Prestarium® 2.5 mg: detailed information

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT PRESTARIUM® 2.5 mg (PRESTARIUM® 2.5 mg) PRESTARIUM® 5 mg (PRESTARIUM® 5 mg) PRESTARIUM® 10 mg (PRESTARIUM® 10 mg)

Composition:

Prestarium® 2.5 mg:

Active substance: perindopril arginine;

One tablet contains 2.5 mg of perindopril arginine, equivalent to 1.6975 mg of perindopril;

Excipients: lactose monohydrate, magnesium stearate, maltodextrin, colloidal anhydrous silica, sodium starch glycolate (type A), glycerol (E 422a), hypromellose (E 464), macrogol 6000, titanium dioxide (E 171);

Prestarium® 5 mg:

Active substance: perindopril arginine;

One tablet contains 5 mg of perindopril arginine, equivalent to 3.395 mg of perindopril;

Prestarium® 10 mg:

Active substance: perindopril arginine;

One tablet contains 10 mg of perindopril arginine, equivalent to 6.790 mg of perindopril;

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics:

Prestarium® 2.5 mg: white, round, convex film-coated tablets.

Prestarium® 5 mg: light green, oval-shaped film-coated tablets, with embossing on one side and notches on both edges.

Prestarium® 10 mg: green, round, biconvex film-coated tablets, with embossing on one side and the other.

Pharmacotherapeutic group. Angiotensin-converting enzyme (ACE) inhibitors.

ATC code C09A A04.

Pharmacological Properties.

Pharmacodynamics.

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

Perindopril arginine acts via its active metabolite—perindoprilat. Other metabolites do not demonstrate activity in ACE inhibition under experimental conditions.

Arterial Hypertension.

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

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

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

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

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

Upon discontinuation of perindopril arginine, no rebound effect occurs.

Perindopril reduces left ventricular hypertrophy.

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

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

Heart Failure.

Perindopril arginine reduces cardiac workload by decreasing preload and afterload on the heart.

Studies involving patients with heart failure have demonstrated:

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

In comparative studies, initial administration of 2.5 mg perindopril arginine 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 evaluated 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 (equivalent to perindopril arginine 2.5 mg) once daily, followed by 2 weeks of 4 mg (equivalent to perindopril arginine 5 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 (equivalent to perindopril arginine 5 mg) as monotherapy or in combination with indapamide (n=3051). Indapamide was added to patients who had indications for diuretic therapy and no contraindications to its use.

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

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

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

Significant risk reductions were also observed for:

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 (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, type of stroke, or presence of diabetes. The results of the PROGRESS study showed that after 5 years of treatment, one stroke could be prevented per 23 patients treated, and one major cardiovascular complication per 18 patients treated.

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 (equivalent to perindopril arginine 10 mg) and 6108 received placebo. Patients enrolled had confirmed ischemic heart disease without clinical symptoms of heart failure. Overall, 90% of patients had a history of myocardial infarction and/or revascularization surgery. Most patients in the study received perindopril in addition to standard therapy: antiplatelet agents, lipid-lowering drugs, and β-blockers.

The primary efficacy endpoint was a composite of cardiovascular mortality, non-fatal myocardial infarction, and/or cardiac arrest followed by successful resuscitation. Treatment with perindopril 8 mg (equivalent to perindopril arginine 10 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, an absolute reduction of 2.2% in the primary endpoint was observed, corresponding to a 22.4% relative risk reduction (95% CI [12.0; 31.6], p<0.001) compared to placebo.

Pediatric Use.

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 glomerular filtration rate >30 mL/min/1.73 m² received 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 depending on patient profile and blood pressure response to treatment. 59 patients participated in the study for 3 months, and 36 continued treatment for at least 24 months (mean study duration 44 months). Systolic and diastolic blood pressure remained stable (from study entry to last visit) in patients previously treated with other antihypertensive agents and decreased in those previously untreated. More than 75% of children had systolic and diastolic blood pressure below the 95th percentile at their last study visit. The safety profile in children corresponded to the known safety profile of perindopril.

Pharmacokinetics.

Absorption. After oral administration, perindopril is rapidly absorbed, with peak plasma concentration reached within 1 hour. The half-life of perindopril in plasma is 1 hour.

Perindopril is a prodrug. 27% of the total administered perindopril is detected 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 arginine is recommended to be taken once daily in the morning before meals.

A linear relationship between perindopril dose and plasma concentration is observed.

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

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

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

Dialysis clearance of perindoprilat is 70 mL/min.

Perindopril kinetics are altered in patients with liver cirrhosis: hepatic clearance of perindopril is reduced by half. 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, 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;
Pregnancy or women planning to become pregnant (see section "Use during pregnancy or breastfeeding");
Concomitant use with medicinal products containing aliskiren in patients with diabetes mellitus or renal impairment (glomerular filtration rate < 60 mL/min/1.73 m²) (see section "Interaction with other medicinal products and other forms of interaction");
Concomitant use with sacubitril/valsartan. Treatment with PRESTARIUM® must not be initiated 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");
Extracorporeal treatment methods leading to blood contact with negatively charged surfaces (see section "Interaction with other medicinal products and other forms of interaction");
Severe 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 trial 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 hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to use of a single RAAS-acting agent (see sections "Contraindications" and "Special precautions").

Medicinal products increasing the risk of angioedema

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema (see section "Contraindications", "Special precautions"). 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").

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").

Medicinal products causing hyperkalemia.

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

Concomitant use contraindicated (see section "Contraindications").

Aliskiren: in patients with diabetes mellitus or renal impairment, the risk of hyperkalemia, worsening renal function, 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 low-density lipoprotein apheresis with dextran sulfate, may increase the risk of severe anaphylactoid reactions (see section "Contraindications"). If such treatment is required, consideration should be given to using a different type of dialysis membrane or another class of antihypertensive agents.

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

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

Concomitant use of an ACE inhibitor and an angiotensin receptor blocker

Literature data indicate that in patients with established atherosclerosis, heart failure, or diabetes with target organ damage, concomitant use of ACE inhibitors and angiotensin receptor blockers is associated with increased incidence of arterial hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared to monotherapy with agents affecting the renin-angiotensin-aldosterone system. 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.

Estrogen: 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 agents are not recommended for concomitant use with perindopril (see section "Special precautions"). However, if concomitant use is necessary, they should be used with caution and frequent monitoring of serum potassium levels. For use of spironolactone in heart failure, see the section “Concomitant use requiring special attention”.

Lithium. Use of ACE inhibitors with lithium-containing preparations has been associated with reversible increases in serum lithium concentrations and lithium toxicity. Concomitant use of perindopril with lithium is not recommended. If such use 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 suggest that concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemic agents) may enhance the glucose-lowering effect, increasing the risk of hypoglycemia. This phenomenon is more likely during the first weeks of combination therapy and in patients with renal impairment.

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

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

Potassium-sparing diuretics (eplerenone, spironolactone). When eplerenone or spironolactone (12.5–50 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 is recommended weekly during the first month and monthly thereafter.

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

Concomitant use requiring attention.

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

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

Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.

Gold: nitrate-like reactions (symptoms include facial flushing, nausea, vomiting, and arterial hypotension) have rarely been 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 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 occurs less frequently 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, or patients with diarrhea or vomiting, as well as in patients with severe renin-dependent arterial hypertension (see sections "Interaction with other medicinal products and other forms of interaction" and "Side effects"). Symptomatic arterial hypotension has been observed in patients with symptomatic heart failure, with or without concomitant renal impairment. The occurrence of symptomatic arterial hypotension is most likely in patients with more severe degrees of heart failure who are receiving high doses of loop diuretics, have hyponatremia, or have functional renal impairment. Patients at increased risk of symptomatic arterial hypotension should be closely monitored by a physician during initiation of therapy and dose titration (see sections "Dosage and administration" and "Side effects"). The same precautions apply to patients with ischemic heart disease or cerebrovascular disorders, in whom excessive reduction in blood pressure may lead to myocardial infarction or stroke.

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

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

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

Renal function impairment.

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

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

In some patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney, increases in blood urea nitrogen and serum creatinine levels have been observed during ACE inhibitor therapy, which usually return to normal after discontinuation of treatment. 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 view of the above, diuretic therapy may predispose to arterial hypotension; therefore, diuretics should be discontinued and renal function should be monitored during the first weeks of treatment with perindopril arginine.

In some patients with arterial hypertension who had no pre-existing renovascular disease, increases in blood urea nitrogen and serum creatinine levels have been observed, usually mild and transient, especially when perindopril arginine was administered concomitantly with diuretics. However, this is more typical for patients with pre-existing renal impairment. Dose reduction and/or discontinuation of the diuretic and/or perindopril arginine may become necessary.

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

Patients after kidney transplantation. Experience with the use of perindopril arginine in patients after recent kidney transplantation is lacking.

Renovascular hypertension.

When ACE inhibitors are prescribed to patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney, the risk of hypotension and renal failure increases (see section "Contraindications"). 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 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 arginine (see section "Side effects"). This may occur at any time during treatment. In such cases, the drug must be discontinued immediately, and appropriate monitoring of the patient should be 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 antihistamines may be helpful in reducing symptoms.

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

Rare cases of intestinal angioedema have been reported in patients receiving ACE inhibitors. These patients 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 computed tomography of the abdomen, 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"). Initiation of sacubitril/valsartan should not occur earlier than 36 hours after the last dose of perindopril. If treatment with sacubitril/valsartan is discontinued, therapy with perindopril should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Concomitant use of ACE inhibitors with neutral endopeptidase inhibitors (NEP) (e.g., racecadotril), mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) may increase the risk of angioedema (e.g., airway or tongue swelling, with or without respiratory compromise) (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 session.

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

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

Neutropenia/agranulocytosis, thrombocytopenia, and anemia.

Cases of neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported in patients receiving ACE inhibitors. Neutropenia occurs rarely in patients with normal renal function and in the absence of other risk factors. Perindopril should be used with extreme caution in patients with collagen vascular diseases, those receiving immunosuppressants, allopurinol, or procainamide, or in combination with these risk factors, especially if renal function is impaired. Some of these patients developed severe 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 to report any signs of infection (sore throat, fever).

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

Cough. Cough has been reported during ACE inhibitor therapy. The cough is typically non-productive 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 anesthesia with hypotensive agents, perindopril may block the secondary formation of angiotensin II in response to compensatory renin release. The drug should be discontinued one day before surgery. If arterial hypotension develops and is considered to be due to this mechanism, the patient's condition can be normalized by increasing circulating blood volume.

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

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

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

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

Dual blockade of the renin-angiotensin-aldosterone system (RAAS). Data indicate that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of hypotension, hyperkalemia, and 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 dual blockade therapy with two RAAS blockers is considered absolutely necessary, it should be performed only under specialist supervision and with frequent careful monitoring of renal function, electrolyte levels, and blood pressure. ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

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

Excipients. The drug contains lactose; therefore, patients with rare hereditary intolerance to galactose, glucose-galactose malabsorption syndrome, or severe lactase deficiency should not take perindopril arginine.

Sodium content: PRESTARIL® contains less than 1 mmol of sodium (23 mg) per tablet, i.e., it is almost sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy

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

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

Breastfeeding

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

Fertility

No effect on reproductive capacity or fertility has been observed.

Ability to affect reaction speed when driving or operating machinery.

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

Method of Administration and Dosage

For oral use.

The 2.5 mg tablets (Prestarium® 2.5 mg) and 10 mg tablets (Prestarium® 10 mg) must not be divided. The 5 mg tablets (Prestarium® 5 mg) may be divided into two equal doses.

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

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

Arterial Hypertension.

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

The recommended initial dose is 5 mg once daily in the morning.

Patients with high activity of the renin-angiotensin-aldosterone system (particularly those with renovascular hypertension, fluid and electrolyte imbalance, cardiac decompensation, or severe hypertension) may experience excessive reduction in blood pressure after the first dose. Such patients should start treatment with a 2.5 mg dose, and therapy initiation should be under medical supervision.

The dose may be increased to 10 mg once daily after 1 month of treatment.

Symptomatic arterial hypotension may occur at the beginning of perindopril arginine 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 perindopril arginine (see section "Special Instructions").

For hypertensive patients in whom diuretic therapy cannot be discontinued, treatment should begin with a 2.5 mg dose. In such patients, renal function and serum potassium levels should be monitored. Further dose escalation of perindopril arginine should be based on blood pressure response. If necessary, diuretic therapy may be resumed.

Elderly patients should start treatment with a 2.5 mg dose, which may be increased to 5 mg after 1 month of treatment, and then, if necessary, to 10 mg, taking into account renal function (see table below).

Symptomatic Heart Failure.

For patients with heart failure, perindopril arginine is usually prescribed in combination with a potassium-depleting diuretic and/or digoxin and/or a β-blocker. Therapy should be initiated under close medical supervision with an initial morning dose of 2.5 mg. After 2 weeks, if well tolerated, the dose should be increased to 5 mg once daily. Subsequently, the dose should be individually adjusted according to the patient's clinical response to treatment.

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

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

Prevention of Recurrent Stroke in Patients with Cerebrovascular Disease.

The recommended initial dose is 2.5 mg (½ tablet of Prestarium® 5 mg) once daily in the morning. After 2 weeks of treatment, the dose should be increased to 5 mg (1 tablet of Prestarium® 5 mg) once daily in the morning.

If additional blood pressure control is required after 2 weeks of treatment with Prestarium® 5 mg, 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 Prestarium® 10 mg (1 tablet daily) reduces the risk of myocardial infarction and heart failure (based on a 4-year EUROPA study). Treatment should be initiated with Prestarium® 5 mg (1 tablet once daily in the morning). After 2 weeks, if well tolerated, the dose should be increased to 10 mg for long-term use of Prestarium® 10 mg (1 tablet daily in the morning).

In elderly patients with documented ischemic heart disease, treatment should begin with a dose of 2.5 mg (½ tablet of Prestarium® 5 mg) once daily in the morning; after one week, the dose should be increased to 5 mg (1 tablet of Prestarium® 5 mg); after 2 weeks, if well tolerated and depending on renal function, the dose should be increased to 10 mg (Prestarium® 10 mg, 1 tablet daily) to begin long-term treatment.

Dose Adjustment in Renal Impairment.

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

Table 1: Dose adjustment in renal impairment

Creatinine clearance (mL/min)	Recommended dosage
ClCR ≥ 60	5 mg once daily
30 < ClCR < 60	2.5 mg once daily
15 < ClCR < 30	2.5 mg every other day
Patients undergoing hemodialysis*
ClCR < 15	2.5 mg on dialysis days

٭Dialysis clearance of perindoprilat is 70 mL/min.

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

Dose adjustment in hepatic impairment.

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

Children.

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

Overdose.

Information on perindopril overdose is limited. Symptoms associated with overdose of ACE inhibitors 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 infusions and/or intravenous catecholamines should be administered. Perindopril can be removed from systemic circulation by hemodialysis (see section "Special precautions"). In case of treatment-resistant bradycardia, a pacemaker is indicated. Continuous monitoring of vital signs, serum electrolytes, and creatinine levels is necessary.

Adverse reactions.

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

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

Organ systems by MedDRA classification	Adverse reactions	Frequency
Blood and lymphatic system disorders	Eosinophilia	Uncommon*
	Agranulocytosis or pancytopenia	Very rare
	Decreased hemoglobin and hematocrit levels	Very rare
	Leukopenia/neutropenia	Very rare
	Hemolytic anemia in patients with congenital glucose-6-phosphate dehydrogenase deficiency	Very rare
	Thrombocytopenia	Very rare
Endocrine disorders	Syndrome of inappropriate antidiuretic hormone secretion (SIADH)	Uncommon
Metabolism and nutrition disorders	Hypoglycemia	Uncommon*
	Reversible hyperkalemia after discontinuation of the drug	Uncommon*
	Hypokalemia	Uncommon*
Psychiatric disorders	Depression	Uncommon*
	Mood disturbances	Uncommon
	Sleep disturbances	Uncommon
Nervous system disorders	Dizziness	Common
	Headache	Common
	Paresthesia	Common
	Vertigo	Common
	Somnolence	Uncommon*
	Syncope	Uncommon*
	Confusion	Very rare
Eye disorders	Visual disturbances	Common
Ear and labyrinth disorders	Tinnitus	Common
Cardiac disorders	Palpitations	Uncommon*
	Tachycardia	Uncommon*
	Angina pectoris	Very rare
	Arrhythmia	Very rare
	Myocardial infarction may occur due to excessive reduction in blood pressure in high-risk patients	Very rare
Vascular disorders	Hypotension (and associated symptoms)	Common
	Vasculitis	Uncommon*
	Hot flushes	Rare*
	Stroke may occur due to excessive reduction in blood pressure in high-risk patients	Very rare
	Raynaud's phenomenon	Frequency unknown
Respiratory, thoracic and mediastinal disorders	Cough	Common
	Dyspnea	Common
	Bronchospasm	Uncommon
	Eosinophilic pneumonia	Very rare
	Rhinitis	Very rare
Gastrointestinal disorders	Abdominal pain	Common
	Constipation	Common
	Diarrhea	Common
	Disturbance of taste (dysgeusia)	Common
	Dyspepsia	Common
	Nausea	Common
	Vomiting	Common
	Dry mouth	Uncommon
	Pancreatitis	Very rare
Hepatobiliary disorders	Cytolytic or cholestatic hepatitis	Very rare
Skin and subcutaneous tissue disorders	Pruritus	Common
	Rash	Common
	Urticaria	Uncommon
	Angioedema of the face, limbs, lips, mucous membranes, tongue, glottis and/or larynx	Uncommon
	Photosensitivity reactions	Uncommon*
	Pemphigoid	Uncommon*
	Hyperhidrosis	Uncommon
	Worsening of psoriasis symptoms	Rare
	Multiform erythema	Very rare
Musculoskeletal and connective tissue disorders	Muscle cramps	Common
	Arthralgia	Uncommon*
	Myalgia	Uncommon*
Renal and urinary disorders	Renal impairment	Uncommon
	Acute renal failure	Rare
	Anuria/oliguria	Rare*
Reproductive system and breast disorders	Erectile dysfunction	Uncommon
General disorders	Asthenia	Common
	Chest pain	Uncommon*
	Malaise	Uncommon*
	Peripheral edema	Uncommon*
	Hyperthermia	Uncommon*
Investigations	Increased blood urea levels	Uncommon*
	Elevated blood creatinine levels	Uncommon*
	Elevated blood bilirubin levels	Rare
	Elevated liver enzymes	Rare
Injury, poisoning and procedural complications	Falls	Uncommon*

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

Clinical trials

During the randomized period of the EUROPA study, information was collected only on serious adverse reactions. A small number of patients experienced serious adverse reactions: 16 (0.3%) out of 6122 patients in the perindopril group and 12 (0.2%) out of 6107 patients in the placebo group. Among patients receiving perindopril, hypotension was observed in 6 patients, angioneurotic edema 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 suspected adverse reactions. Reporting suspected adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national reporting system.

Shelf life. 3 years.

Storage conditions.

Store tablets in a tightly closed container. Keep out of reach of children.

Packaging.

14 or 30 tablets per tablet container; 1 tablet container per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Laboratoires Servier Industrie /
Les Laboratoires Servier Industrie.

Manufacturer's address and location of manufacturing site.

905 route de Saran, 45520 Gidy, France /
905 route de Saran, 45520 Gidy, France.

Manufacturer.

Servier (Ireland) Industries Ltd. /
Servier (Ireland) Industries Ltd.

Manufacturer's address and location of manufacturing site.

Moneylands, Gorey Road, Arklow, Co. Wicklow, Ireland /
Moneylands, Gorey Road, Arklow, Co. Wicklow, Ireland.

Marketing Authorization Holder.

LES LABORATOIRES SERVIER /
LES LABORATOIRES SERVIER.

Address of the Marketing Authorization Holder.

50, rue Carnot, 92284 Suresnes Cedex, France /
50, rue Carnot, 92284 Suresnes Cedex, France.

For any information regarding this medicinal product, please contact LLC "Servier Ukraine" by phone: (044) 490 3441, fax: (044) 490 3440.