Perindopril 10 / indapamide 2.5 krka

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Perindopril 5/indapamide 1.25 KRKA Perindopril 10/indapamide 2.5 KRKA (Perindopril 5/indapamide 1.25 KRKA Perindopril 10/indapamide 2.5 KRKA)

Composition:

Active substances: perindopril, indapamide;

One tablet contains 5 mg of perindopril arginine (equivalent to 3.395 mg of perindopril) and 1.25 mg of indapamide, or 10 mg of perindopril arginine (equivalent to 6.79 mg of perindopril) and 2.5 mg of indapamide;

Excipients: calcium chloride, hexahydrate; microcrystalline cellulose; silicified microcrystalline cellulose (type 90); pregelatinized starch; sodium hydrogencarbonate; colloidal hydrated silicon dioxide; magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

tablets 5 mg/1.25 mg: white or almost white capsule-shaped tablets with a score line on both sides. One side of the score line is marked with the letter A, the other with the number 1;

tablets 10 mg/2.5 mg: white or almost white round, biconvex tablets marked with A2 on one side of the tablet.

Pharmacotherapeutic group. Combined preparations of angiotensin-converting enzyme inhibitors. Perindopril and diuretics.

ATC code C09B A04.

Pharmacological Properties

Pharmacodynamics

Perindopril/indapamide is a combination of perindopril arginine, an angiotensin-converting enzyme (ACE) inhibitor, and indapamide, a sulfonamide diuretic. The pharmacological effect of the medicinal product is due to the properties of each component (perindopril and indapamide) and their additive synergism.

Mechanism of Action

Perindopril/Indapamide

The combination of perindopril/indapamide is characterized by an additional enhancement of the antihypertensive effect of both components.

Perindopril

Perindopril is an ACE inhibitor that converts angiotensin I into angiotensin II, a vasoconstrictor substance; in addition, the enzyme stimulates aldosterone secretion by the adrenal cortex and promotes the breakdown of the vasodilator bradykinin into an inactive heptapeptide.

This leads to:

• reduction in aldosterone secretion;
• increased plasma renin activity due to loss of negative feedback by aldosterone;
• with long-term treatment — reduction in total peripheral resistance, predominantly affecting vascular beds in muscles and kidneys, without concomitant salt and water retention or reflex tachycardia.

Perindopril also exerts antihypertensive effects in patients with low or normal plasma renin levels.

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

With continuous treatment, this leads to a reduction in peripheral vascular resistance due to effects on muscle and renal vessels, without salt and water retention or reflex tachycardia.

Perindopril reduces cardiac load:

• through a vasodilatory effect on veins, possibly due to changes in prostaglandin metabolism (reduction in preload);
• by reducing total peripheral resistance (reduction in afterload).

In studies conducted in patients with heart failure, the following effects were observed:

• reduction in filling pressure of the left and right ventricles;
• reduction in total peripheral vascular resistance;
• increase in cardiac output and normalization of cardiac index;
• increase in regional blood flow in muscles. Significant improvement in exercise tolerance tests.

Indapamide

Indapamide is a sulfonamide derivative with an indole ring, pharmacologically related to thiazide diuretics. Indapamide reduces sodium reabsorption in the cortical segment. It increases urinary excretion of sodium and chloride, and to a lesser extent, potassium and magnesium, thereby promoting diuresis and antihypertensive action.

Pharmacodynamic Effect

Perindopril/Indapamide

In patients with arterial hypertension, regardless of age, the medicinal product demonstrates a dose-dependent reduction in diastolic and systolic arterial pressure in both supine and standing positions.

This antihypertensive effect lasts for 24 hours.

Normalization of arterial pressure occurs within one month and is maintained without development of tachyphylaxis.

Upon discontinuation of the drug, no rebound effect occurs.

In clinical trials, concomitant administration of perindopril and indapamide resulted in synergistic antihypertensive effects compared to each individual component.

Perindopril

Perindopril is effective in mild, moderate, and severe arterial hypertension. It reduces systolic and diastolic arterial pressure in both supine and standing positions. Maximum hypotensive effect is achieved 4–6 hours after a single dose and lasts for at least 24 hours. Perindopril demonstrates a high level of sustained ACE inhibition (approximately 80%) 24 hours after administration.

In patients with a reversible response, arterial pressure stabilization occurs on average within 1 month of treatment and is maintained without tachyphylaxis.

Discontinuation of treatment is not associated with withdrawal syndrome.

Perindopril has vasodilatory properties, improves elasticity of large arteries, corrects structural changes in arteries, and reduces left ventricular hypertrophy. Additional therapy with a thiazide diuretic results in additional synergism.

The combination of an ACE inhibitor and a thiazide reduces the risk of diuretic-induced hypokalemia compared to monotherapy with either component.

Clinical Data on Dual Blockade of the Renin-Angiotensin-Aldosterone System (RAAS)

Studies have reported on the concomitant use of ACE inhibitors and angiotensin II receptor blockers in patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes with evidence of target organ damage, and in patients with type 2 diabetes and diabetic nephropathy.

These studies did not demonstrate significant beneficial effects in patients with kidney and/or cardiovascular disease or reduced mortality; however, compared to monotherapy, there was an increased risk of hyperkalemia, acute kidney injury, and/or hypotension. Given the similar pharmacodynamic properties, these findings 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.

Studies on aliskiren in type 2 diabetes with cardiovascular and kidney disease endpoints have been reported, 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 and cardiovascular disease. The study was prematurely discontinued due to an increased risk of adverse outcomes. Cardiovascular mortality, incidence of stroke, and reports of adverse events and serious complications (hyperkalemia, arterial hypotension, or impaired renal function) were more frequent in the aliskiren group compared to placebo.

Indapamide

Indapamide as monotherapy demonstrates an antihypertensive effect lasting 24 hours. This occurs at doses where the diuretic effect is mild.

Its antihypertensive action is proportional to improved arterial status and reduction in total and arteriolar peripheral vascular resistance. Indapamide reduces left ventricular hypertrophy.

With increasing doses of thiazide and thiazide-like diuretics, the antihypertensive effect reaches a plateau, while adverse effects continue to increase. If treatment is ineffective, the dose should not be increased.

Furthermore, it has been demonstrated that short-, medium-, and long-term treatment of patients with arterial hypertension with indapamide does not affect lipid metabolism (triglycerides, low- and high-density lipoproteins) or carbohydrate metabolism, even in patients with arterial hypertension and diabetes mellitus.

Use in Children

There are no data on the use of the perindopril/indapamide combination in children.

Pharmacokinetics

Perindopril/Indapamide

Concomitant administration of perindopril and indapamide does not alter their pharmacokinetic properties compared to administration of individual components.

Perindopril

Absorption and Bioavailability

After oral administration, perindopril is rapidly absorbed in the gastrointestinal tract, with maximum plasma concentration reached within 1 hour. The elimination half-life of perindopril in plasma is 1 hour.

Since food intake reduces the conversion of perindopril to perindoprilat, thereby decreasing its bioavailability, perindopril arginine should be taken orally as a single daily dose in the morning before a meal.

Distribution

The volume of distribution of unbound perindoprilat is approximately 0.2 L/kg. Protein binding is low (less than 20% of perindoprilat binds to ACE), but depends on concentration.

Metabolism

Perindopril is a prodrug. 27% of the 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 elimination 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.

Elderly Patients

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

Renal Impairment

In patients with impaired renal function, dosage adjustment is recommended depending on the degree of impairment (creatinine clearance).

Dialysis

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

Cirrhosis

In liver cirrhosis, perindopril kinetics are altered, with hepatic clearance of the parent compound reduced by half; however, the amount of formed perindoprilat remains unchanged. Therefore, dosage adjustment is not required in this condition (see sections "Special Warnings" and "Dosage and Administration").

Indapamide

Absorption

Indapamide is rapidly and almost completely absorbed in the gastrointestinal tract. Maximum plasma concentration of indapamide is reached approximately 1 hour after administration.

Distribution

Plasma protein binding of indapamide is 79%.

Biotransformation and Excretion

The elimination half-life from plasma ranges from 14 to 24 hours (average 18 hours). Regular administration does not lead to accumulation of indapamide. Approximately 70% of indapamide is excreted primarily via the kidneys, and 22% is excreted in feces as inactive metabolites.

Renal Impairment

Pharmacokinetic parameters of the drug remain unchanged in patients with impaired renal function.

Clinical characteristics.

Indications.

Perindopril 5/indapamide 1.25 KRKA

Treatment of essential hypertension in adult patients whose blood pressure is not adequately controlled by perindopril alone.

Perindopril 10/indapamide 2.5 KRKA

As replacement therapy in essential hypertension in patients whose condition is adequately controlled by concomitant administration of perindopril and indapamide monotherapies at corresponding doses.

Contraindications.

Related to perindopril

• Hypersensitivity to perindopril or to other angiotensin-converting enzyme (ACE) inhibitors.
• History of angioedema (Quincke's edema) associated with previous ACE inhibitor therapy (see section "Special precautions").
• Hereditary or idiopathic angioedema.
• Concomitant administration with medicinal products containing aliskiren in patients with diabetes mellitus or renal impairment (glomerular filtration rate < 60 mL/min/1.73 m²) (see sections "Pharmacodynamics" and "Interaction with other medicinal products and other forms of interaction").
• Pregnancy or planned pregnancy (see sections "Special precautions" and "Use during pregnancy or lactation").
• Concomitant use with sacubitril/valsartan. The medicinal product should not be administered earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions").
• 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").

Related to indapamide

• Hypersensitivity to indapamide or to other sulfonamides.
• Hepatic encephalopathy or severe hepatic dysfunction.
• Hypokalemia.

Related to the medicinal product Perindopril 5/indapamide 1.25 KRKA

• Severe renal impairment (creatinine clearance < 30 mL/min).
• Hypersensitivity to any component of the medicinal product.

Related to the medicinal product Perindopril 10/indapamide 2.5 KRKA

• Severe and moderate renal function impairment (creatinine clearance < 60 mL/min).

Due to insufficient therapeutic experience, the medicinal product should not be used:

• in patients undergoing hemodialysis;
• in patients with untreated decompensated heart failure.

Interaction with other medicinal products and other forms of interaction.

Perindopril/indapamide

Concomitant use not recommended

Lithium

Concomitant use of lithium with ACE inhibitors has been associated with reversible increases in serum lithium concentration and signs of toxicity. The use of perindopril with lithium is not recommended, but if combination therapy is necessary, careful monitoring of serum lithium levels is required (see section "Special precautions").

Concomitant use requires special monitoring

• Baclofen:* enhanced antihypertensive effect. Monitoring of blood pressure and renal function is required, and dosage adjustment may be necessary.

Nonsteroidal anti-inflammatory drugs (NSAIDs) (including acetylsalicylic acid at doses ≥ 3 g/day)

Administration of NSAIDs, including acetylsalicylic acid at anti-inflammatory doses, cyclooxygenase-2 inhibitors, and nonselective NSAIDs, may reduce the antihypertensive effect of ACE inhibitors. Moreover, NSAIDs and ACE inhibitors may additionally increase serum potassium levels, potentially leading to worsening of renal function, including acute renal failure, especially in patients with pre-existing renal impairment. This combination should be used with caution, particularly in elderly patients. Adequate hydration should be ensured, and monitoring of renal function should be considered at initiation of concomitant therapy and periodically thereafter.

Concomitant use requires monitoring

Tricyclic antidepressants (imipramine-like), neuroleptics: enhanced hypotensive effect and increased risk of orthostatic hypotension (additive effect).

Perindopril

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

Medicinal products that may cause hyperkalemia

Serum potassium levels usually remain within normal limits, but hyperkalemia may occur in some patients receiving perindopril/indapamide combination therapy. Certain medicinal products or therapeutic classes may induce hyperkalemia, namely: aliskiren, potassium salts, potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), ACE inhibitors, angiotensin II receptor antagonists, nonsteroidal anti-inflammatory agents, heparins, immunosuppressive agents such as cyclosporine or tacrolimus, trimethoprim, and co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim acts as a potassium-sparing diuretic similar to amiloride. Combination with these agents increases the risk of hyperkalemia. Therefore, concomitant use of the medicinal product with the above-mentioned agents is not recommended. If concomitant use is necessary, it should be done with caution and careful monitoring of serum potassium levels.

Contraindicated combinations (see section "Contraindications")

Aliskiren

Concomitant use of perindopril and aliskiren in patients with diabetes mellitus or renal impairment is contraindicated due to increased risk of hyperkalemia, worsening renal function, and cardiovascular morbidity and mortality (see section "Contraindications").

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

Sacubitril/valsartan

Concomitant use of perindopril with sacubitril/valsartan is contraindicated, as concomitant use of ACE inhibitors and sacubitril/valsartan increases the risk of angioedema. Initiation of sacubitril/valsartan should not occur 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").

Concomitant use not recommended

Aliskiren

Concomitant use of perindopril and aliskiren in all other patient groups, except those with diabetes mellitus or renal impairment, is not recommended due to increased risk of hyperkalemia, worsening renal function, and cardiovascular morbidity and mortality (see section "Special precautions").

Concomitant therapy with ACE inhibitors and angiotensin receptor blockers

Reports indicate that in patients with established atherosclerosis, heart failure, or diabetes mellitus with end-organ damage, concomitant use of ACE inhibitors and angiotensin receptor blockers is associated with increased incidence of arterial hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to monotherapy with RAAS-acting agents. Dual blockade (i.e., combination of an ACE inhibitor with angiotensin II receptor antagonists) may be considered only in selected cases with careful monitoring of renal function, serum potassium, and blood pressure (see section "Special precautions").

Estramustine

Increased risk of adverse reactions such as angioedema.

Co-trimoxazole (trimethoprim/sulfamethoxazole)

Increased risk of hyperkalemia in patients receiving co-trimoxazole (trimethoprim/sulfamethoxazole) concomitantly (see section "Special precautions").

Potassium-sparing diuretics (e.g., triamterene, amiloride), potassium (salts)

Hyperkalemia (potentially fatal), especially in combination with renal dysfunction (additive hyperkalemic effect). Combination of perindopril with the above-mentioned agents is not recommended (see section "Special precautions"). However, if concomitant administration is necessary, it should be done with caution and careful monitoring of plasma potassium levels. For use of spironolactone in heart failure, see the subsection "Concomitant use requires special monitoring" below.

Concomitant use requires special monitoring

Antidiabetic agents (insulin, oral hypoglycemic agents)

Epidemiological studies have shown that concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemic agents) may enhance glucose-lowering effects, increasing the risk of hypoglycemia. This phenomenon is more likely during the first weeks of combination therapy and in patients with renal impairment.

Diuretics not containing potassium

In patients receiving 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, or increasing salt intake prior to starting perindopril therapy. Treatment should begin with low doses and gradually increase.

In arterial hypertension, when a previously prescribed diuretic may have caused water/electrolyte depletion, 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 on diuretic therapy, ACE inhibitor therapy should be initiated at the lowest dose, possibly after reducing the diuretic dose.

In all cases, renal function (creatinine levels) should be monitored during the first weeks of ACE inhibitor therapy.

Potassium-sparing diuretics (eplerenone or spironolactone)

When eplerenone or spironolactone (12.5–50 mg daily) is used concomitantly with low-dose ACE inhibitors in patients with NYHA class II–IV heart failure and ejection fraction < 40%, who have previously received ACE inhibitors and loop diuretics, there is a risk of hyperkalemia, potentially fatal, especially if recommendations for use of this combination are not followed.

Before initiating this combination, absence of hyperkalemia and renal impairment should be confirmed.

Careful monitoring of serum potassium and creatinine is recommended weekly during the first month of treatment and monthly thereafter.

Racecadotril

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

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

Increased risk of angioedema in patients receiving mTOR inhibitors concomitantly (see section "Special precautions").

Concomitant use requires monitoring

Antihypertensive agents and vasodilators

Concomitant use of antihypertensive agents may enhance the hypotensive effect of perindopril. Concomitant use with nitroglycerin and other nitrates or other vasodilators may lead to additional blood pressure reduction.

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

Anesthetics: ACE inhibitors may enhance the hypotensive effects of certain anesthetics (see section "Special precautions").

Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.

Gold compounds: rarely, when ACE inhibitors, including perindopril, are used concomitantly with injectable gold preparations (sodium aurothiomalate), reactions similar to those seen with nitrates (facial flushing, nausea, vomiting, and arterial hypotension) may occur.

Indapamide

Concomitant use requires special monitoring

Medicinal products causing torsades de pointes ventricular tachycardia. Due to the risk of hypokalemia, indapamide should be used with caution when co-administered with medicinal products that may cause torsades de pointes ventricular tachycardia, such as: class Ia antiarrhythmics (e.g., quinidine, hydroquinidine, disopyramide); class III antiarrhythmics (e.g., amiodarone, sotalol, dofetilide, ibutilide, bretylium); certain phenothiazine antipsychotics (e.g., chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine), benzamides (e.g., amisulpride, sulpiride, sultopride, tiapride), butyrophenones (e.g., droperidol, haloperidol), other antipsychotics (pimozide); other substances such as bepridil, cisapride, difemanil, erythromycin (intravenous), halofantrine, mizolastine, pentamidine, sparfloxacin, moxifloxacin, vinca alkaloids (intravenous), methadone, astemizole, terfenadine. Hypokalemia should be prevented and corrected if necessary; QT interval should be monitored.

Medicinal products that reduce potassium levels, amphotericin B (intravenous), systemic glucocorticoids and mineralocorticoids (systemic administration), tetracosactide, stimulant laxatives: increased risk of hypokalemia (additive effect). Serum potassium levels should be checked and corrected if necessary; particular caution is required when using cardiac glycosides. Stimulant laxatives should not be used.

Digitalis glycosides: hypokalemia and/or hyponatremia may potentiate the toxic effects of digitalis. Monitoring of plasma potassium and magnesium levels and ECG is recommended, and therapy should be reviewed if necessary.

Allopurinol: concomitant use with indapamide may increase the frequency of hypersensitivity reactions to allopurinol.

Concomitant use requires monitoring

Potassium-sparing diuretics (amiloride, spironolactone, triamterene)

Although this combination may be rational in certain patients, hypokalemia or hyperkalemia may occur (especially in patients with renal impairment or diabetes mellitus). Plasma potassium levels should be monitored, ECG monitoring should be performed, and therapy should be reviewed if necessary.

Metformin: in functional renal impairment associated with diuretic use, particularly loop diuretics, the risk of lactic acidosis with metformin increases. Metformin should not be used if plasma creatinine levels exceed 15 mg/L (135 µmol/L) in men and 12 mg/L (110 µmol/L) in women.

Iodinated contrast agents: dehydration associated with diuretic use increases the risk of acute renal failure when iodinated contrast agents, particularly at high doses, are administered. Adequate hydration must be restored before administration of iodinated contrast agents.

Calcium salts: risk of hypercalcemia due to reduced renal excretion of calcium.

Cyclosporine, tacrolimus: risk of increased plasma creatinine concentration without changes in blood cyclosporine levels, even without fluid/salt volume depletion.

Corticosteroids, tetracosactide (systemic administration): reduced antihypertensive effect (salt and water retention due to corticosteroids).

Special precautions for use.

Special warnings

Perindopril/indapamide

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").

Perindopril

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

Concomitant use of ACE inhibitors and angiotensin II receptor blockers or aliskiren has been associated with increased incidence of arterial hypotension, loss of consciousness, hyperkalaemia, and deterioration of renal function (including acute renal failure). Dual blockade (i.e., combination of an ACE inhibitor with angiotensin II receptor antagonists or aliskiren) is not recommended (see sections "Pharmacodynamics" and "Interaction with other medicinal products and other forms of interaction").

However, if dual blockade is necessary, it may be applied in individual cases under careful monitoring of renal function, potassium levels, and blood pressure.

Concomitant use of ACE inhibitors and angiotensin II receptor blockers is not recommended in patients with diabetic nephropathy.

Potassium-sparing agents, potassium supplements, or potassium-containing salt substitutes

Combining potassium-sparing agents, potassium supplements, or potassium-containing salt substitutes with perindopril is generally not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Neutropenia/agranulocytosis/thrombocytopenia/anaemia

Neutropenia/agranulocytosis, thrombocytopenia, and anaemia have occurred in patients receiving ACE inhibitors. Neutropenia is rare in patients with normal renal function and no other risk factors during ACE inhibitor therapy. Perindopril should be used with particular caution in patients with collagen vascular diseases or those receiving immunosuppressants, allopurinol, or procainamide, as well as in patients with a combination of some of these risk factors, especially in the presence of impaired renal function. Severe infections, sometimes resistant to intensive antibiotic therapy, have developed in some patients. If perindopril is administered to such patients, periodic monitoring of white blood cell count is required, and patients should be instructed to report any signs of infection, such as sore throat or fever (see sections "Interaction with other medicinal products and other forms of interaction" and "Undesirable effects").

Renovascular hypertension

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 failure (see section "Contraindications"). The use of diuretics may be a contributing factor. Decreased renal function may be accompanied only by minor changes in serum creatinine levels, even in patients with unilateral renal artery stenosis.

Hypersensitivity/angioedema

Angioedema of the face, lips, mucous membranes, tongue, pharynx, and/or larynx has occurred in some patients treated with ACE inhibitors, including perindopril (see section "Undesirable effects"). It may occur at any time during treatment. In such cases, perindopril must be discontinued immediately, and thorough examination should be initiated until symptoms completely resolve. In case of facial or lip swelling, the condition may improve without treatment, but antihistamines may relieve symptoms.

Laryngeal angioedema may be fatal. Swelling of the tongue, glottis, or larynx may lead to airway obstruction. In such cases, emergency treatment is required, which may include subcutaneous administration of epinephrine 1:1000 solution (0.3–0.5 ml) and/or maintaining airway patency.

ACE inhibitors cause angioedema more frequently in patients of African descent than in other racial groups.

Patients with a history of angioedema unrelated to ACE inhibitor use have an increased risk of developing angioedema when taking ACE inhibitors (see section "Contraindications").

Rare cases of intestinal angioedema have been reported in patients taking ACE inhibitors. These patients experienced abdominal pain (with or without nausea or vomiting); intestinal angioedema sometimes occurred without prior facial angioedema, and C1-esterase inhibitor levels were normal. Diagnosis of intestinal angioedema was confirmed by procedures such as abdominal computed tomography or ultrasound, or during surgical intervention; symptoms resolved after discontinuation of the ACE inhibitor. In patients taking ACE inhibitors who develop abdominal pain, differential diagnosis should be performed to exclude intestinal angioedema.

Concomitant use of perindopril with sacubitril/valsartan is contraindicated due to increased risk of angioedema (see section "Contraindications"). Sacubitril/valsartan should not be initiated earlier than 36 hours after the last dose of perindopril. If treatment with sacubitril/valsartan is discontinued, perindopril therapy should not be started earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction"). Concomitant use of other neutral endopeptidase (NEP) inhibitors (e.g., racecadotril) and ACE inhibitors also increases the risk of angioedema (see section "Interaction with other medicinal products and other forms of interaction"). Therefore, careful benefit-risk assessment is required before initiating NEP inhibitors (e.g., racecadotril) in patients receiving perindopril.

Concomitant use with mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus) and gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) increases the risk of angioedema (including airway or tongue swelling, with or without respiratory impairment) (see section "Interaction with other medicinal products and other forms of interaction"). Caution is advised when initiating treatment with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) in patients already taking ACE inhibitors.

Anaphylactoid reactions during desensitization

In patients taking ACE inhibitors during desensitization procedures (e.g., to wasp or bee venom), isolated cases of prolonged, life-threatening anaphylactoid reactions have been reported. ACE inhibitors should be used cautiously in patients with allergies undergoing desensitization and avoided in patients undergoing immunotherapy with venom. However, these reactions can be avoided by temporarily discontinuing ACE inhibitors at least 24 hours before treatment in patients requiring both ACE inhibitors and desensitization.

Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis

Rarely, life-threatening anaphylactoid reactions occur in patients taking ACE inhibitors during LDL apheresis with dextran sulfate. These reactions can be prevented by temporarily discontinuing ACE inhibitors before each apheresis.

Patients undergoing haemodialysis

Anaphylactoid reactions have been observed in patients undergoing haemodialysis with high-flux membranes (e.g., AN 69®) while concurrently receiving ACE inhibitor therapy. For such patients, consideration should be given to using alternative types of dialysis membranes or another class of antihypertensive agents.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism usually do not respond to antihypertensive agents acting via inhibition of the renin-angiotensin system. Therefore, this medicinal product is not recommended for such patients.

Pregnancy

ACE inhibitor therapy should not be initiated during pregnancy. If continuation of antihypertensive therapy is considered necessary, women planning pregnancy should be switched to alternative antihypertensive agents with established safety during pregnancy. If pregnancy is confirmed during treatment, ACE inhibitor therapy should be discontinued immediately, and, if necessary, alternative therapy with a medicinal product approved for use in pregnant women should be initiated (see sections "Contraindications" and "Use in pregnancy or lactation").

Indapamide

Hepatic encephalopathy

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

Photosensitization

Cases of photosensitivity reactions have been reported in patients taking thiazide and thiazide-like diuretics. If such reactions occur, diuretic therapy should be discontinued. If diuretics must be reintroduced, vulnerable areas should be protected from sunlight or artificial ultraviolet sources.

Other warnings

Perindopril/indapamide

Renal function impairment

Perindopril 5/indapamide 1.25 SR

Treatment is contraindicated in severe renal impairment (creatinine clearance < 30 ml/min).

Perindopril 10/indapamide 2.5 SR

Treatment is contraindicated in moderate to severe renal impairment (creatinine clearance < 60 ml/min).

If laboratory signs of renal impairment develop in patients with arterial hypertension without apparent renal dysfunction during treatment, the medicinal product should be discontinued. Treatment may be resumed at a lower dose or with one of the components. In such patients, potassium and creatinine levels should be monitored 2 weeks after initiation of treatment and every 2 months during therapeutic stabilization. Cases of renal impairment have primarily occurred in patients with severe heart failure or pre-existing renal dysfunction, including those with renal artery stenosis.

The medicinal product is not recommended for patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney.

Arterial hypotension and water and electrolyte deficiency

There is a risk of sudden blood pressure reduction in patients with sodium deficiency (especially in patients with renal artery stenosis). Therefore, symptoms of water and electrolyte deficiency resulting from vomiting or diarrhoea should be systematically checked. Such patients require regular monitoring of plasma electrolyte levels.

In cases of significant arterial hypotension, intravenous administration of 0.9% sodium chloride solution may be required. Temporary arterial hypotension does not contraindicate further use of the medicinal product. After restoration of circulating blood volume and normalization of blood pressure, treatment may be resumed at a lower dose or with one of the components.

Potassium levels

The combination of perindopril and indapamide does not exclude the possibility of hypokalaemia, especially in patients with diabetes mellitus or renal impairment. As with any diuretic-containing product, regular monitoring of potassium levels is required.

Perindopril

Cough

A dry, non-productive, persistent cough may occur during ACE inhibitor therapy, resolving after discontinuation of treatment. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough. If ACE inhibitor therapy remains preferable, continuation of treatment may be considered.

Children

Safety and efficacy of perindopril (alone or in combination) in children and adolescents have not been established.

Risk of arterial hypotension and/or renal impairment (in heart failure, fluid and electrolyte imbalance)

Significant stimulation of the RAAS, particularly in the presence of marked fluid and electrolyte imbalance (strict low-sodium diet or prolonged diuretic therapy), has been observed in patients with initially low blood pressure, renal artery stenosis, congestive heart failure, or cirrhosis with oedema and ascites.

Thus, blockade of this system by an ACE inhibitor, especially at initial administration and during the first 2 weeks of treatment, may cause unexpected reduction in blood pressure and/or increased plasma creatinine levels, indicating functional renal impairment. This may occasionally present as an acute episode, although rarely, with varying onset periods.

In such cases, treatment should be initiated at a lower dose with gradual dose escalation.

Elderly patients

Renal function and plasma potassium levels should be checked before initiating treatment. Initial dose should be adjusted according to blood pressure response, especially in cases of fluid and electrolyte imbalance, to avoid unexpected occurrence of arterial hypotension.

Atherosclerosis

The risk of arterial hypotension exists in all patients, but particular attention should be paid to patients with ischaemic heart disease or cerebral circulation insufficiency. Such patients should start treatment with a low dose.

Renovascular hypertension

Treatment of renovascular hypertension is revascularization. However, ACE inhibitors may be acceptable for patients with renovascular hypertension awaiting surgical correction or when surgery is not feasible.

Perindopril 5/indapamide 1.25 SR

If perindopril/indapamide is prescribed to patients with renal artery stenosis or suspected stenosis, treatment should be initiated in hospital at a low dose with monitoring of renal function and potassium levels, as functional renal impairment, reversible upon discontinuation of treatment, has occurred in some patients.

Perindopril 10/indapamide 2.5 SR

Perindopril 10/indapamide 2.5 SR is not recommended for patients with existing or suspected renal artery stenosis, as treatment of such patients should be initiated in hospital at a dose lower than 10 mg/2.5 mg.

Heart failure/severe heart failure

Treatment of patients with severe heart failure (NYHA class IV) should be initiated under medical supervision with a reduced initial dose; therefore, Perindopril 10/indapamide 2.5 SR is not suitable as an initial dose. Beta-blockers should not be discontinued in hypersensitive patients with coronary insufficiency—ACE inhibitors should be added to beta-blocker therapy.

Diabetic patients

For patients with insulin-dependent diabetes mellitus (with a spontaneous tendency to increased potassium levels), use of Perindopril 10/indapamide 2.5 SR is not advisable; treatment should be initiated under medical supervision with a reduced initial dose.

Patients with diabetes mellitus taking oral antidiabetic agents or insulin require careful monitoring of blood glucose levels during the first months of ACE inhibitor therapy (see section "Interaction with other medicinal products and other forms of interaction").

Racial origin

Perindopril, like other ACE inhibitors, is less effective in reducing blood pressure in hypertensive patients of African descent than in patients of other races, possibly due to low plasma renin levels in these patients.

Surgery/general anaesthesia

ACE inhibitors may cause arterial hypotension during anaesthesia, especially when the administered anaesthetic has hypotensive potential.

Therefore, it is recommended to discontinue treatment with long-acting ACE inhibitors, such as perindopril, one day before surgery, if possible.

Stenosis of aortic or mitral valve/hypertrophic cardiomyopathy

ACE inhibitors should be used with caution in patients with aortic valve stenosis.

Hepatic impairment

Treatment with ACE inhibitors has occasionally been associated with a syndrome beginning as cholestatic jaundice progressing to fulminant hepatic necrosis, sometimes fatal. The mechanism of this syndrome is not established. If jaundice or significant elevation of liver enzyme activity occurs, ACE inhibitor therapy should be discontinued, and medical observation and treatment initiated (see section "Undesirable effects").

Hyperkalaemia

ACE inhibitors may cause hyperkalaemia due to suppression of aldosterone release. In patients with normal liver function, the hyperglycaemic effect is not increased.

Risk factors for hyperkalaemia include: renal impairment or reduced 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, potassium-containing salt substitutes, or other agents causing increased serum potassium concentration (e.g., heparin, trimethoprim or cotrimoxazole [trimethoprim/sulfamethoxazole], aldosterone antagonists, angiotensin receptor blockers, acetylsalicylic acid ≥ 3 g/day, COX-2 inhibitors, non-selective NSAIDs, immunosuppressants such as cyclosporine or tacrolimus). Use of potassium supplements, potassium-sparing diuretics, or potassium-containing salt substitutes, particularly in patients with impaired renal function, may lead to significant increase in serum potassium concentration. Hyperkalaemia may cause serious, sometimes fatal, arrhythmias. Patients taking ACE inhibitors should use potassium-sparing diuretics and angiotensin receptor blockers cautiously and undergo careful monitoring of serum potassium levels and renal function (see section "Interaction with other medicinal products and other forms of interaction").

Indapamide

Water and electrolyte balance

Plasma sodium levels Plasma sodium concentration should be determined before starting treatment and at regular intervals during treatment. Since decreased plasma sodium concentration may initially be asymptomatic, careful monitoring is required. In elderly patients and patients with liver cirrhosis, plasma sodium concentration should be determined more frequently (see sections "Overdose" and "Undesirable effects").

Any diuretic therapy may cause hyponatraemia, sometimes with very serious consequences. Hyponatraemia with hypovolaemia may lead to dehydration and orthostatic hypotension. Concomitant chloride ion loss may lead to secondary compensatory metabolic alkalosis—this effect is infrequent and mild.

Plasma potassium levels The main risk of thiazide and thiazide-like diuretic therapy is decreased potassium concentration and hypokalaemia. Hypokalaemia may cause muscle disorders. Cases of rhabdomyolysis, mainly associated with severe hypoglycaemia, have been reported. In poorly nourished patients and/or those taking multiple medications, elderly patients, patients with liver cirrhosis and ascites, ischaemic heart disease, and heart failure, hypokalaemia (< 3.4 mmol/l) should be prevented.

In such patients, hypokalaemia increases the cardiotoxicity of digitalis preparations and the risk of arrhythmias.

Patients with prolonged QT interval also have some risk, whether congenital or iatrogenic. Hypokalaemia (and bradycardia) are thus factors predisposing to dangerous arrhythmias, including polymorphic ventricular tachycardia of the torsade de pointes type, sometimes fatal.

In all such cases, plasma potassium levels should be monitored more frequently in these patients. The first measurement of plasma potassium concentration should be performed within the first week after starting treatment.

If potassium levels are reduced, dose adjustment should be performed. Hypokalaemia associated with low serum magnesium concentration may be resistant to treatment unless serum magnesium levels are corrected.

Magnesium levels Thiazide and thiazide-like diuretics, including indapamide, have been shown to increase urinary magnesium excretion, potentially leading to hypomagnesaemia (see sections "Interaction with other medicinal products and other forms of interaction" and "Undesirable effects").

Calcium levels Thiazide and related diuretics may reduce urinary calcium excretion and cause slight transient increase in plasma calcium concentration. Persistent hypercalcaemia may indicate hyperparathyroidism. Therefore, diuretic therapy should be discontinued until parathyroid function is evaluated.

Blood glucose In patients with diabetes mellitus, blood glucose levels should be carefully monitored, particularly in the presence of hypokalaemia.

Uric acid Patients with hyperuricaemia may show a tendency to gout attacks.

Renal function and diuretics

Thiazide and related diuretics are more effective with normal or mildly impaired renal function (plasma creatinine level in adults < 25 mg/l or 220 µmol/l).

In elderly patients, plasma creatinine levels should be age-, body weight-, and sex-appropriate.

Creatinine clearance can be calculated using the Cockcroft formula:

For elderly men:

Creatinine clearance = (140 – age) × body weight / 0.814 × plasma creatinine level,

where: age in years, body weight in kilograms, plasma creatinine level in µmol/l.

For women: multiply the result obtained by the formula by 0.85.

Hypovolaemia occurring at the beginning of treatment due to water and sodium loss from diuretic use may reduce glomerular filtration. This may lead to increased blood urea and creatinine levels. In patients with normal renal function, this transient functional renal impairment resolves without consequences, but pre-existing renal impairment may worsen.

Sportsmen

Athletes should be aware that the active substance indapamide may lead to a positive doping test.

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

Sulphonamide or sulphonamide-derived drugs may cause an idiosyncratic reaction leading to choroidal effusion with visual field defects, transient myopia, and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or eye pain and usually occur within hours or weeks of starting the drug. Untreated acute angle-closure glaucoma may lead to permanent vision loss. Primary treatment is prompt 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 is a history of allergy to sulphonamides or penicillin.

Excipients

The medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding

Pregnancy

The medicinal product is contraindicated in pregnant women or women planning pregnancy (see sections "Contraindications" and "Special precautions for use").

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. When continuation of antihypertensive therapy is considered necessary, women planning pregnancy should be switched to alternative antihypertensive agents with established 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 (renal dysfunction, oligohydramnios, delayed ossification of the skull bones) and on the newborn (renal failure, arterial hypotension, hyperkalaemia).

If ACE inhibitors were used during the second and third trimesters, ultrasound examination of renal function and skull structure in 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").

Indapamide

Data on indapamide use during pregnancy are limited (fewer than 300 pregnancy cases). Prolonged use of a thiazide diuretic during the third trimester may reduce circulating blood volume in the pregnant woman and uteroplacental perfusion, potentially causing fetoplacental ischaemia and delayed fetal development. Animal studies do not indicate direct or indirect harmful effects on reproductive function.

Use of indapamide during pregnancy is not recommended.

Period of breastfeeding

The medicinal product is not recommended during breastfeeding.

Perindopril

Perindopril use during breastfeeding is not recommended due to lack of data in this patient group. Alternative therapy with a proven safety profile should be preferred, especially during breastfeeding of newborns or preterm infants.

Indapamide

There is insufficient information on indapamide/metabolite excretion into human milk. Increased sensitivity to sulphonamide derivatives and hypokalaemia may occur. Risk to newborns/infants cannot be excluded. Indapamide belongs to thiazide diuretics, which during lactation suppress milk secretion.

Indapamide is not recommended during breastfeeding.

Fertility

Reproductive toxicity studies did not show effects on fertility in male and female rats. No effect on human fertility has been established.

Ability to affect reaction speed when driving or operating machinery

The active substances of the medicinal product, perindopril and indapamide, alone or in combination, do not affect the ability to drive or operate machinery. However, individual reactions related to reduced blood pressure may occur in some patients, especially at the beginning of treatment or during concomitant use with other antihypertensive agents. As a result, the ability to drive or operate machinery may be impaired.

Method of Administration and Dosage

For oral use.

Perindopril 5/Indapamide 1.25 KRKA

The usual dose is 1 tablet of Perindopril 5/Indapamide 1.25 KRKA once daily, preferably taken in the morning before a meal.

Whenever possible, it is recommended to individually titrate the doses of the separate components. Tablets Perindopril 5/Indapamide 1.25 KRKA should be prescribed when arterial pressure is not adequately controlled with tablets of perindopril/indapamide 2.5 mg/0.625 mg (when feasible).

If there are clinical indications, a direct transition from monotherapy with perindopril to treatment with Perindopril 5/Indapamide 1.25 KRKA tablets may be considered.

Perindopril 10/Indapamide 2.5 KRKA

The usual dose is 1 tablet of Perindopril 10/Indapamide 2.5 KRKA once daily, preferably taken in the morning before a meal.

The maximum daily dose is 1 tablet of Perindopril 10/Indapamide 2.5 KRKA.

Elderly patients (see section "Special Instructions")

Perindopril 5/Indapamide 1.25 KRKA

Treatment should be initiated according to the response of arterial pressure and renal function.

Perindopril 10/Indapamide 2.5 KRKA

In elderly patients, plasma creatinine levels should be appropriate for age, body weight, and gender. If renal function is normal, elderly patients may be treated according to the response of arterial pressure.

Renal impairment (see section "Special Instructions")

Perindopril 5/Indapamide 1.25 KRKA

The medicinal product is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min). For patients with moderate renal impairment (creatinine clearance 30–60 mL/min), it is recommended to initiate treatment with appropriate doses of the individual components of the medicinal product. Patients with creatinine clearance ≥ 60 mL/min do not require dose adjustment. Routine medical monitoring should include careful monitoring of plasma creatinine and potassium levels.

Perindopril 10/Indapamide 2.5 mg KRKA

The medicinal product is contraindicated in patients with moderate to severe renal impairment (creatinine clearance < 60 mL/min).

Routine medical monitoring should include careful monitoring of plasma creatinine and potassium levels.

Hepatic impairment (see sections "Pharmacokinetics", "Contraindications", and "Special Instructions")

The medicinal product is contraindicated in patients with severe hepatic impairment.

Dose adjustment is not required in patients with moderate hepatic impairment.

Children

The medicinal product is not recommended for use in children due to insufficient data on safety and efficacy in this patient group.

Overdose.

Symptoms. The following symptoms may occur: arterial hypotension, nausea, vomiting, convulsions, dizziness, drowsiness, confusion, oliguria progressing to anuria (due to hypovolemia). Electrolyte and fluid imbalances may occur (decreased plasma potassium and sodium levels).

Treatment. Emergency measures include rapid elimination of the drug from the body—gastric lavage and/or administration of activated charcoal, followed by correction of fluid and electrolyte imbalances under hospital conditions. In case of significant arterial hypotension, the patient should be placed in a supine position with elevated lower limbs. Intravenous administration of 0.9% sodium chloride solution or any other volume-expanding method is recommended. Perindopril can be removed from systemic circulation by hemodialysis (see section "Pharmacokinetics").

Adverse reactions.

Summary of safety profile

The use of perindopril suppresses the RAAS and tends to reduce potassium loss caused by indapamide.

The most commonly observed adverse reactions 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 cramps, and asthenia;
• caused by indapamide: hypokalaemia, hypersensitivity reactions, predominantly dermatological, in patients predisposed to allergic and asthmatic reactions, and maculopapular rashes.

List of adverse reactions

Adverse effects that may occur during treatment are classified by frequency: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000), very rare (< 1/10,000), and not known (cannot be estimated from the available data).

Body System	Adverse Reactions	Frequency
		Perindopril	Indapamide
Infections and infestations	Rhinitis	Very rare	-
Blood and lymphatic system	Eosinophilia	Unknown1	-
	Agranulocytosis2	Very rare	Very rare
	Aplastic anemia	-	Very rare
	Pancytopenia	Very rare	-
	Leukopenia	Very rare	Very rare
	Neutropenia2	Very rare	-
	Hemolytic anemia	Very rare	Very rare
	Thrombocytopenia2	Very rare	Very rare
Immune system	Hypersensitivity reactions (mainly dermatological, in patients predisposed to allergic and asthmatic reactions)	-	Common
Endocrine system	Syndrome of inappropriate antidiuretic hormone secretion (SIADH)	Uncommon	-
Metabolism and nutrition	Hypoglycemia3	Uncommon1	-
	Hyperkalemia, reversible upon discontinuation2	Uncommon1	-
	Hyponatremia2	Uncommon1	Uncommon
	Hypercalcemia	-	Very rare
	Hypokalemia2	-	Common
	Hypochloremia	-	Uncommon
	Hypomagnesemia	-	Uncommon
Psychiatric disorders	Mood disorders	Uncommon	-
	Sleep disorders	Uncommon	-
	Depression	Uncommon	-
	Confusion	Very rare	-
Nervous system	Dizziness	Common	-
	Headache	Common	Uncommon
	Paresthesia	Common	Uncommon
	Disturbance of taste	Common	-
	Somnolence	Uncommon1	-
	Syncope	Uncommon1	Unknown
	Stroke, possibly secondary to excessive hypotension in patients at high risk2	Very rare	-
	Development of hepatic encephalopathy in case of liver insufficiency4	-	Unknown
Eye	Visual disturbance	Common	Unknown
	Myopia2	-	Unknown
	Blurred vision	-	Unknown
	Acute angle-closure glaucoma	-	Unknown
	Choroidal effusion	-	Unknown
Ear and labyrinth disorders	Vertigo	Common	Uncommon
	Tinnitus	Common	-
Cardiac disorders	Palpitations	Uncommon1	-
	Tachycardia	Uncommon1	-
	Angina pectoris2	Very rare	-
	Arrhythmia (including bradycardia, ventricular tachycardia, atrial fibrillation)	Very rare	Very rare
	Myocardial infarction, possibly after excessive hypotension in patients at high risk2	Very rare	-
	Paroxysmal ventricular tachycardia of the "torsades de pointes" type (potentially fatal)3	-	Unknown
Vascular disorders	Arterial hypotension (and symptoms related to hypotension)2	Common	Very rare
	Vasculitis	Uncommon1	-
	Flushing	Uncommon	-
	Raynaud's phenomenon	Unknown	-
Respiratory, thoracic and mediastinal disorders	Cough2	Common	-
	Dyspnea	Common	-
	Bronchospasm	Uncommon	-
	Eosinophilic pneumonia	Very rare	-
Gastrointestinal disorders	Abdominal pain	Common	-
	Constipation	Common	Uncommon
	Diarrhea	Common	-
	Dyspepsia	Common	-
	Nausea	Common	Uncommon
	Vomiting	Common	Uncommon
	Dry mouth	Uncommon	Uncommon
	Pancreatitis	Very rare	Very rare
Hepatobiliary disorders	Hepatitis2	Very rare	Unknown
	Liver function abnormalities	-	Very rare
Skin and subcutaneous tissue	Pruritus	Common	-
	Rash	Common	-
	Maculopapular rash	-	Common
	Urticaria2	Uncommon	Very rare
	Angioedema2	Uncommon	Very rare
	Purpura	-	Uncommon
	Hyperhidrosis	Uncommon	-
	Photosensitivity reaction	Uncommon1	Unknown
	Pemphigoid	Uncommon1	-
	Worsening of psoriasis symptoms	Uncommon1	-
	Multiform erythema	Very rare	-
	Toxic epidermal necrolysis	-	Very rare
	Stevens-Johnson syndrome	-	Very rare
Musculoskeletal and connective tissue disorders	Muscle cramps	Common	-
	Exacerbation of pre-existing systemic lupus erythematosus	-	Unknown
	Arthralgia	Uncommon1	-
	Myalgia	Uncommon1	-
	Muscle weakness	-	Unknown
	Rhabdomyolysis	-	Unknown
Renal and urinary system	Renal impairment	Uncommon	-
	Acute renal failure	Uncommon	Very rare
	Anuria/oliguria	Uncommon	-
Reproductive system and breast	Erectile dysfunction	Uncommon	Uncommon
General disorders and administration site conditions	Asthenia	Common	-
	Chest pain	Uncommon1	-
	Malaise	Uncommon1	-
	Peripheral edema	Uncommon1	-
	Pyrexia	Uncommon1	-
	Fatigue	-	Uncommon
Investigations	Increased plasma urea levels	Uncommon1	-
	Increased plasma creatinine levels	Uncommon1	-
	Increased plasma bilirubin levels	Uncommon	-
	Elevated liver enzymes	Uncommon	Unknown
	Decreased hemoglobin and red blood cell count2	Very rare	-
	Increased plasma glucose levels	-	Unknown
	Increased plasma uric acid levels	-	Unknown
	QT interval prolongation on ECG3	-	Unknown
Injury, poisoning and procedural complications	Falls	Uncommon1	-

1 Frequency of adverse reactions identified from spontaneous reports calculated based on data.

2 See section "Special precautions for use".

3 See sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use".

4 See sections "Contraindications" and "Special precautions for use".

Description of selected adverse reactions

During phase II and III studies comparing indapamide doses of 1.5 mg and 2.5 mg, analysis of plasma potassium levels showed 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 average 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 average decrease in plasma potassium level was 0.41 mmol/L.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is of great importance. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions. Store in the original packaging to protect from light.

The medicinal product does not require special storage temperature conditions.

Keep out of reach and sight of children.

Packaging. 10 tablets per blister; 3 or 9 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. KRKA, d.d., Novo mesto / KRKA, d.d., Novo mesto.

Manufacturer's address and place of business.

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