Corderya mono

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Corderia MONO (Corderia MONO)

Composition:

Active substance: perindopril;

1 tablet contains 4 mg of perindopril tert-butylamine, equivalent to 3.338 mg of perindopril

or 8 mg of perindopril tert-butylamine, equivalent to 6.676 mg of perindopril;

Excipients: lactose monohydrate; microcrystalline cellulose; colloidal anhydrous silicon dioxide; magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical characteristics: round, biconvex tablets, white to almost white in color.

Pharmacotherapeutic group. Cardiovascular system agents.

Angiotensin-converting enzyme (ACE) inhibitors, single-component preparations.

Perindopril. ATC code C09A A04.

Pharmacological Properties.

Pharmacodynamics.

Perindopril is an inhibitor of the enzyme converting angiotensin I to angiotensin II (angiotensin-converting enzyme, ACE). The converting enzyme, or kininase, is an exopeptidase that enables the conversion of angiotensin I into the vasoconstrictor angiotensin II, and also causes the breakdown of the vasodilator bradykinin into an inactive heptapeptide. Inhibition of ACE leads to a reduction in angiotensin II concentration in plasma, which increases plasma renin activity (due to suppression of negative feedback on renin release) and reduces aldosterone secretion. Since ACE inactivates bradykinin, ACE inhibition also leads to increased activity of circulating and local kallikrein-kinin systems (and thus also leads to activation of the prostaglandin system). This mechanism of action underlies the blood pressure-lowering effect of ACE inhibitors and partially accounts for the occurrence of certain adverse effects (e.g., cough).

Perindopril tert-butylamine acts via its active metabolite—perindoprilat. Other metabolites do not demonstrate activity in inhibiting ACE under experimental conditions.

Arterial Hypertension.

Perindopril effectively reduces arterial blood pressure in all stages of arterial hypertension: mild, moderate, and severe. Reduction of systolic and diastolic blood pressure is observed both in the supine and standing positions.

Perindopril reduces peripheral vascular resistance, leading to a decrease in arterial blood pressure. As a result, peripheral blood flow increases without affecting heart rate.

Renal blood flow usually increases, while glomerular filtration rate (GFR) typically remains unchanged.

The maximum antihypertensive effect develops within 4–6 hours after a single dose and lasts at least 24 hours: the T/R ratio (trough-to-peak—minimum/maximum effectiveness over 24 hours) of perindopril ranges from 87% to 100%.

Arterial blood pressure decreases rapidly. In patients who respond to treatment, normalization of blood pressure occurs within one month and is maintained without the development of tachyphylaxis.

Upon discontinuation of perindopril, no rebound effect occurs.

Perindopril reduces left ventricular hypertrophy.

Clinical studies have demonstrated that perindopril has vasodilatory properties. It improves the elasticity of large arteries and reduces the wall-to-lumen ratio in small arteries.

Additional therapy with a thiazide diuretic has a synergistic effect. The combination of an ACE inhibitor and a thiazide diuretic also reduces the risk of diuretic-induced hypokalemia.

Heart Failure.

Perindopril tert-butylamine reduces cardiac workload by decreasing preload and afterload.

Studies involving patients with heart failure have demonstrated:

• reduction in filling pressure of the right and left ventricles;
• reduction in systemic peripheral resistance;
• increase in cardiac index and improvement in cardiac output.

In comparative studies, initial administration of 2 mg perindopril to patients with mild to moderate heart failure was not associated with any significant reduction in blood pressure compared to placebo.

Patients with a History of Cerebrovascular Disease.

The multicenter, international, double-blind, randomized, placebo-controlled PROGRESS study established the benefits of 4-year treatment with perindopril (as monotherapy or in combination with indapamide) in preventing recurrent stroke in patients with a history of cerebrovascular disease.

The primary endpoint was stroke.

After a 2-week (run-in) period of taking perindopril tert-butylamine 2 mg once daily, followed by 2 weeks of 4 mg once daily, 6105 patients were randomized into two groups: one group received placebo (n=3054), and the other received perindopril tert-butylamine 4 mg as monotherapy or in combination with indapamide (n=3051). Indapamide was added to patients who had indications for diuretic therapy and no contraindications to its use.

This therapy was administered in addition to standard treatment for stroke and/or arterial hypertension or any other pathological conditions.

All patients included in the study had a history of cerebrovascular disease (stroke or transient ischemic attack) within the past 5 years. Blood pressure was not a criterion for inclusion in the study: 2916 patients had arterial hypertension, and 3189 had normal blood pressure.

After a mean follow-up of 3.9 years, systolic/diastolic blood pressure decreased on average by 9.0/4.0 mm Hg, and the risk of recurrent stroke (both ischemic and hemorrhagic) was significantly reduced by 28% (95% CI [17;38], p<0.0001) compared to placebo recipients (10.1% vs. 13.8%).

Significant reductions were also observed in the risk of:

• fatal or disabling stroke (4% vs. 5.9%, corresponding to a 33% risk reduction);
• total major cardiovascular events, defined as cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (15% vs. 19.8%, corresponding to a 26% risk reduction);
• post-stroke dementia (1.4% vs. 2.1%, corresponding to a 34% risk reduction), and severe post-stroke cognitive impairment (1.6% vs. 2.8%, corresponding to a 45% risk reduction);
• major coronary events, including non-fatal myocardial infarction or fatal outcome due to ischemic heart disease (3.8% vs. 5%, corresponding to a 26% risk reduction).

These therapeutic benefits were observed in patients regardless of the presence or absence of arterial hypertension, age, sex, stroke type, or diabetes. Results of the PROGRESS study showed that after 5 years of treatment, one stroke could be prevented per 23 patients treated, and one major cardiovascular complication per 18 patients.

Patients with Stable Ischemic Heart Disease (IHD).

EUROPA is a 4-year, international, multicenter, randomized, double-blind, placebo-controlled clinical trial. A total of 12,218 patients aged 18 years and older were randomized: 6,110 patients received 8 mg of perindopril tert-butylamine, and 6,108 received placebo. The study included patients with confirmed ischemic heart disease and without clinical symptoms of heart failure. Overall, 90% of patients had a history of myocardial infarction and/or revascularization surgery. Most patients in the study received perindopril in addition to standard therapy: antiplatelet agents, lipid-lowering agents, and β-blockers.

The primary efficacy endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, and/or cardiac arrest with successful resuscitation. Treatment with perindopril 8 mg once daily resulted in a significant absolute reduction of the primary endpoint by 1.9% (relative risk reduction of 20%, 95% CI [9.4; 28.6], p<0.001).

In patients with a history of myocardial infarction and/or revascularization, an absolute reduction of 2.2% in the primary endpoint was observed, corresponding to a 22.4% relative risk reduction (95% CI [12.0; 31.6], p<0.001) compared to placebo.

Use in Children.

The safety and efficacy of perindopril in children and adolescents under 18 years of age have not been established.

In an open-label, non-comparative clinical study, 62 children aged 2 to 15 years with a glomerular filtration rate >30 mL/min/1.73 m² were administered perindopril at a mean dose of 0.07 mg/kg. The dose was individually adjusted, increasing up to a maximum of 0.135 mg/kg/day depending on patient profile and blood pressure response. Fifty-nine patients participated in the study for 3 months, and 36 continued treatment for at least 24 months (mean study duration: 44 months). Systolic and diastolic blood pressure remained stable (from study entry to last visit) in patients previously treated with other antihypertensive agents and decreased in those previously untreated. More than 75% of children had systolic and diastolic blood pressure below the 95th percentile at their last study visit. The safety profile in children was consistent with the known safety profile of perindopril.

Pharmacokinetics.

Absorption.

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. 27% of the administered perindopril is detected in blood as the active metabolite—perindoprilat. In addition to the active metabolite perindoprilat, the drug forms five inactive metabolites. Peak plasma concentration of perindoprilat is reached 3–4 hours after administration.

Food intake reduces the conversion of perindopril to perindoprilat, thereby decreasing its bioavailability. Therefore, the daily dose of perindopril tert-butylamine should be taken once daily in the morning before a meal.

A linear relationship exists between perindopril dose and its plasma concentration.

Distribution.

The volume of distribution of unbound perindoprilat is approximately 0.2 L/kg. Protein binding of perindoprilat to plasma proteins is 20%, primarily to angiotensin-converting enzyme, but this value is dose-dependent.

Elimination.

Perindoprilat is excreted in urine. The terminal elimination half-life of the unbound fraction is approximately 17 hours. Steady-state plasma concentration is achieved within 4 days of starting treatment.

Special Patient Groups.

Elimination of perindoprilat is slowed in elderly patients and in patients with heart or kidney failure. Dose adjustment is recommended for patients with renal impairment, based on the degree of impairment (creatinine clearance).

Dialysis clearance of perindoprilat is 70 mL/min.

Perindopril kinetics are altered in patients with liver cirrhosis: hepatic clearance of perindopril is halved. However, the amount of perindoprilat formed is not reduced. Therefore, dose adjustment is not required in these patients.

Clinical characteristics.

Indications.

• Arterial hypertension.
• Heart failure.
• Prevention of recurrent stroke in patients with cerebrovascular disease.
• Prevention of cardiovascular complications in patients with documented stable ischaemic heart disease.

Long-term treatment reduces the risk of myocardial infarction and heart failure (based on the EUROPA study results).

Contraindications.

• Hypersensitivity to perindopril or to any of the excipients, or to any other ACE inhibitor;
• history of angioedema associated with previous treatment with an ACE inhibitor (see section "Special precautions for use");
• idiopathic or hereditary angioedema;
• concomitant use with medicinal products containing aliskiren in patients with diabetes mellitus, or with impaired renal function (glomerular filtration rate < 60 ml/min/1.73 m²) (see section "Interaction with other medicinal products and other forms of interaction");
• pregnancy or women planning to become pregnant (see section "Use during pregnancy or breast-feeding");
• concomitant use with sacubitril/valsartan. Initiation of Coradia Mono must not be started earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction");
• extracorporeal treatment methods leading to blood contact with negatively charged surfaces (see section "Interaction with other medicinal products and other forms of interaction");
• significant bilateral renal artery stenosis or stenosis of the artery of a solitary functioning kidney (see section "Special precautions for use").

Interaction with other medicinal products and other forms of interaction.

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

Medicinal products increasing the risk of angioedema

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema (see section "Contraindications", "Special precautions for use"). Initiation of sacubitril/valsartan should not occur earlier than 36 hours after the last dose of perindopril. Perindopril therapy should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Special precautions for use").

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

Medicinal products causing hyperkalaemia.

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

Concomitant use is contraindicated (see section "Contraindications").

Aliskiren: in patients with diabetes mellitus or impaired renal function, the risk of hyperkalaemia, worsening renal function, cardiovascular morbidity, and mortality is increased.

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

Concomitant use is not recommended (see section "Special precautions for use").

Aliskiren: in any other patients, including those with diabetes mellitus or impaired renal function, the risk of hyperkalaemia, worsening renal function, cardiovascular morbidity, and mortality is increased.

Concomitant use of an ACE inhibitor and an angiotensin receptor blocker

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

Estrogenic agents: increased risk of adverse reactions such as angioedema.

Potassium-sparing diuretics (e.g. triamterene, amiloride, etc.), potassium salts: risk of hyperkalaemia (potentially fatal), particularly in patients with impaired renal function (additive hyperkalaemic effect). These agents are not recommended for concomitant use with perindopril (see section "Special precautions for use"). However, if concomitant use is necessary, it should be done with caution and frequent monitoring of serum potassium. For use of spironolactone in heart failure, see section “Concomitant use requiring special attention”.

Lithium. Increased serum lithium concentrations and lithium toxicity have been reported during concomitant use of ACE inhibitors with lithium-containing agents. Concomitant use of perindopril with lithium is not recommended. If such combination is necessary, serum lithium levels must be closely monitored (see section "Special precautions for use").

Concomitant use requiring special attention.

Antidiabetic agents (insulin, oral hypoglycaemic agents).

Epidemiological data suggest that concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycaemic agents) may enhance the blood glucose-lowering effect, increasing the risk of hypoglycaemia. This phenomenon is more likely to occur during the first weeks of combination therapy and in patients with renal impairment.

Baclofen potentiates the antihypertensive effect. Blood pressure should be monitored and, if necessary, the dose of antihypertensive agent adjusted.

Diuretics. In patients receiving diuretics, especially those with disturbed water-electrolyte balance, excessive reduction in blood pressure may occur after initiation of ACE inhibitor therapy. The risk of hypotensive effects may be reduced by discontinuing the diuretic, increasing circulating blood volume, or salt intake prior to starting perindopril therapy, which should begin with a low dose and be gradually increased. In arterial hypertension, if a previously prescribed diuretic may have caused water/electrolyte deficiency, it should be discontinued before starting ACE inhibitor therapy (diuretic therapy may be resumed later) or the ACE inhibitor should be initiated at a low dose with gradual dose escalation. In congestive heart failure on diuretic therapy, ACE inhibitor therapy should be initiated at the lowest dose, possibly after reducing the diuretic dose. In all cases, renal function (creatinine levels) should be monitored during the first weeks of ACE inhibitor therapy.

Potassium-sparing diuretics (eplerenone, spironolactone). When eplerenone or spironolactone (12.5 mg to 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 hyperkalaemia (potentially fatal), especially if recommendations for use of this combination are not followed. Before initiating such combination therapy, absence of hyperkalaemia and impaired renal function should be confirmed. Close monitoring of serum potassium and creatinine is recommended weekly during the first month and monthly thereafter.

Non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid ≥ 3 g/day. The antihypertensive effect may be attenuated when ACE inhibitors are used concomitantly with NSAIDs such as acetylsalicylic acid at anti-inflammatory doses, COX-2 inhibitors, or non-selective NSAIDs. Concomitant use of ACE inhibitors and NSAIDs may increase the risk of worsening renal function, including acute renal failure, and elevated serum potassium, particularly in patients with a history of renal impairment. Such combinations should be used cautiously, especially in elderly patients. Patients should be adequately hydrated, and renal function should be monitored after initiation and during continued combination therapy.

Concomitant use requiring attention.

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

Concomitant use of certain tricyclic antidepressants or antipsychotics, or anaesthetics with ACE inhibitors may lead to further reduction in blood pressure (see section "Special precautions for use").

Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.

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

Special precautions for use.

Stable ischemic heart disease. If an episode of unstable angina (of any severity) occurred during the first month of perindopril treatment, the risk/benefit ratio should be carefully evaluated before deciding on continuing therapy.

Arterial hypotension. Administration of ACE inhibitors may cause a reduction in blood pressure. Symptomatic arterial hypotension is less common in patients with uncomplicated arterial hypertension and is more likely to occur in patients with hypovolemia, those receiving diuretics, those on a low-salt diet, patients undergoing dialysis, patients with diarrhea or vomiting, or patients with severe renin-dependent arterial hypertension (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions"). Symptomatic arterial hypotension has been observed 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 degrees of heart failure who are receiving high doses of loop diuretics, have hyponatremia, or have functional renal impairment. Patients at increased risk of symptomatic arterial hypotension should be closely monitored by a physician during initiation of therapy and dose titration (see sections "Dosage and administration" and "Adverse reactions"). The same precautions apply to patients with ischemic heart disease or cerebrovascular disorders, in whom excessive reduction in blood pressure may lead to myocardial infarction or stroke.

In case of arterial hypotension, the patient should be placed in a supine position and, if necessary, receive an intravenous infusion of 0.9% (9 mg/mL) sodium chloride solution. Transient hypotension is not a contraindication for further use of the drug, which can usually be continued without difficulty after restoration of blood volume and blood pressure elevation.

In some patients with congestive heart failure and normal or low blood pressure, perindopril tert-butylamine may cause additional reduction in systemic arterial pressure. This effect is expected and usually does not require discontinuation of the drug. If hypotension becomes symptomatic, dose reduction or discontinuation of the drug may be necessary.

Stenosis of the aortic and mitral valves/hypertrophic cardiomyopathy. As with other ACE inhibitors, perindopril tert-butylamine should be administered with caution to patients with mitral valve stenosis or left ventricular outflow tract obstruction (aortic stenosis or hypertrophic cardiomyopathy).

Renal function impairment.

In case of renal impairment (creatinine clearance < 60 mL/min), the initial dose of perindopril should be adjusted according to the patient's creatinine clearance (see section "Dosage and administration"), and subsequently based on the patient's response to treatment. Regular monitoring of potassium and creatinine levels is part of standard medical practice for such patients (see section "Adverse reactions").

In patients with symptomatic heart failure, arterial hypotension occurring at the beginning of ACE inhibitor therapy may lead to deterioration of renal function, in some cases resulting in acute renal failure, which is usually reversible.

In some patients with bilateral renal artery stenosis or stenosis of the artery of a solitary kidney, treatment with ACE inhibitors has been associated with increases in blood urea nitrogen and serum creatinine levels, which usually return to normal after discontinuation of treatment. This is particularly relevant for patients with pre-existing renal impairment. In patients with concomitant renovascular hypertension, the risk of severe arterial hypotension and renal failure is increased. For such patients, treatment should be initiated under close medical supervision with low doses and cautious dose titration. In view of the above, diuretic therapy may predispose to arterial hypotension; therefore, diuretics should be discontinued and renal function should be monitored during the first weeks of treatment with perindopril tert-butylamine.

In some patients with arterial hypertension, in whom no renovascular disease was detected before treatment initiation, increases in blood urea and serum creatinine have occurred, usually mild and transient, especially when perindopril tert-butylamine was administered concomitantly with a diuretic. However, this is more typical for patients with pre-existing renal impairment. Dose reduction and/or discontinuation of the diuretic and/or perindopril tert-butylamine may become necessary.

Patients undergoing hemodialysis. Cases of anaphylactoid reactions have been reported in patients receiving ACE inhibitors during hemodialysis with high-flux membranes. Such patients should use a different type of dialysis membrane or be prescribed another class of antihypertensive agents.

Patients after kidney transplantation. There is no experience regarding the use of perindopril tert-butylamine in patients after recent kidney transplantation surgery.

Renovascular hypertension.

When ACE inhibitors are prescribed to patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney, the risk of hypotension and renal failure increases (see section "Contraindications"). Concomitant diuretic therapy may be a contributing factor. Loss of kidney function may manifest as minimal changes in serum creatinine levels even in patients with stenosis of the artery of one kidney.

Hypersensitivity/angioedema.

Rare cases of angioedema of the face, extremities, lips, mucous membranes, tongue, glottis, and/or larynx have been reported in patients receiving ACE inhibitors, including perindopril tert-butylamine (see section "Adverse reactions"). This may occur at any time during treatment. In such cases, the drug must be discontinued immediately and appropriate monitoring of the patient should be maintained until symptoms completely resolve. In isolated cases where swelling is limited to the face and lips, the patient's condition usually improves without treatment. Administration of antihistamines may be helpful in relieving symptoms.

Angioedema involving laryngeal swelling may be fatal. In cases where swelling involves the tongue, glottis, or larynx, causing airway obstruction, emergency treatment is required, which may include administration of adrenaline and/or securing airway patency. The patient should remain under close medical supervision until symptoms have completely resolved and the condition is stabilized. Patients with a history of angioedema unrelated to ACE inhibitor use belong to a high-risk group for developing angioedema during ACE inhibitor therapy (see section "Contraindications").

Rare cases of intestinal angioedema have been reported in patients receiving ACE inhibitors. These patients experienced abdominal pain (with or without nausea or vomiting); in some cases, prior facial angioedema was not observed and C1 esterase levels were normal. The diagnosis of intestinal angioedema was established by abdominal computed tomography or ultrasound, or during surgical intervention. Symptoms of angioedema resolved after discontinuation of the ACE inhibitor. Intestinal angioedema should be considered in the differential diagnosis of patients presenting with abdominal pain while receiving ACE inhibitors.

Concomitant use of perindopril with sacubitril/valsartan is contraindicated due to increased risk of angioedema (see section "Contraindications"). Initiation of sacubitril/valsartan should not begin earlier than 36 hours after the last dose of perindopril. In case of discontinuation of sacubitril/valsartan therapy, perindopril treatment should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Concomitant use of ACE inhibitors with neutral endopeptidase inhibitors (NEP) (e.g., racecadotril), mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) may increase the risk of angioedema (e.g., airway or tongue swelling, with or without respiratory impairment) (see section "Interaction with other medicinal products and other forms of interaction"). Caution should be exercised when initiating treatment with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) in patients already receiving ACE inhibitors.

Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis. Rarely, life-threatening anaphylactoid reactions have occurred in patients receiving ACE inhibitors during LDL apheresis using dextran sulfate. Anaphylactoid reactions can be avoided by temporarily discontinuing ACE inhibitor therapy before each apheresis procedure.

Anaphylactoid reactions during desensitization therapy. Patients receiving ACE inhibitors during desensitization therapy (e.g., with bee venom preparations) may experience life-threatening anaphylactoid reactions. These reactions can be avoided by temporarily discontinuing ACE inhibitors, but may reoccur if provocation tests are performed carelessly.

Hepatic impairment. Rarely, use of ACE inhibitors has 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 or elevated liver enzymes while taking ACE inhibitors should discontinue the ACE inhibitor and receive appropriate medical evaluation and treatment (see section "Adverse reactions").

Neutropenia/agranulocytosis, thrombocytopenia, and anemia.

Cases of neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported among patients receiving ACE inhibitors. In patients with normal renal function and no other risk factors, neutropenia is rare. Perindopril should be used with extreme caution in patients with collagen diseases, those receiving immunosuppressants, allopurinol, or procainamide, or in combination with these risk factors, especially if renal function is impaired. Some of these patients developed severe infectious diseases, which in several cases did not respond to intensive antibiotic therapy. In patients receiving perindopril, periodic monitoring of white blood cell count is recommended. Patients should also be informed that they must report any signs of infection (sore throat, fever).

Racial characteristics. ACE inhibitors cause angioedema more frequently in black patients than in non-black patients. Perindopril, like other ACE inhibitors, is less effective in lowering blood pressure in black patients compared to individuals of other races. This may be explained by the low plasma renin levels in hypertensive patients in this population.

Cough. Cough has been reported during therapy with ACE inhibitors. The cough is typically non-productive, persistent, and resolves after discontinuation of the drug. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.

During surgical procedures or administration of anesthetics causing hypotension, perindopril may block the secondary formation of angiotensin II in response to compensatory renin release. The drug should be discontinued one day before surgery. If hypotension develops and is considered to be due to this mechanism, the patient's condition can be normalized by increasing circulating blood volume.

Hyperkalemia. In some patients receiving ACE inhibitors, including perindopril, increased serum potassium levels have been observed. ACE inhibitors may cause hyperkalemia because they suppress aldosterone release. In patients with normal renal function, this effect is usually mild. Risk factors for hyperkalemia include renal impairment, worsening renal function, age (≥70 years), diabetes mellitus, intercurrent conditions such as dehydration, acute heart decompensation, metabolic acidosis, and concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium-containing dietary supplements, potassium-containing salt substitutes, or other drugs that increase serum potassium concentration (e.g., heparin, co-trimoxazole, also known as trimethoprim/sulfamethoxazole), and especially aldosterone antagonists or angiotensin receptor blockers. Use of potassium-containing dietary supplements, potassium-sparing diuretics, or potassium-containing salt substitutes, particularly in patients with impaired renal function, may lead to significant increases in serum potassium levels. Hyperkalemia may lead to serious, sometimes fatal, arrhythmias. Patients receiving ACE inhibitors should be prescribed potassium-sparing diuretics and angiotensin receptor blockers cautiously, and serum potassium levels and renal function should be closely monitored. If concomitant use of perindopril and any of the above-mentioned substances is considered appropriate, they should be used with caution and with frequent monitoring of serum potassium levels (see section "Interaction with other medicinal products and other forms of interaction").

Patients with diabetes mellitus receiving oral antidiabetic agents or insulin should have their blood glucose levels closely monitored during the first month of ACE inhibitor therapy (see section "Interaction with other medicinal products and other forms of interaction").

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

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

Dual blockade of the renin-angiotensin-aldosterone system (RAAS). Data indicate that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of hypotension, hyperkalemia, and renal function impairment (including acute renal failure). Therefore, dual blockade of the RAAS by concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see section "Interaction with other medicinal products and other forms of interaction"). If treatment with two RAAS blockers is considered absolutely necessary, it should be performed only under specialist supervision and with frequent careful monitoring of renal function, electrolyte levels, and blood pressure. ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

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.

Excipients.

The medicinal product contains lactose; therefore, patients with rare hereditary intolerance to galactose, glucose-galactose malabsorption syndrome, or Lapp lactase deficiency should not take the medicinal product Corderia Mono.

Use during pregnancy or breastfeeding.

Pregnancy

The medicinal product is contraindicated in pregnant women or women planning to become pregnant. If pregnancy is confirmed during treatment with this medicinal product, its use must be immediately discontinued and replaced with another medicinal product permitted for use during pregnancy.

If a woman has taken an ACE inhibitor during the second trimester of pregnancy, ultrasound examination of fetal kidney function and skull bones is recommended for the child. Newborns whose mothers received ACE inhibitors during pregnancy should be closely monitored due to the possibility of developing arterial hypotension.

Breastfeeding

Use of perindopril tert-butylamine during breastfeeding is not recommended due to lack of data on its passage into breast milk. During breastfeeding, it is preferable to prescribe alternative treatment with a better-investigated safety profile, especially when feeding a newborn or premature infant.

Fertility

No effect on reproductive capacity or fertility has been observed.

Ability to affect reaction speed when driving vehicles or operating machinery.

Perindopril tert-butylamine does not directly affect the ability to drive vehicles or operate machinery. However, some patients may experience individual reactions related to reduced blood pressure, especially at the beginning of treatment or when used concomitantly with other antihypertensive drugs. As a result, the ability to drive vehicles or operate machinery may be impaired.

Dosage and Administration.

For oral use. The tablets must not be divided.

The tablets are recommended to be taken once daily in the morning before meals.

The dosage should be individually adjusted according to the patient's profile, blood pressure levels, and response to treatment (see section "Special Precautions for Use").

Arterial Hypertension.

Perindopril tert-butylamine may be prescribed as monotherapy or in combination with antihypertensive agents of other classes.

The recommended initial dose is 4 mg once daily in the morning.

Patients with high activity of the renin-angiotensin-aldosterone system (particularly those with renovascular hypertension, fluid and electrolyte imbalance, cardiac decompensation, or severe hypertension) may experience excessive reduction in arterial blood pressure after the first dose. Such patients should start treatment with a dose of 2 mg (use another medicinal product with corresponding dosage strength) and therapy initiation should be under medical supervision.

The dose may be increased to 8 mg once daily after 1 month of treatment.

Symptomatic arterial hypotension may occur at the beginning of perindopril tert-butylamine therapy; this is more likely in patients concurrently taking diuretics. Such patients should start perindopril therapy with caution, as they may have volume and/or salt depletion.

If possible, diuretic therapy should be discontinued 2–3 days before starting treatment with perindopril tert-butylamine (see section "Special Precautions for Use").

For patients with arterial hypertension in whom discontinuation of diuretics is not feasible, treatment should be initiated at a dose of 2 mg (use another medicinal product with corresponding dosage strength). In such patients, renal function and serum potassium levels should be monitored. Further dose escalation of perindopril tert-butylamine should be based on blood pressure response. If necessary, diuretic therapy may be resumed.

Elderly patients should start treatment with a dose of 2 mg (use another medicinal product with corresponding dosage strength), which may be increased to 4 mg after 1 month of treatment, and subsequently, if necessary, to 8 mg, taking into account renal function (see table below).

Symptomatic Heart Failure.

In patients with heart failure, perindopril tert-butylamine is usually prescribed concomitantly with a potassium-excreting diuretic and/or digoxin and/or a β-blocker. Therapy should be initiated under close medical supervision with an initial dose of 2 mg (use another medicinal product with corresponding dosage strength), taken in the morning. After 2 weeks, if well tolerated, the dose should be increased to 4 mg once daily. Thereafter, the dose should be individually adjusted according to the patient's clinical response to treatment.

Patients with severe heart failure and other high-risk patients (those with impaired renal function and tendency to electrolyte disturbances, or those receiving concomitant therapy with diuretics and/or vasodilators) should start treatment under close medical supervision (see section "Special Precautions for Use").

In patients at high risk of symptomatic arterial hypotension—namely those with electrolyte depletion with or without hyponatremia, hypovolemia, or those who have received intensive diuretic therapy—these conditions should be corrected, if possible, prior to initiating treatment. Blood pressure, renal function, and serum potassium levels must be closely monitored both before and during treatment (see section "Special Precautions for Use").

Prevention of Recurrent Stroke in Patients with Cerebrovascular Disease.

The recommended initial dose is 2 mg (use another medicinal product with corresponding dosage strength) once daily in the morning. After 2 weeks of treatment, the dose should be increased to 4 mg once daily in the morning.

If additional blood pressure control is required after 2 weeks of treatment with Corderia Mono, indapamide may be added at a dose of 1 tablet daily. Treatment may be initiated at any time from 2 weeks to several years after the initial stroke.

Prevention of Cardiovascular Complications in Patients with Documented Stable Ischemic Heart Disease.

Long-term treatment with perindopril 8 mg (1 tablet daily) reduces the risk of myocardial infarction and heart failure (based on results from the 4-year EUROPA study).

Treatment should be initiated at a dose of 4 mg (1 tablet daily in the morning). After 2 weeks, if well tolerated, the dose should be increased to 8 mg for long-term use of Corderia Mono 8 mg tablets (1 tablet daily in the morning).

In elderly patients with documented ischemic heart disease, treatment should be initiated at a dose of 2 mg (use another medicinal product with corresponding dosage strength) once daily in the morning; after one week, the dose should be increased to 4 mg; after 2 weeks, if well tolerated and depending on renal function, the dose should be increased to 8 mg (1 tablet daily) to begin long-term treatment.

Dose Adjustment in Renal Impairment.

Dosing in patients with renal impairment should be based on creatinine clearance, as indicated in the table below:

Table – Dose Adjustment in Renal Impairment

Creatinine clearance (ml/min)	Recommended dosage
ClCR ≥ 60	4 mg once daily
30 < ClCR < 60	2 mg (use alternative medicinal product at appropriate dosage) once daily
15 < ClCR < 30	2 mg (use alternative medicinal product at appropriate dosage) every other day
Patients undergoing hemodialysis
ClCR < 15	2 mg (use alternative medicinal product at appropriate dosage) on dialysis days

٭Dialysis clearance of perindoprilat is 70 mL/min.

In patients undergoing hemodialysis, the dose should be administered after hemodialysis.

Dose adjustment in hepatic impairment.

Dose adjustment is not required in patients with hepatic impairment (see sections "Special precautions for use" and "Pharmacokinetics").

Children.

The efficacy and safety of use in children under 18 years of age have not been established. Available information is provided in the section "Pharmacodynamics", but dosage recommendations cannot be given. Therefore, perindopril tert-butylamine is not recommended for use in children.

Overdose.

Information on perindopril overdose is limited. Symptoms associated with ACE inhibitor overdose may include: arterial hypotension, circulatory shock, electrolyte imbalance, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, cough, etc.

In case of overdose, intravenous administration of 0.9% sodium chloride solution (9 mg/mL) is recommended. If arterial hypotension occurs, the patient should be placed in a supine position with low head elevation. Infusion of angiotensin II and/or intravenous administration of catecholamines should be considered if available. Perindopril can be removed from systemic circulation by hemodialysis (see section "Special precautions for use"). In case of treatment-resistant bradycardia, a pacemaker should be used. Continuous monitoring of vital signs, serum electrolyte concentrations, and creatinine levels is required.

Adverse reactions.

The safety profile of perindopril is consistent with the safety profile of ACE inhibitors. The most commonly reported adverse reactions during clinical trials with perindopril include: dizziness, headache, paraesthesia, vertigo, visual disturbances, tinnitus, hypotension, cough, dyspnoea, abdominal pain, constipation, diarrhoea, taste disturbances (dysgeusia), dyspepsia, nausea, vomiting, pruritus, rash, maculopapular eruptions, muscle cramps, and asthenia.

The following adverse reactions have been observed during clinical trials and post-marketing use of perindopril, with the following frequency of occurrence: 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 the available data).

Blood and lymphatic system disorders : eosinophilia – uncommon*; agranulocytosis or pancytopenia – very rare; decreased haemoglobin and haematocrit levels – very rare; leucopenia/neutropenia – very rare; haemolytic anaemia in patients with congenital glucose-6-phosphate dehydrogenase deficiency – very rare; thrombocytopenia – very rare.

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

Metabolism and nutrition disorders : hypoglycaemia – uncommon*; hyperkalaemia, reversible upon discontinuation of the drug – uncommon*; hyponatraemia – uncommon*.

Psychiatric disorders : depression – uncommon*; mood disturbances – uncommon; sleep disorders – uncommon.

Nervous system disorders : dizziness – common; headache – common; paraesthesia – common; vertigo – common; somnolence – uncommon*; loss of consciousness – uncommon*; confusion – very rare.

Eye disorders : visual disturbances – common.

Ear and labyrinth disorders : tinnitus – common.

Cardiac disorders : palpitations – uncommon*; tachycardia – uncommon*; angina pectoris – very rare; arrhythmia – very rare; myocardial infarction may occur due to excessive reduction in blood pressure in high-risk patients – very rare.

Vascular disorders : hypotension (and associated symptoms) – common; vasculitis – uncommon*; hot flushes – rare*; stroke may occur due to excessive reduction in blood pressure in high-risk patients – very rare; Raynaud's phenomenon – frequency not known.

Respiratory, thoracic and mediastinal disorders : cough – common; dyspnoea – common; bronchospasm – uncommon; eosinophilic pneumonia – very rare; rhinitis – very rare.

Gastrointestinal disorders : abdominal pain – common; constipation – common; diarrhoea – common; taste disturbances (dysgeusia) – common; dyspepsia – common; nausea – common; vomiting – common; dry mouth – uncommon; pancreatitis – very rare.

Hepatobiliary disorders : cytolytic or cholestatic hepatitis – very rare.

Skin and subcutaneous tissue disorders : pruritus – common; rash – common; urticaria – uncommon; angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and/or larynx – uncommon; photosensitivity reactions – uncommon*; pemphigoid – uncommon*; hyperhidrosis – uncommon; exacerbation of psoriasis symptoms – rare; erythema multiforme – very rare.

Musculoskeletal and connective tissue disorders : muscle cramps – common; arthralgia – uncommon*; myalgia – uncommon*.

Renal and urinary disorders : renal failure – uncommon; acute renal failure – rare; anuria/oliguria – rare*.

Reproductive system and breast disorders : erectile dysfunction – uncommon.

General disorders : asthenia – common; chest pain – uncommon*; malaise – uncommon*; peripheral oedema – uncommon*; hyperthermia – uncommon*.

Investigations : increased blood urea levels – uncommon*; increased blood creatinine levels – uncommon*; increased blood bilirubin levels – rare; increased liver enzyme levels – rare.

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

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

Clinical trials

During the randomization period of the EUROPA study, only serious adverse events were recorded. A small number of patients experienced serious adverse reactions: 16 (0.3%) out of 6122 patients in the perindopril group and 12 (0.2%) out of 6107 patients in the placebo group. Among patients receiving perindopril, hypotension occurred in 6 patients, angioedema in 3 patients, and sudden cardiac arrest in 1 patient. Of the patients who discontinued the study, 6.0% (n=366) reported cough, arterial hypotension, or any other intolerance to perindopril, compared to 2.1% (n=129) of patients receiving placebo.

Reporting of suspected adverse reactions after drug registration is of great importance. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life.

2 years.

Storage conditions.

Store at temperatures not exceeding 30°C in the original packaging.

Keep out of reach of children.

Packaging.

10 tablets per blister, 3 blisters with the package leaflet in a cardboard carton.

Prescription status.

Prescription only.

Manufacturer.

JSC "Farmak".

Manufacturer's address and location of operations.

74 Kyrylivska Street, Kyiv, 04080, Ukraine.