Perindopril/indapamide-teva

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Perindopril/Indapamide-Teva (Perindopril/Indapamide-Teva)

Composition:

Active substances: perindopril (as perindopril tosylate) and indapamide;

One tablet contains 2.5 mg of perindopril tosylate (equivalent to 1.7 mg of perindopril) and 0.625 mg of indapamide;

Excipients: lactose monohydrate, maize starch, sodium bicarbonate, pregelatinized starch, povidone, magnesium stearate;

Coating (Opadry II white 85F18422): polyvinyl alcohol partially hydrolyzed, titanium dioxide (E 171), polyethylene glycol, talc.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: biconvex capsule-shaped tablets, film-coated, white in color, approximately 4 mm wide and 8 mm long, with a break line on one side and smooth on the other.

Pharmacotherapeutic group. Combined preparations of angiotensin-converting enzyme (ACE) inhibitors. Perindopril and diuretics. ATC code C09BA04.

Pharmacological properties.

Pharmacodynamics.

Perindopril/Indapamide-Teva is a combination of the angiotensin-converting enzyme (ACE) inhibitor perindopril tosylate and the sulfonamide diuretic indapamide. Its pharmacological action is due to the properties of each component (perindopril and indapamide) and their additive synergism. The pharmacological mechanism of action of the drug is based on the additive synergistic effect of the two antihypertensive components. Perindopril/Indapamide-Teva reduces systolic and diastolic blood pressure in patients with arterial hypertension of any age, both in the supine and standing positions. The antihypertensive effect is dose-dependent and lasts for 24 hours. Reduction in blood pressure is achieved within less than 1 month without development of tachyphylaxis; discontinuation of treatment does not cause withdrawal syndrome. It has been demonstrated that the concomitant use of perindopril and indapamide exerts a synergistic antihypertensive effect resulting from the individual effects of the components of the drug. Perindopril is an ACE inhibitor that converts angiotensin I to angiotensin II (a vasoconstrictive substance), stimulates aldosterone secretion by the adrenal cortex, and promotes bradykinin (a vasodilatory substance) degradation into inactive heptapeptides. Inhibition of ACE leads to: reduced aldosterone secretion; increased plasma renin activity, while aldosterone does not exert a negative influence; decreased total peripheral vascular resistance due to predominant effects on muscular and renal vessels. Water and salt retention and reflex tachycardia are not observed during prolonged treatment. Perindopril reduces blood pressure even in patients with normal or low plasma renin levels. Perindopril acts via its active metabolite, perindoprilat. Other metabolites are inactive. Perindopril reduces cardiac workload through: vasodilatory action on veins (possibly due to changes in prostaglandin metabolism) – reduction in preload; reduction in total peripheral vascular resistance – reduction in afterload on the heart. Studies conducted in patients with heart failure have demonstrated that perindopril administration leads to: – reduction in filling pressure of the left and right ventricles; – reduction in total peripheral vascular resistance; – increased cardiac output and improved cardiac index; – increased regional blood flow in muscles. Exercise tolerance tests show significant improvement. Characteristics of the antihypertensive action of perindopril. Perindopril effectively reduces blood pressure in all stages of arterial hypertension: mild, moderate, and severe; reduction in systolic and diastolic blood pressure is observed both in the supine and standing positions. The maximum antihypertensive effect develops within 4–6 hours after a single dose and persists for more than 24 hours. Perindopril has a high level of sustained ACE inhibition – approximately 80% at 24 hours after administration. In patients who respond to treatment, normalization of blood pressure occurs within one month and is maintained without tachyphylaxis. Discontinuation of treatment is not associated with a rebound effect. Perindopril has vasodilatory properties, restores elasticity of large arteries, corrects histomorphometric changes in resistance arteries, and reduces left ventricular hypertrophy. Addition of a thiazide diuretic when necessary results in additional synergism. The combination of an ACE inhibitor and a thiazide diuretic reduces the risk of hypokalemia that may occur with diuretic monotherapy. Indapamide is a sulfonamide diuretic 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, to a lesser extent – excretion of potassium and magnesium, thereby increasing diuresis. This mechanism provides antihypertensive action with minimal diuretic effect. Characteristics of the antihypertensive action of indapamide. The antihypertensive effect of indapamide during monotherapy lasts 24 hours and is proportional to improved arterial elasticity, reduced arteriolar resistance, and decreased total peripheral vascular resistance. Indapamide reduces left ventricular hypertrophy. When the recommended dose is exceeded, the antihypertensive effect of thiazides and thiazide-like diuretics does not increase, while the number of adverse effects increases. If treatment is insufficiently effective, dose escalation is not recommended. Moreover, it has been shown that indapamide: – does not affect lipid metabolism (triglycerides, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C)); – does not affect carbohydrate metabolism, even in patients with arterial hypertension and diabetes mellitus.

Pharmacokinetics.

The pharmacokinetic parameters of perindopril and indapamide in the Perindopril/Indapamide-Teva formulation do not differ from those of perindopril and indapamide as monotherapeutic agents. Perindopril. 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. Perindopril is a prodrug. 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 inactive metabolites. Maximum plasma concentration of perindoprilat is achieved within 3–4 hours. Since food intake reduces the conversion of perindopril to perindoprilat, thereby decreasing its bioavailability, perindopril is recommended to be taken orally as a single daily dose in the morning before meals. A linear relationship exists between perindopril dose and its plasma concentration. The volume of distribution of unbound perindoprilat is approximately 0.2 L/kg. Plasma protein binding of perindoprilat is 20%, primarily to ACE, and is dose-dependent. Perindoprilat is excreted in urine; the terminal elimination half-life of unbound perindoprilat is approximately 17 hours. Steady state is achieved within 4 days. Elimination of perindoprilat is reduced in elderly patients and in patients with heart or renal failure. For patients with renal impairment, dosage adjustment is required based on the degree of renal function impairment (creatinine clearance). Dialysis clearance of perindoprilat is 70 mL/min. Perindopril kinetics are altered in patients with liver cirrhosis: hepatic clearance of the parent molecule is halved. However, the amount of formed perindoprilat does not decrease. Therefore, dose adjustment is not required in such patients. Indapamide. Indapamide is rapidly and completely absorbed in the gastrointestinal tract. Maximum plasma concentration (Tmax) is reached approximately 1 hour after oral administration. Plasma protein binding is 79%. The elimination half-life ranges from 14 to 24 hours (average 18 hours). With regular administration, no accumulation occurs. Indapamide is excreted in urine (70% of dose) and feces (22%) as inactive metabolites. In patients with renal impairment, pharmacokinetic parameters do not change.

Clinical characteristics.

Indications. Perindopril/Indapamide-Teva is indicated for the treatment of essential hypertension in adult patients.

Contraindications.

Related to perindopril: hypersensitivity to perindopril or to any other angiotensin-converting enzyme (ACE) inhibitors; history of angioedema (Quincke's edema) associated with previous ACE inhibitor therapy; hereditary or idiopathic angioedema; pregnancy or planned pregnancy; concomitant use with aliskiren-containing medicinal products in patients with diabetes or renal dysfunction (eGFR <60 mL/min/1.73 m²); concomitant use with sacubitril/valsartan; extracorporeal treatment methods leading to contact of blood with negatively charged surfaces; significant bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney.

Related to indapamide: hypersensitivity to indapamide or to any other sulfonamide-containing drugs; severe renal impairment (creatinine clearance <30 mL/min); severe hepatic dysfunction and hepatic encephalopathy; hypokalemia; combination with non-antiarrhythmic drugs that may provoke development of paroxysmal ventricular tachycardia of the "torsades de pointes" type; breastfeeding.

Related to Perindopril/Indapamide-Teva: hypersensitivity to any component of the medicinal product. Due to lack of sufficient clinical experience, Perindopril/Indapamide-Teva should not be used in patients undergoing hemodialysis or 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, reversible serum lithium concentrations and lithium toxicity have been reported during concomitant use of lithium and ACE inhibitors. Concomitant use of perindopril in combination with indapamide and lithium-containing medicinal products is not recommended. However, if such combination is absolutely necessary, serum lithium concentrations should be closely monitored.

Concomitant use requiring special attention. Baclofen. Enhances the antihypertensive effect of the medicinal product. Monitoring of blood pressure and renal function is required, with dose adjustment if necessary. Nonsteroidal anti-inflammatory drugs (NSAIDs) (including acetylsalicylic acid at doses ≥3 g/day). Concomitant use of NSAIDs (e.g., acetylsalicylic acid at anti-inflammatory doses, COX-2 inhibitors, and nonselective NSAIDs) may reduce the antihypertensive effect of the medicinal product. Concomitant use of ACE inhibitors and NSAIDs may increase the risk of worsening renal function, including development of 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 have adequate hydration prior to initiation of treatment, and renal function should be monitored at the beginning and throughout combination therapy.

Concomitant use requiring attention. Imipramine-like (tricyclic) antidepressants, neuroleptics. Enhanced hypotensive effect and increased risk of orthostatic hypotension (additive effect).

Interactions related to perindopril

Clinical data indicate that dual blockade of the renin-angiotensin-aldosterone system (RAAS) using combinations of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with higher incidence of adverse effects such as arterial hypotension, hyperkalemia, and renal dysfunction (including acute renal failure), compared to monotherapy affecting the RAAS. Medicinal products causing hyperkalemia. Certain drugs or therapeutic classes, such as aliskiren, potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, NSAIDs, heparins, immunosuppressants (e.g., cyclosporine or tacrolimus), and trimethoprim, may cause hyperkalemia. Combining these agents increases the risk of hyperkalemia.

Concomitant use contraindicated. Aliskiren. In patients with diabetes or renal dysfunction, there is an increased risk of hyperkalemia, worsening renal function, cardiovascular morbidity, and mortality. Extracorporeal treatment methods. Extracorporeal treatments involving 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, increase the risk of severe anaphylactoid reactions. If such treatment is required, consideration should be given to using a different type of dialysis membrane or switching to another class of antihypertensive agents. Sacubitril/valsartan. Concomitant use of perindopril with sacubitril/valsartan is contraindicated, as dual inhibition of neprilysin and ACE may increase the risk of angioedema. Initiation of sacubitril/valsartan should not occur earlier than 36 hours after the last dose of perindopril. Perindopril therapy should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan.

Concomitant use not recommended. Aliskiren. In all patient groups, including those with diabetes or impaired renal function, there is an increased risk of hyperkalemia, worsening renal function, cardiovascular morbidity, and mortality. Concomitant therapy with an ACE inhibitor and an angiotensin receptor blocker. Published data indicate that in patients with established atherosclerosis, heart failure, or diabetes 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 monotherapy affecting the RAAS. Dual blockade (i.e., combination of an ACE inhibitor and an angiotensin II receptor antagonist) may be considered only in selected cases with strict monitoring of renal function, serum potassium levels, and blood pressure. Estramustine. Increased risk of adverse reactions such as angioedema. Potassium-sparing diuretics (e.g., triamterene, amiloride), potassium supplements. 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. If concomitant use is indicated, these agents should be used 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." Co-trimoxazole (trimethoprim/sulfamethoxazole). Increased risk of hyperkalemia in patients receiving co-trimoxazole.

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, increasing the risk of hypoglycemia. This phenomenon is more likely during the first weeks of combination therapy and in patients with renal impairment. Diuretics. In patients receiving diuretics, especially those 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 the diuretic, increasing intravascular volume, or increasing salt intake prior to starting perindopril, which should be initiated at a low dose with gradual titration. In hypertensive patients previously treated with diuretics who may have volume/sodium depletion, the diuretic should be discontinued before starting an ACE inhibitor (the diuretic may later be reintroduced), or ACE inhibitor therapy should be initiated at a low dose with gradual titration. In patients with congestive heart failure receiving diuretics, ACE inhibitor therapy should be initiated at the lowest dose, possibly after reducing the diuretic dose. 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 daily) 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, especially if recommendations are not followed. Hyperkalemia and renal dysfunction should be excluded before initiating such combination. Serum potassium and creatinine should be closely monitored weekly during the first month and monthly thereafter. Racecadotril. ACE inhibitors (e.g., perindopril) may cause angioedema. This risk may increase with concomitant use of racecadotril (a medicinal product used to treat acute diarrhea). mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus). Increased risk of angioedema in patients receiving mTOR inhibitors concomitantly.

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 blood pressure reduction. Allopurinol, cytostatic agents, immunosuppressants, systemic corticosteroids, or procainamide. Concomitant use with ACE inhibitors may increase the risk of leukopenia. Anesthetic agents. ACE inhibitors may potentiate the hypotensive effect of certain anesthetics. Gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin). Concomitant use with an ACE inhibitor increases the risk of angioedema due to inhibition of dipeptidyl peptidase-IV (DPP-IV) by gliptins. Sympathomimetics. Sympathomimetics may attenuate the antihypertensive effect of ACE inhibitors. Gold compounds. Rarely, nitritoid reactions (facial flushing, nausea, vomiting, and arterial hypotension) have been reported in patients receiving injectable gold compounds (sodium aurothiomalate) and concomitant ACE inhibitor therapy, including perindopril.

Interactions related to indapamide

Concomitant use requiring special attention. Medicinal products that may provoke development of paroxysmal ventricular tachycardia of the "torsades de pointes" type. Due to the risk of hypokalemia, indapamide should be used cautiously in combination with medicinal products that may provoke "torsades de pointes," such as class IA antiarrhythmics (quinidine, hydroquinidine, disopyramide), class III antiarrhythmics (amiodarone, dofetilide, ibutilide, bretylium, sotalol), certain neuroleptics (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine), benzamides (amisulpride, sulpiride, sulthiapride, tiapride), butyrophenones (droperidol, haloperidol), other neuroleptics (pimozide), and other agents such as bepridil, cisapride, difemanil, intravenous erythromycin, halofantrine, mizolastine, pentamidine, moxifloxacin, sparfloxacin, intravenous vinpocetine, methadone, astemizole, terfenadine. Plasma potassium levels should be maintained and corrected if necessary, and QT interval should be monitored. Medicinal products that reduce plasma potassium levels. Intravenous amphotericin B, systemic glucocorticoids and mineralocorticoids, tetracosactide, and stimulant laxatives increase the risk of hypokalemia (additive effect). Plasma potassium levels should be monitored and corrected if necessary, especially during concomitant therapy with cardiac glycosides. Non-stimulant laxatives should be used. Cardiac glycosides. Hypokalemia increases the risk of toxic effects of cardiac glycosides. Plasma potassium levels and ECG should be monitored, and therapy 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). Plasma potassium levels should be monitored, ECG monitoring should be performed, and therapy should be adjusted if necessary. Metformin. May cause lactic acidosis due to functional renal impairment associated with diuretic use, particularly 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. Hydration should be restored before administration of iodinated contrast agents. Calcium (salts). Risk of increased serum calcium levels due to reduced urinary excretion. Cyclosporine, tacrolimus. Risk of increased serum creatinine without changes in circulating cyclosporine levels, even in the absence of volume or sodium depletion. Corticosteroids, tetracosactide (systemic). May reduce antihypertensive efficacy (due to water and sodium retention caused by corticosteroids).

Special precautions.

Special warnings

Special warnings common to perindopril and indapamide

For the medicinal product Perindopril/Indapamide-Teva, tablets 2.5 mg/0.625 mg (low-dose combination), no significant reduction in the frequency of adverse reactions has been observed compared to the use of each component at the lowest approved doses, except for hypokalemia. The increased frequency of idiosyncratic reactions cannot be excluded if a patient is simultaneously taking two new antihypertensive drugs. To minimize the risk, careful monitoring of the patient is required.

Lithium. Concomitant use of lithium and the perindopril/indapamide combination is generally not recommended.

Special warnings related to perindopril

Dual blockade of the RAAS. It is known that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of adverse effects such as arterial hypotension, hyperkalemia, and renal dysfunction (including acute renal failure). Therefore, dual blockade of the RAAS using this combination is not recommended. If dual RAAS blockade is absolutely necessary, it should be performed under physician supervision with strict monitoring of renal function, electrolytes, and blood pressure. ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Potassium-sparing agents, potassium-containing supplements or salt substitutes. The combination of perindopril with potassium-sparing agents, potassium-containing supplements, or salt substitutes is generally not recommended.

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 without 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 have developed severe infections, sometimes resistant to intensive antibiotic therapy. In such patients, periodic monitoring of white blood cell counts is recommended, and patients should be informed to report any signs of infection (sore throat, fever) to their physician.

Renovascular hypertension. In patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney, treatment with ACE inhibitors increases the risk of arterial hypotension and renal failure. The use of diuretics may be a contributing factor. Renal function impairment may be accompanied by 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 receiving ACE inhibitors, including perindopril. This may occur at any time during treatment. In such cases, the drug should be discontinued immediately, and appropriate monitoring should be initiated until symptoms resolve completely. When swelling is limited to the face and lips, the condition usually improves without treatment, although antihistamines may alleviate symptoms. Angioedema involving the larynx may be fatal. If swelling extends to the tongue, glottis, or larynx, potentially causing airway obstruction, immediate emergency treatment is required, which may include subcutaneous administration of epinephrine 1:1000 solution (0.3–0.5 mL) and/or securing airway patency.

It has been reported that angioedema occurs more frequently in patients of African descent receiving ACE inhibitors compared to other racial groups. Patients with a history of angioedema unrelated to ACE inhibitor use may have an increased risk of developing angioedema while taking ACE inhibitors. Rare cases of intestinal angioedema have been reported in patients receiving ACE inhibitors. These patients experienced abdominal pain (with or without nausea and vomiting); some cases of intestinal angioedema occurred without prior facial angioedema, and serum C1 esterase inhibitor levels were normal. The diagnosis of intestinal angioedema was confirmed by computed tomography, ultrasound, or during surgical intervention. Symptoms of angioedema 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 ACE inhibitors with sacubitril/valsartan is contraindicated due to an increased risk of angioedema. Treatment with sacubitril/valsartan should not be initiated earlier than 36 hours after the last dose of Perindopril/Indapamide-Teva. Treatment with Perindopril/Indapamide-Teva should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan. Concomitant use of ACE inhibitors with other neprilysin inhibitors (NEP) (e.g., racecadotril), mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin may increase the risk of angioedema (e.g., airway or tongue swelling with or without respiratory compromise). Caution should be exercised when initiating racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin in patients already receiving an ACE inhibitor.

Anaphylactoid reactions during desensitization therapy. Isolated cases of life-threatening anaphylactoid reactions have been reported in patients receiving ACE inhibitors during desensitization therapy with insect venom preparations (bees, wasps). ACE inhibitors should be used cautiously in patients with allergies after desensitization and avoided during immunotherapy with venom-containing preparations. However, in patients requiring both ACE inhibitors and desensitization, such reactions may be avoided by temporarily discontinuing the ACE inhibitor at least 24 hours before desensitization therapy.

Anaphylactoid reactions during LDL apheresis. Rare cases of life-threatening anaphylactoid reactions have been reported in patients receiving ACE inhibitors during LDL apheresis using dextran sulfate. These reactions may be avoided by temporarily discontinuing ACE inhibitor therapy before each apheresis session.

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

Primary hyperaldosteronism. Patients with primary hyperaldosteronism usually do not respond to antihypertensive drugs acting via suppression of the renin-angiotensin system. Therefore, this drug is not recommended for such patients.

Patients after kidney transplantation. There is no experience with the use of perindopril tosylate in patients who have recently undergone kidney transplantation.

Arterial hypotension. Symptomatic arterial hypotension has been reported in patients with symptomatic heart failure, with or without concomitant renal impairment. The occurrence of symptomatic arterial hypotension is most likely in patients with more severe heart failure who are receiving high doses of loop diuretics, have hyponatremia, or have functional renal impairment. To reduce the risk of symptomatic arterial hypotension, close medical supervision is required at the beginning of therapy and during dose titration. Similar precautions apply to patients with ischemic heart disease or cerebrovascular disease, in whom excessive reduction in blood pressure may lead to 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 on continuing therapy.

Special warnings related to indapamide

Hepatic encephalopathy. In patients with impaired liver function, the use of thiazide and thiazide-like diuretics may precipitate hepatic encephalopathy. In such cases, diuretic therapy should be discontinued immediately.

Photosensitivity. Cases of photosensitivity reactions have been reported in patients receiving thiazide and thiazide-like diuretics. If such reactions occur, diuretic therapy should be discontinued. If reinitiating diuretic therapy is necessary, protection of exposed skin from sunlight or artificial UV sources is recommended.

Precautions

Precautions common to perindopril and indapamide

Renal impairment. The use of this drug is contraindicated in severe renal impairment (creatinine clearance <30 mL/min). If, during treatment of patients with arterial hypertension without existing visible signs of renal impairment, laboratory blood tests show signs of functional renal impairment, treatment should be discontinued, with possible resumption at a lower dose or with one of the components. Such patients require monitoring of serum potassium and creatinine levels: 2 weeks after initiation of treatment and every 2 months thereafter during therapeutic stabilization. Cases of renal impairment have mainly been observed in patients with severe heart failure or pre-existing renal dysfunction, including those with renal artery stenosis. This drug should not be used in patients with significant bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney.

Arterial hypotension and water and electrolyte depletion. There is a risk of a sudden drop in blood pressure in patients with sodium depletion (especially in patients with renal artery stenosis). Therefore, systematic monitoring for clinical signs of water and electrolyte depletion is required, which may occur during intercurrent episodes of vomiting or diarrhea. In such patients, plasma electrolyte levels should be monitored regularly. In cases of significant arterial hypotension, intravenous administration of 0.9% sodium chloride solution may be necessary. Transient hypotension is not a contraindication for further use of the drug. After restoration of circulating volume and normalization of blood pressure, treatment may be resumed at a lower dose or with one of the components.

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

Precautions related to perindopril

Cough. As with other ACE inhibitors, a dry cough may occur. 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 necessary for the patient, continuation of therapy may be considered.

Risk of arterial hypotension and/or renal impairment (in the presence of heart failure, water and electrolyte depletion). Significant activation of the RAAS has been observed 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 patients with cirrhosis and edema/ascites. Blockade of this system by an ACE inhibitor may cause, especially after the first dose and during the first two weeks of treatment, a sharp drop in blood pressure and/or an increase in plasma creatinine levels, confirming functional renal impairment. Occasionally, although rarely, this may have an acute onset and occur at any time. In such cases, treatment should be initiated with a lower dose, gradually increasing it.

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

Atherosclerosis. The risk of arterial hypotension exists in all patients, but particular caution is required in patients with ischemic heart disease or cerebral circulation insufficiency. Such patients should start treatment with a low dose.

Renovascular hypertension. The treatment of renovascular hypertension is revascularization. However, ACE inhibitors may be beneficial for patients with renovascular hypertension awaiting surgery or when surgery is not possible. If the drug is prescribed to patients with known or suspected renal artery stenosis, treatment should be initiated in a hospital setting with low doses and under monitoring of renal function and potassium levels, as some patients developed reversible functional renal impairment after discontinuation of treatment.

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. Beta-blocker therapy in patients with arterial hypertension and coronary insufficiency should not be discontinued: the ACE inhibitor should be added to the beta-blocker.

Patients with diabetes mellitus. Treatment of patients with insulin-dependent diabetes mellitus (with a spontaneous tendency to elevated blood potassium levels) should be initiated under medical supervision with a reduced initial dose. In patients with diabetes mellitus receiving oral antidiabetic drugs or insulin, blood glucose levels should be closely monitored, especially during the first month of ACE inhibitor therapy.

Racial characteristics. As with other ACE inhibitors, perindopril is less effective in lowering blood pressure in hypertensive patients of African descent compared to patients of other races, possibly due to lower plasma renin levels in these patients.

Surgery/anesthesia. ACE inhibitors may cause a hypotensive effect during anesthesia, especially when using anesthetics that lower blood pressure. Therefore, in patients receiving long-acting ACE inhibitors such as perindopril, the drug should be discontinued, if possible, 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, the use of ACE inhibitors has been associated with a syndrome beginning with cholestatic jaundice and progressing to rapidly progressive liver necrosis, sometimes fatal. The mechanism of this syndrome is unclear. Patients who develop jaundice with elevated liver enzymes while taking ACE inhibitors should discontinue the ACE inhibitor and receive appropriate medical monitoring.

Hyperkalemia. Increased serum potassium concentration has been observed in some patients receiving ACE inhibitors, including perindopril. Risk factors for hyperkalemia include renal impairment or reduced renal function, age (>70 years), diabetes mellitus, hypoaldosteronism, and intercurrent conditions such as dehydration, acute heart decompensation, and metabolic acidosis.

ACE inhibitors may cause hyperkalemia due to inhibition of aldosterone release. This effect is usually mild in patients with normal renal function. However, in patients with impaired renal function and/or those taking potassium-containing dietary supplements (including salt substitutes), potassium-sparing diuretics (spironolactone, eplerenone, triamterene, or amiloride), or other drugs that increase serum potassium levels (e.g., heparin, trimethoprim or co-trimoxazole, also known as trimethoprim/sulfamethoxazole, other ACE inhibitors, angiotensin II receptor antagonists, acetylsalicylic acid at doses ≥3 g/day, COX-2 inhibitors and non-selective NSAIDs, immunosuppressive agents such as cyclosporine or tacrolimus), especially aldosterone antagonists or angiotensin receptor antagonists, hyperkalemia may occur. Caution is required when using potassium-sparing diuretics and angiotensin receptor antagonists in patients receiving ACE inhibitors. In such patients, serum potassium levels and renal function should be monitored.

Hyperkalemia may lead to serious, sometimes fatal, arrhythmias. If concomitant use of perindopril and any of the above-mentioned substances is considered appropriate, they should be used with caution and serum potassium levels should be monitored frequently.

Precautions related to indapamide

Water and electrolyte balance

Sodium levels. Plasma sodium levels should be checked before starting treatment and regularly during treatment. Any diuretic may cause hyponatremia, which may sometimes have serious consequences. Hyponatremia combined with hypovolemia 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. Decreased plasma sodium may initially be asymptomatic, so regular monitoring is required. Monitoring should be more frequent in elderly patients and those with liver cirrhosis.

Potassium levels. Decreased plasma potassium levels leading to hypokalemia are the main risk factor associated with the use of thiazide and thiazide-like diuretics. The risk of hypokalemia (<3.4 mmol/L) should be prevented in certain high-risk patient groups (elderly patients and/or those with poor nutrition, regardless of concomitant medication use, patients with cirrhosis with edema and ascites, patients with ischemic heart disease and heart failure). In such cases, hypokalemia increases the cardiotoxicity of cardiac glycosides and the risk of cardiac arrhythmias.

Patients with congenital or iatrogenic prolonged QT interval also belong to the risk group. In such patients, hypokalemia, as well as bradycardia, may promote the development of severe cardiac arrhythmias, including paroxysmal ventricular tachycardia of the torsades de pointes type, which may be fatal. In all these cases, more frequent monitoring of blood potassium levels is required. The first determination of plasma potassium levels should be performed within the first week of treatment. If potassium levels are low, correction is required.

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

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

Uric acid. In patients with elevated blood uric acid levels, an increased frequency of gout attacks is possible.

Renal function and diuretics. Thiazide and thiazide-like diuretics are most effective when renal function is not impaired or only mildly impaired (blood creatinine <25 mg/L, i.e., 220 µmol/L in adults). In elderly patients, plasma creatinine levels should be assessed considering age, body weight, and sex using the Cockcroft formula: creatinine clearance (Clcr) = (140 – age) × body weight / 0.814 × plasma creatinine level; where age is in years, body weight in kg, and plasma creatinine in µmol/L. This formula is used for elderly men and should be adapted for women by multiplying the result by 0.85.

Hypovolemia caused by loss of water and sodium due to diuretic use at the beginning of treatment leads to a decrease in glomerular filtration rate. This may result in increased blood urea and plasma creatinine levels. This transient functional renal impairment has no consequences in individuals with normal renal function but may worsen pre-existing renal impairment.

Choroidal effusion, acute myopia, and secondary angle-closure glaucoma. Sulfonamide drugs 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 after starting the drug. Untreated acute angle-closure glaucoma may lead to irreversible vision loss. Initial treatment includes immediate discontinuation of the drug. If intraocular pressure remains uncontrolled, prompt medical or surgical treatment may be required. Risk factors for acute angle-closure glaucoma may include a history of allergy to sulfonamides or penicillin.

Sportsmen. This drug contains an active substance that may cause a positive result in doping tests in athletes.

Excipients. Lactose. The drug should not be used in patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption. Sodium. This medicinal product contains less than 1 mmol (23 mg) of sodium per tablet, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy. The use of this drug is contraindicated in pregnant women or women planning to become pregnant. Warnings related to perindopril. Convincing epidemiological evidence of teratogenic risk with ACE inhibitors during the first trimester of pregnancy is lacking; however, a small increased risk cannot be excluded. If continued treatment with ACE inhibitors is considered essential, women planning pregnancy should be switched to alternative antihypertensive drugs with proven safety during pregnancy. If pregnancy is confirmed during treatment, ACE inhibitor therapy should be discontinued immediately and, if necessary, replaced with another drug 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 ossification of the skull bones) and on the newborn (renal failure, arterial hypotension, hyperkalemia). If ACE inhibitors were used during the second and third trimesters of pregnancy, ultrasound examination of the newborn's 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 the use of indapamide in pregnant women are lacking or limited. Prolonged use of a thiazide diuretic during the third trimester of pregnancy may reduce the circulating blood volume of the pregnant woman and uteroplacental perfusion, potentially causing fetoplacental ischemia and delayed fetal development. Animal studies have not shown direct or indirect toxic effects on reproductive function. As a precaution, it is advisable to avoid the use of indapamide during pregnancy.

Breastfeeding. The drug is contraindicated during breastfeeding. A decision should be made whether to discontinue breastfeeding or to discontinue the drug, considering the importance of therapy for the mother. Warnings related to perindopril. The use of perindopril during breastfeeding is not recommended due to lack of data. An alternative treatment with a proven safety profile should be preferred, especially during breastfeeding of a newborn or premature infant. Warnings related to indapamide. Data on the passage of indapamide/metabolites into breast milk are insufficient. Hypersensitivity to sulfonamide derivatives and hypokalemia may develop. Risk to newborns/infants cannot be excluded. Indapamide belongs to thiazide-like diuretics, the use of which during breastfeeding is associated with reduced or even suppressed lactation. Indapamide is contraindicated 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 vehicles or operating machinery.

The two active ingredients, either separately or in combination, do not affect the ability to drive vehicles or operate machinery. However, in some patients, especially at the beginning of treatment or when using the drug in combination with another antihypertensive drug, individual reactions related to low blood pressure may occur, potentially impairing the ability to drive vehicles or operate machinery.

Method of Administration and Dosage.

The medication is intended for oral administration. Tablets must not be divided into two equal doses. The score line on the tablets is intended for breaking the tablet to facilitate swallowing.

Perindopril/Indapamide-Teva 2.5 mg/0.625 mg tablets. For adults, administer 1 tablet once daily, preferably in the morning before meals. If blood pressure has not normalized within one month, the dose may be doubled.

Elderly patients. Treatment should be initiated at the usual dose – 1 tablet of Perindopril/Indapamide-Teva 2.5 mg/0.625 mg once daily.

Patients with renal impairment. Treatment 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), the maximum daily dose is 1 tablet of Perindopril/Indapamide-Teva 2.5 mg/0.625 mg. Dose adjustment is not required for patients with creatinine clearance ≥60 mL/min. Routine medical monitoring includes frequent assessment of creatinine and potassium levels.

Patients with hepatic impairment. Treatment is contraindicated in patients with severe hepatic impairment. Dose adjustment is not required for patients with moderate hepatic impairment.

Children.

Perindopril/Indapamide-Teva should not be used for the treatment of children and adolescents. Safety and efficacy in pediatric patients have not been established. Data are lacking.

Overdose.

Symptoms. The most likely adverse reaction due to overdose is arterial hypotension, sometimes associated with nausea, vomiting, convulsions, dizziness, somnolence, 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, cough, and other symptoms may occur.

Treatment. Emergency measures include rapid removal of the drug by gastric lavage and/or administration of activated charcoal, followed by restoration of fluid and electrolyte balance under hospital conditions. In case of significant hypotension, the patient should be placed in a supine position with low head elevation. If necessary, intravenous administration of isotonic saline 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.

Adverse reactions.

Administration of perindopril inhibits the RAAS and helps reduce potassium loss caused by indapamide. Hypokalemia (potassium level <3.4 mmol/L) occurs in 2% of patients treated with this medication. The most commonly reported adverse reactions are as follows: with perindopril — dizziness, headache, paraesthesia, dysgeusia, visual disturbances, vertigo, tinnitus, arterial hypotension, cough, dyspnea, abdominal pain, constipation, dyspepsia, diarrhea, nausea, vomiting, pruritus, rash, muscle cramps, and asthenia; with indapamide — hypersensitivity reactions, mainly dermatological, in patients predisposed to allergic and asthmatic reactions, and maculopapular rash. Adverse reactions are categorized by frequency as follows: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000); frequency not known (cannot be estimated from available data).

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

Blood and lymphatic system disorders: eosinophilia (uncommon* − perindopril); agranulocytosis (very rare − perindopril and indapamide); aplastic anemia (very rare − indapamide); pancytopenia (very rare − perindopril); leukopenia (very rare − perindopril and indapamide); neutropenia (very rare − perindopril); hemolytic anemia (very rare − perindopril and indapamide); thrombocytopenia (very rare − perindopril and indapamide).

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

Endocrine disorders: syndrome of inappropriate antidiuretic hormone secretion (rare − perindopril).

Metabolism and nutrition disorders: hypoglycemia (uncommon* − perindopril); hyperkalemia, reversible upon discontinuation of the drug (uncommon* − perindopril); hyponatremia (uncommon* − perindopril, frequency not known − indapamide); hypercalcemia (very rare − indapamide); decrease in blood potassium levels leading to hypokalemia, including severe cases in some high-risk patients (frequency not known − 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); paraesthesia (common − perindopril, rare − indapamide); dysgeusia (common − perindopril); somnolence (uncommon* − perindopril); syncope (uncommon* − perindopril, frequency not known − indapamide); stroke may occur as a result of excessive arterial hypotension in high-risk patients (very rare − perindopril); hepatic encephalopathy may occur in case of liver insufficiency (frequency not known − indapamide).

Eye disorders: visual disturbances (common − perindopril, frequency not known − indapamide); myopia (frequency not known − indapamide); blurred vision (frequency not known − indapamide); choroidal effusion (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 (very rare − perindopril); arrhythmia (including bradycardia, ventricular tachycardia, atrial fibrillation) (very rare − perindopril and indapamide); myocardial infarction may occur as a result of excessive arterial hypotension in high-risk patients (very rare − perindopril); paroxysmal torsades de pointes ventricular tachycardia (potentially fatal) (frequency not known − indapamide).

Vascular disorders: arterial hypotension (and symptoms associated with hypotension) (common − perindopril, very rare − indapamide); vasculitis (uncommon* − perindopril); flushing (rare − perindopril); Raynaud's phenomenon (frequency not known − perindopril).

Respiratory, thoracic and mediastinal disorders: cough (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); intestinal angioedema.

Hepatobiliary disorders: hepatitis (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 (uncommon − perindopril, very rare − indapamide); angioedema (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); possible worsening of pre-existing systemic lupus erythematosus (frequency not known − indapamide); arthralgia (uncommon* − perindopril); myalgia (uncommon* − perindopril).

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

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

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 (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 (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. All suspected adverse reactions and lack of efficacy should be reported via the following link: https://aisf.dec.gov.ua/.

Shelf life. 28 months. After first opening of the container − 6 months.

Storage conditions. Store in a tightly closed container to protect from moisture. The medicinal product does not require special storage temperature conditions. Keep out of reach of children.

Packaging. 30 tablets in a container; 1 container per carton.

Prescription status. Prescription only.

Manufacturer. JSC "Pharmaceutical Plant Teva".

Manufacturer's address and location of operations. District 1; H-4042 Debrecen, Pallagi Street 13, Hungary.