Noliprel® bi-forte

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

Composition:

Active substances: perindopril (perindopril)/indapamide (indapamide);

One tablet contains 6.79 mg of perindopril corresponding to 10 mg of perindopril arginine and 2.5 mg of indapamide;

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

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, round, film-coated tablet.

Pharmacotherapeutic group. Combined preparations of angiotensin-converting enzyme (ACE) inhibitors. Perindopril and diuretics. ATC code C09B A04.

Pharmacological properties.

Pharmacodynamics.

Noliprel® Bi-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

Mechanism of action of perindopril

Perindopril is an ACE inhibitor that converts angiotensin I into angiotensin II (a vasoconstrictive substance), additionally stimulates aldosterone secretion by the adrenal cortex, and promotes the breakdown of bradykinin (a vasodilatory substance) into inactive heptapeptides. Inhibition of ACE leads to: reduced aldosterone secretion; increased plasma renin activity, while aldosterone does not exert a negative effect; decreased total peripheral vascular resistance due to a predominant effect on muscle and renal vessels; water and salt retention or reflex tachycardia are not observed, even during prolonged treatment. Moreover, perindopril reduces arterial 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 pressure in the left and right ventricles, decreased total peripheral vascular resistance, increased cardiac output and cardiac index, and improved regional blood flow in muscles. Exercise test parameters are also 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 chlorides, and to a lesser extent potassium and magnesium, thereby enhancing diuresis and providing antihypertensive effects.

Pharmacodynamic effects

Noliprel® Bi-Forte exerts dose-dependent antihypertensive effects on systolic (SBP) and diastolic (DBP) blood pressure in patients of any age with arterial hypertension, both in supine and standing positions.

PICXEL—a multicenter, randomized, double-blind, controlled study—evaluated the effect of the combination of perindopril and indapamide on left ventricular hypertrophy compared to enalapril monotherapy, using echocardiography. In the PICXEL study, patients with arterial hypertension and left ventricular hypertrophy (with a left ventricular mass index >120 g/m² in men and >100 g/m² in women) were randomized into two groups: 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. 34% of patients in the perindopril/indapamide group (2 mg perindopril and 0.625 mg indapamide) and 20% in the enalapril group (10 mg) continued treatment at the initial dose. At the end of treatment, the 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). Better reduction in left ventricular mass index was achieved with the dose of 8 mg perindopril (equivalent to 10 mg perindopril arginine)/2.5 mg indapamide. Blood pressure reduction was more effective in the perindopril/indapamide group: the mean difference in BP reduction between the two 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.

Pharmacodynamic effects associated with perindopril

Perindopril effectively reduces BP in all stages of arterial hypertension: mild, moderate, and severe. Reduction in SBP and DBP is 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 residual ACE inhibition (approximately 80%) 24 hours after administration. In patients who respond to treatment, BP normalization is achieved within one month and is maintained without tachyphylaxis. Discontinuation of therapy is not associated with a withdrawal syndrome. Perindopril has vasodilatory properties, restores elasticity of large arteries, corrects histomorphometric changes in arterial resistance, and reduces left ventricular hypertrophy. The 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 when a diuretic is used as monotherapy.

Pharmacodynamic effects associated with indapamide

When used as monotherapy, indapamide exerts antihypertensive effects lasting 24 hours. This effect is evident 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. When the dose is exceeded, the antihypertensive effect of thiazide and thiazide-like diuretics reaches a plateau, while the number of adverse effects increases. 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. Protein binding of perindoprilat to plasma proteins is 20%, primarily to ACE, and is concentration-dependent.

Biotransformation. Perindopril is a prodrug. Thus, 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 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 heart or renal failure.

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

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

Liver cirrhosis. Perindopril kinetics are altered in patients with liver 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 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 ranges from 14 to 24 hours (average 18 hours). Repeated dosing does not lead to accumulation. Elimination occurs mainly via urine (70% of dose) and feces (22%) as inactive metabolites.

Special patient populations

Renal impairment. Pharmacokinetic parameters of indapamide are not altered in patients with renal impairment.

Clinical characteristics.

Indications.

Treatment of arterial hypertension in patients requiring perindopril arginine 10 mg and indapamide 2.5 mg.

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 treatment with ACE inhibitors (see section "Special precautions");
• Hereditary or idiopathic angioedema;
• Pregnancy or planned pregnancy (see section "Use in pregnancy or lactation");
• Concomitant use with aliskiren-containing medicinal products in patients with diabetes or renal impairment (glomerular filtration rate < 60 mL/min/1.73 m²) (see section "Interaction with other medicinal products and other forms of interaction");
• Concomitant use with sacubitril/valsartan. Noliprel® Bi-Forte must not be administered 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 treatments leading to blood contact with negatively charged surfaces (see section "Interaction with other medicinal products and other forms of interaction");
• Severe bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney (see section "Special precautions").

Related to indapamide:

• Hypersensitivity to the active substance or to any other sulfonamides;
• Moderate to severe renal impairment (creatinine clearance < 60 mL/min);
• Hepatic encephalopathy;
• Severe hepatic impairment;
• Hypokalemia.

Related to Noliprel® Bi-Forte:

• Hypersensitivity to any excipient.

Due to insufficient clinical experience, Noliprel® Bi-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. Increased serum lithium concentrations and lithium toxicity have been reported during concomitant use of lithium and ACE inhibitors. Concomitant use of perindopril with indapamide and lithium is not recommended; however, if such combination is considered necessary, serum lithium concentrations should be closely monitored (see section "Special precautions").

Concomitant use requiring special attention

Baclofen. Antihypertensive effect is enhanced. Blood pressure should be monitored and the dose of antihypertensive agent adjusted if necessary.

Non-steroidal anti-inflammatory drugs (NSAIDs) (including acetylsalicylic acid at doses ≥ 3 g/day). Concomitant use of ACE inhibitors and NSAIDs, such as acetylsalicylic acid at anti-inflammatory doses, COX-2 inhibitors, and non-selective NSAIDs, may result in reduced antihypertensive effect. Concomitant use of ACE inhibitors and NSAIDs may increase the risk of worsening renal function, including acute renal failure, and elevate serum potassium levels, particularly in patients with renal impairment. This combination should be used 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

Imipramine-like (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 agent affecting the RAAS (see sections "Contraindications" and "Special precautions").

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 racecadotril, 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® Bi-Forte. Some medicinal products 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 such as cyclosporine or tacrolimus, trimethoprim, and co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim acts as a potassium-sparing diuretic similar to amiloride, may cause hyperkalemia. Combination with these medicinal products increases the risk of hyperkalemia. Therefore, concomitant use of Noliprel® Bi-Forte with the above-mentioned agents 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, increased risk of hyperkalemia, worsening renal function, cardiovascular morbidity, and mortality.

Extracorporeal treatments. Extracorporeal treatments leading to blood contact with negatively charged surfaces, such as dialysis or hemofiltration using certain high-flux membranes (e.g., polyacrylonitrile) and low-density lipoprotein apheresis using dextran sulfate, due to increased risk of severe anaphylactoid reactions (see section "Contraindications"). If such treatment is required, 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, increased risk of hyperkalemia, worsening renal function, cardiovascular morbidity, and mortality (see section "Special precautions").

Concomitant therapy with an ACE inhibitor and an angiotensin receptor blocker. Published reports indicate that in patients with established atherosclerosis, heart failure, or diabetic patients with target organ damage, concomitant therapy with an ACE inhibitor and an angiotensin receptor blocker is associated with increased incidence of arterial hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to use of a single agent affecting the renin-angiotensin-aldosterone system. Dual blockade (i.e., combination of an ACE inhibitor and an angiotensin II receptor antagonist) may be considered only in selected cases with careful monitoring of renal function, serum potassium levels, and blood pressure (see section "Special precautions").

Estramustine. Risk of increased incidence 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 medicinal products is not recommended (see section "Special precautions"). If concomitant use is indicated, 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 in the section "Concomitant use requiring special attention".

Concomitant use requiring special attention

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

Diuretics. In patients taking diuretics, especially with volume and sodium depletion, excessive reduction in blood pressure may occur after initiation of ACE inhibitor therapy. The risk of hypotensive effects may be reduced by discontinuing diuretic therapy, increasing circulating volume, or salt intake prior to starting perindopril, 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, diuretic therapy should be discontinued before starting ACE inhibitor treatment (diuretic therapy may be resumed later) 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 level) should be monitored during the first few weeks of ACE inhibitor therapy.

Potassium-sparing diuretics (eplerenone, spironolactone). When eplerenone or spironolactone is used concomitantly with low doses of 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 such combination, absence of hyperkalemia and renal impairment should be confirmed. Careful 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 medicinal products may enhance the hypotensive effects of perindopril. Concomitant use with nitroglycerin and other nitrates or with 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 enhance the hypotensive effect of some anesthetic agents (see section "Special precautions").

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

Gold preparations. Rarely, nitritoid reactions (flushing, nausea, vomiting, and arterial hypotension) have been reported in patients treated with injectable gold preparations (sodium aurothiomalate) and concomitantly receiving ACE inhibitors, including perindopril.

Interactions related to indapamide

Concomitant use requiring special attention

Medicinal products that may induce torsades de pointes ventricular tachycardia. Indapamide should be used with caution in combination with medicinal products that may induce torsades de pointes ventricular tachycardia due to the risk of hypokalemia. These include (the list is not exhaustive): class IA antiarrhythmics (e.g., quinidine, hydroquinidine, disopyramide); class III antiarrhythmics (e.g., amiodarone, dofetilide, ibutilide, bretylium, sotalol); some antipsychotics: phenothiazines (e.g., chlorpromazine, thiamylal, levomepromazine, thioridazine, trifluoperazine), benzamides (e.g., amisulpride, sulpiride, sulthiame, tiapride), butyrophenones (e.g., droperidol, haloperidol), other antipsychotics (e.g., pimozide); other agents (e.g., bepridil, cisapride, difemanil, intravenous erythromycin, halofantrine, mizolastine, moxifloxacin, pentamidine, sparfloxacin, intravenous vinpocetine, methadone, astemizole, terfenadine). Plasma potassium levels should be prevented from decreasing and corrected if necessary, and QT interval should be monitored.

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

Cardiac glycosides. Hypokalemia and/or hypomagnesemia may predispose to toxic effects of cardiac glycosides. Monitoring of plasma potassium and magnesium levels and ECG monitoring are recommended, and treatment should be adjusted if necessary.

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

Concomitant use requiring attention

Potassium-sparing diuretics (amiloride, spironolactone, triamterene). Despite the rationale for using this combination in certain patients, hypokalemia or hyperkalemia may occur (especially in patients with renal impairment or diabetes). Serum potassium levels should be monitored, ECG monitoring performed, and therapy reviewed if necessary.

Metformin. May cause lactic acidosis due to functional renal impairment induced by diuretics, especially loop diuretics. Metformin should not be used if plasma creatinine exceeds 15 mg/L (135 µmol/L) in men and 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. Adequate hydration should be ensured 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 without change in circulating cyclosporine concentration, even in the absence of volume or sodium depletion.

Corticosteroids, tetracosactide (systemic). Reduce antihypertensive effect (water and sodium retention induced by corticosteroids).

Special precautions for use.

Special warnings

Special warnings common to perindopril and 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").

Special warnings related to perindopril

Double 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 hypotension, hyperkalaemia, and renal dysfunction (including acute renal failure). Therefore, dual blockade of the RAAS by concomitant administration of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see section "Interaction with other medicinal products and other forms of interaction"). If dual RAAS blockade therapy is considered absolutely necessary, it should be conducted 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 treatment with ACE inhibitors and angiotensin II receptor blockers.

Potassium-sparing agents, potassium supplements, or potassium-containing salt substitutes. Combination of perindopril with potassium-sparing agents, 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/anaemia. Cases of neutropenia/agranulocytosis, thrombocytopenia, and anaemia 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 immunosuppressive therapy, allopurinol, or procainamide, or in combination with these risk factors, especially if renal function is impaired. Some of these patients developed severe infections, sometimes resistant to intensive antibiotic therapy. In such patients, periodic monitoring of white blood cell count is recommended during perindopril therapy. 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 "Undesirable 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 hypotension and renal failure (see section "Contraindications"). Diuretic use may be a contributing factor. Renal dysfunction may be associated with only minor changes in serum creatinine levels, even in patients with unilateral renal artery stenosis.

Hypersensitivity/angioneurotic oedema (angioedema). Rare cases of angioneurotic oedema of the face, extremities, lips, tongue, glottis, and/or larynx have been reported in patients receiving ACE inhibitors, including perindopril (see section "Undesirable 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 completely resolve. If oedema is limited to the face and lips, the condition usually improves without treatment, although antihistamines may help relieve symptoms. Angioneurotic oedema involving laryngeal oedema can be fatal. If oedema 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 black patients 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 C1 esterase inhibitor levels were normal. 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 increased risk of angioedema (see section "Contraindications"). Initiation of sacubitril/valsartan should not occur earlier than 36 hours after the last dose of perindopril. If treatment with 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 oedema, with or without respiratory compromise) (see section "Interaction with other medicinal products and other forms of interaction"). Caution is advised when initiating therapy with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) in patients already receiving ACE inhibitors.

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

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

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

Primary aldosteronism. 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 shortly after kidney transplantation is lacking.

Arterial hypotension. Symptomatic hypotension has been reported in patients with symptomatic heart failure, with or without concomitant renal impairment. Symptomatic hypotension is more likely in patients with more severe heart failure who are on high-dose loop diuretics, have hyponatraemia, or 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 ischaemic heart disease or cerebrovascular disease, in whom excessive blood pressure reduction may precipitate myocardial infarction or stroke.

Ischaemic heart disease. If an episode of unstable angina (of any severity) occurs within the first month of perindopril treatment, the benefit-risk ratio should be carefully evaluated before deciding 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 "Undesirable effects"). If a photosensitivity reaction occurs during treatment, drug discontinuation is recommended. If re-initiation is necessary, protection of exposed skin from sunlight or artificial UV sources is advised.

Precautions

Precautions common to perindopril and indapamide

Renal impairment. The medication is contraindicated in patients with moderate to severe renal impairment (creatinine clearance < 60 ml/min). In some patients with arterial hypertension and no apparent renal dysfunction, laboratory tests may reveal signs of functional renal impairment; in such cases, treatment should be discontinued, possibly to be resumed at a lower dose or with one of its components. These patients require frequent monitoring of serum potassium and creatinine: 2 weeks after initiation of treatment and every 2 months thereafter during therapeutic stabilisation. Renal impairment has been observed primarily in patients with severe heart failure or renal dysfunction, including 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 with renal artery stenosis) are at risk of a sudden drop in blood pressure. Regular monitoring for clinical signs of water and electrolyte depletion due to intercurrent vomiting or diarrhoea is necessary. Serum electrolyte levels should be regularly monitored in such patients. In cases of significant hypotension, intravenous infusion of isotonic sodium chloride solution may be required. Transient hypotension is not a contraindication to continuing treatment. After restoration of circulating blood volume and normalisation of blood pressure, treatment may be resumed at a reduced dose or with one of its components.

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

Excipients. Patients with rare hereditary galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medication.

Sodium content. Noliprel® Bi-Forte contains less than 1 mmol sodium (23 mg) per tablet, i.e., it is almost sodium-free.

Precautions related to perindopril

Cough. Dry cough has been reported during ACE inhibitor therapy. This cough is persistent and resolves after discontinuation of the drug. If this symptom occurs, a possible iatrogenic cause should be considered. If ACE inhibitor therapy is necessary for patient management, continuation of treatment may be considered.

Risk of arterial hypotension and/or renal impairment (in patients with heart failure, water and electrolyte depletion). Marked activation of the renin-angiotensin-aldosterone system occurs during 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 oedema and ascites. Blocking this system with an ACE inhibitor, particularly at initiation and during the first 2 weeks of treatment, may cause a marked drop in blood pressure and/or increased plasma creatinine levels, indicating 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 serum potassium levels should be checked before initiating treatment. To reduce the risk of sudden hypotension, particularly with water or electrolyte depletion, the initial dose should be adjusted based on the blood pressure response to treatment.

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

Renovascular hypertension. Revascularisation is the treatment for renovascular hypertension. However, ACE inhibitors may be beneficial in patients with renovascular hypertension awaiting surgery or when surgery is not feasible. Noliprel® Bi-Forte should not be prescribed to patients with known or suspected renal artery stenosis. In such cases, treatment should be initiated in a hospital setting with a lower dose than the recommended dose.

Heart failure/severe heart failure. Noliprel® Bi-Forte should not be prescribed to patients with severe heart failure (Class IV), as treatment 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; an ACE inhibitor should be added to the β-blocker.

Patients with diabetes mellitus. Noliprel® Bi-Forte should not be prescribed to patients with insulin-dependent diabetes mellitus (due to spontaneous tendency to increased serum potassium), as treatment should be initiated under medical supervision with a reduced initial dose. In patients with diabetes mellitus previously treated with oral hypoglycaemic agents or insulin, blood glucose levels should be closely monitored, especially during the first month of ACE inhibitor therapy (see section "Interaction with other medicinal products and other forms of interaction").

Racial characteristics. Perindopril, like other ACE inhibitors, is less effective in reducing blood pressure in black hypertensive patients compared to other racial groups, possibly due to lower plasma renin levels in these patients.

Surgery/anaesthesia. ACE inhibitors may cause hypotension during anaesthesia, especially with anaesthetics having hypotensive potential. Therefore, therapy with long-acting ACE inhibitors such as perindopril is recommended to be discontinued 1 day before surgery, if possible.

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

Hepatic impairment. Rarely, ACE inhibitors have been associated with a syndrome beginning with cholestatic jaundice and progressing to fulminant hepatic necrosis, sometimes fatal. The mechanism of this syndrome is unclear. Patients who develop jaundice with elevated liver enzymes while on ACE inhibitors should discontinue the ACE inhibitor and receive appropriate medical supervision (see section "Undesirable effects").

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

Precautions related to indapamide

Water and electrolyte balance

Sodium levels. Serum sodium levels should be determined before starting treatment and at regular intervals thereafter. Hyponatraemia may initially be asymptomatic, so regular monitoring is necessary. Monitoring should be more frequent in elderly patients and patients with liver cirrhosis (see sections "Undesirable 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 loss may lead to secondary compensatory metabolic alkalosis: the frequency and severity of this effect are low.

Potassium levels. Hypokalaemia is the main risk factor associated with thiazide and thiazide-like diuretics. Hypokalaemia may cause muscle disorders. Cases of rhabdomyolysis, mainly with concomitant severe hypokalaemia, have been reported. Hypokalaemia (< 3.4 mmol/l) should be prevented in high-risk patient groups, such as elderly patients and/or those with poor nutrition, regardless of other medications, patients with cirrhosis with oedema and ascites, and patients with ischaemic heart disease and heart failure. In these cases, hypokalaemia increases the cardiotoxicity of cardiac glycosides and the risk of cardiac arrhythmias. Patients with congenital or iatrogenic prolonged QT interval are also at risk. Hypokalaemia, like bradycardia, is a predisposing factor for severe cardiac arrhythmias, particularly paroxysmal ventricular tachycardia of the torsades de pointes type, which may be fatal. More frequent monitoring of serum potassium levels is required in all such cases. The first serum potassium measurement should be performed within the first week of treatment. Hypokalaemia requires correction. Hypokalaemia associated with low serum magnesium levels may be refractory to treatment unless serum magnesium levels are corrected.

Calcium levels. Thiazide and thiazide-like diuretics may reduce urinary calcium excretion and cause a slight transient increase in serum calcium. Marked hypercalcaemia may be associated with undiagnosed hyperparathyroidism. In such cases, treatment should be discontinued and parathyroid function monitored.

Magnesium in plasma. 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 "Undesirable effects").

Blood glucose levels. Monitoring blood glucose levels is very important in patients with diabetes mellitus, especially with low potassium levels.

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

Renal function and diuretics. Thiazide and thiazide-like diuretics are most effective when renal function is normal or only slightly impaired (serum creatinine < 25 mg/l, i.e., 220 µmol/l in adults). In elderly patients, plasma creatinine levels should be assessed 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 in µmol/l. This formula is suitable for estimating 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.

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

Choroidal effusion, acute myopia (short-sightedness), 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 prompt discontinuation of the medicinal product. If intraocular pressure remains uncontrolled, medical or surgical treatment may be necessary. Risk factors for acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

Use during pregnancy or breastfeeding.

Pregnancy

The medication is contraindicated in pregnant women or women planning to become pregnant.

Warnings related to perindopril

There are no convincing epidemiological data on teratogenic risk with ACE inhibitors during the first trimester of pregnancy; however, a small increased risk cannot be excluded. If continued ACE inhibitor 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 pregnancy. It is known that ACE inhibitors used during the second and third trimesters of pregnancy have toxic effects on the fetus (impaired renal function, oligohydramnios, delayed skull ossification) and on the newborn (renal failure, hypotension, hyperkalaemia). If ACE inhibitors were used during the second and third trimesters of pregnancy, ultrasound assessment of renal function and skull development in the newborn is recommended. Newborns whose mothers received ACE inhibitors during pregnancy should be monitored for timely detection and correction of 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 circulating blood volume in the pregnant woman and uteroplacental perfusion, potentially causing fetoplacental ischaemia and delayed fetal development. Animal studies did not reveal direct or indirect toxic effects on reproductive performance. As a precaution, indapamide use during pregnancy should be avoided.

Breastfeeding

Noliprel® Bi-Forte is not recommended during breastfeeding. A decision should be made whether to discontinue breastfeeding or to discontinue the medication during breastfeeding, 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 transfer into breast milk are insufficient. Hypersensitivity to sulfonamide derivatives and hypokalaemia may develop. Risk to newborns/infants cannot be excluded. Indapamide is a thiazide-like diuretic, and 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. No effect on human fertility is expected.

Ability to influence reaction speed when driving or operating machinery.

The two active substances, when used separately or in combination as Noliprel® Bi-Forte, 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 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 the medicinal product Noliprel® Bi-Forte is 1 tablet per day, taken once daily, preferably in the morning before a meal.

Special Patient Categories

Elderly patients (see section "Special Warnings and Precautions for Use"). Plasma creatinine levels should be determined in elderly patients, taking into account age, body weight, and gender. Treatment in elderly patients may be initiated if renal function is normal and after considering the blood pressure response to therapy.

Renal impairment (see section "Special Warnings and Precautions for Use"). Noliprel® Bi-Forte is contraindicated in patients with moderate to severe renal impairment (creatinine clearance < 60 mL/min). Routine 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® Bi-Forte is contraindicated in patients with severe hepatic impairment. Patients with moderate hepatic impairment do not require dose adjustment.

Children

Noliprel® Bi-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, somnolence, confusion, oliguria, potentially progressing 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 removal 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 elevation of the head. If necessary, intravenous administration of isotonic sodium chloride solution or any other method to restore blood volume should be performed. Perindoprilat, the active metabolite of perindopril, may be removed from the body by hemodialysis (see section "Pharmacokinetics").

Adverse reactions.

The use 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 6% of patients treated with Noliprel® Bi-Forte. The most commonly reported adverse reactions were: 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 rash.

During clinical trials and/or post-marketing use of the medicinal product, the following adverse reactions have been observed, 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 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 precautions for use") (very rare – perindopril); hemolytic anemia (very rare – perindopril and indapamide); thrombocytopenia (see section "Special 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 precautions for use") (common – indapamide); hypoglycemia (see sections "Special 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 precautions for use") (uncommon* – perindopril); hyponatremia (see section "Special 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 precautions for use") (very rare – perindopril); hepatic encephalopathy may occur in patients with liver insufficiency (see sections "Contraindications" and "Special precautions for use") (frequency not known – indapamide).

Eye disorders: visual disturbances (common – perindopril, frequency not known – indapamide); myopia (see section "Special 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 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 precautions for use") (very rare – perindopril); paroxysmal ventricular tachycardia of the "torsades de pointes" type (potentially fatal) (see sections "Special 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 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 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 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 rash (common – indapamide); urticaria (see section "Special precautions for use") (uncommon – perindopril, very rare – indapamide); angioedema (see section "Special 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 existing 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 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 failure (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 enzyme levels (rare – perindopril, frequency not known – indapamide); decreased hemoglobin and hematocrit levels (see section "Special 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 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 based on clinical trial data.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after authorization of the medicinal product is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives are encouraged to 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 to protect from moisture. No special temperature storage conditions required. Keep out of reach and sight of children.

Packaging.

30 tablets per container; 1 or 3 containers per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Laboratoires Servier Industrie / Les Laboratoires Servier Industrie.

Manufacturer's location and address of operations.

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 operations.

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

Marketing Authorization Holder.

Les Laboratoires Servier.

Holder's location.

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

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