ENAT 200
How to use ENAT 200
INSTRUCTIONS 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;
1 tablet contains perindopril arginine 2.5 mg, which corresponds to 1.6975 mg of perindopril;
excipients: lactose monohydrate, magnesium stearate, maltodextrin, colloidal silicon dioxide, sodium carboxymethyl starch (type A), glycerin (E 422a), hypromellose (E 464), macrogol 6000, titanium dioxide (E 171);
PRESTARIUM®5 mg:
active substance: perindopril arginine;
1 tablet contains perindopril arginine 5 mg, which corresponds to 3.395 mg of perindopril;
excipients: lactose monohydrate, magnesium stearate, maltodextrin, colloidal silicon dioxide, sodium carboxymethyl starch (type A), glycerin (E 422a), hypromellose (E 464), macrogol 6000, titanium dioxide (E 171), copper chlorophyllin (E 141ii);
PRESTARIUM®10 mg:
active substance: perindopril arginine;
1 tablet contains perindopril arginine 10 mg, which corresponds to 6.790 mg of perindopril;
excipients: lactose monohydrate, magnesium stearate, maltodextrin, colloidal silicon dioxide, sodium carboxymethyl starch (type A), glycerin (E 422a), hypromellose (E 464), macrogol 6000, titanium dioxide (E 171), copper chlorophyllin (E 141ii).
Pharmaceutical form.
Tablets, film-coated.
Main physical and chemical properties:
PRESTARIUM®2.5 mg: white, round, biconvex tablets, film-coated.
PRESTARIUM®5 mg: light green, oval-shaped tablets, film-coated, with engraving on one side and a notch on both edges.
PRESTARIUM®10 mg: green, round, biconvex tablets, film-coated, with engraving on one side and a notch on the other.
Pharmacotherapeutic group.
Angiotensin-converting enzyme inhibitors (ACE inhibitors).
ATC code C09A A04.
Pharmacological properties.
Pharmacodynamics.
Perindopril is an inhibitor of the enzyme that converts angiotensin I to angiotensin II (angiotensin-converting enzyme, ACE). The converting enzyme, or kinase, is an exopeptidase that makes it possible to convert angiotensin I into vasoconstrictive angiotensin II, and also causes the breakdown of the vasodilator bradykinin into an inactive heptapeptide. Inhibition of ACE leads to a decrease in the concentration of angiotensin II in the blood plasma, which increases the activity of renin in the blood plasma (due to the suppression of negative feedback on the release of renin) and reduces the secretion of aldosterone. Since ACE inactivates bradykinin, ACE inhibition also leads to an increase in the activity of the circulating and local kallikrein-kinin system (and thus also leads to the activation of the prostaglandin system). This mechanism of action causes a decrease in blood pressure in ACE inhibitors and is partly responsible for the occurrence of some side effects (such as cough).
Perindopril arginine acts through its active metabolite, perindoprilat. Other metabolites do not demonstrate activity in inhibiting ACE in experimental conditions.
Hypertension.
Perindopril effectively lowers blood pressure in all stages of hypertension: mild, moderate, and severe; a decrease in systolic and diastolic blood pressure is observed both in the supine and standing positions.
Perindopril reduces peripheral vascular resistance, which leads to a decrease in blood pressure. As a result, peripheral blood flow increases without affecting heart rate.
Usually, renal blood flow also increases, while the glomerular filtration rate (GFR) usually does not change.
The maximum antihypertensive effect develops within 4-6 hours after a single dose and is maintained for at least 24 hours: the T/R ratio (trough/peak - minimum efficacy/maximum efficacy throughout the day) of perindopril is 87-100%.
Blood pressure decreases rapidly. In patients who respond to treatment, normalization of blood pressure occurs within a month and is maintained without the development of tachyphylaxis.
When perindopril arginine is discontinued, there is no withdrawal effect.
Perindopril reduces left ventricular hypertrophy.
Clinical studies have shown that perindopril has vasodilating properties.
It improves the elasticity of large arteries and reduces the ratio of wall thickness to vessel lumen for 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 hypokalemia caused by the diuretic.
Heart failure.
Perindopril arginine reduces the workload on the heart by reducing both preload and afterload on the heart.
Studies in patients with heart failure have demonstrated:
- a decrease in the pressure of filling the right and left ventricles,
- a decrease in systemic peripheral resistance,
- an increase in cardiac index and improvement in cardiac output.
In comparative studies, the initial appointment of 2.5 mg of perindopril arginine to patients with heart failure of mild and moderate severity was not associated with any significant decrease in blood pressure compared to placebo.
Patients with a history of cerebrovascular diseases.
The multicenter international double-blind randomized placebo-controlled PROGRESS study determined the benefits of 4-year treatment with perindopril (in monotherapy or in combination with indapamide) in preventing recurrent stroke in patients with a history of cerebrovascular diseases.
The primary endpoint was stroke.
After 2 weeks (run-in period) of taking perindopril tert-butylamine at a dose of 2 mg (which is equivalent to perindopril arginine 2.5 mg) 1 time per day, and subsequent 2 weeks of taking at a dose of 4 mg (which is equivalent to perindopril arginine 5 mg) 1 time per day, 6105 patients were randomized into two groups: in one group, patients took a placebo (n = 3054), and in the other, perindopril tert-butylamine 4 mg (which is equivalent to perindopril arginine 5 mg) in monotherapy or in combination with indapamide (n = 3051). Indapamide was added to patients who had indications for diuretic therapy and did not have contraindications to its use.
This therapy was prescribed in addition to traditional treatment for stroke and/or hypertension or any other pathological conditions.
All patients who participated in the study had a history of cerebrovascular diseases (stroke or transient ischemic attack) within the last 5 years. Blood pressure was not a criterion for inclusion in the study: 2916 patients had hypertension, 3189 patients had normal blood pressure.
After an average of 3.9 years of observation, systolic/diastolic blood pressure decreased by an average of 9.0/4.0 mmHg, and the risk of recurrent strokes (both ischemic and hemorrhagic) decreased significantly by 28% (95% CI [17; 38], p <0.0001) compared to patients taking a placebo (10.1% versus 13.8%).
Also, a significant reduction in the risk of:
- fatal or disabling stroke (4% versus 5.9%, which corresponds to a 33% reduction in risk);
- the total number of significant cardiovascular events, which include cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke (15% versus 19.8%, which corresponds to a 26% reduction in risk);
- dementia resulting from stroke (1.4% versus 2.1%, which corresponds to a 34% reduction in risk), and severe cognitive impairment resulting from stroke (1.6% versus 2.8%, which corresponds to a 45% reduction in risk);
- significant coronary events, including non-fatal myocardial infarction or death resulting from ischemic heart disease (3.8% versus 5%, which corresponds to a 26% reduction in risk).
These therapeutic benefits were observed in patients regardless of the presence or absence of hypertension, regardless of age, sex, type of stroke, or presence of diabetes. The results of the PROGRESS study showed that after 5 years of treatment, it is possible to avoid the occurrence of one stroke in every 23 patients and one serious cardiovascular complication in every 18 patients.
Patients with stable ischemic heart disease.
EUROPA is an international multicenter randomized double-blind placebo-controlled clinical study that lasted 4 years. 12,218 patients aged 18 years and older were randomized into groups: 6,110 patients took 8 mg of perindopril tert-butylamine (which is equivalent to perindopril arginine 10 mg) and 6,108 patients took a placebo. The study included patients with confirmed ischemic heart disease and without clinical symptoms of heart failure. In total, 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, hypolipidemic agents, and beta-blockers.
The primary efficacy criterion was the combined assessment of the occurrence of cardiovascular mortality, non-fatal myocardial infarction, and/or cardiac arrest with subsequent successful resuscitation. Treatment with perindopril at a dose of 8 mg (which is equivalent to perindopril arginine 10 mg) once a day led to a significant absolute reduction in the primary endpoint of the study by 1.9% (a 20% reduction in relative risk, 95% CI [9.4; 28.6] - p <0.001).
In patients with a history of myocardial infarction and/or revascularization, an absolute reduction in the primary endpoint of 2.2% was observed, which corresponds to a 22.4% reduction in relative risk (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 clinical study without a comparison group, 62 children aged 2 to 15 years with a glomerular filtration rate of > 30 mL/min/1.73 m2were prescribed perindopril at an average dose of 0.07 mg/kg. The dose of the drug was selected individually, with an increase to a maximum of 0.135 mg/kg/day, depending on the patient's profile and response to treatment. 59 patients participated in the study for 3 months, 36 patients continued treatment for at least 24 months (average study duration 44 months). Systolic and diastolic blood pressure remained stable (from the moment of inclusion in the study to the last visit) in patients who were previously treated with other antihypertensive drugs and decreased in patients who were not previously treated. More than 75% of children had systolic and diastolic blood pressure below the 95th percentile during their last visit to the study. The safety profile of perindopril in children was consistent with the known safety profile of perindopril.
Pharmacokinetics.
Absorption.
After oral administration, perindopril is rapidly absorbed, with a maximum concentration in blood plasma reached within 1 hour. The half-life of perindopril in blood plasma is 1 hour.
Perindopril is a prodrug. 27% of the total amount of perindopril taken is determined in the blood as an active metabolite - perindoprilat. In addition to the active metabolite - perindoprilat, the drug forms 5 metabolites that are inactive. The maximum concentration of perindoprilat in blood plasma is reached within 3-4 hours after administration.
Food intake reduces the conversion of perindopril to perindoprilat, thereby reducing its bioavailability, so the daily dose of perindopril arginine is recommended to be taken once in the morning before meals.
A linear relationship is observed between the dose of perindopril and its concentration in blood plasma.
Distribution.
The volume of distribution of unbound perindoprilat is approximately 0.2 L/kg. Binding of perindoprilat to plasma proteins is 20%, mainly with 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. The steady-state concentration in blood plasma is reached within 4 days of starting treatment.
Special patient groups.
The elimination of perindoprilat is slowed down in elderly patients, as well as in patients with heart or kidney failure. It is recommended to select a dose for patients with kidney failure, taking into account the degree of failure (creatinine clearance).
The dialysis clearance of perindoprilat is 70 mL/min.
The kinetics of perindopril changes in patients with liver cirrhosis: the hepatic clearance of perindopril is reduced by half. However, the amount of perindoprilat formed does not decrease. Therefore, such patients do not need to adjust the dose.
Clinical characteristics.
Indications.
- Hypertension.
- Heart failure.
- Prevention of recurrent stroke in patients with a history of cerebrovascular diseases.
- Prevention of cardiovascular complications in patients with documented stable ischemic heart disease. Long-term treatment reduces the risk of myocardial infarction and heart failure (according to the results of the EUROPA study).
Contraindications.
- Increased sensitivity to perindopril or to any of the excipients, or to any other ACE inhibitor;
- angioedema in history, associated with previous treatment with an ACE inhibitor (see section "Special warnings and precautions for use");
- idiopathic or hereditary angioedema;
- pregnant or women who plan to become pregnant (see section "Pregnancy and lactation");
- concomitant use with drugs containing the active substance aliskiren, patients with diabetes or impaired renal function (glomerular filtration rate < 60 mL/min/1.73 m2) (see section "Interactions with other medicinal products and other forms of interaction");
- concomitant use with sacubitril/valsartan. The use of the PRESTARIUM®preparation cannot be started earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Interactions with other medicinal products and other forms of interaction");
- extracorporeal treatments that lead to contact between blood and negatively charged surfaces (see section "Interactions with other medicinal products and other forms of interaction");
- significant bilateral stenosis of the renal arteries or stenosis of the artery of a single functioning kidney (see section "Special warnings and precautions for use").
Interactions with other medicinal products and other forms of interaction.
Clinical data indicate that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with a higher frequency of adverse reactions such as hypotension, hyperkalemia, and decreased renal function (including acute renal failure) compared to monotherapy with RAAS-acting drugs (see sections "Contraindications" and "Special warnings and precautions for use").
Medicines that increase the risk of angioedema
Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated, as it increases the risk of angioedema (see section "Contraindications", "Special warnings and precautions for use"). Sacubitril/valsartan should not be started earlier than 36 hours after the last dose of perindopril. Perindopril therapy should not be started earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Interactions with other medicinal products and other forms of interaction").
Concomitant use of ACE inhibitors with raccadotril, mTOR inhibitors (such as sirolimus, everolimus, temsirolimus), and gliptins (such as linagliptin, saxagliptin, sitagliptin, vildagliptin) may increase the risk of angioedema (see section "Special warnings and precautions for use").
Medicines that cause hyperkalemia.
The level of potassium in the blood serum is usually normal, but in some patients taking the PRESTARIUM®preparation, hyperkalemia may occur. Some medicines or therapeutic classes of medicines may cause hyperkalemia, namely: aliskiren, potassium salts, potassium-sparing diuretics (such as 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 substances increases the risk of hyperkalemia. Therefore, concomitant use of the PRESTARIUM®preparation with the above-mentioned substances is not recommended. If concomitant use of these substances is necessary, they should be used with caution and frequent monitoring of potassium levels in the blood serum.
Concomitant use is contraindicated (see section "Contraindications").
Aliskiren: in patients with diabetes or impaired renal function, the risk of hyperkalemia, decreased renal function, and cardiovascular disease and mortality increases.
Extracorporeal treatments that lead to contact between blood and negatively charged surfaces, such as high-flux membranes for dialysis or hemofiltration (e.g., polyacrylate membranes) and for apheresis of low-density lipoproteins with dextran sulfate, may increase the risk of severe anaphylactoid reactions (see section "Contraindications"). In case of need for such treatment, it is recommended to consider the possibility of using a dialysis membrane of a different type or applying a different class of antihypertensive drugs.
Concomitant use is not recommended (see section "Special warnings and precautions for use").
Aliskiren: in any other patients, as well as in patients with diabetes or impaired renal function, the risk of hyperkalemia, decreased renal function, and cardiovascular disease and mortality increases.
Concomitant use of an ACE inhibitor and an angiotensin II receptor blocker
According to the literature, in patients with established atherosclerosis, heart failure, or diabetes with target organ damage, concomitant use of ACE inhibitors and angiotensin II receptor blockers is associated with an increased frequency of hypotension, syncope, hyperkalemia, and decreased renal function (including acute renal failure) compared to monotherapy with RAAS-acting drugs. The use of dual blockade (i.e., the combination of an ACE inhibitor with an angiotensin II receptor antagonist) is possible only in individual cases, subject to careful monitoring of renal function, potassium levels, and blood pressure.
Estramustine: increased risk of side effects, such as angioedema (angioedema).
Potassium-sparing diuretics (e.g., triamterene, amiloride, and others), potassium salts: the occurrence of hyperkalemia (potentially fatal), especially in patients with impaired renal function (additive hyperkalemic effect). These drugs are not recommended for concomitant use with perindopril (see section "Special warnings and precautions for use"). However, if concomitant use of these substances is necessary, they should be used with caution and frequent monitoring of potassium levels in the blood serum. Regarding the use of spironolactone in heart failure, see the "Concomitant use requiring special attention" section.
Lithium. When ACE inhibitors are used with lithium preparations, reversible increases in lithium concentrations in the blood serum and its toxicity have been reported. It is not recommended to use perindopril with lithium preparations. If such use is necessary, it is mandatory to carefully monitor the lithium level in the blood serum (see section "Special warnings and precautions for use").
Concomitant use requiring special attention.
Antidiabetic agents (insulin, oral hypoglycemic agents).
The results of epidemiological studies suggest that concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemic agents) may enhance the hypoglycemic effect, with a risk of hypoglycemia. This phenomenon is more likely to occur in the first weeks of combination therapy and in patients with renal impairment.
Baclofen enhances the antihypertensive effect. It is necessary to monitor blood pressure and, if necessary, adjust the dose of the antihypertensive agent.
Diuretics. In patients taking diuretics, especially those with impaired water and electrolyte balance, the risk of excessive hypotension after starting treatment with an ACE inhibitor is increased. The likelihood of developing a hypotensive effect can be reduced by discontinuing the diuretic, increasing the circulating blood volume, or consuming salt before starting therapy with perindopril, which should be started at a low dose with gradual increase. In patients with hypertension, when a previously prescribed diuretic may have caused water and electrolyte deficiency, it is recommended to discontinue the diuretic before starting treatment with an ACE inhibitor (in such cases, the diuretic can be resumed over time). In patients with congestive heart failure on diuretic therapy, ACE inhibitor therapy should be started with a minimal dose, possibly after reducing the diuretic dose. In any case, it is necessary to monitor renal function (creatinine level) during the first weeks of treatment with an ACE inhibitor.
Concomitant use requiring attention.
Antihypertensive agents and vasodilators: concomitant use of antihypertensive agents may increase the hypotensive effect of perindopril. Concomitant use with nitroglycerin and other nitrates or with other vasodilators may contribute to additional blood pressure reduction.
Concomitant use of certain tricyclic antidepressants or antipsychotic agents, or anesthetics with ACE inhibitors may lead to further blood pressure reduction (see section "Special warnings and precautions for use").
Sympathomimetics may weaken the antihypertensive effect of ACE inhibitors.
Gold: a nitrate-like reaction (symptoms include flushing of the face, nausea, vomiting, and hypotension) has been rarely observed in patients who concomitantly took ACE inhibitors, including perindopril, and injectable gold preparations (sodium aurothiomalate).
Special warnings and precautions for use.
Stable ischemic heart disease.
In case of unstable angina pectoris of any severity during the first month of treatment with perindopril, it is necessary to carefully weigh the risk/benefit ratio before deciding on further treatment.
Hypotension.
The use of ACE inhibitors can cause a decrease in blood pressure. Symptomatic hypotension is rare in patients with uncomplicated hypertension and is more likely in patients with hypovolemia, those taking diuretics, on a low-sodium diet, on dialysis, with diarrhea or vomiting, or with severe renin-dependent hypertension (see sections "Interactions with other medicinal products and other forms of interaction" and "Adverse reactions"). Symptomatic hypotension has been observed in patients with symptomatic heart failure, with or without associated impaired renal function. The occurrence of symptomatic hypotension is most likely in patients with more severe heart failure, who are taking high doses of loop diuretics, have hyponatremia, or have functional renal insufficiency. Patients at increased risk of symptomatic hypotension should be under close medical supervision during the initiation of therapy and during the dose titration period (see sections "Posology and method of administration" and "Adverse reactions"). The same precautions apply to patients with ischemic heart disease or cerebrovascular diseases, in whom excessive blood pressure reduction may cause myocardial infarction or stroke.
In the event of hypotension, the patient should be placed in a horizontal position and, if necessary, administered intravenously with 0.9% (9 mg/mL) sodium chloride solution. Transient hypotension is not a contraindication to further use of the drug, which can usually be used without any obstacles after restoration of blood volume and blood pressure.
In some patients with congestive heart failure with normal or low blood pressure, perindopril arginine may cause a further decrease in systemic blood pressure. This effect is predictable and usually does not require discontinuation of the drug. If hypotension becomes symptomatic, it may be necessary to reduce the dose or discontinue the drug.
Aortic and mitral stenosis/hypertrophic cardiomyopathy.
As with other ACE inhibitors, perindopril arginine should be prescribed with caution to patients with mitral stenosis or outflow obstruction from the left ventricle (aortic stenosis or hypertrophic cardiomyopathy).
Impaired renal function.
In case of renal insufficiency (creatinine clearance < 60 mL/min), the initial dose of perindopril should be prescribed according to the patient's creatinine clearance (see section "Posology and method of administration"), and then - depending on the patient's response to treatment. Regular monitoring of potassium and creatinine levels is part of the usual medical practice for such patients (see section "Adverse reactions").
In patients with symptomatic heart failure, hypotension that occurs at the beginning of ACE inhibitor therapy may lead to impaired renal function, sometimes with the development of acute renal failure, which is usually reversible.
In some patients with bilateral stenosis of the renal arteries or stenosis of the artery of a single kidney, the use of ACE inhibitors has been associated with increased levels of urea and creatinine in the blood serum, which usually return to normal after discontinuation of treatment. This is especially true for patients with renal insufficiency. In the presence of associated renovascular hypertension, the risk of severe hypotension and renal failure increases. For such patients, treatment should be started under close medical supervision with small doses and cautious titration of doses. Given the above, treatment with diuretics may contribute to the development of hypotension, so they should be discontinued and renal function should be monitored in the first weeks of treatment with perindopril arginine.
In some patients with hypertension, in whom no renovascular diseases were detected before treatment, an increase in urea and creatinine levels in the blood serum was observed, usually insignificant and transient, especially when perindopril arginine was prescribed concomitantly with a diuretic. However, this is more characteristic of patients with already existing renal insufficiency. It may become necessary to reduce the dose and/or discontinue the diuretic and/or perindopril arginine.
Patients on hemodialysis. There have been reports of anaphylactoid reactions in patients taking ACE inhibitors during hemodialysis using high-flux membranes. Such patients should be given a different type of dialysis membrane or prescribed a different class of antihypertensive drugs.
Patients after kidney transplantation. There is no experience with the use of perindopril arginine in patients who have recently undergone kidney transplantation.
Renovascular hypertension.
In case of prescription of ACE inhibitors to patients with bilateral stenosis of the renal arteries or stenosis of the artery of a single functioning kidney, the risk of hypotension and renal failure increases (see section "Contraindications"). A contributing factor may be treatment with diuretics. Loss of renal function may manifest as minimal changes in creatinine levels in the blood serum, even in patients with stenosis of the artery of one kidney.
Hypersensitivity/angioedema.
Rare cases of angioedema of the face, limbs, lips, mucous membranes, tongue, glottis, and/or larynx have been reported in patients taking ACE inhibitors, including perindopril arginine (see section "Adverse reactions"). This can occur at any time during treatment. In such cases, the drug should be discontinued immediately and the patient should be monitored until the symptoms disappear. In those individual cases where edema is limited to the face and lips, the patient's condition usually improves without treatment. The appointment of antihistamines may be useful for reducing symptoms.
Angioedema associated with edema of the glottis may be life-threatening. In cases where edema spreads to the tongue, glottis, or larynx, causing airway obstruction, emergency therapy is necessary, which may include the administration of adrenaline and/or ensuring the patency of the airways. The patient should be under close medical supervision until the symptoms disappear and their condition stabilizes. Patients with a history of angioedema not associated with ACE inhibitors are at increased risk of developing angioedema when taking ACE inhibitors (see section "Contraindications").
There have been rare reports of intestinal angioedema in patients taking ACE inhibitors. In these patients, abdominal pain (with or without nausea and vomiting) was observed; in some cases, there was no previous angioedema of the face, and the C-1 esterase level was normal. The diagnosis of intestinal angioedema was established during computed tomography of the abdominal cavity or ultrasound examination, or during surgical intervention. After discontinuation of the ACE inhibitor, the symptoms of angioedema disappeared. Intestinal angioedema should be considered in the differential diagnosis of patients with abdominal pain who are taking ACE inhibitors.
Concomitant use of perindopril with sacubitril/valsartan is contraindicated due to the increased risk of angioedema (see section "Contraindications"). Sacubitril/valsartan should not be started earlier than 36 hours after the last dose of perindopril. In case of discontinuation of sacubitril/valsartan, perindopril therapy should not be started earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Interactions with other medicinal products and other forms of interaction").
Concomitant use of ACE inhibitors with inhibitors of neutral endopeptidase (NEP) (e.g., raccadotril), mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) may increase the risk of angioedema (e.g., edema of the respiratory tract or tongue, with impaired breathing or without) (see section "Interactions with other medicinal products and other forms of interaction"). It is recommended to start treatment with raccadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin) with caution in patients who are already taking ACE inhibitors.
Anaphylactoid reactions during lipoprotein apheresis.
Rarely, in patients taking ACE inhibitors during lipoprotein apheresis with dextran sulfate, life-threatening anaphylactoid reactions have occurred. The development of anaphylactoid reactions can be avoided by temporarily discontinuing ACE inhibitor therapy before each apheresis.
Anaphylactoid reactions during desensitization therapy.
In patients taking ACE inhibitors during desensitization therapy (e.g., with bee venom preparations), anaphylactoid reactions that threaten life have been reported. These reactions can be avoided by temporarily discontinuing ACE inhibitor therapy, but reactions may recur when desensitization therapy is resumed.
Liver failure.
Rarely, the use of ACE inhibitors has been associated with the development of a syndrome that begins with cholestatic jaundice and progresses to rapid necrosis of the liver, sometimes with a fatal outcome. The mechanism of this syndrome is unclear. Patients who develop jaundice or an increase in liver enzymes while taking ACE inhibitors should discontinue the drug and receive appropriate medical examination and treatment (see section "Adverse reactions").
Neutropenia/agranulocytosis, thrombocytopenia, and anemia.
Among patients taking ACE inhibitors, cases of neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported. In patients with normal renal function, neutropenia is rare. Perindopril should be prescribed with extreme caution to patients with collagen diseases, during immunosuppressive therapy, or with allopurinol or procainamide, or with a combination of these factors, especially if there is impaired renal function. In some of these patients, the development of serious infectious diseases has been observed, which in several cases did not respond to intensive antibiotic therapy. In the case of perindopril therapy in such patients, it is recommended to periodically monitor the white blood cell count. Patients should also be informed that they should report any signs of infectious disease (sore throat, fever).
Racial characteristics.
ACE inhibitors more often cause angioedema in patients of the Negroid race than in patients of other races. Perindopril, like other ACE inhibitors, is less effective in lowering blood pressure in patients of the Negroid race than in patients of other races. This may be due to the low renin level in the blood of patients with hypertension in this population.
Cough.
There have been reports of coughing during therapy with ACE inhibitors. The cough is characterized as non-productive, persistent, and stops after discontinuation of the drug. Cough caused by ACE inhibitors should be considered in the differential diagnosis of cough.
During surgical intervention or during anesthesia with hypotensive drugs, perindopril may block the secondary formation of angiotensin II in response to compensatory renin release.
The drug should be discontinued one day before surgery. If hypotension develops and is considered to be caused by this mechanism, the patient's condition can be normalized by increasing the blood volume.
Hyperkalemia.
In some patients taking ACE inhibitors, including perindopril, an increase in potassium levels in the blood serum has been observed. ACE inhibitors can cause hyperkalemia, as they inhibit the release of aldosterone. In patients with normal renal function, this effect is usually insignificant. The risk factors for hyperkalemia include renal insufficiency, impaired renal function, age (over 70 years), diabetes, concomitant conditions such as dehydration, acute heart failure, metabolic acidosis, and concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium supplements, or salt substitutes with potassium; or taking other drugs that increase potassium levels in the blood serum (e.g., heparin, co-trimoxazole, also known as trimethoprim/sulfamethoxazole). The use of potassium supplements, potassium-sparing diuretics, or salt substitutes with potassium, especially in patients with impaired renal function, can lead to a significant increase in potassium levels in the blood serum. Hyperkalemia can cause serious, sometimes life-threatening arrhythmias. Patients taking ACE inhibitors should be prescribed potassium-sparing diuretics and angiotensin II receptor blockers with caution and frequent monitoring of potassium levels in the blood serum and renal function. If concomitant use of perindopril and any of the above substances is considered necessary, they should be used with caution and frequent monitoring of potassium levels in the blood serum (see section "Interactions with other medicinal products and other forms of interaction").
Patients with diabetes who are taking oral hypoglycemic agents or receiving insulin should be carefully monitored for blood glucose levels during the first month of ACE inhibitor therapy (see section "Interactions with other medicinal products and other forms of interaction").
Lithium.
Concomitant use of lithium and perindopril is usually not recommended (see section "Interactions with other medicinal products and other forms of interaction").
Concomitant use of perindopril with potassium-sparing diuretics, potassium supplements, or salt substitutes with potassium is not recommended (see section "Interactions with other medicinal products and other forms of interaction").
Dual blockade of the renin-angiotensin-aldosterone system (RAAS).
There are data 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 RAAS by concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see section "Interactions with other medicinal products and other forms of interaction"). If treatment with dual blockade of RAAS is considered necessary, it can only be performed under the supervision of a specialist and with frequent careful monitoring of renal function, electrolyte levels, and blood pressure.
Primary aldosteronism.
Patients with primary hyperaldosteronism usually do not respond to treatment with antihypertensive agents that act by inhibiting the renin-angiotensin system. Therefore, such patients should not be given this drug.
Excipients.
The preparation contains lactose, so it is not recommended for patients with rare hereditary galactose intolerance, glucose-galactose malabsorption syndrome, or total lactase deficiency.
Sodium level: PRESTARIUM®contains less than 1 mmol of sodium (23 mg) per tablet, i.e., it is almost sodium-free.
Pregnancy and lactation.
Pregnancy
The drug is contraindicated in pregnant women or women who plan to become pregnant. If pregnancy is confirmed during treatment with this drug, its use should be discontinued immediately and replaced with another drug allowed for use in pregnant women.
In the event that a woman took an ACE inhibitor during the second trimester of pregnancy, it is recommended to perform an ultrasound examination of the kidneys and skull bones of the fetus. Newborns whose mothers took ACE inhibitors during pregnancy should be under close supervision due to the possibility of hypotension.
Breastfeeding
The use of perindopril arginine is not recommended during breastfeeding due to the lack of data on its penetration into breast milk. During breastfeeding, it is desirable to prescribe an alternative treatment with a more studied safety profile, especially during breastfeeding of a newborn or premature infant.
Fertility
No effect on reproductive ability or fertility has been found.
Ability to influence the speed of reaction when driving vehicles or using mechanisms.
Perindopril arginine does not have a direct effect on the ability to drive vehicles or use mechanisms. However, in some patients, individual reactions associated with a decrease in blood pressure may occur, especially at the beginning of treatment or with concomitant use of other antihypertensive agents. As a result, the ability to drive vehicles or use mechanisms may be impaired.
Method of Administration and Dosage
The recommended initial dose is 5 mg once daily in the morning.
Patients with high activity of the renin-angiotensin-aldosterone system (especially patients with renovascular hypertension, water and electrolyte imbalance, heart failure, or severe hypertension) may experience excessive blood pressure reduction after taking the first dose. Such patients are recommended to start treatment with a dose of 2.5 mg and begin therapy under medical supervision.
The dose can be increased to 10 mg once daily after 1 month of treatment.
At the beginning of perindopril arginine administration, symptomatic arterial hypotension may occur; this is more likely in patients who are also taking diuretics. Such patients should start treatment with perindopril with caution, as they may have a water and/or salt deficiency.
If possible, diuretic administration should be discontinued 2-3 days before starting perindopril arginine therapy (see "Special Instructions").
Patients with arterial hypertension who cannot discontinue diuretic use should start treatment with a dose of 2.5 mg. In such patients, kidney function and potassium levels in the blood serum should be monitored. Further dose increases of perindopril arginine should be based on blood pressure indicators. If necessary, diuretic therapy can be resumed.
Elderly patients should start treatment with a dose of 2.5 mg, which can be increased to 5 mg after 1 month of treatment, and then, if necessary, to 10 mg, taking into account kidney function (see the table below).
Symptomatic Heart Failure
Patients with heart failure who are usually prescribed perindopril arginine in combination with a potassium-excreting diuretic and/or digoxin and/or beta-blocker should start treatment under close medical supervision and with an initial dose of 2.5 mg, taken in the morning. After 2 weeks, if the treatment is well tolerated, the dose can be increased to 5 mg once daily. The dose should then be adjusted individually based on the patient's clinical response to treatment.
Patients with severe heart failure and other high-risk patients (patients with impaired kidney function and a tendency to electrolyte disturbances, patients receiving concurrent diuretic and/or vasodilator therapy) should start treatment under close medical supervision (see "Special Instructions").
In patients at high risk of developing symptomatic arterial hypotension, namely patients with electrolyte deficiency with or without hyponatremia, patients with hypovolemia, or those receiving intensive diuretic therapy, correction of these conditions should be performed, if possible, before prescribing the drug. Blood pressure, kidney function, and potassium levels in the blood serum should be closely monitored both before and during treatment (see "Special Instructions").
Prevention of Recurrent Stroke in Patients with Cerebrovascular Diseases
The recommended initial dose is 2.5 mg (1/2 tablet of Prestarium 5 mg) once daily in the morning. After 2 weeks of treatment, the dose can be increased to 5 mg (1 tablet of Prestarium 5 mg) once daily in the morning.
If after 2 weeks of treatment with Prestarium 5 mg, the patient requires additional blood pressure control, indapamide can be prescribed at a dose of 1 tablet per day. Treatment can be started 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 per day) reduces the risk of myocardial infarction and heart failure (according to the results of a 4-year EUROPA study). Treatment should be started with Prestarium 5 mg (1 tablet per day in the morning). After 2 weeks, if the treatment is well tolerated, the dose can be increased to 10 mg for long-term administration of Prestarium 10 mg, 1 tablet per day in the morning.
Elderly patients with documented ischemic heart disease should start treatment with a dose of 2.5 mg (1/2 tablet of Prestarium 5 mg) once daily in the morning; after 1 week, the dose can be increased to 5 mg (1 tablet of Prestarium 5 mg); after 2 weeks, if the treatment is well tolerated and depending on kidney function, the dose can be increased to 10 mg (Prestarium 10 mg, 1 tablet per day) and long-term treatment can be started.
Dose Adjustment in Renal Impairment
Dosing in patients with renal impairment should be based on creatinine clearance, as indicated in the table below:
| Creatinine Clearance (ml/min) | Recommended Dosage |
| ClCR ≥ 60 | 5 mg daily |
| 30 < ClCR < 60 | 2.5 mg daily |
| 15 < ClCR < 30 | 2.5 mg every other day |
| Patients on Hemodialysis* | |
| ClCR < 15 | 2.5 mg on the day of dialysis |
*Dialysis clearance of perindopril is 70 ml/min.
Patients on hemodialysis should take the dose after dialysis.
Dose Adjustment in Hepatic Impairment
Patients with hepatic impairment do not require dose adjustment of the drug (see "Special Instructions" and "Pharmacokinetics").
Children
The efficacy and safety of perindopril arginine in children under 18 years of age have not been established. Available information is provided in the "Pharmacodynamics" section, but it is not possible to provide dosage recommendations. Therefore, perindopril arginine is not recommended for children.
Overdose
There is insufficient information about perindopril overdose. Symptoms associated with overdose of ACE inhibitors may include: arterial hypotension, circulatory shock, electrolyte imbalance, kidney failure, hyperventilation, tachycardia, accelerated heart rate, bradycardia, dizziness, anxiety, cough, etc.
In case of overdose, intravenous administration of a 0.9% sodium chloride solution (9 mg/ml) is recommended. If arterial hypotension occurs, the patient should be placed in a horizontal position with a low headboard. If possible, the patient should receive infusions of angiotensin II and/or intravenous administration of catecholamines. Perindopril can be removed from the systemic circulation by hemodialysis (see "Special Instructions"). In case of resistant bradycardia, the use of a pacemaker is indicated. Continuous monitoring of vital signs, electrolyte levels, and creatinine in the blood serum is necessary.
Adverse Reactions
The safety profile of perindopril corresponds to the safety profile of ACE inhibitors. The most common adverse reactions reported during clinical trials of perindopril are: dizziness, headache, paresthesia, vertigo, vision disturbances, tinnitus, arterial hypotension, cough, dyspnea, abdominal pain, constipation, diarrhea, taste disturbances (dysgeusia), dyspepsia, nausea, vomiting, itching, rash, maculopapular rash, muscle spasms, and asthenia.
During clinical trials and post-marketing use of perindopril, the following adverse reactions were observed with the following frequency: very common (≥ 1/10); common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000); frequency unknown (cannot be determined based on available data).
| MedDRA System Organ Class | 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 System Disorders | Syndrome of inappropriate antidiuretic hormone secretion (SIADH) | Rare |
| Metabolic and Nutritional Disorders | Hypoglycemia | Uncommon* |
| Reversible hyperkalemia after discontinuation of the drug | Uncommon* | |
| Hyponatremia | Uncommon* | |
| Psychiatric Disorders | Depression | Uncommon* |
| Mood disturbances | Uncommon | |
| Sleep disturbances | Uncommon | |
| Nervous System Disorders | Dizziness | Common |
| Headache | Common | |
| Paresthesia | 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 blood pressure reduction in high-risk patients | Very rare | |
| Vascular Disorders | Hypotension (and related symptoms) | Common |
| Vasculitis | Uncommon* | |
| Flushing | Rare* | |
| Stroke may occur due to excessive blood pressure reduction 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 | |
| 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 | Itching | Common |
| Rash | Common | |
| Urticaria | Uncommon | |
| Angioedema of the face, limbs, lips, mucous membranes, tongue, and/or glottis | Uncommon | |
| Photosensitivity reactions | Uncommon* | |
| Pemphigoid | Uncommon* | |
| Hyperhidrosis | Uncommon | |
| Exacerbation of psoriasis symptoms | Rare | |
| Multi-form erythema | Very rare | |
| Musculoskeletal and Connective Tissue Disorders | Muscle spasms | Common |
| Arthralgia | Uncommon* | |
| Myalgia | Uncommon* | |
| Renal and Urinary Disorders | Kidney failure | Uncommon |
| Acute kidney 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 edema | Uncommon* | |
| Hyperthermia | Uncommon* | |
| Investigations | Increased blood urea levels | Uncommon* |
| Increased blood creatinine levels | Uncommon* | |
| Increased blood bilirubin levels | Rare | |
| Increased liver enzyme levels | Rare | |
| Injury, Poisoning, and Procedural Complications | Falls | Uncommon* |
