Perindopril-Richter (Tablets) Instructions for Use

Marketing Authorization Holder

Gedeon Richter, Plc. (Hungary)

Manufactured By

Gedeon Richter Poland, Co. Ltd. (Poland)

Or

Gedeon Richter-Rus, JSC (Russia)

Packaged By

GEDEON RICHTER POLAND, Co. Ltd. (Poland)

Or

GEDEON RICHTER-RUS, JSC (Russia)

ATC Code

C09AA04 (Perindopril)

Active Substance

Perindopril (Rec.INN registered by WHO)

Dosage Forms

	Perindopril-Richter	Tablets 4 mg: 30 pcs.
		Tablets 8 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Tablets white, oval, flat, with a score on one side, engraving C53 on the other side.

Excipients: microcrystalline cellulose, lactose monohydrate, colloidal silicon dioxide, magnesium stearate.

10 pcs. – Al/Al blisters (3) – cardboard packs.

Tablets white, round, flat, with a bevel, with engraving C54 on one side.

Excipients: microcrystalline cellulose, lactose monohydrate, colloidal silicon dioxide, magnesium stearate.

10 pcs. – Al/Al blisters (3) – cardboard packs.

Clinical-Pharmacological Group

ACE inhibitor

Pharmacotherapeutic Group

ACE inhibitor

Pharmacological Action

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

ACE, or kininase II, is an exopeptidase that both converts angiotensin I to the vasoconstrictor angiotensin II and degrades bradykinin, which has vasodilatory action, to an inactive heptapeptide. Inhibition of ACE leads to a decrease in plasma angiotensin II concentration, which causes an increase in plasma renin activity (via a “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, and 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 in the treatment of arterial hypertension of any severity. With the use of the drug, a decrease in both systolic and diastolic blood pressure is noted in the “lying” and “standing” position of the patient. Perindopril reduces total peripheral resistance, which leads to a decrease in blood pressure, while peripheral blood flow accelerates without a change in heart rate.

As a rule, Perindopril leads to an increase in renal blood flow, while the glomerular filtration rate does not change.

The antihypertensive effect of the drug 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 a 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.

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

Chronic heart failure (CHF)

Perindopril normalizes heart function by reducing preload and afterload.

In patients with CHF treated with Perindopril, the following was revealed

• Reduction of filling pressure in the left and right ventricles of the heart;
• Decrease in total peripheral resistance;
• Increase in cardiac output and increase in cardiac index.

Taking an initial dose of perindopril 2 mg in patients with CHF (NYHA functional class II-III) was not accompanied by a statistically significant decrease in blood pressure in the placebo group.

Cerebrovascular diseases

In patients with a history of cerebrovascular disease, active therapy with perindopril for 4 years (monotherapy or in combination with indapamide) in addition to standard therapy reduced blood pressure (systolic/diastolic); significantly reduced the risk of recurrent stroke (both ischemic and hemorrhagic), the risk of fatal or disabling strokes, the risk of major cardiovascular complications (including myocardial infarction, including fatal), the risk of developing dementia associated with stroke, and serious deterioration of 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 and type of stroke.

Stable coronary artery disease

In patients with stable coronary artery disease without clinical symptoms of CHF, therapy with perindopril at a dose of 8 mg/day for 4 years led to a significant reduction in the absolute risk of complications, such as mortality from cardiovascular diseases, non-fatal myocardial infarction and/or cardiac arrest with subsequent successful resuscitation by 1.9%. In patients who had previously had a myocardial infarction or revascularization procedure, the absolute risk reduction was 2.2% compared to the placebo group.

Children and adolescents (under 18 years)

The efficacy and safety of perindopril in children and adolescents under 18 years of age have not been established.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

The use of a combination of an ACE inhibitor with an angiotensin II receptor antagonist (ARA II) in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by confirmed target organ damage or with diabetic nephropathy, did not reveal a significant positive effect 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. Therefore, ACE inhibitors and ARA II should not be used simultaneously in patients with diabetic nephropathy.

Adding aliskiren to standard therapy with an ACE inhibitor or ARA II in patients with type 2 diabetes and chronic kidney disease or cardiovascular disease, or a combination of these diseases, increases the risk of adverse events and serious adverse events, such as hyperkalemia, arterial hypotension, impaired renal function, cardiovascular death and stroke.

Pharmacokinetics

Absorption

When taken orally, Perindopril is rapidly absorbed from the gastrointestinal tract, C_max in plasma is reached after 1 hour. T_1/2 of perindopril from plasma is 1 hour.

Food intake slows down the conversion of perindopril to perindoprilat, thus affecting bioavailability. Therefore, the drug should be taken orally once a day in the morning, before meals.

The relationship between the dose of perindopril and its plasma concentration has been shown to be linear.

Distribution and metabolism

Perindopril does not have pharmacological activity. Approximately 27% of the total absorbed perindopril enters the bloodstream as the active metabolite perindoprilat. In addition to perindoprilat, 5 more metabolites are formed that do not have pharmacological activity. C_max of perindoprilat in plasma is reached 3-4 hours after oral administration.

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

Excretion

Perindoprilat is excreted from the body by the kidneys, and the final T_1/2 of the free fraction is approximately 17 hours, as a result, equilibrium is reached within 4 days.

Pharmacokinetics in special patient groups

The excretion of perindoprilat is slowed down in elderly patients, as well as in patients with CHF or renal failure. The dialysis clearance of perindoprilat is 70 ml/min.

In patients with liver cirrhosis, the hepatic clearance of perindopril is reduced by half. However, the total amount of perindoprilat formed does not change, and therefore no dose adjustment is required.

Indications

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

ICD codes

Dosage Regimen

Orally, 1 tablet once a day, preferably in the morning, before meals.

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

Arterial hypertension

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

The recommended initial dose is 4 mg once a day.

In patients with high RAAS activity (especially in renovascular hypertension, hypovolemia and/or decreased plasma electrolyte levels, decompensated chronic heart failure or severe arterial hypertension), a pronounced decrease in blood pressure may develop after taking 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 a day.

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

Symptomatic arterial hypotension may occur at the beginning of therapy with Perindopril-Richter. 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 Perindopril-Richter in this group of patients. It is recommended, if possible, to stop taking diuretics 2-3 days before the intended start of therapy with Perindopril-Richter (see section “Special Instructions”).

If it is impossible to cancel diuretics, the initial dose of Perindopril-Richter should be 2 mg. In this case, it is necessary to monitor renal function and serum potassium levels. Subsequently, if necessary, the dose of the drug can be increased. If necessary, diuretic therapy can be resumed.

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

Chronic heart failure

Treatment of patients with CHF with Perindopril-Richter 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 a day, in the morning. After two weeks of treatment, the dose of the drug can be increased to 4 mg once a day, 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 patients at high risk (patients with impaired renal function and a tendency to water-electrolyte imbalance, patients simultaneously receiving diuretics and/or vasodilator drugs), 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 conditions should be corrected, if possible, before starting Perindopril-Richter. Indicators such as blood pressure, renal function and plasma potassium levels 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-Richter should be started at a dose of 2 mg for the first 2 weeks, then increasing the dose to 4 mg for the next 2 weeks before using indapamide. Therapy should be started at any time (from 2 weeks to several years) after a stroke.

Stable coronary artery disease: reduction of the risk of cardiovascular complications in patients with stable coronary artery disease

In patients with stable coronary artery disease, therapy with Perindopril-Richter should be started at a dose of 4 mg once a day. After 2 weeks, with good tolerability of the drug and taking into account the state of renal function, the dose can be increased to 8 mg once a day.

In elderly patients, therapy should be started with a dose of 2 mg once a day for one week, then 4 mg once a day for the next week. Then, taking into account the state of renal function, the dose can be increased to 8 mg once a day (see Table 1). The dose of the drug can be increased only 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 taking into account CCr.

Table 1. Dose of Perindopril-Richter in renal impairment

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

Patients with hepatic impairment. No dose adjustment is required for patients with impaired liver function.

Children and adolescents under 18 years. Currently, there is insufficient data on the safety and efficacy of perindopril in children and adolescents under 18 years of age. The available data do not allow making recommendations on the method of use and dosage of the drug in patients of this age group.

Adverse Reactions

The safety profile of perindopril is consistent with the safety profile of ACE inhibitors. The most common adverse events reported in clinical studies and observed with the use of perindopril are: dizziness, headache, paresthesia, vertigo, visual disturbances, tinnitus, excessive decrease in blood pressure, cough, shortness of breath, abdominal pain, constipation, diarrhea, taste disturbance, dyspepsia, nausea, vomiting, skin itching, skin rash, muscle cramps and asthenia.

The frequency of adverse reactions that were noted during clinical studies and/or post-registration use of perindopril is given in the following gradation: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000); frequency not known (frequency cannot be calculated from the available data). WHO frequency classification.

Blood and lymphatic system disorders uncommon* – eosinophilia; very rare – decrease in hemoglobin and hematocrit, thrombocytopenia, leukopenia/neutropenia, agranulocytosis, pancytopenia, hemolytic anemia in patients with congenital glucose-6-phosphate dehydrogenase deficiency.

Metabolism and nutrition disorders uncommon* – hypoglycemia, hyperkalemia, reversible after drug withdrawal, hyponatremia.

Nervous system disorders common – paresthesia, headache, dizziness, vertigo; uncommon – drowsiness*, syncope*; very rare – confusion.

Psychiatric disorders uncommon – sleep disorders, mood lability.

Eye disorders common – visual disturbances.

Ear and labyrinth disorders common – tinnitus.

Cardiac disorders uncommon* – palpitations, tachycardia; very rare – angina pectoris, cardiac arrhythmias, myocardial infarction, possibly due to excessive decrease in blood pressure in high-risk patients.

Vascular disorders common – excessive decrease in blood pressure and associated symptoms; uncommon* – vasculitis; very rare – stroke, possibly due to excessive decrease in blood pressure in high-risk patients.

Respiratory system disorders Common – cough, dyspnea; Uncommon – bronchospasm; Very rare – eosinophilic pneumonia, rhinitis.

Gastrointestinal system disorders Common – constipation, nausea, vomiting, abdominal pain, taste disturbance, dyspepsia, diarrhea; Uncommon – dry mouth; Very rare – pancreatitis.

Hepatobiliary disorders Very rare – hepatitis (cholestatic or cytolytic).

Skin and subcutaneous tissue disorders Common – pruritus, skin rash; Uncommon – angioedema of the face, lips, upper and lower extremities, mucous membranes, tongue, vocal folds and/or larynx, photosensitivity*, pemphigus*, hyperhidrosis; Rare* – exacerbation of psoriasis; Very rare – erythema multiforme.

Musculoskeletal and connective tissue disorders: Common – muscle cramps; Uncommon* – arthralgia, myalgia.

Renal and urinary disorders: Uncommon – renal failure; Very rare – acute renal failure.

Reproductive system and breast disorders Uncommon – erectile dysfunction.

General disorders and administration site conditions Common – asthenia; Uncommon* – chest pain, peripheral edema, malaise, pyrexia, falls.

Investigations: Uncommon* – increased blood urea and plasma creatinine; Rare – increased serum hepatic enzymes and bilirubin.

*Frequency assessment of adverse reactions identified from spontaneous reports is based on data from clinical trials of perindopril.

Contraindications

• Hypersensitivity to the active substance, other ACE inhibitors or any excipients of the drug;
• History of angioedema (Quincke’s edema) associated with previous ACE inhibitor therapy;
• Hereditary/idiopathic angioedema;
• Pregnancy;
• Breast-feeding period;
• Concomitant use with aliskiren or medicines containing aliskiren in patients with diabetes mellitus and/or moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m² body surface area);
• Concomitant use with angiotensin II receptor antagonists in patients with diabetic nephropathy;
• Lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome;
• Age under 18 years (efficacy and safety not established).

With caution

(see also sections “Special Precautions” and “Drug Interactions”)

Bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney, renal failure, systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma), therapy with immunosuppressants, allopurinol, procainamide (risk of neutropenia, agranulocytosis), reduced blood volume (diuretic therapy, salt-restricted diet, vomiting, diarrhea), angina pectoris, cerebrovascular diseases, renovascular hypertension, diabetes mellitus, chronic heart failure NYHA functional class IV, concomitant use of potassium-sparing diuretics, potassium preparations, potassium-containing salt substitutes and lithium preparations, hyperkalemia, surgery/general anesthesia, hemodialysis using high-flux membranes, desensitizing therapy, LDL apheresis, condition after kidney transplantation, aortic stenosis, mitral stenosis, hypertrophic obstructive cardiomyopathy, use in Black patients.

Use in Pregnancy and Lactation

Pregnancy

Perindopril-Richter is contraindicated during pregnancy.

Currently, there is no conclusive epidemiological data on the teratogenic risk when taking ACE inhibitors in the first trimester of pregnancy. However, a small increased risk of fetal developmental disorders cannot be excluded. When planning pregnancy or if pregnancy occurs during the use of Perindopril-Richter, the drug should be discontinued immediately and, if necessary, another antihypertensive therapy with a proven safety profile for use during pregnancy should be prescribed.

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

If the patient received ACE inhibitors during the second or third trimester of pregnancy, an ultrasound examination is recommended to assess the condition of the skull bones and renal function of the newborn.

Newborns whose mothers received ACE inhibitors during pregnancy should be under observation due to the risk of arterial hypotension.

Breast-feeding period

It is currently not established whether Perindopril passes into breast milk. 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

Preclinical studies have shown no effect of perindopril on reproductive function in rats of both sexes.

Use in Hepatic Impairment

No dose adjustment is required for patients with impaired liver function.

Pediatric Use

Use in children and adolescents under 18 years of age is contraindicated.

Special Precautions

Coronary artery disease

If unstable angina develops during the first month of therapy with Perindopril-Richter, 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-restricted diet, hemodialysis, diarrhea and vomiting, as well as in patients with severe hypertension with high renin activity. Symptomatic arterial hypotension may be observed in patients with clinical manifestations of heart failure, with or without renal failure. This risk 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 with an increased risk of developing symptomatic arterial hypotension, blood pressure, renal function and serum potassium levels should be carefully monitored during therapy with Perindopril-Richter. 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-Richter may cause an additional decrease in blood pressure. This effect is predictable and usually does not require discontinuation of therapy. If symptoms of a pronounced decrease in blood pressure appear, the dose of the drug should be reduced or its use should be discontinued.

Mitral stenosis, aortic stenosis, hypertrophic obstructive cardiomyopathy

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

Renal impairment

For patients with renal failure (creatinine clearance less than 60 ml/min), the initial dose of Perindopril-Richter is selected depending on the creatinine clearance value (see section “Dosage and Administration”) and then depending on the therapeutic effect. Such patients require regular monitoring of serum creatinine and potassium levels.

Arterial hypotension, which sometimes develops at the beginning of ACE inhibitor use in patients with symptomatic CHF, 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 therapy with ACE inhibitors, an increase in serum urea and creatinine levels is possible, usually resolving upon discontinuation of therapy. The additional presence of renovascular hypertension increases the risk of severe arterial hypotension and renal failure in such patients.

Treatment of such patients should be initiated under close medical supervision with low doses of the drug and subsequent adequate dose titration. Diuretic therapy should be temporarily discontinued and regular monitoring of plasma potassium and creatinine levels should be carried out during the first few weeks of therapy.

In some patients with arterial hypertension without a history of pre-existing renal vascular disease, serum urea and creatinine levels may increase, especially with the simultaneous use of diuretics. These changes are usually minor and reversible. The likelihood of developing these disorders is higher in patients with a history of renal failure. In such cases, discontinuation or reduction of the dose of Perindopril-Richter and/or the diuretic may be required.

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-Richter in patients after kidney transplantation.

Hypersensitivity/Angioedema

When taking ACE inhibitors, including perindopril, in rare cases and at any period of 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 affects only the face and lips, its manifestations usually resolve on their own, although antihistamines may be used to treat the symptoms. Angioedema accompanied by laryngeal edema can be fatal. Swelling of the tongue, vocal folds, or larynx can lead to airway obstruction. If such symptoms appear, emergency therapy is required, including subcutaneous administration of epinephrine (adrenaline) and/or ensuring airway patency. The patient should be under medical supervision until the symptoms completely and permanently disappear. 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.

In rare cases, intestinal angioedema has developed during therapy with ACE inhibitors. In this case, patients experienced abdominal pain as an isolated symptom or in combination with nausea and vomiting, in some cases without preceding facial angioedema and with normal C1-esterase levels. The diagnosis was established using computed tomography of the abdominal organs, ultrasound, or during surgery. Symptoms disappeared after discontinuation of ACE inhibitors. Therefore, in patients with abdominal pain receiving ACE inhibitors, the possibility of intestinal angioedema should be considered in the differential diagnosis.

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

In patients simultaneously receiving therapy with mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), the risk of developing angioedema (e.g., swelling of the airways or tongue with or without impaired breathing) may be increased (see section “Drug Interactions”).

Anaphylactoid reactions during LDL apheresis

In rare cases, life-threatening anaphylactoid reactions may develop in patients receiving ACE inhibitors during LDL apheresis using 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 the development 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 temporary withdrawal of ACE inhibitors, but if treatment was resumed accidentally or carelessly, reactions could develop again.

Hepatic impairment

In rare cases, a syndrome of cholestatic jaundice progressing to fulminant liver necrosis, sometimes fatal, has been observed during ACE inhibitor use. The mechanism of development of this syndrome is unclear. If jaundice appears or a significant increase in “liver” enzyme activity occurs during ACE inhibitor use, 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 ACE inhibitor use. In patients with normal renal function and in the absence of other complicating factors, neutropenia rarely develops. Perindopril-Richter should be used with particular caution in patients with systemic connective tissue diseases, during treatment with immunosuppressants, allopurinol or procainamide, or with a combination of these risk factors, especially in the presence of pre-existing renal impairment.

Some patients developed severe infections, in some cases resistant to intensive antibiotic therapy. When prescribing Perindopril-Richter to such patients, periodic monitoring of white blood cell count is recommended. Patients should inform their doctor of any signs of infectious diseases (e.g., sore throat, fever).

Ethnic differences

It should be taken into account that Black patients have a higher risk of developing angioedema. Like other ACE inhibitors, Perindopril-Richter is less effective in reducing blood pressure in Black patients.

This effect is possibly associated with a pronounced predominance of low-renin status in Black patients with arterial hypertension.

Cough

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

Surgery/General anesthesia

In patients scheduled for major surgery or the use of anesthetic agents that cause arterial hypotension, the use of perindopril may block the formation of angiotensin II against the background of 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 replenishing blood volume.

Hyperkalemia

Hyperkalemia may develop during treatment with ACE inhibitors, including perindopril. Risk factors for hyperkalemia are renal failure, decreased renal function, age over 70 years, diabetes mellitus, some concomitant conditions (dehydration, acute heart failure, metabolic acidosis), simultaneous use of potassium-sparing diuretics (such as spironolactone and its derivative eplerenone, triamterene, amiloride), potassium supplements/preparations or potassium-containing salt substitutes, as well as the use of other drugs that contribute to an increase in serum potassium levels (e.g., heparin). The use of potassium supplements/preparations, potassium-sparing diuretics, potassium-containing salt substitutes can lead to a significant increase in blood potassium levels, especially in patients with reduced renal function. Hyperkalemia can lead to serious, sometimes fatal, cardiac arrhythmias. If concomitant use of Perindopril-Richter and the above drugs is necessary, treatment should be carried out with caution with regular monitoring of serum potassium levels.

Patients with diabetes mellitus

When prescribing ACE inhibitors to patients with diabetes mellitus receiving oral hypoglycemic agents or insulin, blood glucose concentration should be regularly monitored during the first month of therapy.

Lithium preparations

Concomitant use of Perindopril-Richter and lithium preparations is not recommended.

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

Concomitant use of Perindopril-Richter and potassium-sparing diuretics, as well as potassium preparations, potassium-containing salt substitutes and supplements, is not recommended.

Dual blockade of the RAAS

There is evidence that the combined use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren increases the risk of arterial hypotension, hyperkalemia and impaired renal function (including acute renal failure). Thus, dual blockade of the RAAS by combined use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren is not recommended. If therapy with dual blockade is considered absolutely necessary, it should be carried out only under strict medical supervision and with regular monitoring of renal function, plasma electrolyte levels and blood pressure.

Concomitant use of Perindopril-Richter with aliskiren or medicines containing aliskiren is contraindicated in patients with diabetes mellitus and/or moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m² body surface area) and is not recommended in other patients.

Concomitant use of ACE inhibitors with angiotensin II receptor antagonists is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Lactose

Perindopril-Richter contains lactose monohydrate. Patients with rare hereditary lactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take this drug.

Effect on ability to drive and operate machinery

Perindopril-Richter should be prescribed with caution to patients driving vehicles or engaging in activities requiring increased concentration and rapid reaction, due to the risk of arterial hypotension and dizziness.

Overdose

Data on drug overdose are limited.

Symptoms pronounced decrease in BP, shock, water-electrolyte balance disorders, renal failure, hyperventilation, tachycardia, palpitation sensation, bradycardia, dizziness, anxiety, cough.

Treatment in case of a pronounced decrease in BP, the patient should be placed in the “supine” position on their back with legs elevated. If necessary, a 0.9% sodium chloride solution should be administered intravenously. If necessary, a solution of catecholamines and/or angiotensin II can be administered intravenously. Perindopril can be removed from the body by dialysis. In case of therapy-resistant bradycardia, the installation of an artificial pacemaker may be required. It is necessary to constantly monitor the indicators of the main vital functions of the body, serum creatinine concentration and electrolyte levels.

Drug Interactions

Clinical trial data show that dual blockade of the RAAS resulting from the simultaneous use of ACE inhibitors, ARBs, or aliskiren leads to an increased frequency of adverse events such as arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to situations where only one drug affecting the RAAS is used.

Medicinal products causing hyperkalemia

Some drugs may increase the risk of hyperkalemia: aliskiren and aliskiren-containing drugs, potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, NSAIDs, heparin, immunosuppressants such as cyclosporine or tacrolimus, drugs containing trimethoprim, including the fixed combination of trimethoprim and sulfamethoxazole (co-trimoxazole). The combination of these drugs increases the risk of hyperkalemia.

Concomitant use is contraindicated (see section “Contraindications”)

Aliskiren and drugs containing aliskiren

Contraindicated in patients with diabetes mellitus and/or with moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m² body surface area) and not recommended in other patients: the risk of hyperkalemia, worsening of renal function and increased frequency of cardiovascular morbidity and mortality is increased. The use of ACE inhibitors in combination with angiotensin II receptor antagonists is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Concomitant use is not recommended (see section “Special Instructions”)

Aliskiren

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

Combination therapy with ACE inhibitors and angiotensin receptor antagonists

Literature reports that in patients with established atherosclerotic disease, heart failure, or diabetes mellitus with target organ damage, simultaneous therapy with an ACE inhibitor and an ARB is associated with a higher frequency of arterial 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 with an ARB) should be limited to individual cases with careful monitoring of renal function, serum potassium levels and BP.

Estramustine

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

Racecadotril

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

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

In patients simultaneously receiving therapy with mTOR inhibitors, the risk of developing angioedema may be increased (see section “Special Instructions”).

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

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

The combination of perindopril with the aforementioned drugs is not recommended. If, nevertheless, concomitant use is indicated, they should be used with precautions and regular monitoring of serum potassium levels.

Features of the use of spironolactone in heart failure are described further in the text.

Lithium preparations

With the simultaneous use of lithium preparations and ACE inhibitors, a reversible increase in serum lithium concentration and associated toxic effects may be noted. The simultaneous use of perindopril and lithium preparations is not recommended. If such therapy is necessary, regular monitoring of plasma lithium concentration should be carried out.

Concomitant use requiring special caution

Hypoglycemic agents (insulin, oral hypoglycemic agents)

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 levels should be carefully monitored and, if necessary, the dosage of antihypertensive drugs adjusted.

Non-potassium-sparing diuretics

In patients receiving diuretics, especially those excreting fluid and/or salts, an excessive decrease in BP may be observed at the beginning of perindopril therapy, the risk of which can be reduced by discontinuing the diuretic, replenishing fluid or salt loss before starting perindopril therapy, and by prescribing perindopril at a low dose with its subsequent gradual increase.

In arterial hypertension in patients receiving diuretics, especially those excreting fluid and/or salts, diuretics should either be discontinued before starting the ACE inhibitor (in which case a non-potassium-sparing diuretic may be re-prescribed later), or the ACE inhibitor should be prescribed at a low dose with its subsequent gradual increase.

When using diuretics in case of CHF, the ACE inhibitor should be prescribed at a low dose, possibly after reducing the dose of the concurrently 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 mg to 50 mg per 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 previously used ACE inhibitors and “loop” diuretics, there is a risk of hyperkalemia (potentially fatal), especially in case of non-compliance with recommendations regarding this drug combination.

Before using this combination of drugs, it is necessary to ensure the absence of hyperkalemia and renal impairment.

It is recommended to regularly monitor serum creatinine concentration 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, COX-2 inhibitors and non-selective NSAIDs) may lead to a reduction in the antihypertensive effect of ACE inhibitors. Concomitant use of ACE inhibitors and NSAIDs may lead to worsening of renal function, including the development of acute renal failure, and an increase in serum potassium levels, especially in patients with reduced renal function. Caution should be exercised when prescribing this combination, especially in elderly patients. Patients should receive adequate amounts of fluid, and it is recommended to carefully monitor renal function, both at the beginning and during treatment.

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 suppression of dipeptidyl peptidase IV (DPP-IV) activity by the gliptin.

Tricyclic antidepressants, antipsychotics and general anesthetics

Concomitant use with ACE inhibitors may lead to an enhancement of the antihypertensive effect.

Sympathomimetics

May weaken the antihypertensive effect of ACE inhibitors.

Gold preparations

When using ACE inhibitors, including perindopril, in patients receiving intravenous gold preparation (sodium aurothiomalate), nitritoid reactions have been reported in rare cases – a symptom complex including facial skin flushing, nausea, vomiting, arterial hypotension.

Storage Conditions

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

Shelf Life

The shelf life is 3 years.

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.