhythmics (quinidine, hydroquinidine, disopyramide);
• Class III antiarrhythmics (amiodarone, sotalol, dofetilide, ibutilide, bretylium);
• Certain neuroleptics (chlorpromazine, tiaramide, levomepromazine, thioridazine, trifluoperazine), benzamides (amisulpride, sulpiride, sultopride, tiapride), butyrophenones (droperidol, haloperidol), other neuroleptics (pimozide);
• Other agents such as bepridil, cisapride, difemanyl, intravenous erythromycin, halofantrine, mizolastine, pentamidine, moxifloxacin, sparfloxacin, intravenous vinpocetine, methadone, astemizole, terfenadine.

Plasma potassium levels should be prevented from decreasing and corrected if necessary; QT interval should be monitored.

Medicinal products that reduce potassium levels (amphotericin B (intravenous), glucocorticoids and mineralocorticoids (systemic), tetracosactide, laxatives (stimulating peristalsis)) increase the risk of reduced serum potassium (additive effect). Plasma potassium levels should be monitored and corrected as needed, especially when used concomitantly with cardiac glycosides. Laxatives that do not stimulate peristalsis are recommended.

Cardiac glycosides

Toxic effects of cardiac glycosides are favored by hypokalemia and/or hypomagnesemia. Monitoring of plasma potassium and magnesium levels, ECG monitoring, and treatment adjustment if needed are recommended.

Allopurinol

Concomitant use with indapamide increases the risk of hypersensitivity reactions to allopurinol.

Concomitant use with caution advised

Potassium-sparing diuretics (amiloride, spironolactone, triamterene)

Although rational combinations may be beneficial for some patients, hypokalemia or hyperkalemia (especially in patients with renal impairment or diabetes) may still occur. Plasma potassium levels should be monitored, ECG monitoring performed, and treatment adjusted if needed.

Perindopril/indapamide/amlodipine

Imipramine-like (tricyclic) antidepressants, neuroleptics increase antihypertensive effects and risk of orthostatic hypotension (additive effect).

Other antihypertensive agents

Concomitant use of other antihypertensive agents with Co-Amalessa may cause additional reduction in blood pressure.

Corticosteroids, tetracosactide (systemic use)

Weakening of antihypertensive effect (due to water and salt retention by corticosteroids).

Perindopril

Antihypertensive agents and vasodilators: concomitant use with nitroglycerin and other nitrates or other vasodilators may lead to additional reduction in blood pressure.

Allopurinol, cytostatics, immunosuppressants, systemic corticosteroids or procainamide: concomitant use with ACE inhibitors increases the risk of leukopenia (see section "Special precautions for use").

Anesthetic agents

ACE inhibitors may potentiate the hypotensive effect of certain anesthetic agents (see section "Special precautions for use").

Diuretics

Prior treatment with high-dose diuretics may cause dehydration, increasing the risk of hypotension at the start of perindopril therapy.

Gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin): in patients receiving a combination of a gliptin and an ACE inhibitor, the risk of angioedema increases because gliptins reduce dipeptidyl peptidase-IV (DPP-IV) activity.

Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.

Gold preparations

Concomitant use of ACE inhibitors, including perindopril, and injectable gold preparations (sodium aurothiomalate) may rarely cause reactions similar to those seen with nitrates (symptoms: facial flushing, nausea, vomiting, and hypotension).

Racecadotril

ACE inhibitors (e.g., perindopril) are known to cause angioedema. This risk increases with concomitant use of racecadotril (a medicinal product used for treatment of acute diarrhea).

mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus)

In patients receiving concomitant mTOR inhibitors, the risk of angioedema increases (see section "Special precautions for use").

Indapamide

Metformin may cause lactic acidosis due to functional renal impairment associated with diuretic use, especially loop diuretics. Metformin should not be prescribed if plasma creatinine exceeds 15 mg/L (135 µmol/L) in men and 12 mg/L (110 µmol/L) in women.

Iodinated contrast agents

In cases of dehydration associated with diuretic use, the risk of acute renal failure increases, especially with high doses of iodinated contrast agents. Fluid balance should be restored before administration of such agents.

Calcium (salts)

There is a risk of hypercalcemia due to reduced urinary calcium excretion.

Cyclosporine

There is a risk of increased creatinine concentration without affecting circulating cyclosporine levels, even in the absence of water and sodium deficiency.

Amlodipine

Effect of other medicinal products on amlodipine

CYP3A4 inhibitors

Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil or diltiazem) may lead to significant increase in amlodipine exposure, potentially increasing the risk of hypotension. The clinical significance of these changes may be more pronounced in elderly patients. Clinical monitoring and dose adjustment may be necessary.

Grapefruit juice

Concomitant use of amlodipine with grapefruit or grapefruit juice is not recommended, as in some patients, amlodipine bioavailability may increase, leading to enhanced hypotensive effects.

Clarithromycin

Clarithromycin is a CYP3A4 inhibitor. Concomitant use of clarithromycin with amlodipine increases the risk of hypotension. Therefore, careful monitoring of patients is recommended when amlodipine is used concomitantly with clarithromycin.

mTOR inhibitors (mammalian target of rapamycin)

mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are CYP3A substrates. Amlodipine is a weak CYP3A inhibitor. Amlodipine may increase the effects of mTOR inhibitors when used concomitantly.

CYP3A4 inducers

When known CYP3A4 inducers are used concomitantly, plasma concentrations of amlodipine may change. Therefore, blood pressure should be monitored and dose adjustment considered during and after concomitant use, especially with strong CYP3A4 inducers (e.g., rifampicin, St. John's wort).

Dantrolene (infusions)

In animals, ventricular fibrillation with fatal outcome and cardiovascular collapse associated with hyperkalemia were observed after intravenous administration of verapamil and dantrolene. Due to the risk of hyperkalemia, calcium channel blockers such as amlodipine should be avoided in patients susceptible to malignant hyperthermia and during treatment of malignant hyperthermia.

Effect of amlodipine on other medicinal products

The hypotensive effect of amlodipine potentiates the hypotensive effects of other antihypertensive agents.

Tacrolimus

There is a risk of increased blood levels of tacrolimus with concomitant use of amlodipine, although the pharmacokinetic mechanism of this interaction is not fully understood. To avoid tacrolimus toxicity, regular monitoring of blood tacrolimus levels and dose adjustment if necessary are required when amlodipine is used concomitantly.

Cyclosporine

Interaction studies between cyclosporine and amlodipine have not been conducted in healthy volunteers or other groups, except in kidney transplant recipients, where variable increases in cyclosporine trough concentrations (on average 0–40%) were observed. For kidney transplant recipients taking amlodipine, cyclosporine concentration monitoring should be considered, and cyclosporine dose reduction may be necessary.

Simvastatin

Concomitant use of multiple doses of amlodipine 10 mg and simvastatin 80 mg resulted in a 77% increase in simvastatin exposure compared to simvastatin alone. For patients taking amlodipine, the simvastatin dose should be limited to 20 mg daily.

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

Special precautions for use

All the warnings below regarding individual components also apply to the medicinal product Co-Amlessa as a whole.

Lithium

Concomitant use of lithium and the perindopril/indapamide combination is generally not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Potassium-sparing medicinal products, potassium-containing dietary supplements or potassium salt substitutes

Concomitant use of perindopril with potassium-sparing medicinal products or potassium-containing dietary supplements is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Neutropenia/agranulocytosis/thrombocytopenia/anemia

Cases of neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported in patients receiving angiotensin-converting enzyme (ACE) inhibitors. Neutropenia is rare in patients with normal renal function and in the absence of other risk factors. Perindopril should be administered with great caution to patients with collagen vascular diseases, those receiving immunosuppressive therapy, allopurinol, procainamide, or a combination of these factors, especially if renal function is impaired. In some of these patients, serious infectious diseases have been observed, in several cases resistant to intensive antibiotic therapy. If perindopril is prescribed to such patients, periodic monitoring of white blood cell count is recommended. They should also be advised to report any signs of infection (sore throat, fever) (see section "Side effects").

Hypersensitivity/angioedema

Rare cases of angioedema of the face, extremities, lips, tongue, glottis and/or larynx have been reported during treatment with ACE inhibitors, including perindopril (see section "Side effects"). This may occur at any time during treatment.

In such cases, perindopril must be discontinued immediately and appropriate monitoring of the patient should be instituted until symptoms completely resolve. If swelling is limited to the face and lips, the patient's condition usually improves without treatment, and antihistamine therapy may help relieve symptoms.

Angioedema associated with laryngeal swelling can be fatal. If swelling extends to the tongue, glottis or larynx, with a risk of airway obstruction, emergency treatment is required, which may include subcutaneous administration of epinephrine 1:1000 solution (0.3–0.5 mL) and/or securing airway patency.

It has been reported that ACE inhibitors cause angioedema more frequently in patients of African descent than in patients of other races.

Patients with a history of angioedema not related to ACE inhibitor use have an increased risk of developing it during ACE inhibitor therapy (see section "Contraindications").

Rare cases of intestinal angioedema have been observed in patients receiving ACE inhibitors. These patients experienced abdominal pain (with or without nausea and vomiting); in some cases, prior angioedema of the face was not observed, and C-1 esterase levels were normal. The diagnosis of intestinal angioedema was established by computed tomography, ultrasound, or surgical intervention. Symptoms of angioedema resolved after discontinuation of the ACE inhibitor. Intestinal angioedema should be considered in the differential diagnosis of abdominal pain occurring in patients receiving ACE inhibitors.

Sacubitril/valsartan

Concomitant use of perindopril with sacubitril/valsartan is contraindicated due to increased risk of angioedema. Initiation of sacubitril/valsartan should not begin earlier than 36 hours after the last dose of perindopril. Perindopril therapy should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Special precautions for use").

mTOR inhibitors

Concomitant use of ACE inhibitors with neutral endopeptidase inhibitors (racecadotril), mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) increases the risk of angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) (see section "Interaction with other medicinal products and other forms of interaction").

Caution is required when initiating racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin in patients already receiving an ACE inhibitor.

Anaphylactoid reactions during desensitization therapy

Isolated cases of life-threatening, prolonged anaphylactoid reactions have been reported in patients receiving ACE inhibitors during desensitization therapy with bee or wasp venom. ACE inhibitors should be used with caution in patients with allergies after desensitization and avoided during immunotherapy with animal-derived venomous substances.

However, in patients requiring both ACE inhibitors and desensitization therapy, such reactions can be avoided by temporarily discontinuing the ACE inhibitor at least 24 hours before desensitization.

Anaphylactoid reactions during low-density lipoprotein (LDL) plasmapheresis

Rarely, life-threatening anaphylactoid reactions have occurred in patients receiving ACE inhibitors during LDL plasmapheresis using dextran sulfate. These reactions can be avoided by temporarily discontinuing ACE inhibitor therapy before each plasmapheresis session.

Patients undergoing hemodialysis

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

Primary hyperaldosteronism

Patients with primary hyperaldosteronism generally do not respond to antihypertensive therapy acting via inhibition of the renin-angiotensin-aldosterone system (RAAS). Therefore, this medicinal product is not recommended for such patients.

Hepatic encephalopathy

Indapamide: in patients with impaired liver function, the use of thiazide and thiazide-like diuretics, especially in the presence of electrolyte imbalance, may precipitate hepatic encephalopathy, which may progress to hepatic coma. In such cases, diuretic therapy should be discontinued immediately.

Photosensitization

Cases of photosensitization reactions have been reported in patients receiving thiazide and thiazide-like diuretics (see section "Side effects"). If such reactions occur, diuretic therapy should be discontinued. If diuretic therapy must be resumed, vulnerable areas should be protected from sunlight or artificial ultraviolet sources.

Renal function

• The use of the medicinal product is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min).
• The use of Co-Amlessa containing the perindopril/indapamide combination at doses of 8 mg/2.5 mg (i.e., Co-Amlessa 8 mg/2.5 mg/5 mg and 8 mg/2.5 mg/10 mg) is contraindicated in patients with moderate renal impairment (creatinine clearance < 60 mL/min).
• If laboratory signs of renal impairment develop in patients with arterial hypertension without pre-existing signs of renal dysfunction, the drug should be discontinued; therapy may be resumed at a lower dose or with one of the components.
• These patients require frequent monitoring of potassium and creatinine: 2 weeks after initiation of therapy and every 2 months thereafter during therapeutic stabilization. Cases of renal impairment have been observed predominantly in patients with severe heart failure or renal dysfunction, including renal artery stenosis.
• This combination is not recommended for patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney.
• Risk of arterial hypotension and/or renal impairment (in heart failure, water and electrolyte deficiency, etc.): significant activation of the RAAS occurs in cases of marked water and electrolyte deficiency (strict salt-free diet or prolonged diuretic therapy) in patients with low blood pressure, renal artery stenosis, congestive heart failure, or patients with cirrhosis with edema and ascites.

Blocking this system with an ACE inhibitor, especially during the first dose and the first two weeks of treatment, may cause a sharp drop in blood pressure and/or an increase in plasma creatinine levels, confirming functional renal impairment. This may occasionally have an acute onset and occur at any time. In such cases, therapy should be initiated at a lower dose with gradual dose escalation. In patients with ischemic heart disease (IHD) or cerebrovascular disease, significant blood pressure reduction may lead to myocardial infarction or stroke.

• Thiazide and thiazide-like diuretics show the greatest efficacy when there is no renal dysfunction or when it is mild (serum creatinine below approximately 25 mg/L, i.e., 220 µmol/L in adults).

In elderly patients, serum creatinine levels should correspond to age, body weight, and sex.

• Hypovolemia caused by loss of water and sodium due to diuretic use at the start of therapy leads to decreased glomerular filtration. This may result in increased blood urea and creatinine levels. This transient functional renal impairment has no consequences in patients with normal renal function but may exacerbate existing renal impairment.
• Amlodipine can be used in standard doses in patients with renal impairment. Plasma concentration fluctuations of amlodipine do not depend on the degree of renal impairment.
• Studies on the use of Co-Amlessa in patients with renal impairment have not been conducted. For patients with renal impairment, Co-Amlessa dosing should correspond to individually adjusted doses of the monocomponents.

Hypotension, water and electrolyte deficiency

There is a risk of sudden drop in blood pressure in patients with sodium deficiency (particularly in patients with renal artery stenosis). Therefore, patients should be systematically monitored for signs of water and electrolyte deficiency, which may occur with vomiting or diarrhea. In such patients, plasma electrolyte levels should be regularly monitored.

In case of pronounced hypotension, intravenous administration of isotonic sodium chloride solution may be required. Transient hypotension is not a contraindication for further use of the drug. After restoration of circulating blood volume (CBV) and normalization of blood pressure, therapy may be resumed at a lower dose or with one of the drug components.

Sodium levels

• Treatment with any diuretic may cause hyponatremia, which may sometimes lead to serious consequences. Initial sodium concentration reduction may be asymptomatic; therefore, this parameter should be regularly monitored in laboratory tests. More frequent monitoring is required for elderly patients and patients with liver cirrhosis (see sections "Side effects" and "Overdose").
• Hyponatremia with hypovolemia may cause dehydration and orthostatic hypotension. Concomitant chloride ion loss may lead to secondary compensatory metabolic alkalosis: the frequency and degree of this effect are minor.

Potassium levels

• Treatment with the combination of indapamide, perindopril, and amlodipine does not exclude the possibility of hypokalemia, particularly in patients with diabetes mellitus or renal impairment. As with any antihypertensive drug combined with a diuretic, plasma potassium levels should be regularly monitored.
• ACE inhibitors may cause hyperkalemia due to suppression of aldosterone release. In patients with normal renal function, this effect is usually minor. Risk factors for hyperkalemia include renal impairment, worsening renal function, age over 70 years, diabetes mellitus, intercurrent conditions such as dehydration, acute heart failure, metabolic acidosis, and concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium-containing dietary supplements, or potassium salt substitutes; use of other drugs causing increased plasma potassium concentration (e.g., heparin, trimethoprim or cotrimoxazole, also known as trimethoprim/sulfamethoxazole, angiotensin receptor antagonists or angiotensin receptor blockers, acetylsalicylic acid ≥ 3 g/day, COX-2 inhibitors and non-selective NSAIDs, immunosuppressants such as cyclosporine or tacrolimus). Use of potassium-containing dietary supplements, potassium-sparing diuretics, or potassium salt substitutes, especially in patients with impaired renal function, may also lead to significant increase in plasma potassium levels. Hyperkalemia may cause serious, sometimes fatal, arrhythmias. Potassium-sparing diuretics and angiotensin receptor blockers should be used with caution in patients receiving ACE inhibitors, with careful monitoring of renal function and regular determination of serum potassium levels (see section "Interaction with other medicinal products and other forms of interaction").
• Decreased plasma potassium levels and hypokalemia are the main risk associated with thiazide and thiazide-like diuretics. Hypokalemia may cause muscle disorders. Cases of rhabdomyolysis have been reported, mainly in the context of severe hypokalemia. Hypokalemia (< 3.4 mmol/L) should be prevented in high-risk patients (elderly patients or those poorly nourished, patients taking multiple medications, patients with cirrhosis with edema and ascites, patients with IHD, and patients with heart failure). In case of hypokalemia, cardiotoxicity of cardiac glycosides and the risk of arrhythmias increase. Patients with congenital or iatrogenic prolonged QT interval also belong to the risk group. Hypokalemia, as well as bradycardia, may promote the development of severe cardiac arrhythmias, including paroxysmal ventricular tachycardia of the "torsade de pointes" type, which may be fatal.

In all these cases, more frequent monitoring of plasma potassium levels is required. The first measurement should be performed within the first week of treatment.

If serum potassium levels are decreased, correction is necessary.

Hypokalemia associated with low serum magnesium levels may be resistant to treatment unless serum magnesium levels are corrected.

Magnesium levels

Thiazides and related diuretics, including indapamide, have been shown to increase urinary magnesium excretion, which may lead to hypomagnesemia (see sections "Interaction with other medicinal products and other forms of interaction" and "Side effects").

Calcium levels

Thiazide and thiazide-like diuretics may reduce calcium excretion in urine and lead to slight and transient increase in plasma calcium levels. Markedly elevated calcium levels may indicate previously undiagnosed hyperparathyroidism. Treatment should be discontinued until parathyroid function is evaluated (see section "Side effects").

Dual blockade of the RAAS

There are reports that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of arterial hypotension, syncope, stroke, hyperkalemia, and renal impairment (including acute renal failure) in susceptible individuals, especially when combined with drugs affecting the RAAS.

Concomitant use with aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (glomerular filtration rate < 60 mL/min/1.73 m²) (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Combination of ACE inhibitors, angiotensin receptor blockers, or aliskiren due to dual RAAS blockade is not recommended (see sections "Pharmacodynamics" and "Interaction with other medicinal products and other forms of interaction").

If dual blockade is considered absolutely necessary, treatment should be conducted only under physician supervision 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.

Renovascular hypertension

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

In patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney, treatment with ACE inhibitors increases the risk of arterial hypotension and renal impairment (see section "Contraindications"). Diuretic use may be a contributing factor. Decreased renal function may be accompanied by only minor changes in serum creatinine levels even in patients with unilateral renal artery stenosis.

If Co-Amlessa is prescribed to patients with diagnosed or suspected renal artery stenosis, therapy should be initiated in a hospital setting at low doses with potassium level monitoring. Functional renal impairment, reversible upon discontinuation of treatment, has been observed in some patients.

Patients with existing or suspected renal artery stenosis should not use the 8 mg/2.5 mg/5 mg and 8 mg/2.5 mg/10 mg doses, as therapy should be initiated in a hospital setting at a lower dose.

Cough

Dry cough has been reported during treatment with ACE inhibitors. This cough is persistent and resolves after discontinuation of the drug. Iatrogenic etiology of cough should be considered if this symptom occurs. If ACE inhibitor therapy is desired, continuation of therapy may be considered.

Atherosclerosis

The risk of hypotension exists in all patients, but perindopril should be prescribed with particular caution to patients with IHD or cerebral circulation insufficiency. In such cases, therapy should be initiated at a low dose.

Hypertensive crisis

The safety and efficacy of amlodipine in patients with hypertensive crisis have not been studied.

Heart failure/severe heart failure

Amlodipine should be administered with caution in patients with heart failure. In a long-term placebo-controlled study involving patients with severe heart failure (NYHA class III, IV), the incidence of pulmonary angioedema with amlodipine was higher compared to placebo (see section "Pharmacodynamics"). Calcium antagonists, including amlodipine, should be prescribed with caution in patients with congestive heart failure, as they increase the risk of cardiovascular complications and fatal outcomes.

In patients with severe heart failure (class IV), therapy should be initiated under medical supervision at a reduced initial dose. β-blocker therapy in patients with arterial hypertension and coronary insufficiency should not be discontinued: the ACE inhibitor is added to the β-blocker.

Aortic or mitral valve stenosis/hypertrophic cardiomyopathy

ACE inhibitors should be prescribed with caution to patients with left ventricular outflow obstruction.

Diabetic patients

In patients with insulin-dependent diabetes mellitus (due to tendency to spontaneous increase in potassium levels), therapy should be initiated under medical supervision at a reduced initial dose.

In patients with diabetes mellitus receiving oral antidiabetic agents or insulin, blood glucose levels should be carefully monitored, especially during the first month of ACE inhibitor therapy (see section "Interaction with other medicinal products and other forms of interaction").

In patients with diabetes mellitus, blood glucose levels should be monitored carefully, particularly when potassium levels are low.

Racial characteristics

Perindopril, like other ACE inhibitors, is likely to be less effective in lowering blood pressure in hypertensive patients of African descent compared to others, possibly due to low plasma renin levels in these patients.

Surgery/anesthesia

ACE inhibitors may cause hypotension during anesthesia, particularly when anesthetics that lower blood pressure are used. Therefore, when treating with long-acting ACE inhibitors such as perindopril, the drug should be discontinued, if possible, one day before surgery.

Hepatic impairment

Rarely, ACE inhibitor use has been associated with a syndrome beginning with cholestatic jaundice and progressing to fulminant hepatic necrosis, sometimes fatal. The mechanism of this syndrome is unknown. Patients who develop jaundice or significant elevation of liver enzymes while taking an ACE inhibitor should discontinue the ACE inhibitor and undergo appropriate medical evaluation and treatment (see section "Side effects").

In patients with impaired liver function, prolonged elimination half-life and high AUC values for amlodipine are observed; dosing recommendations are lacking. Amlodipine therapy should be initiated at the lowest doses, with caution at the beginning of therapy and during dose escalation. Patients with severe hepatic impairment may require gradual dose titration and careful monitoring.

Studies on the use of Co-Amlessa in patients with hepatic impairment have not been conducted. Since the effects of individual components of Co-Amlessa are known, this medicinal product is contraindicated in patients with severe hepatic impairment and should be used with caution in mild to moderate hepatic impairment.

Uric acid

In patients with elevated uric acid levels, an increased number of gout attacks may occur.

Athletes

Athletes should be aware that the medicinal product contains an active substance (indapamide) that may cause a positive doping test.

Choroidal effusion, acute myopia, and secondary angle-closure glaucoma

Medicinal products containing sulfonamides or sulfonamide derivatives may cause an idiosyncratic reaction leading to choroidal effusion with visual field defects, transient myopia, and acute angle-closure glaucoma. Symptoms include sudden decrease in visual acuity or eye pain and usually occur within hours to weeks after starting the drug. Untreated acute angle-closure glaucoma may lead to permanent vision loss. Primary treatment is immediate discontinuation of the drug. If intraocular pressure remains uncontrolled, rapid medical or surgical treatment may be required. A risk factor for developing acute angle-closure glaucoma may be a history of allergy to sulfonamides or penicillin.

Elderly patients

Renal function and potassium levels should be checked before starting therapy. To reduce the risk of sudden hypotension, especially in the presence of water or electrolyte deficiency, the initial dose should be adjusted according to the blood pressure response to treatment. Dose escalation in elderly patients should be done cautiously (see sections "Pharmacokinetics" and "Method of administration and dosage").

Use during pregnancy or breastfeeding.

Pregnancy

The medicinal product Co-Amlessa is contraindicated in pregnant women or women planning pregnancy.

Warnings related to perindopril

There are no convincing epidemiological data on teratogenic risk with ACE inhibitors during the first trimester of pregnancy, but a slight increase in this risk cannot be excluded. In cases where continued antihypertensive therapy is considered mandatory, patients planning pregnancy should be switched to alternative antihypertensive agents with proven safety during pregnancy. If pregnancy is confirmed during treatment, ACE inhibitor therapy should be discontinued immediately and, if necessary, replaced with another medicinal product approved for use in pregnant women.

It is known that ACE inhibitor use during the second and third trimesters of pregnancy has toxic effects on the embryo (impaired renal function, oligohydramnios, delayed skull ossification) and on the newborn (renal failure, arterial hypotension, hyperkalemia).

If ACE inhibitors were used during the second and third trimesters, ultrasound evaluation of renal function and skull structure of the newborn is recommended.

Newborns whose mothers took ACE inhibitors during pregnancy should be closely monitored for timely detection and correction of arterial hypotension (see sections "Contraindications" and "Special precautions for use").

Warnings related to indapamide

The amount of data (less than 300 pregnancy cases) on indapamide use during pregnancy is limited. Prolonged use of a thiazide diuretic during the third trimester may lead to reduced circulating blood volume in the pregnant woman and uteroplacental perfusion, potentially causing fetoplacental ischemia and delayed fetal development. Animal studies do not indicate direct or indirect harmful effects on reproduction.

As a precautionary measure, indapamide use during pregnancy should be avoided.

Warnings related to amlodipine

Some data on amlodipine use during pregnancy suggest that amlodipine or other calcium channel antagonists may adversely affect fetal development. However, there is a risk of prolonged effect. Reproductive toxicity was observed in animal studies at high doses.

Lactation period

The medicinal product is not recommended for use during breastfeeding.

Warnings related to perindopril

There is insufficient information on perindopril use during breastfeeding.

Warnings related to indapamide

Information on indapamide/metabolite penetration into human milk is insufficient. Increased sensitivity to sulfonamide derivatives and hypokalemia may occur. Risk to newborns/infants cannot be excluded. Indapamide belongs to thiazide diuretics, which suppress milk secretion during breastfeeding.

Indapamide is not recommended for use during breastfeeding.

Warnings related to amlodipine

Amlodipine passes into human milk. The fraction of maternal dose received by the infant is estimated at 3–7%, maximum 15%. The effect of amlodipine on infants is unknown.

Fertility

Warnings related to perindopril and indapamide

Reproductive toxicity studies did not show effects on fertility in male and female rats. There is no effect on human fertility.

Warnings related to amlodipine

Reversible biochemical changes in sperm heads have been reported in some patients receiving calcium channel blockers. Clinical data on the potential effect of amlodipine on fertility are insufficient. An adverse effect on male fertility was observed in one rat study.

Ability to affect reaction speed when driving vehicles or operating machinery.

The effect of the medicinal product Co-Amlessa on the ability to affect reaction speed when driving vehicles or operating machinery has not been studied. Perindopril and indapamide do not affect the ability to drive vehicles or operate machinery. However, individual reactions related to decreased blood pressure may occur in some patients.

Amlodipine may slightly or moderately affect the ability to drive vehicles and operate machinery. Impaired reaction may occur if the patient experiences dizziness, headache, weakness, fatigue, or nausea.

Method of Administration and Dosage

Dosage

For oral use.

One tablet of Co-Amlessa daily, preferably in the morning before food.

Fixed-dose combination therapy is not intended for initial treatment.

If necessary, the dose of Co-Amlessa may be adjusted, or individual dose titration of each component separately may be recommended.

The maximum recommended dose of Co-Amlessa is 8 mg/2.5 mg/10 mg per day.

Patients with renal impairment (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use")

Treatment with Co-Amlessa is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min).

Co-Amlessa doses of 8 mg/2.5 mg/5 mg and 8 mg/2.5 mg/10 mg are contraindicated in patients with moderate renal impairment (creatinine clearance 30–60 mL/min). Individual dose titration using monocomponent formulations is recommended for these patients. Regular medical monitoring should include careful control of creatinine and potassium levels.

Concomitant use with aliskiren is contraindicated in patients with renal impairment (glomerular filtration rate < 60 mL/min/1.73 m²) (see section "Contraindications").

Patients with hepatic impairment

Treatment with Co-Amlessa is contraindicated in patients with severe hepatic impairment. Co-Amlessa should be used with caution in patients with mild to moderate hepatic impairment due to the lack of dosage recommendations for amlodipine.

Elderly patients (see section "Special Warnings and Precautions for Use")

Note that perindoprilat elimination is reduced in elderly patients. Co-Amlessa may be prescribed to elderly patients, taking renal function into account (see section "Contraindications").

Children

Safety and efficacy data for the use of Co-Amlessa in children are lacking; therefore, it is not administered to this age group.

Overdose

Data regarding Co-Amlessa overdose are unavailable.

When using the combination of perindopril/indapamide, the most common adverse reaction in case of overdose is arterial hypotension. Reflex tachycardia may also occur, sometimes accompanied by nausea, vomiting, seizures, dizziness, drowsiness, confusion, oliguria, which may progress to anuria (due to hypovolemia). Disturbances in water-electrolyte balance (decreased plasma potassium and sodium levels) may occur.

First-aid measures include rapid elimination of the drug from the body: gastric lavage and/or administration of activated charcoal, followed by restoration of water-electrolyte balance under hospital conditions until these parameters return to normal.

In case of significant hypotension, the patient should be placed in a horizontal position with low head elevation. If necessary, isotonic saline solution should be administered intravenously or any other method used to restore blood volume.

Perindoprilat, the active form of perindopril, can be removed from the body by hemodialysis. Since amlodipine is highly protein-bound, dialysis is unlikely to be beneficial.

Data on intentional amlodipine overdose are limited.

Based on available data, ingestion of very high doses is expected to cause excessive peripheral vasodilation and reflex tachycardia. Severe, possibly prolonged systemic hypotension and shock with fatal outcome have been reported.

Non-cardiogenic pulmonary edema has been rarely observed as a consequence of amlodipine overdose, which may not manifest immediately (within 24–48 hours after ingestion) and may require mechanical ventilation. Early resuscitative measures (including fluid loading) to support perfusion and cardiac output may be provocative factors.

Clinically significant hypotension caused by amlodipine overdose requires active cardiovascular support, including continuous monitoring of cardiac and respiratory function, elevation of lower limbs, and monitoring of circulating blood volume and urine output.

Administration of a vasoconstrictor may be helpful to restore vascular tone and arterial pressure, provided there are no contraindications. Intravenous calcium gluconate may help counteract the effects of calcium channel blockade.

In some cases, gastric lavage may be appropriate. Studies in healthy volunteers have shown that administration of activated charcoal 2 hours after ingestion of 10 mg amlodipine reduces the rate of amlodipine absorption. Since amlodipine is highly protein-bound, hemodialysis is considered ineffective.

Adverse Reactions

The most commonly observed adverse reactions during the use of the medicinal product are:

• caused by perindopril: dizziness, headache, paraesthesia, dysgeusia, visual disturbances, vertigo, tinnitus, hypotension, cough, dyspnea, abdominal pain, constipation, dyspepsia, diarrhea, nausea, vomiting, pruritus, rash, muscle spasms and asthenia;
• caused by indapamide: hypokalaemia, hypersensitivity reactions, predominantly dermatological, in individuals predisposed to allergic and asthmatic reactions and maculopapular rashes;
• caused by amlodipine: somnolence, dizziness, headache, palpitations, flushing, abdominal pain, nausea, ankle swelling, oedema and fatigue.

The adverse reactions listed below have been observed during treatment with perindopril, indapamide or amlodipine, and are categorized by frequency as follows: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (> 1/1000, < 1/100); rare (> 1/10000, < 1/1000); very rare (< 1/10000); not known (cannot be estimated from the available data).

Body system	Adverse reactions	Frequency
		Perindopril	Indapamide	Amlodipine
Infections and infestations	Rhinitis	Very rare	-	Uncommon
Blood and lymphatic system disorders	Eosinophilia	Unknown1)	-	-
	Agranulocytosis2)	Very rare	Very rare	-
	Aplastic anemia	-	Very rare	-
	Pancytopenia	Very rare	-	-
	Leukopenia	Very rare	Very rare	Very rare
	Neutropenia2)	Very rare	-	-
	Hemolytic anemia	Very rare	Very rare	-
	Thrombocytopenia2)	Very rare	Very rare	Very rare
Immune system disorders	Hypersensitivity reactions (mainly dermatological, in patients predisposed to allergic and asthmatic reactions and maculopapular rashes)	-	Common	Very rare
Endocrine system disorders	Syndrome of inappropriate antidiuretic hormone secretion (SIADH)	Uncommon	-	-
Metabolism and nutrition disorders	Hypoglycemia3)	Uncommon1)	-	-
	Hyperkalemia, reversible upon discontinuation2)	Uncommon1)	-	-
	Hypokalemia2)	Uncommon1)	Uncommon	-
	Hypercalcemia	-	Very rare	-
	Hypokalemia (see section "Special precautions")	-	Common	-
	Hypochloremia	-	Uncommon	-
	Hypomagnesemia	-	Uncommon	-
Psychiatric disorders	Insomnia	-	-	Uncommon
	Mood disorders	Uncommon	-	Uncommon
	Depression	Uncommon	-	Uncommon
	Sleep disorders	Uncommon	-	-
	Confusion	Very rare	-	Uncommon
Nervous system disorders	Dizziness	Common	-	Common
	Headache	Common	Uncommon	Common
	Tremor	-	-	Uncommon
	Hypesthesia	-	-	Uncommon
	Paresthesia	Common	Uncommon	Uncommon
	Hypertonia	-	-	Very rare
	Peripheral neuropathy	-	-	Very rare
	Extrapyramidal disorder	-	-	Unknown
	Disturbance of taste	Common	-	Uncommon
	Somnolence	Uncommon1)	-	Common
	Syncope	Uncommon1)	Unknown	Uncommon
	Stroke, possibly secondary to excessive hypotension in patients at high risk2)	Very rare	-	-
	Development of hepatic encephalopathy in case of liver insufficiency3)	-	Unknown	-
Eye disorders	Visual disturbance	Common	Unknown	Common
	Myopia2)	-	Unknown	-
	Blurred vision	-	Unknown	-
	Choroidal effusion		Unknown
	Acute angle-closure glaucoma	-	Unknown	-
Ear and labyrinth disorders	Vertigo	Common	Uncommon	-
	Tinnitus	Common	-	Uncommon
Cardiac disorders	Palpitations	Uncommon1)	-	Common
	Tachycardia	Uncommon1)	-	Uncommon
	Angina pectoris2)	Very rare	-
	Arrhythmia (including bradycardia, ventricular tachycardia, atrial fibrillation)	Very rare	Very rare	Uncommon
	Myocardial infarction, possibly after excessive hypotension in patients at high risk2)	Very rare	-	Very rare
	Paroxysmal torsades de pointes tachycardia (potentially fatal)4)	-	Unknown
Vascular disorders	Flushing	Uncommon	-	-
	Arterial hypotension (and symptoms related to hypotension)2)	Common	Very rare	Uncommon
	Vasculitis	Uncommon1)	-	Very rare
	Raynaud's phenomenon	Unknown	-	-
Respiratory, thoracic and mediastinal disorders	Cough2)	Common	-	Uncommon
	Dyspnea	Common	-	Common
	Bronchospasm	Uncommon	-	-
	Eosinophilic pneumonia	Very rare	-	-
Gastrointestinal disorders	Abdominal pain	Common	-	Common
	Constipation	Common	Uncommon	Common
	Diarrhea	Common	-	Common
	Dyspepsia	Common	-	Common
	Nausea	Common	Uncommon	Common
	Vomiting	Common	Uncommon	Uncommon
	Dry mouth	Uncommon	Uncommon	Uncommon
	Pancreatitis	Very rare	Very rare	Very rare
	Gastritis	-	-	Very rare
	Hypertrophic gingivitis	-	-	Very rare
Hepatobiliary disorders	Hepatitis2)	Very rare	Unknown
	Jaundice	-	-	Very rare
	Liver function abnormalities	-	Very rare	-
Skin and subcutaneous tissue disorders	Quincke's edema	-	-	very rare
	Angioedema2)	Uncommon	Very rare	Very rare
	Pruritus	Common	-	Uncommon
	Rash	Common	-	Uncommon
	Maculopapular rash	-	Common	-
	Urticaria2)	Uncommon	Very rare	Uncommon
	Exanthema	-	-	Uncommon
	Alopecia	-	-	Uncommon
	Purpura	-	Uncommon	Uncommon
	Skin discoloration			Uncommon
	Hyperhidrosis	Uncommon	-	Uncommon
	Photosensitivity reaction	Uncommon1)	Unknown	Very rare
	Pemphigoid	Uncommon1)	-	-
	Worsening of psoriasis symptoms	Uncommon1)	-	-
	Multiform erythema	Very rare	-	Very rare
	Toxic epidermal necrolysis	-	Very rare	Unknown
	Exfoliative dermatitis	-	-	Very rare
	Stevens-Johnson syndrome	-	Very rare	Very rare
Musculoskeletal and connective tissue disorders	Muscle cramps	Common	Unknown	Common
	Ankle swelling			Common
	Exacerbation of pre-existing systemic lupus erythematosus	-	Unknown	-
	Arthralgia	Uncommon1)	-	Uncommon
	Myalgia	Uncommon1)	-	Uncommon
	Back pain	-	-	Uncommon
	Muscle weakness	-	Unknown	-
	Rhabdomyolysis	-	Unknown	-
Renal and urinary disorders	Renal impairment	Uncommon	-	Uncommon
	Acute renal failure	Uncommon	Very rare	-
	Urinary disorders, nocturia, increased frequency of urination	-	-	Uncommon
	Anuria/oliguria	Uncommon	-	-
Reproductive system and breast disorders	Erectile dysfunction	Uncommon	-	Uncommon
	Gynecomastia			Uncommon
	Erectile dysfunction	-	Uncommon	-
General disorders and administration site conditions	Asthenia	Common	-	Uncommon
	Chest pain	Uncommon1)	-	Uncommon
	Pain	-		Uncommon
	Malaise	Uncommon1)	-	Uncommon
	Peripheral edema	Uncommon1)	-	Very common
	Pyrexia	Uncommon1)	-	-
	Feeling of fatigue	-	Uncommon	Common
Investigations	Increase in plasma urea levels	Uncommon1)	-	-
	Increase in plasma creatinine levels	Uncommon1)	-	-
	Increase in plasma bilirubin levels	Uncommon	-	-
	Increase in liver enzyme levels	Uncommon	Unknown	Very rare5)
	Decrease in hemoglobin levels and red blood cell count2)	Very rare	-
	Increase in plasma glucose levels	-	Unknown	Very rare
	Increase in plasma uric acid levels	-	Unknown
	Prolongation of QT interval on ECG3)	-	Unknown
	Weight gain or weight loss	-	-	Uncommon
Injury, poisoning and procedural complications	Fall	Uncommon1)	-	-

1. The frequency of adverse reactions is based on spontaneous reports during clinical trials.
2. See section "Special precautions for use".
3. See section "Contraindications".
4. See sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use".
5. Mainly with cholestasis.

Description of selected adverse reactions

During phase II and III clinical trials comparing doses of indapamide 1.5 mg and 2.5 mg, analysis of plasma potassium levels demonstrated a dose-dependent effect of indapamide.

Indapamide 1.5 mg: plasma potassium level < 3.4 mmol/L was observed in 10% of patients and < 3.2 mmol/L in 4% of patients after 4–6 weeks of treatment. After 12 weeks of treatment, the mean decrease in plasma potassium level was 0.23 mmol/L.

Indapamide 2.5 mg: plasma potassium level < 3.4 mmol/L was observed in 25% of patients and < 3.2 mmol/L in 10% of patients after 4–6 weeks of treatment. After 12 weeks of treatment, the mean decrease in plasma potassium level was 0.41 mmol/L.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy of the medicinal product via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life.

Tablets 8 mg/2.5 mg/5 mg, 8 mg/2.5 mg/10 mg, 4 mg/1.25 mg/10 mg, 4 mg/1.25 mg/5 mg:

3 years.

Tablets 2 mg/0.625 mg/5 mg:

2 years.

Storage conditions. Store at temperature not exceeding 30°C, in the original packaging to protect from light and moisture. Keep out of reach of children.

Packaging.

10 tablets in a blister; 3, 6, or 9 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

KRKA, d.d., Novo mesto, Slovenia / KRKA, d.d., Novo mesto, Slovenia.

KRKA Polska Sp. z o.o., Poland / KRKA Polska Sp. z o.o., Poland.

TAD Pharma GmbH, Germany / TAD Pharma GmbH, Germany.

Manufacturer's address and location of operations.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia / Smarjeska cesta 6, 8501 Novo mesto, Slovenia.

ul. Rownolegla 5, 02-235 Warsaw, Poland / ul. Rownolegla 5, 02-235 Warsaw, Poland.

Heinz-Lohmann-Strasse 5, 27472 Cuxhaven, Germany / Heinz-Lohmann-Strasse 5, 27472 Cuxhaven, Germany.