Aliter

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ALITER (ALITER)

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 properties: white to almost white, round biconvex tablets.

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 kininase, 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 blood 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 the circulating and local kallikrein-kinin system (and thus also activates the prostaglandin system). This mechanism of action underlies the antihypertensive 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 degrees of arterial hypertension—mild, moderate, and severe. Reduction in both 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) generally remains unchanged.

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

Blood pressure reduction occurs rapidly. In patients who respond to the drug, normalization of blood pressure is achieved within one month and is maintained without 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 shows 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 pressures 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 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, blood pressure (systolic/diastolic) 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 the placebo group (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, and 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 death due to ischemic heart disease (IHD) (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. The PROGRESS study results showed that after 5 years of treatment, one stroke could be prevented per every 23 patients treated, and one major cardiovascular complication per every 18 patients.

Patients with Stable Ischemic Heart Disease (IHD)

EUROPA is an international, multicenter, randomized, double-blind, placebo-controlled clinical trial lasting 4 years. A total of 12,218 patients aged 18 years and older were randomized: 6110 patients received 8 mg of perindopril tert-butylamine and 6108 received placebo. Patients included in the study had confirmed IHD without clinical signs 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 drugs, and β-blockers.

The primary efficacy endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, and/or resuscitated cardiac arrest. Treatment with perindopril 8 mg once daily resulted in a significant absolute reduction of 1.9% in the primary endpoint (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, there was an absolute reduction of 2.2% in the primary endpoint, 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 GFR >30 mL/min/1.73 m² were administered perindopril at a mean dose of 0.07 mg/kg. The dose was individually adjusted, increased up to a maximum of 0.135 mg/kg/day, based 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 was 44 months). Systolic and diastolic blood pressure remained stable (from study entry to last visit) in patients previously treated with other antihypertensive drugs 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 is recommended to be taken once daily in the morning before meals.

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, 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 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 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 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 or 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 precautions");
• idiopathic or hereditary angioedema;
• concomitant use with medicinal products containing the active substance aliskiren in patients with diabetes mellitus or with renal impairment (eGFR < 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 lactation");
• concomitant use with sacubitril/valsartan; initiation of the medicinal product ALITREX must not occur earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction" and "Special precautions");
• 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").

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 incidence of adverse reactions such as arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to use of a single medicinal product affecting the RAAS (see sections "Contraindications" and "Special precautions").

Medicinal products that increase 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 precautions"). Initiation of sacubitril/valsartan therapy must not occur earlier than 36 hours after the last dose of perindopril. Perindopril therapy should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Special precautions").

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

Medicinal products causing hyperkalemia.

Serum potassium levels usually remain within normal limits, but hyperkalemia may occur in some patients receiving ALITREX. Certain medicinal products or therapeutic classes of medicinal products may cause hyperkalemia, namely: 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 ALITREX with the above-mentioned medicinal products is not recommended. If concomitant use of these agents is necessary, they should be used with caution and frequent monitoring of serum potassium levels should be performed.

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

Aliskiren: in patients with diabetes mellitus or in patients with impaired renal function, the risk of hyperkalemia, worsening 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 for low-density lipoprotein apheresis with dextran sulfate, may lead to an increased risk of severe anaphylactoid reactions (see section "Contraindications"). If such treatment is necessary, consideration should be given to using a dialysis membrane of another type or another class of antihypertensive medicinal products.

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

Aliskiren: in any other patients, as in patients with diabetes mellitus or impaired renal function, the risk of hyperkalemia, worsening 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 has been associated with increased incidence of arterial hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to monotherapy with RAAS-affecting medicinal products. Dual blockade (i.e., combination of an ACE inhibitor with angiotensin II receptor antagonists) may be considered only in selected cases under conditions of careful monitoring of renal function, potassium levels, and blood pressure.

Estramustine: increased risk of adverse reactions such as angioedema.

Potassium-sparing diuretics (e.g., triamterene, amiloride, etc.), potassium salts: risk of hyperkalemia (potentially fatal), especially in patients with impaired renal function (additive hyperkalemic effect). These medicinal products are not recommended for concomitant use with perindopril (see section "Special precautions"). However, if concomitant use of these agents is necessary, they should be used with caution and frequent monitoring of serum potassium levels should be performed. For use of spironolactone in heart failure, see the section "Concomitant use requiring special attention".

Lithium. There have been reports of reversible increases in serum lithium concentrations and lithium toxicity during concomitant use of ACE inhibitors with lithium-containing medicinal products. Concomitant use of perindopril with lithium-containing medicinal products is not recommended. If such combination is necessary, serum lithium levels must be closely monitored (see section "Special precautions").

Concomitant use requiring special attention.

Antidiabetic agents (insulin, oral hypoglycemic agents).

Epidemiological studies indicate that concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemic agents) may enhance the glucose-lowering effect with a risk of hypoglycemia. 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 the antihypertensive agent adjusted.

Diuretics. In patients receiving diuretics, particularly those with impaired water-electrolyte balance, excessive reduction in blood pressure may occur after initiation of ACE inhibitor therapy. The likelihood of hypotensive effects may be reduced by discontinuing the diuretic, increasing circulating blood volume, or salt intake prior to starting perindopril therapy, which should be initiated at a low dose with gradual dose escalation. In arterial hypertension, when a previously prescribed diuretic may have caused water/electrolyte depletion, the diuretic should be discontinued prior to starting ACE inhibitor therapy (in such cases, 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 any case, renal function (creatinine levels) should be monitored during the first weeks of ACE inhibitor therapy.

Potassium-sparing diuretics (eplerenone, spironolactone). When eplerenone or spironolactone (doses from 12.5 mg to 50 mg daily) are used concomitantly with low doses of ACE inhibitors in patients with NYHA class II-IV heart failure and ejection fraction < 40%, who have previously received ACE inhibitors and loop diuretics, there is a risk of hyperkalemia (potentially fatal), especially if recommendations for use of this combination are not followed. Before initiating such combination therapy, absence of hyperkalemia and impaired renal function should be confirmed. Careful monitoring of serum potassium and creatinine levels is recommended weekly during the first month of treatment and monthly thereafter.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid ≥ 3 g/day. The antihypertensive effect of ACE inhibitors may be attenuated when used concomitantly with NSAIDs such as acetylsalicylic acid at anti-inflammatory doses, COX-2 inhibitors, or nonselective NSAIDs. Concomitant use of ACE inhibitors and NSAIDs may increase the risk of impaired renal function, including the development of acute renal failure, and elevated serum potassium levels, particularly in patients with a history of renal impairment. Such combinations should be used with caution, especially in elderly patients. Patients should be adequately hydrated and advised to monitor renal function after initiation of combination therapy and during continued treatment.

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 anesthetics with ACE inhibitors may lead to further reduction in blood pressure (see section "Special precautions").

Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.

Gold: a nitrate-like reaction (symptoms: facial flushing, nausea, vomiting, and arterial hypotension) has 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 therapy, the benefit/risk ratio should be carefully evaluated before deciding on continuing treatment.

Arterial hypotension. Administration of ACE inhibitors may cause a reduction in blood pressure. Symptomatic arterial hypotension is less likely to occur in patients with uncomplicated arterial hypertension and is more likely 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 during initiation of therapy and dose titration should be closely monitored by a physician (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.

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 be necessary.

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

Renal function impairment.

In patients with 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 renal function impairment, 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 therapy. This is particularly relevant for patients with pre-existing renal impairment. The risk of severe arterial hypotension and renal failure is increased in patients with concomitant renovascular hypertension. For such patients, treatment should be initiated under close medical supervision with low doses and cautious dose titration. In this context, diuretic therapy may predispose to arterial hypotension; therefore, diuretics should be discontinued and renal function should be monitored during the first weeks of perindopril tert-butylamine treatment.

In some patients with arterial hypertension who had no evidence of renovascular disease prior to treatment initiation, increases in blood urea nitrogen and serum creatinine have been observed, usually mild and transient, particularly when perindopril tert-butylamine was administered concomitantly with a diuretic. However, this is more common in patients with pre-existing renal impairment. Dose reduction and/or discontinuation of the diuretic and/or perindopril tert-butylamine may be 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 antihypertensive drugs from another class.

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 renal function may manifest as minimal changes in serum creatinine levels even in patients with stenosis of one renal artery.

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 have completely resolved. In isolated cases where swelling is limited to the face and lips, the patient's condition usually improves without treatment. Administration of antihistamine drugs may be helpful in alleviating symptoms.

Angioedema involving 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 unrelated to ACE inhibitor use are at increased risk of 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 abdominal pain in patients receiving ACE inhibitors.

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

Concomitant use of ACE inhibitors with neutral endopeptidase inhibitors (NEP) (e.g., racecadotril), mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) may increase the risk of angioedema (e.g., airway or tongue 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 receiving ACE inhibitors during LDL apheresis using dextran sulfate. Anaphylactoid reactions can be avoided by temporarily discontinuing ACE inhibitor therapy before each apheresis session.

Anaphylactoid reactions during desensitization therapy. Patients receiving ACE inhibitors during desensitization therapy (e.g., medications containing bee venom) may experience life-threatening anaphylactoid reactions. These reactions can be avoided by temporarily discontinuing ACE inhibitors, but may recur upon inadvertent provocation testing.

Hepatic impairment. Rarely, ACE inhibitor use has been associated with a syndrome beginning with cholestatic jaundice and progressing to rapidly progressive 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 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 disease, those receiving immunosuppressants, allopurinol, or procainamide, or in combination of these risk factors, especially if renal function is impaired. Some of these patients developed serious infections that were refractory to intensive antibiotic therapy in several cases. Periodic monitoring of white blood cell counts is recommended in such patients receiving perindopril. Patients should also be informed to report any signs of infection (e.g., sore throat, fever).

Racial characteristics. ACE inhibitors cause angioedema more frequently in patients of Black race than in patients of other races. Perindopril, like other ACE inhibitors, is less effective in reducing blood pressure in patients of Black race compared to other racial groups, possibly due to 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 and persistent, and resolves after discontinuation of the drug. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.

During surgery or administration of anesthetics that cause 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 can 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 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, or potassium-containing salt substitutes; or use of other medicinal products that increase serum potassium (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. Hyperkalemia may lead to serious, sometimes fatal, arrhythmias. Potassium-sparing diuretics and angiotensin receptor blockers should be prescribed with caution in patients receiving ACE inhibitors, 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 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 arterial 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 dual blockade therapy is considered absolutely necessary, it should be performed only 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 via inhibition 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 problems of galactose intolerance, the glucose-galactose malabsorption syndrome, or lactase deficiency (Lapp lactase deficiency) should not take the medicinal product ALITER.

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 ALITER, the drug must be discontinued immediately and replaced with another medicinal product approved for use during pregnancy.

If a woman has taken an ACE inhibitor during the second trimester of pregnancy, ultrasound assessment of fetal renal function and skull ossification is recommended. Newborns whose mothers received ACE inhibitors during pregnancy should be closely monitored for possible development of arterial hypotension.

Period of 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 alternative treatment with a better-studied safety profile, especially when nursing a newborn or premature infant.

Fertility

No effect on reproductive capacity or fertility has been observed.

Ability to affect reaction speed when driving 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, particularly at the beginning of treatment or when used concomitantly with other antihypertensive medicinal products. As a result, the ability to drive vehicles or operate machinery may be impaired.

Dosage and Administration.

For oral use. The tablets should not be divided.

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

The dosage 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 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 (RAAS) (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 initiation of therapy 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 treatment cautiously, as they may have water and/or salt depletion.

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

For patients with arterial hypertension who cannot discontinue diuretics, 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.

For elderly patients, treatment should be initiated at 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 then, if necessary, to 8 mg, taking into account renal function (see table provided below).

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 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. Subsequently, the dose should be individually adjusted based on the patient's clinical response to treatment.

For 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), treatment should be initiated under close medical supervision (see section "Special Instructions").

In patients at high risk of symptomatic arterial hypotension (those with electrolyte depletion with or without hyponatremia, hypovolemia, or those previously receiving intensive diuretic therapy), correction of these conditions should be attempted, if possible, prior to initiating the drug. 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 (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 after 2 weeks of treatment with ALITER the patient requires additional blood pressure control, indapamide may be prescribed 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 tablets (1 tablet daily) reduces the risk of myocardial infarction and heart failure (based on results of the 4-year EUROPA study).

Treatment should be initiated at 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 treatment with ALITER 8 mg tablets (1 tablet daily in the morning).

For 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 1 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 initiate 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

٭Dialysis clearance of perindoprilat is 70 mL/min.

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

Dose adjustment in hepatic impairment.

Patients with hepatic impairment do not require dose adjustment of the medicinal product (see sections “Pharmacokinetics” and “Special precautions for use”).

Children.

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

Overdose.

Information regarding 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, 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. If possible, angiotensin II and/or intravenous catecholamines should be administered. Perindopril can be removed from systemic circulation by hemodialysis (see section “Special precautions for use”). In case of treatment-resistant bradycardia, artificial cardiac pacing is indicated. Continuous monitoring of vital signs, serum electrolyte concentrations, and serum creatinine levels is required.

Adverse reactions.

The safety profile of perindopril corresponds to 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, arterial hypotension, cough, dyspnoea, abdominal pain, constipation, diarrhoea, taste disturbances (dysgeusia), dyspepsia, nausea, vomiting, pruritus, rash, maculopapular eruptions, muscle cramps, and asthenia.

During clinical trials and post-marketing use of perindopril, the following adverse reactions have been observed with the following frequencies: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10000, < 1/1000); very rare (< 1/10000); 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 system 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 disturbances – 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: 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; 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 and administration site conditions: asthenia – common; chest pain – uncommon*; malaise – uncommon*; peripheral oedema – uncommon*; hyperthermia – uncommon*.

Investigations: increased blood urea levels – uncommon*; increased serum creatinine levels – uncommon*; increased serum 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. In patients receiving perindopril, arterial hypotension occurred in 6 patients, angioedema in 3 patients, and sudden cardiac arrest in 1 patient. Among 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 adverse reactions after drug registration is of significant importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: 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 and sight of children.

Packaging.

10 tablets in a blister pack, 3 blisters with the instruction for medical use in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

MICROCHEM LLC.

Manufacturer’s address and location of operations.

24-V Promyslova Street, Sievierodonetsk, Luhansk Oblast, 93400, Ukraine.

Marketing Authorization Holder.

MICROCHEM LLC.

Address of the Marketing Authorization Holder.

5 Budyndustrії Street, Kyiv, 01013, Ukraine.

To report an adverse event related to the use of this medicinal product, please call +38 (050) 309-83-54 (available 24/7).

INSTRUCTIONS

for medical use of the medicinal product

ALITER

(ALITER)

Composition:

Active substance: perindopril (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 physico-chemical properties: round, biconvex tablets, white to almost white.

Pharmacotherapeutic group.

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

Perindopril. ATC code C09AA04.

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 enables the conversion of angiotensin I into the vasoconstrictive 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 blood plasma, resulting in increased plasma renin activity (due to suppression of negative feedback on renin release) and decreased aldosterone secretion. Since ACE inactivates bradykinin, inhibition of ACE also leads to increased activity of the circulating and local kallikrein-kinin system (and thus also leads to activation of the prostaglandin system). This mechanism of action underlies the antihypertensive 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 in 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) generally remains unchanged.

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

Arterial blood pressure decreases rapidly. In patients who respond to the drug, 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 produces 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 pressures of the right and left ventricles;
• reduction in systemic vascular 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 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, blood pressure (systolic/diastolic) 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, and 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 (IHD) (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. The PROGRESS study results 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: 6110 patients received 8 mg of perindopril tert-butylamine and 6108 received placebo. Patients included in the study had confirmed IHD and no 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 drugs, and β-blockers.

The primary efficacy endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, and resuscitated cardiac arrest. Treatment with perindopril 8 mg once daily resulted in a significant absolute reduction of 1.9% in the primary endpoint (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, there was an absolute reduction of 2.2% in the primary endpoint, 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.

In an open-label, non-comparative clinical study, 62 children aged 2 to 15 years with GFR > 30 mL/min/1.73 m² received perindopril at a mean dose of 0.07 mg/kg. The dose was individually adjusted and increased 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 was 44 months). Systolic and diastolic blood pressure remained stable (from study entry to last visit) in patients previously treated with other antihypertensive drugs 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 dose is found in the 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 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, but this value is dose-dependent.

Elimination

Perindoprilat is excreted in the 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 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 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 ischemic 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 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 precautions for use");
• idiopathic or hereditary angioedema;
• concomitant use with medicinal products containing aliskiren in patients with diabetes mellitus or with renal impairment (GFR < 60 mL/min/1.73 m²) (see section "Interaction with other medicinal products and other types of interactions");
• pregnancy or women planning to become pregnant (see section "Use during pregnancy or breastfeeding");
• concomitant use with sacubitril/valsartan; initiation of the medicinal product ALITRE cannot begin earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Special precautions for use", "Interaction with other medicinal products and other types of interactions", and "Special precautions for use");
• extracorporeal treatment methods leading to blood contact with negatively charged surfaces (see section "Interaction with other medicinal products and other types of interactions");
• 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 types of interactions.

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 treatment with a single medicinal product affecting the RAAS (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 sections "Contraindications" and "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 hyperkalemia.

Serum potassium levels usually remain within normal limits, but hyperkalemia may occur in some patients receiving the medicinal product ALITRE. Certain medicinal products or therapeutic classes of medicinal products may cause hyperkalemia, namely: 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 the medicinal product ALITRE with the above-mentioned medicinal products is not recommended. If concomitant use of these agents is necessary, they should be used with caution and frequent monitoring of serum potassium levels should be performed.

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

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

Extracorporeal treatment methods leading to blood contact with negatively charged surfaces, such as high-flux dialysis or hemofiltration membranes (e.g., polyacrylonitrile membranes) or for low-density lipoprotein apheresis with dextran sulfate, may lead to an increased risk of severe anaphylactoid reactions (see section "Contraindications"). If such treatment is necessary, consideration should be given to using a dialysis membrane of another type or another class of antihypertensive medicinal products.

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

Aliskiren: in any other patients, as in patients with diabetes mellitus or with renal impairment, the risk of hyperkalemia, worsening of 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 worsening of renal function (including acute renal failure) compared to monotherapy with RAAS-affecting medicinal products. 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, potassium levels, and blood pressure.

Estramustine: increased risk of adverse reactions such as angioedema.

Potassium-sparing diuretics (e.g., triamterene, amiloride, etc.), potassium salts: risk of hyperkalemia (potentially fatal), especially in patients with renal impairment (additive hyperkalemic effect). These medicinal products are not recommended for concomitant use with perindopril (see section "Special precautions for use"). However, if concomitant use of these agents is necessary, they should be used with caution and frequent monitoring of serum potassium levels should be performed. For use of spironolactone in heart failure, see the section "Concomitant use requiring special attention".

Lithium. Cases of reversible increases in serum lithium concentration and lithium toxicity have been reported during concomitant use of ACE inhibitors with lithium-containing medicinal products. Concomitant use of perindopril with lithium-containing medicinal products 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 hypoglycemic agents).

Epidemiological studies indicate that concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemic agents) may enhance the glucose-lowering effect with a risk of hypoglycemia. 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 the antihypertensive agent adjusted.

Diuretics. In patients taking diuretics, especially those with disturbed water-electrolyte balance, excessive reduction in blood pressure may occur after initiation of ACE inhibitor therapy. The likelihood 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 at a low dose with gradual dose escalation. In arterial hypertension, when a previously prescribed diuretic may have caused water/electrolyte deficiency, the diuretic should be discontinued before starting ACE inhibitor therapy (in such cases, diuretic use 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 any case, renal function (creatinine levels) should be monitored during the first weeks of ACE inhibitor therapy.

Potassium-sparing diuretics (eplerenone, spironolactone). When eplerenone or spironolactone (12.5–50 mg daily) is used concomitantly with low doses of ACE inhibitors in patients with NYHA class II–IV heart failure and ejection fraction < 40%, who have previously received ACE inhibitors and loop diuretics, there is a risk of hyperkalemia (potentially fatal), especially if recommendations for use of this combination are not followed. Before initiating such combination therapy, absence of hyperkalemia and renal impairment should be confirmed. Careful monitoring of serum potassium and creatinine levels is recommended weekly during the first month of treatment and monthly thereafter.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid ≥ 3 g/day. The antihypertensive effect of ACE inhibitors may be attenuated when used concomitantly with NSAIDs such as acetylsalicylic acid at anti-inflammatory doses, COX-2 inhibitors, or nonselective NSAIDs. Concomitant use of ACE inhibitors and NSAIDs may increase the risk of renal dysfunction, including the development of acute renal failure, and elevated serum potassium levels, particularly in patients with a history of renal impairment. This combination should be used with caution, especially in elderly patients. Patients should be adequately hydrated, and monitoring of renal function should be performed after initiation of combination therapy and during ongoing treatment.

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 anesthetics with ACE inhibitors may lead to further reduction in blood pressure (see section "Special 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 benefit/risk 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, patients on a salt-restricted diet, patients on 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 at the beginning of therapy and during dose titration should be closely monitored by a physician (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 horizontal position and, if necessary, 0.9% (9 mg/mL) sodium chloride solution should be administered intravenously. 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 increase in blood pressure.

In some patients with congestive heart failure with normal or reduced 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 be necessary.

Stenosis of aortic and mitral valves/hypertrophic cardiomyopathy. Like 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 patients with 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 adjusted according to 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, 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 solitary 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 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 careful dose titration. In view of the above, 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 before initiation of treatment, increases in blood urea and serum creatinine levels have been observed, 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 be 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 antihypertensive agents from another class.

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

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 predisposing factor. Loss of renal function may be indicated by 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 should be discontinued immediately and appropriate monitoring of the patient should be instituted 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 antihistamine drugs may be helpful in reducing symptoms.

Angioedema involving 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 experienced abdominal pain (with or without nausea or vomiting); in some cases, there was no prior history of facial angioedema and C-1 esterase levels were normal. The diagnosis of intestinal angioedema was established by computed tomography of the abdomen, ultrasound examination, or during surgical intervention. After discontinuation of the ACE inhibitor, symptoms of angioedema resolved. Intestinal angioedema should be considered in the differential diagnosis of patients with abdominal pain who are 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. If treatment with sacubitril/valsartan is discontinued, perindopril therapy should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Concomitant use of ACE inhibitors with neutral endopeptidase (NEP) inhibitors (e.g., with racecadotril), mTOR inhibitors (e.g., with sirolimus, everolimus, temsirolimus), and gliptins (e.g., with linagliptin, saxagliptin, sitagliptin, vildagliptin) may increase the risk of angioedema (e.g., airway or tongue swelling, with or without impaired respiratory function) (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. In patients receiving ACE inhibitors during desensitization therapy (e.g., drugs containing bee venom), life-threatening anaphylactoid reactions may occur. These reactions can be avoided by temporarily discontinuing ACE inhibitors, but reactions may recur upon inadvertent provocation testing.

Hepatic impairment. Rarely, use of ACE inhibitors has been associated with a syndrome beginning with cholestatic jaundice and progressing to rapidly developing hepatic necrosis, sometimes fatal. The mechanism of this syndrome is unclear. Patients who develop jaundice or elevated liver enzymes while receiving 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 in patients receiving ACE inhibitors. In patients with normal renal function and in the absence of other risk factors, neutropenia is rare. Perindopril should be administered with extreme caution to patients with collagenosis, during immunosuppressive therapy, with allopurinol or procainamide, or in combination with these risk factors, especially if renal function is impaired. Some of these patients developed serious infections, which in several cases did not respond to intensive antibiotic therapy. Periodic monitoring of white blood cell count is recommended in patients receiving perindopril. 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 patients of other races. Perindopril, like other ACE inhibitors, is less effective in lowering blood pressure in black patients than in patients of other races, possibly due to lower plasma renin levels in black patients with arterial hypertension.

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

During surgery or anesthesia with agents that cause 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. In some patients receiving ACE inhibitors, including perindopril, increased serum potassium levels have been observed. 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 renal function, age (70 years and older), 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, or potassium-containing salt substitutes; or use of other medicinal products that increase serum potassium concentration (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 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 arterial hypotension, hyperkalemia, and decreased renal function (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 dual RAAS blockade is considered absolutely necessary, it may 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 through 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 galactose intolerance, glucose-galactose malabsorption syndrome, or Lapp lactase deficiency should not take the medicinal product ALITER.

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 ALITER, the drug should be discontinued immediately and replaced with another medicinal product approved for use during pregnancy.

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

Period of 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 therapy 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 affect 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, individual reactions related to reduced blood pressure may occur in some patients, especially at the beginning of treatment or during concomitant use with other antihypertensive medicinal products. 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 recommended dose is one tablet once daily in the morning before a meal.

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 may be prescribed either as monotherapy or in combination with antihypertensive drugs 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 hypertension) may experience excessive hypotension 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 one 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 be treated with caution when starting perindopril, as they may have water and/or salt depletion.

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

For hypertensive patients 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 one month of treatment, and subsequently, if necessary, to 8 mg, depending on renal function (see table below).

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. 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 based on the patient's clinical response to treatment.

Patients with severe heart failure and other high-risk patients (those with renal impairment 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 Instructions").

In patients at high risk of symptomatic arterial hypotension (those with electrolyte depletion with or without hyponatremia, hypovolemia, or those receiving intensive diuretic therapy), correction of these conditions should be attempted, if possible, prior to initiating the drug. Blood pressure, renal function, and serum potassium levels must be closely 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 (use another medicinal product with corresponding dosage strength) once daily in the morning. After 2 weeks of treatment, increase the dose to 4 mg once daily in the morning.

If additional blood pressure control is required after 2 weeks of treatment with ALITER, indapamide may be prescribed at a dose of 1 tablet daily. 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 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 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 treatment with ALITER 8 mg tablets (1 tablet daily in the morning).

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

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

٭Dialysis clearance of perindoprilat is 70 mL/min.

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

Dose adjustment in hepatic impairment.

Patients with hepatic insufficiency do not require dose adjustment of the medicinal product (see sections «Pharmacokinetics» and «Special warnings and precautions for use»).

Children.

The efficacy and safety of the medicinal product in children under 18 years of age have not been established. Available information is presented in the section «Pharmacodynamics», but dosage recommendations cannot be provided. 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, etc.

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 head elevation. If possible, infusion of angiotensin II and/or intravenous administration of catecholamines should be provided. Perindopril can be removed from systemic circulation by hemodialysis (see section «Special warnings and precautions for use»). In case of treatment-resistant bradycardia, temporary cardiac pacing is indicated. Continuous monitoring of vital signs, serum electrolyte concentrations, and serum creatinine levels is required.

Adverse Reactions

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

During clinical trials and post-marketing use of perindopril, the following adverse reactions have been observed with the following frequencies: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10000, < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated from 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 disturbances – 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: 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; 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 and administration site conditions: 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 enzymes – rare.

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

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

Clinical Trials

During the randomized 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. In patients receiving perindopril, arterial hypotension occurred in 6 patients, angioedema in 3 patients, and sudden cardiac arrest in 1 patient. Among 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 adverse reactions after marketing authorization is of great importance. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: 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 and sight of children.

Packaging.

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

Prescription status.

Prescription only.

Manufacturer.

MICROCHEM LLC (responsible for batch release, excluding batch control/testing).

JSC "Farmak" (full-cycle manufacturing).

Manufacturer's address and location of operations.

Ukraine, 01013, Kyiv, Budynstustriyi St., 5.

Ukraine, 04080, Kyiv, Kyrylivska St., 74.

Marketing Authorization Holder.

MICROCHEM LLC.

Address of Marketing Authorization Holder.

Ukraine, 01013, Kyiv, Budynstustriyi St., 5.

You can report an adverse event associated with the use of this medicinal product by calling +38 (050) 309-83-54 (24/7).