Perindopril-SZ (Tablets) Instructions for Use

Marketing Authorization Holder

Severnaya Zvezda NAO (Russia)

Contact Information

SEVERNAYA ZVEZDA NAO (Russia)

ATC Code

C09AA04 (Perindopril)

Active Substance

Perindopril (Rec.INN registered by WHO)

Dosage Forms

	Perindopril-SZ	Tablets 2 mg: 30, 60, or 90 pcs.
		Tablets 4 mg: 30, 60, or 90 pcs.
		Tablets 8 mg: 30, 60, or 90 pcs.

Dosage Form, Packaging, and Composition

Tablets white or almost white, round, flat-cylindrical in shape with a bevel.

Excipients: lactose monohydrate (lactopress) (milk sugar), microcrystalline cellulose 102, sodium bicarbonate, colloidal hydrophobic silicon dioxide (aerosil), calcium stearate.

10 pcs. – contour cell packs (3) – cardboard packs.
10 pcs. – contour cell packs (6) – cardboard packs.
10 pcs. – contour cell packs (9) – cardboard packs.
30 pcs. – contour cell packs (1) – cardboard packs.
30 pcs. – contour cell packs (2) – cardboard packs.
30 pcs. – contour cell packs (3) – cardboard packs.
30 pcs. – polymer jars (1) – cardboard packs.
30 pcs. – polymer bottles (1) – cardboard packs.

Tablets white or almost white, round, flat-cylindrical in shape with a bevel.

Excipients: lactose monohydrate (lactopress) (milk sugar), microcrystalline cellulose 102, sodium bicarbonate, colloidal hydrophobic silicon dioxide (aerosil), calcium stearate.

10 pcs. – contour cell packs (3) – cardboard packs.
10 pcs. – contour cell packs (6) – cardboard packs.
10 pcs. – contour cell packs (9) – cardboard packs.
30 pcs. – contour cell packs (1) – cardboard packs.
30 pcs. – contour cell packs (2) – cardboard packs.
30 pcs. – contour cell packs (3) – cardboard packs.
30 pcs. – polymer jars (1) – cardboard packs.
30 pcs. – polymer bottles (1) – cardboard packs.

Tablets white or almost white, round, flat-cylindrical in shape with a bevel and a score; the tablet can be divided into equal doses.

Excipients: lactose monohydrate (lactopress) (milk sugar), microcrystalline cellulose 102, sodium bicarbonate, colloidal hydrophobic silicon dioxide (aerosil), calcium stearate.

10 pcs. – contour cell packs (3) – cardboard packs.
10 pcs. – contour cell packs (6) – cardboard packs.
10 pcs. – contour cell packs (9) – cardboard packs.
30 pcs. – contour cell packs (1) – cardboard packs.
30 pcs. – contour cell packs (2) – cardboard packs.
30 pcs. – contour cell packs (3) – cardboard packs.
30 pcs. – polymer jars (1) – cardboard packs.
30 pcs. – polymer bottles (1) – cardboard packs.

Clinical-Pharmacological Group

ACE inhibitor

Pharmacotherapeutic Group

Agents acting on the renin-angiotensin system; angiotensin-converting enzyme (ACE) inhibitors

Pharmacological Action

Mechanism of action

Perindopril is an inhibitor of the enzyme that converts angiotensin I to angiotensin II.

Angiotensin-converting enzyme, or kininase II, is an exopeptidase that carries out the conversion of angiotensin I to the vasoconstrictor substance angiotensin II, and also breaks down bradykinin, which has a vasodilatory effect, into an inactive heptapeptide.

Inhibition of ACE leads to a decrease in the concentration of angiotensin II in the blood plasma, which causes an increase in plasma renin activity (via the “negative feedback” mechanism) and a decrease in aldosterone secretion.

Since ACE inactivates bradykinin, suppression of ACE is accompanied by an increase in the activity of both the circulating and tissue kallikrein-kinin system, while the prostaglandin system is also activated. It is possible that this effect is part of the mechanism of the antihypertensive action of ACE inhibitors, as well as the mechanism of development of some side effects of drugs in this class (for example, cough).

Perindopril exerts its therapeutic effect through the active metabolite perindoprilat. Other metabolites do not have an inhibitory effect on ACE in vitro.

Clinical efficacy and safety

Arterial hypertension

Perindopril is effective for the treatment of arterial hypertension (AH) of any severity. Its use leads to a decrease in both systolic and diastolic blood pressure in the patient’s “lying” and “standing” positions.

Perindopril reduces total peripheral vascular resistance (TPVR), which leads to a decrease in blood pressure, while peripheral blood flow accelerates without changing the heart rate (HR).

As a rule, Perindopril leads to an increase in renal blood flow, while GFR does not change.

The antihypertensive effect of perindopril reaches its maximum 4-6 hours after a single oral dose and lasts for 24 hours. 24 hours after oral administration, a pronounced (about 87-100%) residual inhibition of ACE is observed.

The decrease in blood pressure is achieved quite quickly. In patients with a positive response to treatment, normalization of blood pressure occurs within one month and is maintained without the development of tachyphylaxis.

Discontinuation of treatment is not accompanied by the development of a “rebound” effect.

Perindopril has a vasodilatory effect, helps restore the elasticity of large arteries and the structure of the vascular wall of small arteries, and also reduces left ventricular hypertrophy.

Concomitant administration of thiazide diuretics enhances the severity of the antihypertensive effect. In addition, the combination of an ACE inhibitor and a thiazide diuretic also leads to a reduction in the risk of hypokalemia during diuretic use.

Heart failure

Perindopril normalizes heart function by reducing preload and afterload.

In patients with chronic heart failure taking Perindopril, the following was revealed

• Reduction in filling pressure in the left and right ventricles of the heart;
• Reduction in TPVR;
• Increase in cardiac output and increase in cardiac index.

A study of perindopril compared with placebo showed that changes in blood pressure after the first dose of perindopril 2 mg in patients with CHF (functional class II-III according to the NYHA classification) did not differ statistically significantly from changes in blood pressure observed after placebo.

Cerebrovascular diseases

Results of a study that evaluated the effect of active therapy with perindopril (monotherapy or in combination with indapamide) over 4 years on the risk of recurrent stroke in patients with a history of cerebrovascular disease. After a run-in period of perindopril 2 mg once daily for 2 weeks and then 4 mg once daily for the next 2 weeks, 6105 patients were randomized into 2 groups: placebo (n=3054) and Perindopril 4 mg (monotherapy) or in combination with indapamide (n=3051). Indapamide was additionally prescribed to patients who did not have direct indications or contraindications for the use of diuretics. This therapy was prescribed in addition to standard therapy for stroke and/or arterial hypertension or other pathological conditions. All randomized patients had a history of cerebrovascular disease (stroke or transient ischemic attack) within the last 5 years. Blood pressure level was not an inclusion criterion: 2916 patients had arterial hypertension and 3189 had normal blood pressure. After 3.9 years of therapy, blood pressure (systolic/diastolic) decreased by an average of 9.0/4.0 mm Hg. A significant reduction in the risk of recurrent stroke (both ischemic and hemorrhagic) of about 28% compared with placebo (10.1% and 13.8%) was also shown.

Additionally, a significant reduction in the risk was shown

• Fatal or disabling strokes;
• Major cardiovascular complications, including MI, including fatal ones;
• Dementia associated with stroke;
• Serious deterioration in cognitive functions.

This was noted both in patients with arterial hypertension and with normal blood pressure, regardless of age, gender, presence or absence of diabetes mellitus and type of stroke.

Stable coronary artery disease

The effectiveness of perindopril in patients (12218 patients over 18 years of age) with stable CAD without clinical symptoms of CHF was studied during a 4-year study. 90% of the study participants had previously suffered an acute MI and/or a revascularization procedure. Most patients received perindopril in addition to standard therapy, including antiplatelet agents, lipid-lowering agents and beta-blockers. The combined endpoint, including cardiovascular mortality, nonfatal MI and/or cardiac arrest with successful resuscitation, was chosen as the primary efficacy criterion.

Perindopril therapy at a dose of 8 mg/day led to a significant reduction in the absolute risk of the combined endpoint by 1.9% (relative risk reduction – 20%). In patients who had previously suffered a myocardial infarction or a revascularization procedure, the absolute risk reduction was 2.2% (relative risk reduction – 22.4%) compared with the placebo group.

Dual blockade of the RAAS

There is data from clinical studies of combination therapy using an ACE inhibitor and an ARB.

A clinical study was conducted involving patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by confirmed target organ damage, as well as studies involving patients with type 2 diabetes mellitus and diabetic nephropathy.

Data from the studies did not reveal a significant positive effect of combination therapy on the occurrence of renal and/or cardiovascular events and on mortality rates, while the risk of hyperkalemia, acute renal failure and/or arterial hypotension increased compared with monotherapy.

Given the similar intragroup pharmacodynamic properties of ACE inhibitors and ARBs, these results can be expected for the interaction of any other drugs, representatives of the classes of ACE inhibitors and ARBs.

Therefore, the combined use of ACE inhibitors and ARBs is contraindicated in patients with diabetic nephropathy (see section “Contraindications”).

There is data from a clinical study on the positive effect of adding aliskiren to standard therapy with an ACE inhibitor or ARB in patients with type 2 diabetes mellitus and chronic kidney disease or cardiovascular disease, or a combination of these diseases. The study was terminated early due to an increased risk of adverse outcomes. Cardiovascular death and stroke were observed more frequently in the group of patients receiving aliskiren compared with the placebo group; adverse reactions and serious adverse reactions of special interest (hyperkalemia, arterial hypotension and renal dysfunction) were also recorded more frequently in the aliskiren group than in the placebo group.

Pharmacokinetics

Absorption

After oral administration, Perindopril is rapidly absorbed from the gastrointestinal tract. C_max in blood plasma is reached after 1 hour. Bioavailability is 65-70%. C_max of perindoprilat (active metabolite) in blood plasma is reached 3-4 hours after oral administration. Food intake slows down the conversion of perindopril to perindoprilat, affecting bioavailability. Therefore, the drug Perindopril-SZ should be taken orally once a day, in the morning, before meals.

Distribution

The V_d of free perindoprilat is approximately 0.2 l/kg. Binding of perindoprilat to plasma proteins, mainly to ACE, is about 20% and is dose-dependent.

It is insignificant and dose-dependent. Steady state is reached within 4 days. With long-term use, Perindopril does not accumulate.

Metabolism

Perindopril does not have pharmacological activity. Approximately 27% of the total amount of absorbed perindopril enters the bloodstream in the form of the active metabolite – perindoprilat. In addition to perindoprilat, 5 more metabolites are formed that do not have pharmacological activity.

Excretion

T_1/2 of perindopril from blood plasma is 1 hour. Perindoprilat is excreted from the body by the kidneys, the final T_1/2 of the free fraction is about 17 hours, as a result of which the steady state is reached within 4 days.

Linearity (non-linearity)

It has been shown that the relationship between the dose of perindopril and its concentration in blood plasma is linear.

Pharmacokinetics in special patient groups

Elderly age. The excretion of perindoprilat is slowed in elderly patients.

Renal failure. The excretion of perindoprilat is slowed in patients with cardiac and renal failure; it is recommended to adjust the dose of perindopril depending on the degree of impairment of CC.

Dialysis. The dialysis clearance of perindoprilat is 70 ml/min.

Hepatic failure. In patients with liver cirrhosis, the hepatic clearance of perindopril is reduced by 2 times. However, the amount of perindoprilat formed does not decrease and no dose adjustment of the drug is required (see sections “Dosage Regimen” and “Special Instructions”).

Indications

Adults

• Arterial hypertension;
• Chronic heart failure (CHF);
• Prevention of recurrent stroke (combination therapy with indapamide) in patients who have had a stroke or transient ischemic attack;
• Stable coronary artery disease (CAD): reduction of the risk of cardiovascular complications in patients with stable CAD.

ICD codes

Dosage Regimen

The drug is taken orally, once a day, in the morning, before meals, with a glass of water.

When choosing a dose, the features of the clinical situation (see section “Special Instructions”) and the degree of blood pressure reduction during therapy should be taken into account.

Taking into account the method of application indicated below, if it is necessary to take perindopril at a dose of 2 mg, perindopril preparations in the appropriate dosage should be used.

Arterial hypertension

Perindopril-SZ can be used both as monotherapy and as part of combination therapy.

The recommended initial dose is 4 mg once daily.

In patients with marked activation of the RAAS (especially in renovascular hypertension, hypovolemia and/or decreased plasma electrolyte levels, decompensated CHF or severe arterial hypertension), a marked decrease in blood pressure may develop after the first dose of the drug. At the beginning of therapy, such patients should be under careful medical supervision. The recommended initial dose for such patients is 2 mg once daily.

If necessary, one month after the start of therapy, the drug dose can be increased to 8 mg once daily.

Symptomatic arterial hypotension may occur at the beginning of therapy with Perindopril-SZ. In patients simultaneously receiving diuretics, the risk of developing arterial hypotension is higher due to possible hypovolemia and decreased plasma electrolyte levels. Caution should be exercised when using the drug Perindopril-SZ in this group of patients.

It is recommended, if possible, to stop taking diuretics 2-3 days before the expected start of therapy with Perindopril-SZ (see section “Special Instructions”).

If it is not possible to discontinue the diuretic, the initial dose of Perindopril-SZ should be 2 mg. In this case, renal function and serum potassium levels should be monitored. Subsequently, if necessary, the drug dose can be increased. If necessary, diuretic use can be resumed.

In elderly patients, treatment should be started with a dose of 2 mg/day, and then, if necessary, after 1 month from the start of therapy, the dose can be increased to 4 mg/day, and then to the maximum dose – 8 mg/day, taking into account the state of renal function (see Table 1).

Chronic heart failure

Treatment of patients with CHF with perindopril in combination with potassium-sparing diuretics and/or digoxin and/or beta-blockers is recommended to be started under careful medical supervision, prescribing the drug at an initial dose of 2 mg once daily, in the morning. After 2 weeks of treatment, the drug dose can be increased to 4 mg once daily, provided that the 2 mg dose is well tolerated and the response to the therapy is satisfactory.

In patients with severe heart failure, as well as in high-risk patients (patients with impaired renal function and a tendency to water-electrolyte imbalance, patients receiving diuretics and/or vasodilators), treatment should be started under careful medical supervision (see section “Special Instructions”).

In patients at high risk of developing symptomatic arterial hypotension, for example, with reduced electrolyte levels with or without hyponatremia, with hypovolemia or with intensive diuretic therapy, these indicators should be corrected before starting Perindopril-SZ, if possible. Such indicators as blood pressure level, renal function and plasma potassium level should be monitored both before the start and during therapy.

Prevention of recurrent stroke (combination therapy with indapamide)

In patients with a history of cerebrovascular disease, therapy with Perindopril-SZ should be started at a dose of 2 mg once daily for the first 2 weeks, then increasing the dose to 4 mg (1/2 tablet of 8 mg) over the next 2 weeks, before using indapamide.

Therapy can be initiated at any time (from 2 weeks to several years) after a stroke.

Coronary artery disease: reduction of the risk of cardiovascular complications in patients with a history of myocardial infarction and/or coronary revascularization

In patients with stable coronary artery disease, therapy with Perindopril-SZ should be started at a dose of 4 mg (1/2 of an 8 mg tablet) once daily.

After 2 weeks, if the drug is well tolerated and depending on the renal function, the dose may be increased to 8 mg once daily.

Elderly patients should start therapy at a dose of 2 mg once daily for one week, then 4 mg once daily for the next week. Then, depending on the renal function, the dose should be increased to 8 mg once daily (see Table 1). The dose of the drug can only be increased if it is well tolerated at the previously recommended dose.

Special patient groups

Patients with renal impairment

In patients with renal impairment, the dose of the drug should be selected based on creatinine clearance (CrCl).

Table 1. Dosage of Perindopril-SZ in renal failure

* Dialysis clearance of perindoprilat is 70 ml/min. The drug should be taken after the dialysis procedure.

Patients with hepatic impairment

No dose adjustment is required for patients with hepatic impairment.

Children

The safety and efficacy of Perindopril-SZ in children and adolescents aged 0 to 18 years have not been established. Data are not available.

Adverse Reactions

Summary of the safety profile

The safety profile of perindopril corresponds to the safety profile of ACE inhibitors. The most frequent adverse reactions associated with perindopril noted in clinical trials are: dizziness, headache, paresthesia, vertigo, visual impairment, tinnitus, arterial hypotension, cough, dyspnea, abdominal pain, constipation, diarrhea, dysgeusia (taste disturbance), dyspepsia, nausea, vomiting, pruritus, skin rash, muscle spasms, asthenia.

Tabulated summary of adverse reactions

Adverse reactions are listed by system organ class with frequency according to WHO recommendations: very common (≥1/10); common (≥1/100, but <1/10); uncommon (≥1/1000, but <1/100); rare (≥1/10000, but <1/1000); very rare (<1/10000); frequency not known (cannot be estimated from the available data).

* frequency assessment of adverse reactions identified from spontaneous reports is based on data from clinical trial results

Cases of syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been reported with concomitant use of other ACE inhibitors. SIADH is a very rare but possible complication of therapy with ACE inhibitors, including Perindopril.

Adverse reactions noted in clinical trials

In the EUROPA study, only serious adverse reactions were recorded. Serious adverse reactions were noted in 16 (0.3%) patients in the perindopril group and in 12 (0.2%) patients in the placebo group. In the perindopril group, 6 patients had marked decrease in blood pressure, 3 patients had angioedema, 1 patient had sudden cardiac arrest. The frequency of drug discontinuation due to cough, marked decrease in blood pressure or other cases of intolerance was higher in the perindopril group compared to the placebo group.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after drug registration to ensure continuous monitoring of the benefit-risk balance of the drug. Healthcare professionals are recommended to report any suspected adverse drug reactions via the national adverse reaction reporting system of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to perindopril, other ACE inhibitors or to any of the excipients of the drug;
• History of angioedema associated with ACE inhibitor therapy (see section “Special Precautions”);
• Hereditary/idiopathic angioedema;
• Concomitant use with aliskiren and aliskiren-containing drugs in patients with diabetes mellitus and/or moderate or severe renal impairment (glomerular filtration rate (GFR) <60 ml/min/1.73 m² body surface area) (see section “Drug Interactions”);

• Concomitant use with angiotensin II receptor antagonists (ARA II) in patients with diabetic nephropathy (see section “Drug Interactions”);
• Concomitant use with combination drugs containing valsartan+sacubitril (see sections “Special Precautions” and “Drug Interactions”);
• Extracorporeal therapy leading to blood contact with negatively charged surfaces (see section “Drug Interactions”);
• Severe bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney (see section “Special Precautions”);
• Pregnancy;
• Breastfeeding period;
• Lactose intolerance, lactase deficiency or glucose-galactose malabsorption (see section “Special Precautions”);
• Age under 18 years (efficacy and safety have not been established).

With caution

Bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney, renal failure, systemic connective tissue diseases (systemic lupus erythematosus (SLE), scleroderma, etc.), therapy with immunosuppressants, allopurinol, procainamide (risk of neutropenia and agranulocytosis), reduced blood volume (diuretic use, salt-free diet, vomiting, diarrhea), angina pectoris, cerebrovascular diseases, renovascular hypertension, diabetes mellitus, primary hyperaldosteronism, CHF functional class IV according to NYHA, concomitant use of potassium-sparing diuretics, potassium preparations, potassium-containing salt substitutes and lithium, aliskiren and drugs containing aliskiren in patients without diabetes mellitus or renal impairment, ARA II in patients without diabetic nephropathy, hyperkalemia, surgery/anesthesia, hemodialysis using high-flux membranes, desensitizing therapy, low-density lipoprotein (LDL) apheresis, status after kidney transplantation, aortic stenosis/mitral stenosis/hypertrophic obstructive cardiomyopathy, use in patients of Black race.

Use in Pregnancy and Lactation

Pregnancy

Perindopril-SZ is contraindicated during pregnancy (see section “Contraindications”).

Currently, there is no conclusive epidemiological data on the teratogenic risk of ACE inhibitor use in the first trimester of pregnancy. However, a slight increase in the risk of fetal developmental disorders cannot be ruled out. When planning pregnancy, if ACE inhibitor therapy is considered necessary, a switch to other antihypertensive drugs with an established safety profile for use during pregnancy should be made. Upon diagnosis of pregnancy, the drug should be discontinued immediately and, if necessary, alternative therapy should be prescribed.

It is known that exposure to ACE inhibitors during the second and third trimesters of pregnancy can lead to impaired fetal development (decreased renal function, oligohydramnios, delayed skull ossification) and the development of complications in the newborn (renal failure, arterial hypotension, hyperkalemia).

If a patient has received ACE inhibitors during the second or third trimester of pregnancy, fetal ultrasound is recommended to assess the skull bones and renal function.

Newborns whose mothers received ACE inhibitors during pregnancy should be monitored due to the risk of arterial hypotension (see sections “Contraindications”, “Special Precautions”).

Breastfeeding period

Due to the lack of information regarding the use of perindopril during breastfeeding, its use is not recommended. It is preferable to use other drugs with a more studied safety profile during breastfeeding, especially when feeding newborns or premature infants.

Fertility

No effect on reproductive fertility has been established.

Use in Hepatic Impairment

No dose adjustment is required when using Perindopril-SZ in patients with hepatic impairment.

Use in Renal Impairment

The drug should be used with caution in bilateral renal artery stenosis, stenosis of the artery to a single functioning kidney; chronic renal failure, status after kidney transplantation (due to lack of clinical data).

In patients with renal impairment, the dose of the drug should be selected based on creatinine clearance.

Pediatric Use

The use of the drug is contraindicated in patients under 18 years of age.

Geriatric Use

The drug should be used with caution in elderly patients.

Special Precautions

Stable coronary artery disease

If any episode of unstable angina occurs during the first month of therapy with Perindopril-SZ, the benefits and risks should be assessed before continuing therapy.

Arterial hypotension

ACE inhibitors can cause a sharp decrease in blood pressure. Symptomatic arterial hypotension rarely develops in patients with uncomplicated arterial hypertension. The risk of excessive blood pressure reduction is increased in patients with reduced blood volume, which may occur during diuretic therapy, strict salt-free diet, dialysis, diarrhea and vomiting, as well as in patients with severe renin-dependent hypertension (see sections “Drug Interactions” and “Adverse Reactions”). Symptomatic arterial hypotension may be observed in patients with clinical manifestations of heart failure, regardless of the presence of renal failure. This is more likely in patients with severe heart failure, as a reaction to taking high doses of “loop” diuretics, hyponatremia or functional renal failure. In patients at increased risk of symptomatic arterial hypotension, blood pressure, renal function and serum potassium levels should be carefully monitored at the start of therapy and during dose titration of Perindopril-SZ (see sections “Dosage and Administration” and “Adverse Reactions”).

A similar approach applies to patients with coronary artery disease and cerebrovascular diseases, in whom severe arterial hypotension can lead to myocardial infarction or cerebrovascular accident.

In case of arterial hypotension, the patient should be placed in the supine position with legs elevated. If necessary, blood volume should be replenished by intravenous administration of 0.9% sodium chloride solution. Transient arterial hypotension is not a contraindication for further use of the drug. After restoration of blood volume and blood pressure, treatment can be continued.

In some patients with CHF and normal or low blood pressure, Perindopril-SZ may cause an additional decrease in blood pressure. This effect is predictable and usually does not require discontinuation of therapy. If symptoms of a marked decrease in blood pressure appear, the dose of the drug should be reduced or its use discontinued.

Mitral stenosis/aortic stenosis/hypertrophic obstructive cardiomyopathy

Perindopril-SZ, like other ACE inhibitors, should be used with caution in patients with mitral stenosis, as well as in patients with left ventricular outflow tract obstruction (aortic stenosis, hypertrophic obstructive cardiomyopathy).

Renal impairment

In patients with renal failure (CrCl less than 60 ml/min), the initial dose of Perindopril-SZ is selected based on the CrCl value (see section “Dosage and Administration”) and then depending on the therapeutic effect. Such patients require regular monitoring of creatinine concentration and plasma potassium levels (see section “Adverse Reactions”).

Arterial hypotension, which sometimes develops at the start of ACE inhibitor use in patients with symptomatic chronic heart failure, can lead to worsening of renal function. Acute renal failure may develop, usually reversible. In patients with bilateral renal artery stenosis or stenosis of the artery to a single kidney (especially in the presence of renal failure) during ACE inhibitor therapy, an increase in plasma urea and creatinine levels is possible, usually reversible upon discontinuation of therapy. The additional presence of renovascular hypertension increases the risk of severe arterial hypotension and renal failure. Treatment of such patients should be initiated under close medical supervision with low doses of the drug and subsequent adequate dose titration. Diuretic treatment should be temporarily discontinued and regular monitoring of serum potassium and creatinine should be performed during the first few weeks of therapy.

In some patients with arterial hypertension and previously undetected renal failure, especially with concomitant use of diuretics, serum urea and creatinine levels may increase. These changes are usually minor and reversible. In such cases, discontinuation or reduction of the dose of Perindopril-SZ and/or the diuretic may be required.

The likelihood of these disorders is higher in patients with a history of renal impairment.

Hemodialysis

Cases of anaphylactic reactions have been observed in patients undergoing hemodialysis using high-flux membranes during therapy with ACE inhibitors. In such situations, the possibility of prescribing an antihypertensive drug of another class or using a different type of dialysis membrane should be considered.

Kidney transplantation

There are no data on the use of Perindopril-SZ in patients after kidney transplantation.

Renovascular hypertension

In patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney, the risk of arterial hypotension and renal failure increases during therapy with ACE inhibitors (see section “Contraindications”). The use of other diuretics may be an additional risk factor. Worsening of renal function may be observed even with a slight change in serum creatinine concentration, even in patients with unilateral renal artery stenosis.

Hypersensitivity/Angioedema

When taking ACE inhibitors, including perindopril, in rare cases and at any time during therapy, angioedema of the face, upper and lower extremities, lips, mucous membranes, tongue, vocal folds and/or larynx may occur (see section “Adverse Reactions”). If symptoms appear, the drug should be discontinued immediately and the patient should be observed until the signs of edema completely disappear. If the edema involves only the face and lips, its manifestations usually resolve on their own, although antihistamines may be used to treat the symptoms.

Angioedema involving laryngeal edema can be fatal. Edema of the tongue, vocal folds, or larynx can lead to airway obstruction. If such symptoms occur, emergency therapy is required, including subcutaneous administration of epinephrine (adrenaline) or ensuring airway patency. The patient should be under close medical supervision until the symptoms have completely and permanently resolved.

Patients with a history of angioedema not associated with ACE inhibitor use may have an increased risk of its development when taking drugs of this group (see section “Contraindications”).

In rare cases, intestinal angioedema develops during therapy with ACE inhibitors. In this case, patients experience abdominal pain as an isolated symptom or in combination with nausea and vomiting, in some cases without preceding facial angioedema and with normal C-1 esterase enzyme activity. The diagnosis is established by abdominal CT, ultrasound, or at the time of surgery. Symptoms disappear after discontinuation of ACE inhibitors. In patients with abdominal pain receiving ACE inhibitors, the possibility of intestinal angioedema should be considered in the differential diagnosis (see section “Adverse Reactions”).

Concomitant use with combination drugs containing valsartan+sacubitril

Concomitant use of perindopril with combination drugs containing valsartan+sacubitril is contraindicated due to the increased risk of angioedema. Use of the combination drug containing valsartan+sacubitril is possible no earlier than 36 hours after the last dose of perindopril. Use of perindopril is possible no earlier than 36 hours after the last dose of the combination drug containing valsartan+sacubitril (see sections “Contraindications” and “Drug Interactions”).

When ACE inhibitors are taken concomitantly with other neprilysin inhibitors (e.g., racecadotril), the risk of angioedema may be increased (see section “Drug Interactions”). In patients receiving Perindopril, a thorough benefit-risk assessment should be performed before starting treatment with enkephalinase inhibitors (e.g., racecadotril).

Concomitant use with mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus)

Concomitant use of an ACE inhibitor and an mTOR inhibitor (e.g., sirolimus, everolimus, temsirolimus) may be associated with an increased risk of angioedema (e.g., swelling of the airways or tongue, with or without impairment of respiratory function) (see section “Drug Interactions”).

Anaphylactoid reactions during LDL apheresis

In rare cases, patients receiving ACE inhibitors may experience life-threatening anaphylactic reactions during LDL apheresis with dextran sulfate. To prevent an anaphylactoid reaction, ACE inhibitor therapy should be temporarily discontinued before each apheresis procedure.

Anaphylactoid reactions during desensitization

There are isolated reports of anaphylactoid reactions in patients receiving ACE inhibitors during desensitizing therapy, for example, with hymenoptera venom. In these patients, such reactions could be prevented by temporarily discontinuing the ACE inhibitors, but reactions could recur upon accidental or careless resumption of treatment.

Liver function impairment

In rare cases, a syndrome of cholestatic jaundice progressing to fulminant hepatic necrosis, sometimes fatal, has been observed during the use of ACE inhibitors. The mechanism of this syndrome is unclear. If symptoms of jaundice or a significant increase in liver enzyme activity occur during the use of ACE inhibitors, the drug should be discontinued, and the patient should be under appropriate medical supervision.

Neutropenia/agranulocytosis/thrombocytopenia/anemia

Neutropenia/agranulocytosis, thrombocytopenia, and anemia may occur during the use of ACE inhibitors. In patients with normal renal function and no other complicating factors, neutropenia is rare.

Perindopril should be used with particular caution in patients with systemic connective tissue diseases, those receiving immunosuppressants, allopurinol, or procainamide, or when these risk factors are combined, especially in the presence of pre-existing renal impairment.

Some patients have developed severe infections, in some cases resistant to intensive antibiotic therapy. When prescribing Perindopril-SZ to such patients, it is recommended to periodically monitor the white blood cell count. Patients should report any signs of infectious diseases (e.g., sore throat, fever) to their doctor.

Ethnic differences

It should be considered that patients of Black race have a higher risk of developing angioedema. Like other ACE inhibitors, Perindopril-SZ is less effective in reducing blood pressure in Black patients. This effect may be related to the pronounced predominance of low-renin status in Black patients with arterial hypertension.

Cough

A persistent dry cough may occur during therapy with an ACE inhibitor, which resolves after discontinuation of the drug. This should be considered in the differential diagnosis of cough.

Surgery/general anesthesia

In patients scheduled for major surgery or the use of agents causing arterial hypotension during anesthesia, the use of perindopril may block the formation of angiotensin II in response to compensatory renin release. Treatment should be discontinued one day before surgery. If arterial hypotension develops due to this mechanism, blood pressure should be maintained by volume expansion.

Hyperkalemia

Hyperkalemia may develop during treatment with ACE inhibitors, including perindopril. Risk factors for hyperkalemia are renal failure, decreased renal function, age ≥70 years, diabetes mellitus, certain concomitant conditions, particularly dehydration, acute heart failure, metabolic acidosis, and concomitant use of potassium-sparing diuretics (such as spironolactone and its derivative eplerenone, triamterene, amiloride), potassium supplements/potassium preparations or potassium-containing salt substitutes, as well as the use of other drugs that can increase serum potassium levels (e.g., heparin, co-trimoxazole (fixed combination of sulfamethoxazole and trimethoprim)).

The use of potassium supplements/potassium preparations, potassium-sparing diuretics, potassium-containing salt substitutes may lead to a significant increase in serum potassium, especially in patients with reduced renal function. Hyperkalemia can lead to serious, sometimes fatal, cardiac arrhythmias. If concomitant use of Perindopril-SZ and the aforementioned drugs is necessary, treatment should be conducted with caution and with regular monitoring of serum potassium levels (see section “Drug Interactions”).

Diabetes mellitus

When prescribing the drug to patients with diabetes mellitus receiving oral hypoglycemic agents or insulin, blood glucose concentrations should be regularly monitored during the first month of ACE inhibitor therapy (see section “Drug Interactions”).

Lithium preparations

Concomitant use of Perindopril-SZ and lithium preparations is not recommended (see section “Drug Interactions”).

Potassium-sparing diuretics, potassium preparations, potassium-containing salt substitutes and supplements

Concomitant use of perindopril and potassium-sparing diuretics, as well as potassium preparations, potassium-containing salt substitutes and supplements is not recommended (see section “Drug Interactions”).

Dual blockade of the RAAS

There is evidence that concomitant use of ACE inhibitors, ARBs, or aliskiren increases the risk of hypotension, hyperkalemia, and reduced renal function (including acute renal failure). Thus, dual blockade of the RAAS by concomitant use of ACE inhibitors, ARBs, or aliskiren is not recommended (see sections “Drug Interactions” and “Pharmacological Properties”). If dual blockade therapy is considered absolutely necessary, it should only be carried out under strict medical supervision and with regular monitoring of renal function, serum electrolytes, and blood pressure.

The use of ACE inhibitors in combination with ARBs is contraindicated in patients with diabetic nephropathy and is not recommended in other patients (see section “Contraindications”).

Primary hyperaldosteronism

Patients with primary hyperaldosteronism are generally not responsive to antihypertensive drugs whose action is based on inhibition of the RAAS. Therefore, the use of Perindopril-SZ in such patients is not recommended.

Excipients

Perindopril-SZ contains lactose monohydrate. Patients with rare hereditary conditions such as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Effect on ability to drive and operate machinery

Perindopril-SZ has a minor influence on the ability to drive and use machines. Perindopril-SZ should be used with caution in patients driving vehicles or engaging in other activities requiring increased concentration and rapid reactions due to the potential risk of arterial hypotension and dizziness.

Overdose

Data on overdose of the drug in humans are limited.

Symptoms: marked decrease in blood pressure, circulatory shock, water-electrolyte imbalance, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough.

Treatment: The recommended treatment for overdose is intravenous administration of 0.9% sodium chloride solution. In case of a marked decrease in blood pressure, the patient should be placed in a supine position with legs elevated. If necessary, angiotensin II and/or catecholamine solutions can be administered intravenously. Perindopril can be removed from the systemic circulation by dialysis (see section “Special Instructions”). In case of therapy-resistant bradycardia, placement of a cardiac pacemaker may be required.

Vital signs, serum creatinine, and electrolyte levels should be monitored continuously.

Drug Interactions

Clinical trial data indicate that dual blockade of the RAAS due to concomitant use of ACE inhibitors, ARBs, or aliskiren leads to an increased frequency of adverse reactions such as hypotension, hyperkalemia, and impaired renal function (including acute renal failure) compared to situations where only one drug affecting the RAAS is used (see sections “Contraindications”, “Special Instructions”, and “Pharmacological Properties”).

Drugs causing hyperkalemia

Certain drugs or drugs of other pharmacological classes may increase the risk of hyperkalemia: aliskiren and aliskiren-containing drugs, potassium salts, potassium-sparing diuretics, ACE inhibitors, ARBs, NSAIDs, heparin, immunosuppressants such as cyclosporine or tacrolimus, trimethoprim, drugs containing co-trimoxazole (trimethoprim + sulfamethoxazole). The combination of these drugs increases the risk of hyperkalemia.

Concomitant use is contraindicated (see section “Contraindications”)

Aliskiren and aliskiren-containing drugs

Contraindicated in patients with diabetes mellitus and/or moderate or severe renal impairment and not recommended in other patients: increased risk of hyperkalemia, worsening of renal function, and increased cardiovascular morbidity and mortality.

Combination therapy with ACE inhibitors and ARBs

The use of ACE inhibitors in combination with ARBs is contraindicated in patients with diabetic nephropathy (see section “Contraindications”).

Extracorporeal treatments

Extracorporeal treatments leading to contact of blood with negatively charged surfaces, such as dialysis or hemofiltration using certain high-flux membranes (e.g., polyacrylonitrile membranes) and LDL apheresis with dextran sulfate, are contraindicated due to an increased risk of severe anaphylactoid reactions (see section “Contraindications”). If such treatment is necessary, the possibility of using a different type of dialysis membrane or a different class of antihypertensive drug should be considered.

Sacubitril/valsartan

Concomitant use of perindopril with combination products containing valsartan+sacubitril is contraindicated, as suppression of neprilysin concurrently with ACE inhibitor use may increase the risk of angioedema. Use of the combination product containing valsartan+sacubitril is possible no earlier than 36 hours after the last dose of perindopril. Use of perindopril is possible no earlier than 36 hours after the last dose of the combination product containing valsartan+sacubitril (see sections “Contraindications” and “Special Instructions”).

Concomitant use is not recommended

Aliskiren and aliskiren-containing drugs

In patients without diabetes mellitus or renal impairment, there is an increased risk of hyperkalemia, worsening of renal function, and increased cardiovascular morbidity and mortality.

Combination therapy with ACE inhibitors and ARBs

The literature has reported that in patients with established atherosclerotic disease, heart failure, or diabetes with target organ damage, simultaneous therapy with an ACE inhibitor and an ARB is associated with a higher incidence of hypotension, syncope, hyperkalemia, and worsening of renal function (including acute renal failure) compared to the use of only one drug affecting the RAAS. Dual blockade (e.g., by combining an ACE inhibitor and an ARB) should be limited to individual cases with careful monitoring of renal function, potassium levels, and blood pressure.

Estramustine

Concomitant use may lead to an increased risk of side effects such as angioedema.

Co-trimoxazole (sulfamethoxazole+trimethoprim)

When used concomitantly with co-trimoxazole (sulfamethoxazole+trimethoprim), the risk of hyperkalemia may increase (see section “Special Instructions”).

Potassium-sparing diuretics (such as triamterene, amiloride) and potassium salts

Hyperkalemia (potentially fatal), especially in case of impaired renal function (additive effects related to hyperkalemia).

The combination of perindopril with the aforementioned drugs is not recommended (see section “Special Instructions”). If concomitant use is indicated, they should be used with precautions and regular monitoring of serum potassium levels.

The specifics of using spironolactone in heart failure are described further in the text.

Lithium preparations

Concomitant use of lithium preparations and ACE inhibitors may lead to a reversible increase in serum lithium concentrations and related toxic effects. Concomitant use of perindopril and lithium preparations is not recommended. If the use of such a combination is necessary, regular monitoring of plasma lithium concentrations should be performed (see section “Special Instructions”).

Concomitant use requiring special caution

Hypoglycemic agents (insulin, oral hypoglycemic drugs)

According to epidemiological studies, the use of ACE inhibitors may enhance the hypoglycemic effect of insulin and oral hypoglycemic agents, up to the development of hypoglycemia. This is generally observed in the first weeks of concomitant therapy and in patients with impaired renal function.

Baclofen

Enhances the antihypertensive effect of ACE inhibitors. Blood pressure should be carefully monitored and, if necessary, the dose of antihypertensive drugs adjusted.

Non-potassium-sparing diuretics

In patients receiving diuretics, especially those causing fluid and/or salt depletion, an excessive decrease in blood pressure may be observed at the start of ACE inhibitor therapy. The risk of this can be reduced by discontinuing the diuretic, replenishing fluid or salt loss before starting perindopril therapy, and by initiating perindopril at a low dose with subsequent gradual increase.

In arterial hypertension in patients receiving diuretics, especially those causing fluid and/or salt depletion, diuretics should either be discontinued before starting the ACE inhibitor (the non-potassium-sparing diuretic may be reintroduced later), or the ACE inhibitor should be started at a low dose with subsequent gradual increase.

In the use of diuretics in CHF, the ACE inhibitor should be started at a very low dose, possibly after reducing the dose of the concomitantly used non-potassium-sparing diuretic.

In all cases, renal function (creatinine concentration) should be monitored during the first weeks of ACE inhibitor use.

Potassium-sparing diuretics (eplerenone, spironolactone)

Use of eplerenone or spironolactone in doses from 12.5 to 50 mg/day and low doses of ACE inhibitors: in the therapy of heart failure of NYHA functional class II-IV with left ventricular ejection fraction <40% and previous use of ACE inhibitors and “loop” diuretics, there is a risk of hyperkalemia (potentially fatal), especially if the recommendations regarding this drug combination are not followed.

Before using this drug combination, it is necessary to ensure the absence of hyperkalemia and impaired renal function.

It is recommended to regularly monitor serum creatinine and potassium levels: weekly during the first month of treatment and monthly thereafter.

NSAIDs, including high doses of acetylsalicylic acid (≥3 g/day)

Concomitant use of ACE inhibitors with NSAIDs (acetylsalicylic acid at a dose exerting an anti-inflammatory effect, cyclooxygenase-2 (COX-2) inhibitors, and non-selective NSAIDs) may lead to a reduction in the antihypertensive effect of ACE inhibitors. Concomitant use of ACE inhibitors with NSAIDs may lead to worsening of renal function, including the development of acute renal failure, and an increase in serum potassium, especially in patients with pre-existing reduced renal function. Caution should be exercised when prescribing this combination, especially in elderly patients. Patients should receive adequate fluid intake, and it is recommended to carefully monitor renal function, both at the start and during treatment.

Racecadotril

ACE inhibitors (e.g., Perindopril) are known to cause angioedema. The risk of its development may be increased with concomitant use of racecadotril (an enkephalinase inhibitor used to treat acute diarrhea).

mTOR (mammalian target of rapamycin) inhibitors (e.g., sirolimus, everolimus, temsirolimus)

Concomitant use with mTOR inhibitors increases the risk of angioedema (see section “Special Instructions”).

Recombinant tissue plasminogen activators (rtPA, alteplase)

Patients who have received ACE inhibitors and are receiving alteplase for thrombolytic therapy in acute ischemic stroke may have an increased risk of developing angioedema.

Concomitant use requiring certain caution

Antihypertensive drugs and vasodilators

The antihypertensive effect of perindopril may be enhanced when used concomitantly with other antihypertensive, vasodilating agents, including short- and long-acting nitrates.

Gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin)

Concomitant use with ACE inhibitors may increase the risk of angioedema due to reduced dipeptidyl peptidase-4 (DPP-IV) activity under the influence of the gliptin.

Tricyclic antidepressants, antipsychotic agents (neuroleptics) and general anesthetics

Concomitant use with ACE inhibitors may lead to an enhancement of the antihypertensive effect (see section “Special Instructions”).

Sympathomimetics

Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.

Gold preparations

In rare cases, nitritoid reactions – a symptom complex including facial flushing, nausea, vomiting, arterial hypotension – have been reported in patients receiving ACE inhibitors, including Perindopril, who were receiving intravenous gold preparations (sodium aurothiomalate).

Storage Conditions

The drug should be stored out of the reach of children, protected from light, at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 3 years. Do not use after the expiration date stated on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.