Prenelia

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PRENELIA® (PRENELIA)

Composition:

Active substance: perindopril;

1 tablet of Prenelia®, 4 mg, contains 4.0 mg of perindopril tert-butylamine, equivalent to 3.338 mg of perindopril;

1 tablet of Prenelia®, 8 mg, contains 8.0 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 properties:

Prenelia®, 4 mg: white or almost white tablets, capsule-shaped, biconvex, with a score line on both sides;

Prenelia®, 8 mg: white or almost white tablets, round in shape, biconvex.

Pharmacotherapeutic group. Angiotensin-converting enzyme (ACE) inhibitors, single-component. Perindopril. ATC code C09A A04.

Pharmacological Properties

Pharmacodynamics

Perindopril is an inhibitor of the enzyme that converts angiotensin I into angiotensin II (ACE). The converting enzyme, or kinase, is an exopeptidase that catalyzes the conversion of angiotensin I into the vasoconstrictive angiotensin II, and also promotes the breakdown of the vasodilator bradykinin into an inactive heptapeptide. Inhibition of ACE leads to a reduction in angiotensin II concentration in plasma, resulting in increased plasma renin activity (via a feedback mechanism) and reduced aldosterone secretion. Since ACE inactivates bradykinin, inhibition of ACE also increases the activity of the circulating and local kallikrein-kinin system (and thus also leads to activation of the prostaglandin system). This mechanism of action may contribute to the blood pressure-lowering effect of ACE inhibitors and partially accounts for the occurrence of certain adverse reactions (e.g., cough).

Perindopril acts via its active metabolite—perindoprilat. Other metabolites do not demonstrate activity in inhibiting ACE in vitro.

Clinical Efficacy and Safety

Arterial Hypertension

Perindopril effectively reduces arterial blood pressure in all stages of arterial hypertension—mild, moderate, and severe. Reduction in both systolic and diastolic blood pressure is observed in patients 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 for at least 24 hours: the T/R ratio (minimum/maximum effect over 24 hours) of perindopril is 87–100%.

Blood pressure decreases rapidly. In patients responding to treatment, normalization of blood pressure occurs within one month and is maintained without 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 produces an additive synergistic effect. The combination of an ACE inhibitor and a thiazide diuretic also reduces the risk of diuretic-induced hypokalemia.

Heart Failure

Perindopril reduces cardiac workload by decreasing both preload and afterload.

Studies in 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;
• increase in regional myocardial blood flow.

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 demonstrated 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.

Significant risk reductions were also observed in:

• fatal or disabling stroke;
• total number of major cardiovascular events, defined as cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke;
• stroke-related dementia and severe post-stroke cognitive impairment;
• major coronary events, including non-fatal myocardial infarction or fatal outcome due to ischemic heart disease (IHD).

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

Patients with Stable Ischemic Heart Disease (IHD)

An international, multicenter, randomized, double-blind, placebo-controlled clinical trial, EUROPA, lasting 4 years, has been reported. The study included patients with confirmed IHD and without clinical signs of heart failure. Overall, 90% of patients had a history of myocardial infarction and/or revascularization surgery. Most patients received perindopril in addition to standard therapy: antiplatelet agents, lipid-lowering drugs, and β-blockers.

The primary efficacy endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, and/or cardiac arrest followed by successful resuscitation. Treatment with perindopril 8 mg once daily led to a significant absolute reduction in 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 relative risk reduction of 22.4% (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.

Pharmacokinetics

Absorption

After oral administration, perindopril is rapidly absorbed, with maximum plasma concentration (Cmax) reached within 1 hour. The elimination half-life of perindopril in plasma is 1 hour.

Perindopril is a prodrug. 27% of the total administered perindopril is detected in blood as the active metabolite—perindoprilat. In addition to the active metabolite perindoprilat, the drug forms five inactive metabolites. Cmax of perindoprilat in plasma 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 food.

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 ACE, although 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 Populations

Elimination of perindoprilat is slowed in elderly patients, as well as in patients with cardiac or renal impairment. 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 reduced by half. However, the amount of formed perindoprilat does not decrease. Therefore, dose adjustment is not required in these patients (see sections "Special Warnings and Precautions for Use" and "Dosage and Administration").

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 ischemic heart disease.

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

Contraindications

• Hypersensitivity to perindopril, to any of the excipients of the medicinal product, or to any other angiotensin-converting enzyme (ACE) inhibitor;
• History of angioedema associated with previous ACE inhibitor therapy (see section "Special Warnings and Precautions for Use");
• Idiopathic or hereditary angioedema;
• Pregnancy or women planning to become pregnant (see section "Use in Pregnancy or Breastfeeding");
• Concomitant use of medicinal products containing the active substance aliskiren in patients with diabetes mellitus or renal impairment (glomerular filtration rate [GFR] < 60 mL/min/1.73 m²) (see sections "Interaction with Other Medicinal Products and Other Forms of Interaction" and "Special Warnings and Precautions for Use");
• Concomitant use with sacubitril/valsartan; treatment with Prenellya® must not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Interaction with Other Medicinal Products and Other Forms of Interaction" and "Special Warnings and Precautions for Use");
• Extracorporeal treatments 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 Warnings and Precautions for Use").

Interaction with Other Medicinal Products and Other Forms of Interaction

Clinical study 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 incidence of adverse reactions such as arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to use of a single RAAS-acting agent (see sections "Contraindications" and "Special Warnings and 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 sections "Contraindications" and "Special Warnings and Precautions for Use"). Initiation of sacubitril/valsartan should not occur earlier than 36 hours after the last dose of perindopril. Initiation of perindopril therapy should not occur earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Special Warnings and Precautions for Use").

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

Medicinal products causing hyperkalemia

Serum potassium levels usually remain within normal limits, but hyperkalemia may occur in some patients treated with Prenellya®. Certain medicinal products or therapeutic classes may cause hyperkalemia: aliskiren, potassium salts, potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), ACE inhibitors, angiotensin II receptor antagonists, nonsteroidal 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 medicinal products increases the risk of hyperkalemia. Therefore, concomitant use of Prenellya® with the above-mentioned agents is not recommended. If concomitant use is necessary, it should be performed with caution and frequent monitoring of serum potassium levels.

Concomitant use contraindicated (see section "Contraindications")

Aliskiren: In patients with diabetes mellitus or renal impairment, the risk of hyperkalemia, impaired renal function, and cardiovascular morbidity and mortality is increased.

Extracorporeal treatments leading to blood contact with negatively charged surfaces, such as high-flux dialysis or hemofiltration membranes (e.g., polyacrylonitrile membranes) or low-density lipoprotein apheresis with dextran sulfate, 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 not recommended (see section "Special Warnings and Precautions for Use")

Aliskiren: In all other patients, including those with diabetes mellitus or renal impairment, the risk of hyperkalemia, impaired renal function, and 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, hyperkalemia, and impaired 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.

Estromustine: Increased risk of adverse reactions such as angioedema.

Potassium-sparing diuretics (e.g., triamterene, amiloride), potassium salts: Risk of hyperkalemia (potentially fatal), particularly in patients with renal impairment (additive hyperkalemic effect). These agents are not recommended for concomitant use with perindopril (see section "Special Warnings and Precautions for Use"). However, if concomitant use is necessary, it should be performed with caution and frequent monitoring of serum potassium levels. For use of spironolactone in heart failure, see the section "Concomitant Use Requiring Special Attention".

Lithium. Use of ACE inhibitors with lithium-containing medicinal products has been associated with reversible increases in serum lithium concentrations and lithium toxicity. Concomitant use of perindopril with lithium is not recommended. If such combination is unavoidable, serum lithium levels must be closely monitored (see section "Special Warnings and Precautions for Use").

Concomitant use requiring special attention

Antidiabetic agents (insulin, oral hypoglycemic agents)

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

Baclofen potentiates the antihypertensive effect. Blood pressure should be monitored and antihypertensive dosage adjusted if necessary.

Diuretics. In patients receiving diuretics, particularly those with disturbed water-electrolyte balance, excessive reduction in blood pressure may occur after initiation of ACE inhibitor therapy. The risk of hypotensive effect may be reduced by discontinuing the diuretic, increasing circulating blood volume, or increasing salt intake prior to starting perindopril therapy, which should be initiated at a low dose with gradual dose escalation.

In arterial hypertension, if a previously prescribed diuretic may have caused water/electrolyte depletion, it should be discontinued prior to 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 background diuretic therapy, ACE inhibitor therapy should be initiated at the lowest dose, possibly after reducing the diuretic dose. Renal function (serum creatinine) must be monitored during the first weeks of ACE inhibitor therapy.

Potassium-sparing diuretics (eplerenone, spironolactone). Concomitant use of eplerenone or spironolactone (12.5–50 mg daily) 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, carries a risk of hyperkalemia (potentially fatal), especially if prescribing recommendations are not followed. Before initiating such combination therapy, absence of hyperkalemia and impaired renal function should be confirmed. Weekly monitoring of serum potassium and creatinine is recommended during the first month of treatment, followed by monthly monitoring.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid ≥3 g/day. Concomitant use of ACE inhibitors with NSAIDs such as anti-inflammatory doses of acetylsalicylic acid, COX-2 inhibitors, or nonselective NSAIDs may reduce the antihypertensive effect. Concomitant use of ACE inhibitors and NSAIDs may increase the risk of impaired 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 other vasodilators may lead to additional blood pressure reduction.

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

Sympathomimetics may attenuate the antihypertensive effect of ACE inhibitors.

Gold: Nitrate-like reactions (symptoms: facial flushing, nausea, vomiting, and arterial hypotension) have been reported rarely 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) occurs during the first month of treatment with perindopril, the risk/benefit ratio must 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 hypertension and is more likely to occur in patients with hypovolemia, those taking diuretics, those on a low-salt diet, patients undergoing dialysis, or patients with diarrhea or vomiting, as well as in patients with severe renin-dependent hypertension (see sections "Interaction with other medicinal products and other forms of interaction" and "Side effects"). 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 taking 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 at the beginning of therapy and during dose titration (see sections "Dosage and administration" and "Side effects"). 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 horizontal 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 predictable and usually does not require discontinuation of the drug. If hypotension becomes symptomatic, dose reduction or discontinuation of the drug may become necessary.

Stenosis of the aortic and mitral valves/hypertrophic cardiomyopathy. As with other ACE inhibitors, perindopril tert-butylamine should be used with caution in 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 "Side effects").

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

In some patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney, treatment with ACE inhibitors has been associated with increases in blood urea 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. Such patients should start treatment under close medical supervision with low doses and cautious dose titration. In this context, diuretic therapy may lead 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 prior to treatment, 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 in 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 taking 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. Experience with the use of perindopril tert-butylamine in patients after recent kidney transplantation is lacking.

Renovascular hypertension

Administration of ACE inhibitors to patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney increases the risk of arterial hypotension and renal failure (see section "Contraindications"). 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 "Side effects"). 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 reducing symptoms.

Angioedema associated with laryngeal edema 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 not related 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 presented with abdominal pain (with or without nausea or vomiting); in some cases, there was no prior history of facial angioedema and C1 esterase levels were normal. The diagnosis of intestinal angioedema was confirmed by abdominal computed tomography, 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 taking 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 occur earlier than 36 hours after the last dose of perindopril. If treatment with sacubitril/valsartan is discontinued, therapy with perindopril should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

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

Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis. Rarely, life-threatening anaphylactoid reactions have occurred in patients taking 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. In patients receiving ACE inhibitors during desensitization therapy (e.g., with bee venom preparations), potentially life-threatening anaphylactoid reactions may occur. These reactions can be avoided by temporarily discontinuing ACE inhibitors, but may recur upon inadvertent provocation testing.

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

Neutropenia/agranulocytosis, thrombocytopenia, and 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 combination of these risk factors, especially if renal impairment is present. Some of these patients developed serious infections, 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 to report any signs of infection (e.g., sore throat, fever).

Racial factors. ACE inhibitors cause angioedema more frequently in black patients than in patients of other races. Perindopril, like other ACE inhibitors, is less effective in reducing blood pressure in black patients compared to other racial groups. This may be explained by the lower plasma renin levels in hypertensive patients in this population.

Cough. Cough has been reported during ACE inhibitor therapy. 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 surgery or anesthesia with agents causing arterial 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 arterial hypotension develops and is considered to be due to this mechanism, the patient's condition can be normalized by increasing circulating blood volume.

Hyperkalemia. Increased serum potassium levels have been observed in some patients receiving ACE inhibitors, including perindopril. ACE inhibitors may cause hyperkalemia due to suppression of aldosterone release. In patients with normal renal function, this effect is usually mild. Risk factors for hyperkalemia include renal impairment, impaired kidney function, age (≥70 years), diabetes mellitus, intercurrent conditions such as dehydration, acute heart failure, 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 levels (e.g., heparin, co-trimoxazole, also known as trimethoprim/sulfamethoxazole), particularly aldosterone antagonists or angiotensin receptor blockers. Use of potassium-containing dietary supplements, potassium-sparing diuretics, or potassium-containing salt substitutes, especially 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 with caution, and serum potassium levels and renal function should be closely monitored. If concomitant use of perindopril and any of the above-mentioned agents is considered necessary, 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 arterial hypotension, hyperkalemia, and renal 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 dual blockade therapy with two RAAS inhibitors is considered absolutely necessary, it should only be performed under specialist supervision with frequent and 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 through inhibition of the renin-angiotensin system. Therefore, this drug is not recommended for such patients.

Excipients. The drug contains lactose; therefore, perindopril tert-butylamine is not recommended for patients with rare hereditary intolerance to galactose, glucose-galactose malabsorption syndrome, or complete lactase deficiency.

Use during pregnancy or breastfeeding

Pregnancy. Use of ACE inhibitors is contraindicated during pregnancy (see section "Contraindications"). The medicinal product is contraindicated in pregnant women or women planning to become pregnant. If pregnancy is confirmed during treatment with this medicinal product, treatment must be discontinued immediately and replaced with another medicinal product approved for use during pregnancy.

Epidemiological data on the risk of teratogenic effects associated with ACE inhibitor use during the first trimester of pregnancy are inconclusive; therefore, a small increase in risk cannot be excluded. It is known that ACE inhibitor use during the second and third trimesters of pregnancy leads to fetotoxicity and neonatal toxicity.

If a woman took an ACE inhibitor during the second trimester of pregnancy, the child should undergo ultrasound evaluation of kidney function and skull bones. Newborns whose mothers took ACE inhibitors during pregnancy should be closely monitored due to the potential risk of arterial hypotension.

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

Fertility. No effect on reproductive capacity or fertility has been observed.

Ability to influence reaction speed when driving vehicles or operating machinery

Perindopril tert-butylamine has no direct effect on 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.

Administration and Dosage

For oral use.

Prilenium® 4 mg tablets are divisible (have a score line).

Prilenium® 8 mg tablets are not divisible.

The tablets should be taken once daily in the morning before food.

The dose should be individually adjusted depending on the patient's profile, blood pressure levels, and response to treatment (see section "Special Instructions").

Arterial Hypertension

Perindopril tert-butylamine can 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 RAAS activity (particularly those with renovascular hypertension, fluid and electrolyte imbalance, cardiac decompensation, or severe arterial hypertension) may experience excessive reduction in blood pressure after the first dose. Such patients should start treatment with a dose of 2 mg (½ tablet of Prilenium® 4 mg), and therapy initiation should be under medical supervision.

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

Symptomatic arterial hypotension may occur at the beginning of perindopril tert-butylamine therapy, particularly in patients concurrently receiving diuretics. Treatment with perindopril should be initiated cautiously in such patients due to possible volume and/or salt depletion.

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

In hypertensive patients who cannot discontinue diuretic therapy, treatment should be initiated with a 2 mg dose. Renal function and serum potassium levels should be monitored in these patients. Further dose escalation of perindopril tert-butylamine should be based on blood pressure response.

Diuretic therapy may be resumed if necessary.

Elderly patients should start treatment with a 2 mg dose, which may be increased to 4 mg after one month of treatment, and subsequently, if necessary, to 8 mg, taking into account renal function (see Table 1).

Symptomatic Heart Failure

In patients with heart failure, perindopril tert-butylamine is usually prescribed concomitantly with a potassium-wasting diuretic and/or digoxin and/or a β-blocker. Treatment should be initiated under close medical supervision with an initial morning dose of 2 mg. After 2 weeks, if well tolerated, the dose should be increased to 4 mg once daily. Subsequently, the dose should be individually adjusted based on 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 imbalances, or those receiving concomitant therapy with diuretics and/or vasodilators) should start treatment under close medical supervision (see section "Special Instructions").

In patients at high risk of symptomatic arterial hypotension—such as those with electrolyte depletion, with or without hyponatremia, hypovolemic patients, or those receiving intensive diuretic therapy—the above conditions should be corrected, if possible, prior to initiating treatment. Blood pressure, renal function, and serum potassium levels should be carefully monitored both before and during treatment (see section "Special Instructions").

Prevention of Recurrent Stroke in Patients with Cerebrovascular Disease

The recommended initial dose is 2 mg (½ tablet of Prilenium® 4 mg) once daily in the morning. After 2 weeks of treatment, the dose should be increased to 4 mg (1 tablet of Prilenium® 4 mg) once daily in the morning.

If additional blood pressure control is required after 2 weeks of treatment with Prilenium® 4 mg, indapamide may be added at a dose of 1 tablet per day. Treatment may be initiated anytime 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 Prilenium® 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 with Prilenium® 4 mg (1 tablet daily in the morning). After 2 weeks, if well tolerated and considering renal function, the dose should be increased to 8 mg for long-term treatment with Prilenium® 8 mg, 1 tablet daily in the morning.

In elderly patients with documented ischemic heart disease, treatment should be initiated with a dose of 2 mg (½ tablet of Prilenium® 4 mg) once daily in the morning; after one week, the dose should be increased to 4 mg (1 tablet of Prilenium® 4 mg); after 2 weeks, considering renal function, the dose should be increased to 8 mg (Prilenium® 8 mg, 1 tablet daily) (see Table 1) for long-term treatment. Dose escalation is possible only if the previous dose is well tolerated.

Special Patient Groups

Patients with Renal Impairment

Dosing in patients with renal impairment should be based on creatinine clearance, as indicated in Table 1.

Table 1

Dosage Adjustment in Renal Impairment

Creatinine clearance (mL/min)	Recommended dosage
ClCR ≥ 60	4 mg once daily
30 < ClCR < 60	2 mg once daily
15 < ClCR < 30	2 mg every other day
Patients undergoing hemodialysis*
ClCR < 15	2 mg on dialysis days

٭The dialysis clearance of perindoprilat is 70 mL/min. For patients undergoing hemodialysis, the dose should be administered after hemodialysis.

Patients with hepatic impairment

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

Children

The efficacy and safety of the medicinal product in children under 18 years of age have not been established. Therefore, perindopril tert-butylamine is not recommended for use in children.

Overdose

Information on perindopril overdose is limited. Symptoms associated with angiotensin-converting enzyme (ACE) inhibitors overdose may include: arterial hypotension, circulatory shock, electrolyte imbalance, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, cough.

In case of overdose, intravenous administration of 0.9% (9 mg/mL) sodium chloride solution is recommended. If arterial hypotension occurs, the patient should be placed in a supine position with low elevation of the head. If possible, infusions of angiotensin II and/or intravenous catecholamines should be provided. Perindopril can be removed from systemic circulation by hemodialysis (see section "Special precautions"). In case of treatment-resistant bradycardia, use of an artificial pacemaker is indicated. Continuous monitoring of vital signs, serum electrolytes, and creatinine concentration is necessary.

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 of perindopril include: dizziness, headache, paresthesia, vertigo, visual disturbances, tinnitus, arterial hypotension, cough, dyspnea, abdominal pain, constipation, diarrhea, taste disturbances (dysgeusia), dyspepsia, nausea, vomiting, pruritus, rash, maculopapular rash, muscle cramps, and asthenia.

The following adverse reactions have been observed during clinical trials and post-marketing use of perindopril, with the following frequency: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from the available data), as shown in Table 2.

Table 2

Organ systems by MedDRA classification MedDRA	Adverse reactions	Frequency
Blood and lymphatic system disorders	eosinophilia	uncommon*
	agranulocytosis or pancytopenia	very rare
	decreased hemoglobin and hematocrit levels	very rare
	leukopenia/neutropenia	very rare
	hemolytic anemia 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	hypoglycemia	uncommon*
	hyperkalemia, reversible after discontinuation of the drug	uncommon*
	hyponatremia	uncommon*
Psychiatric disorders	depression	uncommon*
	mood disturbance	uncommon
	sleep disturbance	uncommon
Nervous system disorders	dizziness	common
	headache	common
	paraesthesia	common
	vertigo	common
	drowsiness	uncommon*
	syncope	uncommon*
	confusion	very rare
Eye disorders	vision disturbance	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	arterial 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
	dyspnea	common
	bronchospasm	uncommon
	eosinophilic pneumonia	very rare
	rhinitis	very rare
Gastrointestinal disorders	abdominal pain	common
	constipation	common
	diarrhea	common
	taste disturbance (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, limbs, lips, mucous membranes, tongue, glottis and/or larynx	uncommon
	photosensitivity reactions	uncommon*
	pemphigoid	uncommon*
	hyperhidrosis	uncommon
	worsening of psoriasis symptoms	rare
	multiform erythema	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 edema	uncommon*
	hyperthermia	uncommon*
Investigations	increased blood urea levels	uncommon*
	increased blood creatinine levels	uncommon*
	increased blood bilirubin levels	rare
	elevated liver enzymes	rare
Injury, poisoning and procedural complications	falls	uncommon*

*The frequency of adverse reactions identified from spontaneous reports is calculated based on data from clinical trials.

Clinical trials

During the randomization period of the EUROPA study, information was collected only on serious adverse reactions. 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, arterial hypotension was observed in 6 patients, angioneurotic edema in 3 patients, and sudden cardiac arrest in 1 patient. Patients who discontinued the study due to cough, arterial hypotension, or any other intolerance to perindopril accounted for 6.0% (n = 366) compared to 2.1% (n = 129) in the placebo group.

Reporting suspected adverse reactions

Reporting adverse reactions after medicinal product authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and pharmacists, as well as patients or their legal representatives, should 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

In the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging. 10 tablets in a blister, 3 blisters per carton.

Prescription status. Prescription only.

Manufacturer. JSC "Kyivmedpreparat".

Manufacturer's address and location of business activity

139 Saksaganskoho Street, Kyiv, 01032, Ukraine.