Perindopril/indapamide forte-teva

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PERINDOPRIL/INDAPAMIDE FORTE-TEVA (PERINDOPRIL/INDAPAMIDE FORTE-TEVA)

Composition:

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

One tablet contains 5 mg of perindopril tosylate (equivalent to 3.4 mg of perindopril) and 1.25 mg of indapamide;

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

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

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: capsule-shaped, biconvex, film-coated tablets, white in color, approximately 5 mm wide and 10 mm long, with "P", "I" and a break line engraved on one side and smooth on the other.

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

Pharmacological properties.

Pharmacodynamics.

Perindopril/Indapamide Forte-Teva is a combination of the 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 Forte-Teva reduces systolic and diastolic blood pressure in patients with arterial hypertension of any age, both in supine and standing positions. The antihypertensive effect is dose-dependent and lasts for 24 hours. Blood pressure reduction 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 drug components. Perindopril is an ACE inhibitor that converts angiotensin I to angiotensin II (a vasoconstrictor substance), 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 influence; decreased total peripheral vascular resistance due to predominant effects on muscle and renal vessels. There is no water and salt retention or reflex tachycardia during prolonged treatment. Perindopril reduces blood pressure also 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 effects on veins (possibly due to changes in prostaglandin metabolism) – reducing preload; decreasing total peripheral vascular resistance – reducing 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 perindopril's antihypertensive action. Perindopril effectively reduces blood pressure in all degrees of arterial hypertension: mild, moderate, and severe. Reduction in systolic and diastolic blood pressure is observed both in 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 achieves a high level of sustained ACE inhibition – approximately 80% at 24 hours after administration. In patients responding 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, if 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 – potassium and magnesium, thereby increasing diuresis. This mechanism provides antihypertensive action with minimal diuretic effect. Characteristics of indapamide's antihypertensive action. The antihypertensive effect of indapamide in monotherapy lasts for 24 hours and is proportional to improved arterial elasticity and reduced arteriolar resistance and 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 established 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 combination product Perindopril/Indapamide Forte-Teva do not differ from those of perindopril and indapamide as monotherapeutic agents. Perindopril. After oral administration, perindopril is rapidly absorbed, with peak plasma concentration reached within 1 hour. The elimination half-life of perindopril in plasma is 1 hour. Perindopril is a prodrug. Approximately 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. Peak 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 should be taken orally as a single daily dose in the morning before meals. There is a linear relationship between perindopril dose and its plasma concentration. 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 dose-dependent. Perindoprilat is excreted in urine; the terminal half-life of unbound perindoprilat is approximately 17 hours. Steady-state concentrations are achieved by day 4. Elimination of perindoprilat is reduced in elderly patients and in patients with heart or renal insufficiency. For patients with renal impairment, dosage adjustment is required based on the degree of renal dysfunction (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 these patients. Indapamide. Indapamide is rapidly and completely absorbed in the gastrointestinal tract. Maximum plasma concentration (Tmax) is reached approximately 1 hour after oral administration. Protein binding is 79%. The elimination half-life ranges from 14 to 24 hours (average 18 hours). No accumulation occurs with regular administration. Indapamide is excreted in urine (70% of dose) and feces (22%) as inactive metabolites. In patients with renal insufficiency, pharmacokinetic parameters do not change.

Clinical characteristics.

Indications. Treatment of essential hypertension in adult patients.

Perindopril/Indapamide Forte-Teva is indicated when additional blood pressure control is required with perindopril used as monotherapy.

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 treatment with ACE inhibitors; hereditary or idiopathic angioedema; pregnancy or planned pregnancy; concomitant use with aliskiren-containing medicinal products in patients with diabetes mellitus or renal impairment (eGFR <60 mL/min/1.73 m²); concomitant use with sacubitril/valsartan; extracorporeal treatment methods leading to blood contact with negatively charged surfaces; significant bilateral renal artery stenosis or stenosis of the artery of a solitary 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 impairment and hepatic encephalopathy; hypokalemia; combination with non-antiarrhythmic medicinal products that may provoke torsades de pointes-type paroxysmal ventricular tachycardia; breastfeeding period.

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

Concomitant use requiring special attention. Baclofen. Enhances the antihypertensive effect of the medicinal product. Blood pressure and renal function should be monitored, and dosage adjusted 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 acute renal failure, and elevate serum potassium levels, especially in patients with renal impairment. This combination should be prescribed with caution, particularly in elderly patients. Patients should be adequately hydrated before initiation of treatment, and renal function should be monitored at the start and throughout combined 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 trial data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) using a combination of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with a higher incidence of adverse effects such as arterial hypotension, hyperkalemia, and renal dysfunction (including acute renal failure) compared to treatment with a single RAAS-acting agent. Medicinal products causing hyperkalemia. Certain medicinal products or therapeutic classes, such as aliskiren, potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, NSAIDs, heparins, immunosuppressive agents (e.g., cyclosporine or tacrolimus), trimethoprim, may cause hyperkalemia. Combination of these medicinal products increases the risk of hyperkalemia.

Concomitant use contraindicated. Aliskiren. In patients with diabetes mellitus or renal impairment, there is an increased risk of hyperkalemia, worsening renal function, cardiovascular morbidity, and mortality. Extracorporeal treatment methods. Extracorporeal treatment methods leading to blood contact 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 necessary, 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 simultaneous 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 other patient groups, including those with diabetes mellitus 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 diabetic end-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 treatment with a single RAAS-acting agent. Dual blockade (i.e., combination of an ACE inhibitor and an angiotensin II receptor antagonist) may be considered only in selected cases under strict monitoring of renal function, serum potassium levels, and blood pressure. Estramustine. There is a risk of increased incidence of adverse reactions such as angioedema. Potassium-sparing diuretics (e.g., triamterene, amiloride), potassium (salts). There is a 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 nevertheless indicated, these agents should be used with caution and with frequent monitoring of serum potassium levels. Information on the use of spironolactone in patients with heart failure is provided in the section "Concomitant use requiring special attention." Co-trimoxazole (trimethoprim/sulfamethoxazole). In patients receiving co-trimoxazole, there may be an increased risk of hyperkalemia.

Concomitant use requiring special attention. Antidiabetic agents (insulin, oral hypoglycemic agents). Epidemiological studies suggest that concomitant use of ACE inhibitors and antidiabetic medicinal products (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 before starting perindopril therapy, which should be initiated at a low dose with gradual dose escalation. In patients with arterial hypertension where prior diuretic therapy may have caused volume/sodium depletion, the diuretic should be discontinued before starting ACE inhibitor therapy (diuretic therapy may later be resumed), or ACE inhibitor therapy should be initiated at a low dose with gradual dose escalation. In patients with congestive heart failure receiving a diuretic, ACE inhibitor therapy should be initiated at the lowest dose, possibly after reducing the diuretic dose. In all cases, renal function (creatinine levels) should be monitored during the first few weeks of ACE inhibitor therapy. Potassium-sparing diuretics (eplerenone, spironolactone). When eplerenone or spironolactone (12.5–50 mg daily) is used concomitantly with low-dose ACE inhibitors in patients with NYHA class II–IV heart failure and ejection fraction <40% who have previously received ACE inhibitors and loop diuretics, there is a risk of potentially fatal hyperkalemia, especially if recommendations for use are not strictly followed. Before initiating such combination therapy, hyperkalemia and renal impairment should be excluded. Careful monitoring of serum potassium and creatinine is recommended 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 for the treatment of acute diarrhea). mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus). In patients receiving mTOR inhibitors concomitantly, there may be an increased risk of angioedema.

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, cytostatics, immunosuppressive agents, systemic corticosteroids, or procainamide. Concomitant use with ACE inhibitors may increase the risk of leukopenia. Anesthetic agents. ACE inhibitors may enhance the hypotensive effect of certain anesthetic agents. 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) activity by gliptins. Sympathomimetics. Sympathomimetics may attenuate the antihypertensive effect of ACE inhibitors. Gold preparations. Rarely, nitritoid reactions (facial flushing, nausea, vomiting, and arterial hypotension) have been reported in patients treated with injectable gold preparations (sodium aurothiomalate) and concomitant ACE inhibitor therapy, including perindopril.

Interactions related to indapamide

Concomitant use requiring special attention. Medicinal products that may provoke torsades de pointes-type paroxysmal ventricular tachycardia. Due to the risk of hypokalemia, indapamide should be used cautiously in combination with medicinal products that may provoke torsades de pointes-type paroxysmal ventricular tachycardia, 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, sulthiame, 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, glucocorticoids and mineralocorticoids (systemic), tetracosactide, stimulant laxatives increase the risk of reduced serum potassium levels (additive effect). Plasma potassium levels should be monitored and corrected if necessary, especially during concomitant treatment with cardiac glycosides. Laxatives that do not stimulate peristalsis should be used. Cardiac glycosides. Reduced plasma potassium levels may increase the toxic effects of cardiac glycosides. Plasma potassium levels and ECG should be monitored, and therapy reviewed 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 mellitus). Plasma potassium levels should be monitored, ECG monitoring performed, and therapy reviewed 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 levels exceed 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 when high doses of iodinated contrast agents are administered. Adequate hydration should be ensured before administration of iodinated contrast agents. Calcium (salts). There is a risk of increased plasma calcium levels due to reduced urinary excretion. Cyclosporine, tacrolimus. There is a risk of increased plasma creatinine levels without changes in circulating cyclosporine concentrations, even in the absence of volume or sodium depletion. Corticosteroids, tetracosactide (systemic). Reduce antihypertensive effect (water and sodium retention caused 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.

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 considered 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 no other risk factors. Perindopril should be used with extreme caution in patients with collagen vascular diseases, those receiving immunosuppressants, allopurinol, or procainamide, or in patients with a combination of these risk factors, especially if renal function is impaired. In some of these patients, severe infections, sometimes resistant to intensive antibiotic therapy, have been observed. In such patients, periodic monitoring of white blood cell counts is recommended, and patients should be informed to report any signs of infection (e.g., 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 deterioration may be associated with only minor changes in serum creatinine levels, even in patients with unilateral renal artery stenosis.

Hypersensitivity/angioedema. Rare cases of angioedema of the face, extremities, lips, tongue, glottis, and/or larynx have been reported in patients 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 initiated until symptoms resolve completely. When swelling is limited to the face and lips, symptoms usually resolve spontaneously, although antihistamines may help alleviate symptoms. Angioedema involving the larynx may be fatal. If swelling involves the tongue, glottis, or larynx, potentially leading to airway obstruction, emergency treatment is required, which may include subcutaneous administration of 1:1000 epinephrine solution (0.3–0.5 mL) and/or securing airway patency.

Angioedema has been reported to occur more frequently in patients of Black race receiving ACE inhibitors compared to other racial groups. Patients with a history of angioedema unrelated to ACE inhibitor use may have an 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); some cases of intestinal angioedema occurred without prior facial angioedema, and C-1 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 receiving ACE inhibitors who present with 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 Forte-Teva. Treatment with Perindopril/Indapamide Forte-Teva should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan. Concomitant use of ACE inhibitors with other neutral endopeptidase (NEP) inhibitors (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 is advised when initiating racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin in patients already receiving an ACE inhibitor.

Anaphylactoid reactions during desensitization therapy. Isolated cases of life-threatening, prolonged anaphylactoid reactions have been reported in patients receiving ACE inhibitors during desensitization therapy with insect venom products (bees, wasps). ACE inhibitors should be used cautiously in patients with allergies undergoing desensitization and avoided during immunotherapy with venom-containing products. 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 procedure.

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

Primary hyperaldosteronism. Patients with primary hyperaldosteronism generally do not respond to antihypertensive therapy acting via suppression of the renin-angiotensin system. Therefore, this medication 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 risk of symptomatic hypotension is greatest in patients with more severe heart failure, those receiving high doses of loop diuretics, those with hyponatremia, or those with functional renal impairment. Close medical supervision is required at the beginning of therapy and during dose titration to reduce the risk of symptomatic hypotension. Similar precautions apply to patients with ischemic heart disease or cerebrovascular disease, in whom excessive blood pressure reduction may precipitate myocardial infarction or stroke.

Ischemic heart disease. If an episode of unstable angina (of any severity) occurs within the first month of perindopril treatment, the benefit-risk ratio should be carefully evaluated before deciding on continuation of 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. Photosensitivity reactions have been reported in patients receiving thiazide and thiazide-like diuretics. If such reactions occur, diuretic therapy should be discontinued. If reinitiation of diuretic therapy is necessary, protection of exposed skin from sunlight or artificial ultraviolet sources is recommended.

Precautions

Precautions common to perindopril and indapamide

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

Arterial hypotension and fluid and electrolyte depletion. There is a risk of a sudden drop in blood pressure in patients with sodium depletion (especially those with renal artery stenosis). Therefore, regular monitoring for clinical signs of fluid and electrolyte depletion, which may occur during intercurrent episodes of vomiting or diarrhea, is necessary. In such patients, plasma electrolyte levels should be monitored regularly. In cases of severe arterial hypotension, intravenous administration of 0.9% sodium chloride solution may be required. Transient hypotension is not a contraindication for further use of the medication. 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, particularly in patients with diabetes mellitus or renal impairment. As with any diuretic-containing medication, 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 medication. If this symptom occurs, its iatrogenic origin should be considered. If ACE inhibitor therapy is necessary for the patient, continuation of treatment may be considered.

Risk of arterial hypotension and/or renal impairment (in the presence of heart failure, fluid and electrolyte depletion). Significant stimulation of the RAAS has been observed during acute fluid and electrolyte depletion (strict low-salt diet or prolonged diuretic therapy) in patients with low blood pressure, renal artery stenosis, congestive heart failure, or patients with cirrhosis and edema/ascites. Blocking this system with an ACE inhibitor may cause, particularly after the first dose and during the first two weeks of treatment, a marked drop in blood pressure and/or an increase in plasma creatinine levels, indicating 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 fluid or electrolyte depletion, the initial dose should be adjusted according to 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. Revascularization is the treatment for renovascular hypertension. However, ACE inhibitors may be beneficial for patients with renovascular hypertension awaiting surgery or when surgery is not feasible. If the medication 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 functional renal impairment, reversible upon discontinuation, has developed in some patients.

Heart failure/severe heart failure. Treatment of patients with severe heart failure (NYHA class IV) should be initiated under medical supervision with a reduced initial dose. Beta-blocker therapy in patients with hypertension and coronary insufficiency should not be discontinued: the ACE inhibitor should be added to beta-blocker therapy.

Patients with diabetes mellitus. Treatment of patients with insulin-dependent diabetes mellitus (with a spontaneous tendency to elevated serum potassium) should be initiated under medical supervision with a reduced initial dose. In diabetic patients receiving oral antidiabetic agents 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 Black race 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, particularly when anesthetics that lower blood pressure are used. Therefore, in patients receiving long-acting ACE inhibitors such as perindopril, the drug should be discontinued, if possible, one day before surgery.

Stenosis of aortic or mitral valves/hypertrophic cardiomyopathy. ACE inhibitors should be used with caution in patients with left ventricular outflow tract 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 receiving 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, or metabolic acidosis.

ACE inhibitors may cause hyperkalemia because they suppress aldosterone release. This effect is usually minor in patients with normal renal function. However, in patients with renal dysfunction and/or those taking potassium-containing dietary supplements (including salt substitutes), potassium-sparing diuretics (spironolactone, eplerenone, triamterene, or amiloride), other agents that increase serum potassium (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, immunosuppressants such as cyclosporine or tacrolimus), particularly aldosterone antagonists or angiotensin II 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 agents 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 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 be initially asymptomatic, so regular monitoring is necessary. Monitoring should be more frequent in elderly patients and those with liver cirrhosis.

Potassium levels. Decreased plasma potassium levels leading to hypokalemia are a major risk factor with thiazide and thiazide-like diuretics. The risk of hypokalemia (<3.4 mmol/L) should be anticipated in certain high-risk patient groups (elderly patients and/or those with poor nutrition, regardless of concomitant medications, patients with cirrhosis and edema/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 these 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 necessary.

Calcium levels. Thiazide and thiazide-like diuretics may reduce urinary calcium excretion and cause 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 diabetic patients, especially when potassium levels are low.

Uric acid. In patients with elevated blood 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 (blood creatinine <25 mg/L, i.e., 220 µmol/L in adults).

In elderly patients, plasma creatinine levels should be evaluated 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 level 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 fluid and sodium loss due to diuretic use at the beginning of treatment may lead to decreased glomerular filtration. 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 to weeks after starting the medication. Untreated acute angle-closure glaucoma may lead to irreversible vision loss. Initial treatment includes immediate discontinuation of the medication. If intraocular pressure remains uncontrolled, prompt medical or surgical intervention may be necessary. Risk factors for acute angle-closure glaucoma may include a history of allergy to sulfonamides or penicillin.

Athletes. This medication contains an active substance that may cause a positive result in doping controls in athletes.

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

Use during pregnancy or breastfeeding.

Pregnancy. The use of this medication is contraindicated in pregnant women or women planning pregnancy. Warnings related to perindopril. There are no convincing epidemiological data on teratogenic risk with ACE inhibitors during the first trimester of pregnancy; however, a small increase in 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 medication approved for use in pregnancy. It is known that ACE inhibitor use during the second and third trimesters of pregnancy has toxic effects on the fetus (impaired renal function, oligohydramnios, delayed ossification of the fetal skull) and on the newborn (renal failure, arterial hypotension, hyperkalemia). If ACE inhibitors were used during the second and third trimesters of pregnancy, ultrasound evaluation of fetal renal function and skull development 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 pregnant woman's circulating blood volume and uteroplacental perfusion, potentially leading to fetoplacental ischemia and delayed fetal development. Animal studies have not shown direct or indirect toxic effects on reproductive function. As a precautionary measure, indapamide use during pregnancy should be avoided.

Breastfeeding. The medication is contraindicated during breastfeeding. A decision should be made whether to discontinue breastfeeding or to discontinue the medication, taking into account the importance of the 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 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. No effect on human fertility is 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, particularly at the beginning of treatment or when the medication is used in combination with other antihypertensive agents, individual reactions related to low blood pressure may occur. This may impair the ability to drive vehicles or operate machinery.

Method of Administration and Dosage

The medication is intended for oral use. Tablets may be divided into two equal doses.

Perindopril/Indapamide Forte-Teva 5 mg/1.25 mg tablets. Administer 1 tablet once daily to adults, preferably in the morning before a meal. Individual dose adjustment of components may be recommended. Perindopril/Indapamide Forte-Teva 5 mg/1.25 mg tablets should be prescribed when blood pressure is not adequately controlled with Perindopril/Indapamide-Teva 2.5 mg/0.625 mg tablets. If clinically appropriate, direct transition from monotherapy to Perindopril/Indapamide Forte-Teva 5 mg/1.25 mg tablets may be considered.

Elderly patients. Treatment should be prescribed considering blood pressure levels and renal function status.

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), treatment should be initiated with appropriate doses of the individual components of the medication. 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 severe hepatic impairment. Dose adjustment is not required for patients with moderate hepatic impairment.

Children.

Perindopril/Indapamide Forte-Teva should not be used for 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, drowsiness, confusion, oliguria which may progress to anuria (due to hypovolemia), and circulatory shock. Electrolyte and fluid imbalances (decreased plasma potassium and sodium levels), renal failure, hyperventilation, tachycardia, palpitations, bradycardia, anxiety, cough, etc., 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 other measures to restore blood volume should be performed. Perindoprilat—the active metabolite of perindopril—can 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 4% of patients treated with this medication. The most commonly reported adverse reactions are: with perindopril – dizziness, headache, paresthesia, dysgeusia, visual disturbances, vertigo, tinnitus, arterial hypotension, cough, dyspnea, abdominal pain, constipation, dyspepsia, diarrhea, nausea, vomiting, pruritus, rash, muscle cramps, and asthenia; with indapamide – 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 (SIADH) (rare – perindopril).

Metalbolic and nutritional 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); paresthesia (common – perindopril, rare – indapamide); dysgeusia (common – perindopril); somnolence (uncommon* – perindopril); loss of consciousness (uncommon* – perindopril, frequency not known – indapamide); stroke due to excessive arterial hypotension in high-risk patients (very rare – perindopril); hepatic encephalopathy may occur in patients with 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 due to excessive arterial hypotension in high-risk patients (very rare – perindopril); paroxysmal ventricular tachycardia of the "torsades de pointes" type (potentially fatal) (frequency not known – indapamide).

Vascular disorders: arterial hypotension (and symptoms related to 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 acute systemic lupus erythematosus (frequency not known – indapamide); arthralgia (uncommon* – perindopril); myalgia (uncommon* – perindopril).

Renal and urinary disorders: renal failure (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 (very rare – perindopril); increased blood glucose (frequency not known – indapamide); increased blood uric acid (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 drug efficacy should be reported at: 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 temperature storage conditions. Keep out of reach of children.

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

Prescription status. Prescription only.

Manufacturer. Teva Pharmaceutical Works Private Limited Company.

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