INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Noliprel® arginine forte (Noliprel® arginine forte)

Composition:

Active substances: perindopril arginine, indapamide;

1 tablet contains 5 mg of perindopril arginine, equivalent to 3.395 mg of perindopril, and 1.25 mg of indapamide;

Excipients: lactose monohydrate, magnesium stearate (E 470 B), maltodextrin, colloidal anhydrous silicon dioxide (E 551), sodium starch glycolate (type A), macrogol 6000, glycerin (E 422), hypromellose (E 464), titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties:

Manufactured by "Laboratoires Servier Industrie", France: white, elongated shaped tablets, film-coated;

Manufactured by "Servier (Ireland) Industries Ltd", Ireland: white, elongated shaped tablets, film-coated, with imprint « » on one side.

Pharmacotherapeutic group. Perindopril and diuretics. ATC code C09B A04.

Pharmacological Properties

Pharmacodynamics

Noliprel® arginine forte is a combination of the ACE inhibitor perindopril arginine and the sulfonamide diuretic indapamide. Its pharmacological action is determined by the properties of each component (perindopril and indapamide) and their additive synergism.

Mechanism of Action

Noliprel® arginine forte exerts an additive synergistic effect of two antihypertensive components.

Mechanism of Action of Perindopril

Perindopril is an ACE inhibitor that converts angiotensin I to angiotensin II (a vasoconstrictive substance), additionally stimulates aldosterone secretion by the adrenal cortex, and promotes bradykinin (a vasodilatory substance) breakdown into inactive heptapeptides. Inhibition of ACE leads to: reduced aldosterone secretion; increased plasma renin activity, while aldosterone does not exert a negative feedback effect; decreased total peripheral vascular resistance due to predominant effects on muscular and renal vessels; without water and salt retention or reflex tachycardia, even during long-term treatment. Furthermore, perindopril reduces blood pressure (BP) 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)—reducing preload—and by decreasing total peripheral vascular resistance—reducing afterload on the heart. Studies conducted in patients with heart failure have demonstrated that perindopril use leads to reduced filling pressures in the left and right ventricles, decreased total peripheral vascular resistance, increased cardiac output, improved cardiac index, and increased regional blood flow in muscles. Physical exercise test parameters are improved.

Mechanism of Action of 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 potassium and magnesium, thereby increasing diuresis and providing antihypertensive action.

Pharmacodynamic Effects

Noliprel® arginine forte exerts dose-dependent antihypertensive effects on systolic (SBP) and diastolic (DBP) blood pressure in patients with arterial hypertension of any age, both in supine and standing positions. The antihypertensive effect lasts for 24 hours. Blood pressure reduction is achieved within less than one month without development of tachyphylaxis; discontinuation of treatment does not cause withdrawal syndrome. Clinical studies have demonstrated that concomitant administration of perindopril and indapamide results in synergistic antihypertensive effects due to the individual effects of each component.

PICXEL – a multicenter, randomized, double-blind, placebo-controlled study evaluating the effect of the combination of perindopril and indapamide on left ventricular hypertrophy compared to enalapril monotherapy, assessed by echocardiography. In the PICXEL study, patients with arterial hypertension and left ventricular hypertrophy (with 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 (equivalent to 2.5 mg perindopril arginine)/0.625 mg indapamide, and the other received 10 mg enalapril once daily for one year. Doses were adjusted according to BP values: perindopril tert-butylamine dose was increased up to 8 mg (equivalent to 10 mg perindopril arginine), indapamide up to 2.5 mg, and 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 in 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). Greater reduction in left ventricular mass index was achieved with maximum doses of perindopril/indapamide (10 mg/2.5 mg). Blood pressure reduction was more effective in the perindopril/indapamide group: the difference in mean BP reduction between the two patient groups was −5.8 mm Hg (95% CI from −7.9 to −3.7, p < 0.0001) for SBP and −2.3 mm Hg (95% CI from −3.6 to −0.9, p = 0.0004) for DBP.

ADVANCE – an international, multicenter, randomized study with a 2×2 factorial design, aimed at evaluating the benefits of BP reduction with fixed-dose perindopril/indapamide combination versus placebo on top of standard ongoing therapy (double-blind comparison), and the benefits of an intensive glycemic control strategy (HbA1c ≤ 6.5%) based on gliclazide MR (Diabeton® MR) versus standard glycemic control (PROBE design [prospective, randomized, open-label, blinded-endpoint evaluation]) 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 (new onset or worsening nephropathy, retinopathy) events. The study included 11,140 patients with type 2 diabetes. Mean patient age was 66 years, BMI 28 kg/m², diabetes duration 8 years, HbA1c 7.5%, and SBP/DBP 145/81 mm Hg. Among them, 83% had arterial hypertension, 32% and 10% had a history of microvascular and macrovascular disease, respectively, and 27% had microalbuminuria. Concomitant therapy included antihypertensive drugs (75%), lipid-lowering agents (35%, predominantly statins – 28%), and acetylsalicylic acid or other antiplatelet agents (47%). During a 6-week run-in period, patients received perindopril/indapamide combination and continued their usual glucose-lowering therapy. Subsequently, patients were randomized to receive either placebo (n = 5571) or perindopril/indapamide combination (n = 5569). Noliprel® arginine forte, 5 mg/1.25 mg, film-coated tablets, is not suitable for initiating therapy. Treatment was initiated with perindopril arginine 2.5 mg/indapamide 0.625 mg, one tablet once daily. After 3 months, if well tolerated, the dose was increased to Noliprel® arginine forte, 5 mg/1.25 mg, film-coated tablets, one tablet once daily. Treatment with perindopril/indapamide combination over 4.3 years led to a significant 9% relative risk reduction in the primary endpoint (95% CI [0.828; 0.996], p = 0.041). The benefits of perindopril/indapamide treatment versus placebo were due to: a significant 14% relative risk reduction in all-cause mortality (95% CI [0.75; 0.98], p = 0.025); a significant 18% relative risk reduction in cardiovascular mortality (95% CI [0.68; 0.98], p = 0.027); and a significant 21% relative risk reduction in all types of renal complications (95% CI [0.74; 0.86], p < 0.001). In the subgroup of hypertensive patients treated with perindopril/indapamide, a significant 9% relative risk reduction in major macro- and microvascular complications was observed (95% CI [0.82; 1.0], p = 0.052) compared to the placebo group. In the subgroup receiving perindopril/indapamide versus placebo, there was also a significant: 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); and 20% relative risk reduction in all types of renal complications (95% CI [0.73; 0.87], p < 0.001). The benefits of antihypertensive treatment were independent of benefits achieved in patients treated according to the intensive glycemic control strategy.

Pharmacodynamic Effects Related to Perindopril

Perindopril effectively reduces BP in all stages of arterial hypertension: mild, moderate, and severe. Reductions in SBP and DBP are observed both in supine and standing positions. The maximum antihypertensive effect develops 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 responding to treatment, BP normalization is achieved within one month and maintained without tachyphylaxis. Discontinuation of therapy is not associated with withdrawal syndrome. Perindopril has vasodilatory properties, restores elasticity of large arteries, corrects histomorphometric changes in resistance arteries, and reduces left ventricular hypertrophy. Addition of a thiazide diuretic, if necessary, results in additional synergism. Combined use of an ACE inhibitor and a thiazide diuretic reduces the risk of hypokalemia that may occur with diuretic monotherapy.

Pharmacodynamic Effects Related to Indapamide

When used as monotherapy, indapamide exerts an antihypertensive effect lasting 24 hours. This effect occurs at doses where diuretic properties are minimal. The antihypertensive effect of indapamide is proportional to improved arterial elasticity and reduced arteriolar resistance and total peripheral vascular resistance. Indapamide reduces left ventricular hypertrophy. For thiazide and thiazide-like diuretics, antihypertensive effects reach a plateau at higher doses, while adverse effects increase. If treatment is insufficiently effective, the dose should not be increased. 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) and does not affect carbohydrate metabolism, even in patients with arterial hypertension and diabetes mellitus.

Pharmacokinetics

The pharmacokinetic properties of perindopril and indapamide when used in combination do not differ from those of the individual components when administered separately.

Pharmacokinetic Properties of Perindopril

Absorption and Bioavailability. After oral administration, perindopril is rapidly absorbed, with maximum 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 meals.

Distribution. The volume of distribution of unbound perindoprilat is approximately 0.2 L/kg. Perindoprilat binding to plasma proteins is 20%, primarily to ACE, and depends on concentration.

Biotransformation. Perindopril is a prodrug. About 27% of the administered dose of perindopril reaches the systemic circulation as the active metabolite perindoprilat. In addition to the active perindoprilat, perindopril forms five other inactive metabolites. Maximum plasma concentration of perindoprilat is reached within 3–4 hours.

Elimination. Perindoprilat is excreted in urine; the terminal elimination half-life of the unbound fraction is approximately 17 hours. Steady-state is achieved within 4 days.

Linearity/Non-linearity. A linear relationship between perindopril dose and plasma concentration has been demonstrated.

Special Patient Populations

Elderly Patients. Elimination of perindoprilat is reduced in elderly patients and in those with cardiac or renal insufficiency.

Renal Function Impairment. Dose adjustment of perindopril is required in patients with renal impairment depending on the degree of renal dysfunction (creatinine clearance).

Dialysis Requirement. Dialysis clearance of perindoprilat is 70 mL/min.

Hepatic Cirrhosis. Perindopril kinetics are altered in patients with hepatic cirrhosis: hepatic clearance of the parent compound is halved. However, the amount of perindoprilat formed is not reduced; therefore, dose adjustment is not required in these patients (see sections "Dosage and Administration" and "Special Warnings and Precautions").

Pharmacokinetic Properties of Indapamide

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

Distribution. Protein binding in plasma is 79%.

Biotransformation and Elimination. Elimination half-life is 14–24 hours (on average, 18 hours). Repeated administration does not lead to accumulation. Excretion occurs mainly via urine (70% of dose) and feces (22%) as inactive metabolites.

Special Patient Populations

Renal Function Impairment. Pharmacokinetic parameters of indapamide are not altered in patients with renal insufficiency.

Clinical characteristics.

Indications.

Treatment of essential hypertension in adult patients.

Noliprel® arginine forte is indicated when additional blood pressure control is required with perindopril used as monotherapy.

Contraindications.

Related to perindopril:

Hypersensitivity to the active substance or to any other angiotensin-converting enzyme (ACE) inhibitor;
History of angioedema (Quincke's edema) associated with previous ACE inhibitor therapy (see section "Special precautions");
Hereditary or idiopathic angioedema;
Pregnancy or planned pregnancy (see section "Use in pregnancy or breastfeeding");
Concomitant use with aliskiren-containing products in patients with diabetes or renal impairment (glomerular filtration rate < 60 mL/min/1.73 m²) (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacodynamics");
Concomitant use with sacubitril/valsartan. Noliprel® arginine forte must not be used earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction");
Extracorporeal treatment methods leading to contact of blood 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 solitary functioning kidney (see section "Special precautions").

Related to indapamide:

Hypersensitivity to the active substance or to any other sulfonamides;
Severe renal impairment (creatinine clearance < 30 mL/min);
Hepatic encephalopathy;
Severe hepatic dysfunction;
Hypokalemia.

Related to Noliprel® arginine forte:

Hypersensitivity to any excipient.

Due to lack of sufficient clinical experience, Noliprel® arginine forte 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.

Interactions common to perindopril and indapamide

Concomitant use not recommended

Lithium. Reversible increases in serum lithium concentration and lithium toxicity have been reported during concomitant use with ACE inhibitors (ACEIs). Concomitant use of perindopril with indapamide and lithium is not recommended; however, if this is truly necessary, serum lithium concentrations should be monitored carefully (see section "Special precautions").

Concomitant use requiring special attention

Baclofen. Antihypertensive effect is enhanced. Blood pressure should be monitored and dosage of antihypertensive agent adjusted as needed.

Nonsteroidal anti-inflammatory drugs (NSAIDs) (including acetylsalicylic acid at doses ≥ 3 g/day). When ACEIs are used concomitantly with NSAIDs, such as acetylsalicylic acid at anti-inflammatory doses, COX-2 inhibitors, or nonselective NSAIDs, the antihypertensive effect may be attenuated. Concomitant use of ACEIs and NSAIDs may lead to increased risk of worsening renal function, including development of acute renal failure, and increased serum potassium levels, particularly in patients with renal impairment. Such combinations should be prescribed with caution, especially in elderly patients. Patients should be adequately hydrated before starting treatment, and renal function should be monitored at the beginning and throughout combination therapy.

Concomitant use requiring attention

Tricyclic antidepressants, neuroleptics. Enhance antihypertensive effect and increase the risk of orthostatic hypotension (additive effect).

Interactions related to perindopril

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 increased incidence of adverse reactions such as hypotension, hyperkalemia, and worsening renal function (including acute renal failure), compared to use of a single RAAS-acting agent (see sections "Contraindications", "Special precautions", and "Pharmacodynamics").

Medicinal products increasing the risk of angioedema. Concomitant use of ACE inhibitors 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. 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 of ACE inhibitors with racemizedotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) may increase the risk of angioedema (see section "Special precautions").

Medicinal products causing hyperkalemia. Serum potassium levels usually remain within normal limits, but hyperkalemia may occur in some patients treated with Noliprel® arginine forte. Certain drugs or therapeutic classes, such as aliskiren, potassium salts, potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), ACE inhibitors, angiotensin II receptor antagonists, NSAIDs, heparins, immunosuppressants (e.g., cyclosporine or tacrolimus), and co-trimoxazole (trimethoprim/sulfamethoxazole, since trimethoprim acts as a potassium-sparing diuretic similar to amiloride), may cause hyperkalemia. Combination with these agents increases the risk of hyperkalemia. Therefore, concomitant use of Noliprel® arginine forte with the above-mentioned drugs is not recommended. If concomitant use is necessary, it should be done with caution and frequent monitoring of serum potassium levels.

Concomitant use contraindicated (see section "Contraindications")

Aliskiren. In patients with diabetes or renal impairment, there is increased risk of hyperkalemia, worsening renal function, cardiovascular morbidity, and mortality.

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

Concomitant use not recommended

Aliskiren. In all other patient groups, including those with diabetes or renal impairment, there is increased risk of hyperkalemia, worsening renal function, cardiovascular morbidity, and mortality (see section "Special precautions").

Combination therapy with ACE inhibitor and angiotensin receptor blocker. In patients with established atherosclerosis, heart failure, or diabetes with target organ damage, combination therapy with ACE inhibitors and angiotensin receptor blockers has been associated with increased incidence of hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure), compared to monotherapy with a single RAAS-acting agent. Dual blockade (i.e., combination of ACE inhibitor and angiotensin II receptor antagonist) may be considered only in selected cases under strict monitoring of renal function, serum potassium levels, and blood pressure (see section "Special precautions").

Estramustine. Risk of increased frequency of adverse reactions such as angioedema.

Potassium-sparing diuretics (e.g., triamterene, amiloride), potassium (salts). Risk of hyperkalemia (potentially fatal), especially in patients with renal impairment (additive hyperkalemic effect). Combination of perindopril with the above-mentioned agents is not recommended (see section "Special precautions"). If concomitant use is unavoidable, it should be done with caution and frequent monitoring of serum potassium levels. Information on use of spironolactone in patients with heart failure is provided under "Concomitant use requiring special attention".

Concomitant use requiring special attention

Antidiabetic agents (insulin, oral hypoglycemics). Concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemics) may enhance the glucose-lowering effect, increasing the risk of hypoglycemia. This phenomenon may occur during the first weeks of combination therapy and in patients with renal impairment.

Diuretics. In patients taking diuretics, especially those with volume and sodium depletion, excessive reduction in blood pressure may occur after initiation of ACE inhibitor therapy. The likelihood of hypotensive effects may be reduced by discontinuing the diuretic, increasing intravascular volume, or increasing salt intake prior to starting perindopril therapy, which should be initiated at a low dose with gradual dose escalation. In hypertensive patients whose prior diuretic therapy may have caused volume/sodium depletion, the diuretic should be discontinued before starting ACE inhibitor therapy (diuretic therapy may later be resumed) or ACE inhibitor therapy should be initiated at a low dose with gradual dose escalation. In patients with congestive heart failure receiving diuretics, 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 few weeks of ACE inhibitor therapy.

Potassium-sparing diuretics (eplerenone, spironolactone). When eplerenone or spironolactone (12.5–50 mg/day) is used concomitantly with low-dose ACE inhibitors in patients with NYHA class II–IV heart failure and ejection fraction < 40%, previously treated with ACE inhibitors and loop diuretics, there is a risk of potentially fatal hyperkalemia, particularly if recommendations for use of this combination are not followed. Before initiating such combination therapy, absence of hyperkalemia and renal dysfunction should be confirmed. Close monitoring of serum potassium and creatinine is recommended weekly during the first month and monthly thereafter.

Concomitant use requiring attention

Antihypertensive agents and vasodilators. Concomitant use of these agents may enhance the hypotensive effects of perindopril. 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 may increase the risk of leukopenia (see section "Special precautions").

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

Sympathomimetics. Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.

Gold compounds. Rarely, when patients are treated with injectable gold compounds (sodium aurothiomalate) and concomitantly receive ACE inhibitors, including perindopril, nitritoid reactions (facial flushing, nausea, vomiting, and hypotension) have been reported.

Interactions related to indapamide

Concomitant use requiring special attention

Agents that may induce torsades de pointes. Due to the risk of hypokalemia, indapamide should be used cautiously in combination with agents that may induce torsades de pointes, such as (the list is not exhaustive): Class IA antiarrhythmics (e.g., quinidine, hydroquinidine, disopyramide); Class III antiarrhythmics (e.g., amiodarone, dofetilide, ibutilide, bretylium, sotalol); certain antipsychotics: phenothiazines (e.g., chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine), benzamides (e.g., amisulpride, sulpiride, sultopride, tiapride), butyrophenones (e.g., droperidol, haloperidol), other antipsychotics (e.g., pimozide); other substances (e.g., bepridil, cisapride, difemanil, intravenous erythromycin, halofantrine, mizolastine, moxifloxacin, pentamidine, sparfloxacin, intravenous vinca alkaloids, methadone, astemizole, terfenadine). Measures should be taken to prevent plasma potassium depletion and correct it if necessary, and QT interval should be monitored.

Medicinal products reducing blood potassium levels. Intravenous amphotericin B, glucocorticoids and mineralocorticoids (systemic action), tetracosactide, and stimulant laxatives increase the risk of reduced serum potassium levels (additive effect). Serum potassium levels should be monitored and corrected as needed, particularly during concomitant treatment with cardiac glycosides. Non-stimulant laxatives should be used.

Cardiac glycosides. Hypokalemia and/or hypomagnesemia may predispose to glycoside toxicity. Monitoring of plasma potassium and magnesium levels and ECG monitoring are recommended, with treatment adjustment as needed.

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

Concomitant use requiring attention

Potassium-sparing diuretics (amiloride, spironolactone, triamterene). Hypokalemia or hyperkalemia may occur (particularly in patients with renal impairment or diabetes). Serum potassium levels should be monitored, ECG monitoring performed, and therapy reviewed as needed.

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

Iodinated contrast agents. Dehydration caused by diuretic use increases the risk of acute renal failure, especially with high doses of iodinated contrast agents. Fluid balance should be restored before administration of iodinated contrast agents.

Calcium (salts). Risk of increased blood calcium levels due to reduced urinary excretion.

Cyclosporine, tacrolimus. Risk of increased serum creatinine levels without changes in circulating cyclosporine concentration, even in the absence of volume or sodium depletion.

Corticosteroids, tetracosactide (systemic action). Reduce antihypertensive effect (due to water and sodium retention caused by corticosteroids).

Special precautions for use.

Special warnings

Special warnings common to perindopril and indapamide

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

Special warnings related to perindopril

Dual blockade of the renin-angiotensin-aldosterone system (RAAS). Data indicate that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of arterial hypotension, hyperkalaemia, and impaired renal function (including acute renal failure). Therefore, dual blockade of the RAAS by combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacodynamics"). If dual RAAS blockade therapy is considered absolutely necessary, it should be undertaken only under specialist supervision and with frequent careful monitoring of renal function, electrolyte levels, and blood pressure. Patients with diabetic nephropathy should not receive concomitant ACE inhibitors and angiotensin II receptor blockers.

Potassium-sparing agents, potassium supplements, or potassium-containing salt substitutes. The combination of perindopril with potassium-sparing agents, potassium supplements, or potassium-containing salt substitutes is generally 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 ACE inhibitors. Neutropenia is rare in patients with normal renal function and no other risk factors. Perindopril should be used with extreme caution in patients with collagen vascular diseases, those receiving immunosuppressants, allopurinol, or procainamide, or in patients with a combination of these risk factors, especially if renal function is impaired. Some of these patients have developed severe infections, sometimes resistant to intensive antibiotic therapy. Periodic monitoring of white blood cell counts is recommended in such patients receiving perindopril. Patients should also be informed to report any signs of infection (e.g., sore throat, fever) to their physician (see sections "Interaction with other medicinal products and other forms of interaction" and "Side effects").

Renovascular hypertension. In patients with bilateral renal artery stenosis or stenosis of the artery to 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. Impaired renal function may be associated with only minor changes in serum creatinine levels, even in patients with unilateral renal artery stenosis.

Hypersensitivity/angioedema. Rare cases of angioedema of the face, extremities, lips, tongue, glottis, and/or larynx have been reported in patients treated with ACE inhibitors, including perindopril (see section "Side effects"). This may occur at any time during treatment. In such cases, the drug must be discontinued immediately and the patient placed under medical observation until symptoms resolve completely. If swelling is limited to the face and lips, the patient's condition usually improves without treatment, although antihistamines may be helpful in relieving symptoms. Angioedema involving laryngeal swelling may be fatal. If swelling involves the tongue, glottis, or larynx, potentially causing airway obstruction, emergency treatment is required, which may include subcutaneous administration of 1:1000 epinephrine solution (0.3–0.5 mL) and/or measures to ensure airway patency. Angioedema has been reported more frequently in patients of Black race receiving ACE inhibitors compared to other racial groups. Patients with a history of angioedema unrelated to ACE inhibitor use are at increased risk of developing angioedema during ACE inhibitor therapy. Rare cases of intestinal angioedema have been reported in patients receiving ACE inhibitors. These patients presented with abdominal pain (with or without nausea and vomiting); intestinal angioedema sometimes occurred without prior facial angioedema, and serum C1 esterase inhibitor levels were normal. The diagnosis of angioedema was confirmed by procedures such as abdominal computed tomography, ultrasound, or during surgery; 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 an increased risk of angioedema. Initiation of sacubitril/valsartan should not occur earlier than 36 hours after the last dose of perindopril. If sacubitril/valsartan is discontinued, perindopril therapy should not be initiated 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 ACE inhibitors with neutral endopeptidase (NEP) inhibitors (e.g., racecadotril), mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) may increase the risk of angioedema (e.g., airway or tongue swelling, with or without respiratory compromise) (see section "Interaction with other medicinal products and other forms of interaction"). Caution is advised when initiating treatment with racecadotril, mTOR inhibitors, or gliptins in patients already receiving ACE inhibitors.

Anaphylactoid reactions during desensitization. Isolated cases of life-threatening, prolonged anaphylactoid reactions have been reported in patients receiving ACE inhibitors during desensitization therapy with bee venom-containing agents. ACE inhibitors should be used with caution in patients undergoing desensitization and avoided during immunotherapy with bee venom-containing agents. However, in patients requiring both ACE inhibitors and desensitization, such reactions may be avoided by temporarily discontinuing ACE inhibitor therapy at least 24 hours before starting desensitization.

Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis. Life-threatening anaphylactoid reactions have been rarely reported in patients receiving ACE inhibitors during LDL apheresis using dextran sulfate. These reactions may be avoided by temporarily withholding ACE inhibitor therapy before each apheresis session.

Patients undergoing hemodialysis. Cases of anaphylactoid reactions have been reported in patients receiving ACE inhibitors during hemodialysis with 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 agents acting via inhibition of the renin-angiotensin system. Therefore, this medication is not recommended for such patients.

Patients after kidney transplantation. Experience with perindopril arginine in patients after recent kidney transplantation is lacking.

Arterial hypotension. Symptomatic arterial hypotension has been reported in patients with symptomatic heart failure, with or without concomitant renal impairment. The risk of symptomatic hypotension is higher in patients with more severe heart failure, those receiving high-dose loop diuretics, those with hyponatremia, or those with functional renal impairment. Close medical supervision is required at the start of therapy and during dose titration to reduce the risk of symptomatic hypotension. Similar precautions apply to patients with ischemic heart disease or cerebrovascular disease, in whom excessive blood pressure reduction may precipitate myocardial infarction or stroke.

Ischemic heart disease. If an episode of unstable angina (of any severity) occurs during the first month of perindopril treatment, the risk-benefit ratio should be carefully evaluated before deciding whether to continue therapy.

Special warnings related to indapamide

Hepatic encephalopathy. In patients with impaired liver function, use of thiazide and thiazide-like diuretics, particularly 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.

Photosensitivity. Photosensitivity reactions have been reported with thiazide and thiazide-like diuretics (see section "Side effects"). If a photosensitivity reaction occurs during treatment, drug discontinuation is recommended. If reinitiation is necessary, protection of susceptible areas from sunlight or artificial ultraviolet sources is advised.

Precautions

Precautions common to perindopril and indapamide

Renal impairment. The medication is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min). In some patients with arterial hypertension without signs of renal impairment, laboratory blood tests may reveal signs of functional renal impairment; in such cases, treatment should be discontinued, with possible resumption at a lower dose or with one of its components. These patients require frequent monitoring of potassium and creatinine levels: 2 weeks after initiation of treatment and every 2 months thereafter during therapeutic stabilization. Renal impairment has been observed primarily in patients with severe heart failure or renal impairment, including those with renal artery stenosis. This medication should not be used in patients with significant bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney.

Arterial hypotension and water and electrolyte depletion. Patients with sodium depletion (especially those with renal artery stenosis) are at risk of a sudden drop in blood pressure. Regular monitoring for clinical signs of water and electrolyte depletion is necessary, which may occur during intercurrent episodes of vomiting or diarrhea. Plasma electrolyte levels should be regularly monitored in such patients. In cases of significant arterial hypotension, intravenous infusion of isotonic sodium chloride solution may be required. Transient hypotension is not a contraindication for continuing treatment. After restoration of circulating blood volume and normalization of blood pressure, treatment may be resumed at a reduced dose or with one of the components.

Potassium levels. The combination of perindopril and indapamide does not exclude the possibility of hypokalaemia, particularly in patients with diabetes or renal impairment. As with any antihypertensive agent combined with a diuretic, regular monitoring of plasma potassium levels is required.

Excipients. This medication should not be administered to patients with rare hereditary galactose intolerance, severe lactase deficiency, or glucose-galactose malabsorption.

Sodium content.

Noliprel® arginine forte contains less than 1 mmol sodium (23 mg) per tablet, i.e., it is nearly sodium-free.

Precautions related to perindopril

Cough. A dry cough has been reported during ACE inhibitor therapy. This cough is persistent and resolves after discontinuation of the drug. If this symptom occurs, its iatrogenic origin should be considered. If ACE inhibitor therapy is deemed necessary for the patient, a decision may be made to continue treatment.

Risk of arterial hypotension and/or renal impairment (in the presence of heart failure, water and electrolyte depletion). Significant stimulation of the RAAS occurs in acute water and electrolyte depletion (strict salt-free diet or prolonged diuretic therapy) in patients with low blood pressure, renal artery stenosis, congestive heart failure, or cirrhosis with edema and ascites. Blocking this system with ACE inhibitors, especially during initial use and the first 2 weeks of treatment, may cause a sudden drop in blood pressure and/or an increase in plasma creatinine levels, confirming functional renal impairment. Occasionally, although rarely, this may occur at any time and have an acute onset. In such cases, treatment should be initiated with a lower dose and gradually increased.

Elderly patients. Renal function and blood potassium levels should be checked before initiating treatment. To reduce the risk of sudden arterial hypotension, especially in the presence of water or electrolyte depletion, the initial dose should be adjusted according to the blood pressure response.

Atherosclerosis. The risk of arterial hypotension exists in all patient groups, but the medication should be used with particular caution in patients with ischemic heart disease or cerebral circulation insufficiency, starting treatment with a low dose.

Renovascular hypertension. Revascularization is the treatment for renovascular hypertension. However, ACE inhibitors may be beneficial for patients with renovascular hypertension awaiting surgery or for whom surgery is not feasible. If Noliprel® arginine forte is prescribed to patients with known or suspected renal artery stenosis, treatment should be initiated in a hospital setting with a low dose and under potassium level monitoring, as functional renal impairment, reversible upon discontinuation, has been observed in some patients.

Heart failure/severe heart failure. Treatment of patients with severe heart failure (Class IV) should be initiated under medical supervision with a reduced initial dose. β-blocker therapy in patients with hypertension and coronary insufficiency should not be discontinued; ACE inhibitors should be added to β-blocker therapy.

Diabetic patients. Treatment of patients with insulin-dependent diabetes mellitus (with a spontaneous tendency to elevated blood potassium) should be initiated under medical supervision with a reduced initial dose. Blood glucose levels should be carefully monitored in diabetic patients previously treated with oral hypoglycemic agents or insulin, especially during the first month of ACE inhibitor therapy (see section "Interaction with other medicinal products and other forms of interaction").

Racial factors. Perindopril, like other ACE inhibitors, is less effective in reducing blood pressure in hypertensive patients of Black race compared to other racial groups, possibly due to low plasma renin levels in these patients.

Surgery/anesthesia. ACE inhibitors may cause arterial hypotension during anesthesia, particularly when anesthetics with hypotensive potential are used. Therefore, long-acting ACE inhibitors such as perindopril should, if possible, be discontinued 1 day before surgery.

Aortic or mitral valve stenosis/hypertrophic cardiomyopathy. ACE inhibitors should be used with caution in patients with left ventricular outflow tract obstruction.

Hepatic impairment. Rarely, ACE inhibitor use has been associated with a syndrome beginning with cholestatic jaundice and progressing to fulminant hepatic necrosis, sometimes fatal. Patients who develop jaundice with elevated liver enzymes during ACE inhibitor therapy should discontinue the drug and receive appropriate medical monitoring (see section "Side effects").

Hyperkalaemia. Increased serum potassium levels have been observed in some patients receiving ACE inhibitors, including perindopril. ACE inhibitors may cause hyperkalaemia due to suppression of aldosterone release. This effect is usually mild in patients with normal renal function. Risk factors for hyperkalaemia include renal impairment, worsening renal function, age over 70 years, diabetes, intercurrent conditions (especially dehydration, acute heart decompensation, metabolic acidosis), and concomitant use with potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, amiloride), potassium supplements, or potassium-containing salt substitutes; or use of other agents associated with increased serum potassium (e.g., heparin, co-trimoxazole, also known as trimethoprim/sulfamethoxazole, and particularly aldosterone antagonists or angiotensin receptor blockers, other ACE inhibitors, angiotensin II receptor antagonists, acetylsalicylic acid at doses ≥ 3 g/day, COX-2 inhibitors and nonselective NSAIDs, immunosuppressants such as cyclosporine or tacrolimus, trimethoprim). Use of potassium-containing supplements or salt substitutes and potassium-sparing diuretics, especially in patients with impaired renal function, may lead to significant increases in serum potassium. Hyperkalaemia may cause serious, sometimes fatal, arrhythmias. Patients receiving ACE inhibitors should use potassium-sparing diuretics and angiotensin receptor blockers cautiously and undergo careful monitoring of serum potassium and renal function. If concomitant use of the above-mentioned agents is considered appropriate, they should be used with caution and with frequent monitoring of potassium levels (see section "Interaction with other medicinal products and other forms of interaction").

Precautions related to indapamide

Water and electrolyte balance

Sodium levels. Plasma sodium levels should be determined before starting treatment and at regular intervals thereafter. Hyponatraemia may initially be asymptomatic, necessitating regular monitoring. Monitoring should be more frequent in elderly patients and those with liver cirrhosis (see sections "Side effects" and "Overdose"). Any diuretic therapy may cause hyponatraemia, sometimes with very serious consequences. Hyponatraemia combined with hypovolaemia may lead to dehydration and orthostatic hypotension. Concomitant chloride ion loss may lead to secondary compensatory metabolic alkalosis; the frequency and severity of this effect are low.

Potassium levels. Decreased blood potassium levels leading to hypokalaemia are a major risk factor with thiazide and thiazide-like diuretics. Hypokalaemia may cause muscle disorders. Cases of rhabdomyolysis, mainly associated with severe concomitant hypokalaemia, have been reported. Hypokalaemia (< 3.4 mmol/L) should be prevented in certain high-risk patient groups, such as elderly patients and/or those with poor nutrition, regardless of concomitant medication use, patients with liver cirrhosis with edema and ascites, patients with ischemic heart disease and heart failure. In such cases, hypokalaemia increases the cardiotoxicity of cardiac glycosides and the risk of arrhythmias. Patients with congenital or iatrogenic prolonged QT interval also belong to the risk group. Hypokalaemia, like bradycardia, is a predisposing factor for severe arrhythmias, particularly paroxysmal torsades de pointes tachycardia, which may be fatal. More frequent monitoring of blood potassium levels is required. The first plasma potassium determination should be performed within the first week of treatment. If blood potassium levels are low, correction is necessary.

Detection of hypokalaemia requires its correction. Hypokalaemia due to low serum magnesium levels may be refractory to treatment unless magnesium levels are corrected.

Calcium levels. Thiazide and thiazide-like diuretics may reduce urinary calcium excretion and lead to a slight transient increase in blood calcium levels. A marked increase in blood calcium may be associated with undiagnosed hyperparathyroidism. In such cases, treatment should be discontinued and parathyroid function monitored.

Plasma magnesium levels. Thiazides and related 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 "Side effects").

Blood glucose levels. Monitoring blood glucose levels is very important for diabetic patients, especially when potassium levels are low.

Uric acid. In patients with elevated blood uric acid levels, the frequency of gout attacks may increase.

Renal function and diuretics. Thiazide and thiazide-like diuretics are most effective when renal function is normal or only slightly impaired (blood creatinine level < 25 mg/L, i.e., 220 µmol/L in adults). In elderly patients, plasma creatinine levels should be determined using the Cockcroft formula, taking into account age, body weight, and sex: creatinine clearance (clcr) = (140 – age) × body weight / 0.814 × plasma creatinine level, where age is in years, body weight in kilograms, and plasma creatinine level in µmol/L. This formula is suitable for determining plasma creatinine levels in elderly men, but for women, the result should be multiplied by 0.85. Hypovolaemia caused by water and sodium loss due to diuretic use at the start of treatment reduces glomerular filtration, potentially increasing blood urea and creatinine levels. This transient functional renal impairment has no adverse consequences in patients with normal renal function but may worsen pre-existing renal impairment.

Choroidal effusion, acute myopia (nearsightedness), and secondary angle-closure glaucoma. Medicinal products containing sulfonamide 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 acute onset of decreased visual acuity or eye pain and usually occur within hours or weeks of starting the medication. Untreated acute angle-closure glaucoma may lead to permanent vision loss. The primary treatment is to discontinue the drug as quickly as possible. If intraocular pressure remains uncontrolled, medical or surgical interventions may be necessary. Risk factors for acute angle-closure glaucoma may include a history of allergy to sulfonamides or penicillin.

Athletes. Athletes should be aware that this medication contains an active substance that may lead to a positive doping test.

Use during pregnancy or breastfeeding.

Pregnancy

The medication is contraindicated in pregnant women or women planning pregnancy.

Warnings related to perindopril

There are no convincing epidemiological data on teratogenic risk with ACE inhibitor use during the first trimester of pregnancy; however, a small increased risk cannot be excluded. If continued ACE inhibitor therapy is considered mandatory, women planning pregnancy should be switched to alternative antihypertensive agents with established safety data during pregnancy. If pregnancy is confirmed during treatment, ACE inhibitor therapy should be discontinued immediately and, if necessary, replaced with another medication 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 fetus (impaired renal function, oligohydramnios, delayed skull ossification) and on the newborn (renal failure, arterial hypotension, hyperkalaemia). If ACE inhibitors were used during the second and third trimesters of pregnancy, ultrasound assessment of neonatal kidney function and skull structure is recommended. Newborns whose mothers received ACE inhibitors during pregnancy should be monitored for timely detection and correction of arterial hypotension.

Warnings related to indapamide

Data on indapamide use in pregnant women are lacking or limited (fewer than 300 cases). Prolonged use of a thiazide diuretic during the third trimester of pregnancy may reduce the pregnant woman's circulating blood volume and uteroplacental perfusion, potentially causing fetoplacental ischemia and delayed fetal development. Animal studies have not revealed direct or indirect toxic effects on reproductive performance. As a precautionary measure, indapamide use during pregnancy should be avoided.

Breastfeeding

Noliprel® arginine forte is not recommended during breastfeeding. A decision should be made whether to discontinue breastfeeding or discontinue the medication, taking into account the importance of therapy for the mother.

Warnings related to perindopril

Perindopril use during breastfeeding is not recommended due to lack of data. Alternative therapy with a proven safety profile should be preferred, especially during breastfeeding of a newborn or preterm infant.

Warnings related to indapamide

Data on indapamide/metabolite passage into breast milk are insufficient. Hypersensitivity to sulfonamide derivatives and hypokalaemia may develop. Risk to newborns/infants cannot be excluded. Indapamide belongs to thiazide-like diuretics, whose use during breastfeeding is associated with reduced or even suppressed lactation. Indapamide is not recommended during breastfeeding.

Fertility

Warnings common to perindopril and indapamide

Reproductive toxicity studies showed no effect on fertility in male and female animals. An effect on human fertility is not expected.

Ability to affect reaction speed when driving or operating machinery.

The two active substances, when used alone or in combination as Noliprel® arginine forte, do not affect the ability to drive or operate machinery. However, individual reactions related to decreased blood pressure may occur in some patients, especially at the beginning of treatment or when used concomitantly 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.

The recommended dose of Noliprel® Arginine Forte is 1 tablet daily, preferably in the morning before meals. Individual dose titration of the separate components of the drug may be recommended. If clinically appropriate, transition from monotherapy to treatment with Noliprel® Arginine Forte may be considered.

Special Patient Groups

Elderly patients (see section "Special Warnings and Precautions for Use"). Treatment should be initiated taking into account blood pressure readings and renal function.

Renal impairment (see section "Special Warnings and Precautions for Use"). Noliprel® Arginine Forte 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), treatment should be initiated using appropriate doses of the individual components of the drug. Patients with creatinine clearance ≥ 60 mL/min do not require dose adjustment. Routine medical monitoring should include frequent assessment of plasma creatinine and potassium levels.

Hepatic impairment (see sections "Contraindications", "Special Warnings and Precautions for Use", and "Pharmacokinetics"). Noliprel® Arginine Forte is contraindicated in patients with severe hepatic impairment. Patients with moderate hepatic impairment do not require dose adjustment.

Children

Noliprel® Arginine Forte should not be used for the treatment of children and adolescents. The safety and efficacy of perindopril arginine/indapamide in pediatric patients have not been established. Data are lacking.

Overdose

Symptoms. In case of overdose, the most common adverse reaction is arterial hypotension, which may sometimes be accompanied by nausea, vomiting, convulsions, dizziness, drowsiness, confusion, oliguria, which may progress to anuria (due to hypovolemia), and circulatory shock. Electrolyte and fluid imbalances (decreased plasma potassium and sodium levels), renal failure, hyperventilation, tachycardia, palpitations, bradycardia, anxiety, and cough may also occur.

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 balance under hospital conditions. In case of significant arterial hypotension, the patient should be placed in a supine position with low head elevation. If necessary, intravenous infusion of isotonic sodium chloride solution or any other method of restoring blood volume should be administered. Perindoprilat, the active metabolite of perindopril, can be removed from the body by hemodialysis (see section "Pharmacokinetics").

Adverse reactions.

Administration of perindopril inhibits the renin-angiotensin-aldosterone system and helps reduce potassium loss in blood plasma caused by indapamide. Hypokalemia (potassium level < 3.4 mmol/L) occurs in 4% of patients treated with Noliprel® Arginine Forte. The most commonly reported adverse reactions are: with perindopril – dizziness, headache, paresthesia, dysgeusia, visual disturbances, vertigo, tinnitus, arterial hypotension, cough, dyspnea, abdominal pain, constipation, dyspepsia, diarrhea, nausea, vomiting, pruritus, rash, muscle cramps, and asthenia; with indapamide – hypokalemia, hypersensitivity reactions, predominantly dermatological, in individuals predisposed to allergic and asthmatic reactions, and maculopapular rashes.

The following adverse reactions have been observed during clinical trials and/or post-marketing use of the medicinal product, categorized by frequency as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

Infections and infestations: rhinitis (very rare – perindopril).

Endocrine system disorders: syndrome of inappropriate antidiuretic hormone secretion (SIADH) (rare – perindopril).

Blood and lymphatic system disorders: eosinophilia (uncommon* – perindopril); agranulocytosis (see section "Special warnings and precautions for use") (very rare – perindopril and indapamide); aplastic anemia (very rare – indapamide); pancytopenia (very rare – perindopril); leukopenia (very rare – perindopril and indapamide); neutropenia (see section "Special warnings and precautions for use") (very rare – perindopril); hemolytic anemia (very rare – perindopril and indapamide); thrombocytopenia (see section "Special warnings and precautions for use") (very rare – perindopril and indapamide).

Immune system disorders: hypersensitivity (mainly dermatological reactions in patients predisposed to allergic and asthmatic reactions) (common – indapamide).

Metabolism and nutrition disorders: hypokalemia (see section "Special warnings and precautions for use") (common – indapamide); hypoglycemia (see sections "Special warnings and precautions for use" and "Interaction with other medicinal products and other forms of interaction") (uncommon* – perindopril); hyperkalemia, reversible upon discontinuation of the drug (see section "Special warnings and precautions for use") (uncommon* – perindopril); hyponatremia (see section "Special warnings and precautions for use") (uncommon* – perindopril, uncommon – indapamide); hypochloremia (rare – indapamide); hypomagnesemia (rare – indapamide); hypercalcemia (very rare – indapamide).

Psychiatric disorders: mood changes (uncommon – perindopril); sleep disturbances (uncommon – perindopril); depression (uncommon* – perindopril); confusion (very rare – perindopril).

Nervous system disorders: dizziness (common – perindopril); headache (common – perindopril, rare – indapamide); paresthesia (common – perindopril, rare – indapamide); dysgeusia (common – perindopril); somnolence (uncommon* – perindopril); syncope (uncommon* – perindopril, frequency not known – indapamide); excessive arterial hypotension in high-risk patients may lead to stroke (see section "Special warnings and precautions for use") (very rare – perindopril); in case of hepatic insufficiency, hepatic encephalopathy may occur (see sections "Contraindications" and "Special warnings and precautions for use") (frequency not known – indapamide).

Eye disorders: visual disturbances (common – perindopril, frequency not known – indapamide); myopia (see section "Special warnings and precautions for use") (frequency not known – indapamide); blurred vision (frequency not known – indapamide), choroidal effusion (frequency not known – indapamide); acute angle-closure glaucoma (frequency not known – indapamide).

Ear and labyrinth disorders: vertigo (common – perindopril, rare – indapamide); tinnitus (common – perindopril).

Cardiac disorders: palpitations (uncommon* – perindopril); tachycardia (uncommon* – perindopril); angina pectoris (see section "Special warnings and precautions for use") (very rare – perindopril); arrhythmia (including bradycardia, ventricular tachycardia, atrial fibrillation) (very rare – perindopril and indapamide); excessive arterial hypotension in high-risk patients may lead to myocardial infarction (see section "Special warnings and precautions for use") (very rare – perindopril); paroxysmal ventricular tachycardia of the "torsade de pointes" type (potentially fatal) (see sections "Special warnings and precautions for use" and "Interaction with other medicinal products and other forms of interaction") (frequency not known – indapamide).

Vascular disorders: arterial hypotension (and symptoms associated with hypotension) (see section "Special warnings and precautions for use") (common – perindopril, very rare – indapamide); vasculitis (uncommon* – perindopril); hot flushes (rare* – perindopril); Raynaud's phenomenon (frequency not known – perindopril).

Respiratory, thoracic and mediastinal disorders: cough (see section "Special warnings and precautions for use") (common – perindopril); dyspnea (common – perindopril); bronchospasm (uncommon – perindopril); eosinophilic pneumonia (very rare – perindopril).

Gastrointestinal disorders: abdominal pain (common – perindopril); constipation (common – perindopril, rare – indapamide); diarrhea (common – perindopril); dyspepsia (common – perindopril); nausea (common – perindopril, rare – indapamide); vomiting (common – perindopril, uncommon – indapamide); dry mouth (uncommon – perindopril, rare – indapamide); pancreatitis (very rare – perindopril and indapamide).

Hepatobiliary disorders: hepatitis (see section "Special warnings and precautions for use") (very rare – perindopril, frequency not known – indapamide); liver function abnormalities (very rare – indapamide).

Skin and subcutaneous tissue disorders: pruritus (common – perindopril); rash (common – perindopril); maculopapular rashes (common – indapamide); urticaria (see section "Special warnings and precautions for use") (uncommon – perindopril, very rare – indapamide); angioedema (see section "Special warnings and precautions for use") (uncommon – perindopril, very rare – indapamide); purpura (uncommon – indapamide); hyperhidrosis (uncommon – perindopril); photosensitivity reactions (uncommon* – perindopril, frequency not known – indapamide); pemphigoid (uncommon* – perindopril); exacerbation of psoriasis symptoms (rare* – perindopril); erythema multiforme (very rare – perindopril); toxic epidermal necrolysis (very rare – indapamide); Stevens-Johnson syndrome (very rare – indapamide).

Musculoskeletal and connective tissue disorders: muscle cramps (common – perindopril, frequency not known – indapamide); possible worsening of pre-existing systemic lupus erythematosus (frequency not known – indapamide); arthralgia (uncommon* – perindopril); myalgia (uncommon* – perindopril, frequency not known – indapamide); muscle weakness (frequency not known – indapamide); rhabdomyolysis (frequency not known – indapamide).

Renal and urinary disorders: renal impairment (uncommon – perindopril, very rare – indapamide); acute renal failure (rare – perindopril); anuria/oliguria (rare* – perindopril).

Reproductive system and breast disorders: erectile dysfunction (uncommon – perindopril and indapamide).

General disorders and administration site conditions: asthenia (common – perindopril); chest pain (uncommon* – perindopril); malaise (uncommon* – perindopril); peripheral edema (uncommon* – perindopril); pyrexia (uncommon* – perindopril); fatigue (rare – indapamide).

Investigations: increased blood urea levels (uncommon* – perindopril); increased blood creatinine levels (uncommon* – perindopril); increased blood bilirubin levels (rare – perindopril); increased liver enzymes (rare – perindopril, frequency not known – indapamide); decreased hemoglobin and hematocrit levels (see section "Special warnings and precautions for use") (very rare – perindopril); increased blood glucose levels (frequency not known – indapamide); increased blood uric acid levels (frequency not known – indapamide); QT interval prolongation on ECG (see sections "Special warnings and precautions for use" and "Interaction with other medicinal products and other forms of interaction") (frequency not known – indapamide).

Injury, poisoning and procedural complications: falls (uncommon* – perindopril).

* Frequency of adverse reactions identified from spontaneous reports calculated from clinical trial data.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store tablets in a tightly closed container. No special storage conditions required. Keep out of reach and sight of children.

Packaging.

14 tablets in a container; 1 container in a cardboard box.

30 tablets in a container; 1 or 3 containers in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Laboratoires Servier Industrie / Les Laboratoires Servier Industrie.

Manufacturer's location and address of place of business.

905 route de Saran, 45520 Gidy, France / 905 route de Saran, 45520 Gidy, France.

Manufacturer.

Servier (Ireland) Industries Ltd.

Manufacturer's location and address of place of business.

Gorey Road, Arklow, Co. Wicklow, Y14 E284, Ireland / Gorey Road, Arklow, Co. Wicklow, Y14 E284, Ireland.

Marketing Authorization Holder.

Les Laboratoires Servier.

Address of Marketing Authorization Holder.

50, rue Carnot, 92284 Suresnes Cedex, France / 50, rue Carnot, 92284 Suresnes Cedex, France.

For inquiries, please contact LLC "Servier Ukraine" at tel. (044) 490 3441.