Perindopril-Teva, 10 mg 30 pcs

Pharmacotherapeutic group: inhibitor of angiotensin-converting enzyme (ACE)

Code ATX: C09AA04

Pharmacological properties

Pharmacodynamics

Mmechanism of action

Perindopril is an antihypertensive drug from the angiotensin-converting enzyme (ACE) inhibitor group. ACE (also called kininase II) is an exopeptidase that both converts angiotensin I into the vasoconstrictor angiotensin II and degrades bradykinin, which has a vasodilator effect, into an inactive heptapeptide. ACE inhibition leads to a decrease in plasma concentration of angiotensin II, which causes an increase in plasma renin activity (by a “negative feedback” mechanism) and a decrease in aldosterone secretion.

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

Perindopril has a therapeutic effect due to the active metabolite perindoprilat. Other metabolites have no inhibitory effect against ACE in vitro.

Clinical efficacy and safety

Arterial hypertension

Perindopril is effective in the therapy of arterial hypertension of any severity. Both systolic and diastolic blood pressure (BP) decrease with the use of the drug at lying and standing position.

Perindopril decreases total peripheral vascular resistance (TPR) which leads to a decrease in BP, while peripheral blood flow is accelerated without changing heart rate (HR).

In general, perindopril causes an increase in renal blood flow without changing glomerular filtration rate.

The antihypertensive effect of the drug reaches its maximum 4-6 hours after a single oral dose and lasts for 24 hours. In 24 hours after oral administration there is significant (about 87-100%) residual ACE inhibition.

The decrease in BP is achieved fairly quickly. In patients with a positive response to treatment, BP normalization occurs within a month and persists without the development of tachyphylaxis.

The discontinuation of treatment is not accompanied by the development of “withdrawal” syndrome.

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

The concomitant administration of thiazide diuretics increases the severity of the antihypertensive effect. In addition, concomitant use of ACE inhibitor and thiazide diuretic also decreases the risk of hypokalemia when taking diuretics.

Heart failure

Perindopril normalizes heart function by reducing preload and postload.

In patients with chronic heart failure who received perindopril, it was found:

• reduced filling pressures in the left and right ventricles of the heart;
• reduced total peripheral vascular resistance;
• increased cardiac output and increased cardiac index.

The study of perindopril compared to placebo showed that BP changes after the first perindopril administration in patients with chronic heart failure (NYHA functional class II-III), were not statistically significantly different from BP changes observed after placebo administration.

Cerebrovascular disease

. When perindopril tretbutylamine 2-4 mg/day (equivalent to 2.5-5 mg perindopril arginine or perindopril tosylate) is used both in monotherapy and in combination with indapamide, simultaneously with the standard therapy of stroke and/or arterial hypertension or other pathological conditions in patients with a history of cerebrovascular disease (stroke or transient ischemic attack) within the last 5 years, the risk of recurrent stroke (both ischemic and hemorrhagic nature) is significantly reduced. Additionally, the risk of fatal or disabling strokes; major cardiovascular complications, including fatal myocardial infarction; stroke-related dementia; and severe cognitive impairment are reduced.

These therapeutic benefits are seen in patients with both arterial hypertension and normal BP, regardless of age, gender, presence or absence of diabetes mellitus and type of stroke.

Stable coronary heart disease (CHD)

. Against the background of therapy with perindopril tretbutylamine 8 mg (equivalent to 10 mg perindopril arginine or perindopril tosylate) in patients with stable CHD there was a significant reduction of absolute risk of complications, provided by the main criterion of effectiveness (mortality from cardiovascular disease, frequency of nonfatal myocardial infarction and/or cardiac arrest with subsequent successful resuscitation) by 1.9%. Patients who had previously undergone a myocardial infarction or coronary revascularization procedure had a 2.2% reduction in absolute risk compared to the placebo group.

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

There are data from clinical trials of combination therapy with an ACE inhibitor and an angiotensin II receptor antagonist (APA II).

There have been clinical studies involving patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes with confirmed target organ damage, as well as studies involving patients with type 2 diabetes and diabetic nephropathy.

The data from clinical trials showed no significant positive effect of combination therapy on the occurrence of renal and/or cardiovascular events and on mortality rates, while the risk of hyperglycemia, acute renal failure and/or arterial hypotension increased compared to monotherapy.

With consideration of the similar within-group pharmacodynamic properties of ACE inhibitors and ARA II inhibitors, these results would be expected for interactions between any other drugs in the ACE and ARA II classes.

Therefore, ACE inhibitors and ARA II should not be used concomitantly in patients with diabetic nephropathy.

There are data from a clinical trial investigating the beneficial effects of adding the direct renin inhibitor 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 with a combination of these conditions. The study was terminated early due to an increased risk of adverse outcomes. Cardiovascular death and stroke occurred more frequently in the aliskiren group compared to the placebo group; also adverse events and serious adverse events (hyperkalemia, arterial hypotension, and impaired renal function) were reported more frequently in the aliskiren group than in the placebo group.

Pharmacokinetics

absorption. On oral administration, perindopril is rapidly absorbed in the gastrointestinal tract, the maximum concentration (C_max) in plasma is reached after 1 hour. The elimination half-life (T_1/2) of perindopril from blood plasma is 1 hour.

Perindopril has no pharmacological activity. Approximately 27% of the total amount of absorbed perindopril enters the bloodstream as the active metabolite perindoprilat. In addition to perindoprilat, 5 other metabolites without pharmacological activity are formed. C_max of perindoprilat in blood plasma is reached 3-4 hours after oral administration.

Concomitant ingestion slows the conversion of perindopril to perindoprilat, thus affecting bioavailability. It has been shown that the relationship between perindopril dose and plasma concentrations is linear. Therefore, the drug should be taken orally once a day, in the morning, before meals.

Distribution. The volume of distribution of free perindoprilat is approximately 0.2 l/kg.

The binding of perindoprilat to plasma proteins, mainly ACE, is 20% and is dose-dependent.

Elevation. Perindoprilat is excreted by the kidneys. The T_1/2 free fraction is 3-5 hours. “Effective” T_1/2 is approximately 17 hours, the equilibrium state is reached within 4 days.

Special patient groups

The excretion of perindoprilat is delayed in the elderly and in patients with cardiac and renal insufficiency.

The dialysis clearance of perindoprilat is 70 ml/min.

In patients with cirrhosis, hepatic clearance of perindopril decreases by half. However, the amount of perindoprilat produced is not decreased, and no adjustment of the drug dose is required (see sections “Dosage and administration” and “Precautions”).

Indications

Active ingredient

Composition

1 tablet – perindopril (in tosylate form) 10 mg

Excipients:

Lactose monohydrate – 143.924 mg,

corn starch – 5.4 mg,

sodium bicarbonate – 3.172 mg,

pregelatinized corn starch – 14.4 mg,

povidone K30 – 3.6 mg,

magnesium stearate – 1.8 mg.

Shell composition:

opabrai II green 85F210013 (polyvinyl alcohol partially hydrolyzed – 3.6 mg, titanium dioxide (E171) – 2.133 mg, macrogol-3350 – 1.818 mg, talc – 1.332 mg, indigo carmine (E132) – 0.0495 mg, brilliant blue dye (E133) – 0.0315 mg, iron oxide yellow dye (E172) – 0.018 mg, quinoline yellow dye (E104) – 0.018 mg).

How to take, the dosage

Ingestion. It is recommended to take once a day, preferably in the morning, before meals.

The dose of the drug is adjusted individually for each patient, depending on the severity of the disease and the individual response to treatment.

Arterial hypertension

Perindopril-Teva may be used in monotherapy and in combination with other antihypertensive agents.

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

In Patients with significant activation (RAAS) (e.g., with renovascular hypertension, hypovolemia and/or hyponatremia, decompensated CHF or severe arterial hypertension) a pronounced BP decrease may develop after the first dose of the drug. At the beginning of therapy, such patients should be under close medical supervision. The recommended initial dose is 2.5 mg/day in a single dose. If necessary, within a month, the dose may be increased to 10 mg/day in a single dose and in case of good tolerability of the previous dose. The maximum daily dose is 10 mg.

The addition of ACE inhibitors to patients taking diuretics may cause arterial hypotension in them. In this regard it is recommended to treat with caution, to discontinue diuretics 2-3 days before the treatment with Perindopril-Teva or to start the treatment with Perindopril-Teva from initial single dose of 2.5 mg/day. BP, renal function and serum potassium content should be monitored. Subsequently, the drug dose may be increased, depending on the BP dynamics. If necessary the therapy with diuretic may be resumed.

In older patients the recommended initial daily dose is 2.5 mg/day. Thereafter, the dose may be gradually increased to 5 mg/day and, if necessary, to a maximum dose of 10 mg/day in a single dose, taking into account the state of renal function.

Chronic Heart Failure

The recommended starting dose is 2.5 mg/day in one dose in the morning, under medical supervision. After 2 weeks, the dose may be increased to 5 mg/d at a single dose, with BP monitoring. Treatment of CHF with clinical manifestations is usually combined with potassium-saving diuretics, beta-adrenoblockers and/or digoxin.

In Patients with CHF, with renal insufficiency and with a tendency to water-electrolyte disturbances (hyponatremia), as well as in patients simultaneously taking diuretics and/or vasodilators, treatment with Perindopril-Teva is started under close medical supervision.

In patients with high risk of developing clinically significant arterial hypotension (e.g., when taking high doses of diuretics) if possible before starting the drug Perindopril-Teva it is necessary to eliminate hypovolemia and water-electrolyte disorders. It is recommended that BP, renal function and serum potassium levels be monitored closely before and during therapy.

Prevention of recurrent stroke (combined therapy with indapamide)

. In patients with a history of cerebrovascular disease, therapy with Perindopril-Teva should be started with a dose of 2.5 mg for the first two weeks, then increasing the dose to 5 mg for the next two weeks before indapamide.

The therapy should be started any time (from two weeks to several years) after a stroke.

Stable coronary heart disease

In patients with stable CHD, the recommended initial dose of Perindopril-Teva is 5 mg/day in a single dose. After 2 weeks, the dose is increased to 10 mg/day on a single dose if the 5 mg/day dose is well tolerated and renal function is monitored.

The treatment of older patients should begin with a dose of 2.5 mg/day on a single dose, which may be increased to 5 mg/day on a single dose after a week. If necessary, the dose may be increased up to 10 mg/day in one dose with obligatory control of renal function in a week. In elderly patients, the drug dose may be increased only if the previous, lower dose is well tolerated.

In renal failure: In patients with renal impairment, the dose of the drug should be adjusted for creatinine clearance (CK).

Recommended doses:

CK (ml/min.)

Recommended dose

more than or equal to 60

5 mg/d daily

more than 30 and less than 60

/p>

2.5 mg/d daily

more than 15 and less than 30

2.5 mg/d every other day

/p>

Patients on hemodialysis * less than 15

/p>

2.5 mg/d per day of dialysis

*- Dialysis clearance of perindoprilat is 70 ml/min.

Perindopril-Teva should be taken after a dialysis session.

In liver disease dose adjustment is not required.

If one or more doses are missed, Perindopril-Teva should be taken at the usual dose at the next appointment; a higher dose should not be taken.

Interaction

Drugs causing hyperkalemia

Some drugs or drugs in other pharmacological classes may increase the risk of hyperkalemia: aliskiren and aliskiren-containing drugs, potassium salts, potassium-saving diuretics, ACE inhibitors, ARA II receptor antagonists, nonsteroidal anti-inflammatory drugs (NSAIDs), Co-trimoxazole (trimethoprim + sulfamethoxazole) heparin, immunosuppressants such as cyclosporine or tacrolimus, trimethoprim. The combination of these drugs increases the risk of hyperkalemia.

Simultaneous use is contraindicated

.Aliskiren

In patients with diabetes mellitus or impaired renal function (GFR < 60 mL/min/1.73 m2 body surface area) increases the risk of hyperkalemia, impaired renal function, and increased cardiovascular morbidity and mortality.

Simultaneous use is not recommended

Aliskiren

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

Double blockade of the RAAS

. The literature has reported that in patients with established atherosclerotic disease, heart failure, or diabetes mellitus with target organ damage, concurrent therapy with an ACE inhibitor and ARA II is associated with higher rates of hypotension, syncope, hyperkalemia, and impaired renal function (including acute renal failure) compared with use of the RAAS-acting drug alone. Dual blockade (e.g., when ACE inhibitor is combined with ARA II) should be limited to individual cases with close monitoring of renal function, plasma potassium and BP.

Estramustine

Concomitant use may increase the risk of side effects such as angioedema.

Neutral endopeptidase inhibitors (NEIs)

An increased risk of angioedema has been reported with concomitant use of ACE inhibitors and racecadotril (an enkephalinase inhibitor used to treat acute diarrhea).

The simultaneous use of ACE inhibitors with drugs containing sacubitril (neprilysin inhibitor) increases the risk of angioedema, therefore simultaneous use of these drugs is contraindicated. ACE inhibitors should be administered not earlier than 36 hours after withdrawal of drugs containing Sacubitril. Administration of the drugs containing Sacubitril is contraindicated in patients receiving ACE inhibitors and also within 36 hours after withdrawal of ACE inhibitors.

Kalie-saving diuretics (such as triampterene, amiloride), potassium preparations.

Under ACE inhibitor therapy, serum potassium is usually within normal limits, but hyperkalemia may occur in some patients. Combined use of ACE inhibitors and potassium-saving diuretics (e.g., spironolactone and its derivatives eplerenone, triamterene or amiloride), potassium preparations may cause hyperkalemia (with possible lethal outcome), especially if renal function is impaired (additional effects associated with hyperkalemia). Therefore, it is not recommended to combine perindopril with these drugs. Prescribe these combinations only in case of hypokalemia, taking precautions and regularly monitoring the serum potassium content. The peculiarities of spironolactone therapy in cardiac insufficiency are described below.

Lithium

Concomitant use of lithium preparations and ACE inhibitors may cause reversible increase in serum lithium and lithium toxicity. Concomitant use of ACE inhibitors with thiazide diuretics may further increase the serum lithium content and increase the risk of its toxic effects. Simultaneous use of Perindopril-Teva and lithium preparations is not recommended. If such combined therapy is necessary, it is carried out under regular monitoring of lithium content in blood serum.

Simultaneous use with drugs requiring special caution

Kalinergic diuretics

. Patients taking diuretics, especially those with excessive fluid and/or electrolyte excretion, may develop excessive arterial hypotension at the start of therapy with ACE inhibitors. The risk of excessive BP decrease can be reduced by withdrawal of the diuretic, intravenous administration of 0.9% sodium chloride solution, and by prescribing an ACE inhibitor at lower doses. Further increase in perindopril dose should be done with caution.

In arterial hypertension in patients receiving diuretics, especially if excessive fluid and/or electrolyte excretion, diuretics should either be discontinued before starting ACE inhibitor use (and the potassium-saving diuretic may be prescribed again later), or the ACE inhibitor should be prescribed at a low dose with a further gradual increase in dose.

When diuretics are used in cases of CFS, an ACE inhibitor should be prescribed at a low dose, possibly after reducing the dose of the potassium-saving diuretic used simultaneously.

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

Caliberating diuretics (eplerenone, spironolactone)

The use of eplerenone or spironolactone in doses of 12.5 mg to 50 mg daily and low-dose ACE inhibitors:

In the therapy of NYHA functional class II-IV heart failure with left ventricular ejection fraction < 40% and previously used ACE inhibitors and “loop” diuretics, there is a risk of hyperkalemia (with possible death), especially if recommendations for this drug combination are not followed.

Be sure that there is no hyperkalemia or renal dysfunction before using this drug combination.

We recommend regular monitoring of creatinine and potassium concentrations: weekly in the first month of treatment and monthly thereafter.

NSAIDs, including acetylsalicylic acid at doses of 3 g/day or greater

Preventive drugs. Concomitant use of ACE inhibitors and NSAIDs (acetylsalicylic acid at a dose with anti-inflammatory effects, cyclooxygenase-2 inhibitors (COX-2) and non-selective NSAIDs) may lead to a decrease 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 increased serum potassium, 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 fluids, and careful monitoring of renal function is recommended, both at the beginning and during treatment.

Hypoglycemic agents

The simultaneous use of ACE inhibitors and hypoglycemic agents (insulin or oral hypoglycemic agents) may increase the hypoglycemic effect, up to hypoglycemia. As a rule, this phenomenon occurs in the first weeks of concomitant therapy in patients with impaired renal function.

Baclofen

It enhances the antihypertensive effect of ACE inhibitors. BP levels and, if necessary, the dosage of hypotensive drugs should be monitored carefully.

Simultaneous use with drugs requiring some caution

Special Instructions

Stable CHD

If an episode of unstable angina occurs (significant or not) during the first month of therapy with Perindopril-Teva, the benefit/risk ratio of therapy with this drug should be evaluated.

Arterial hypotension

The ACE inhibitors may cause a sharp decrease in BP. In patients with uncomplicated arterial hypertension, symptomatic arterial hypotension rarely occurs after the first dose. The risk of excessive BP decrease is increased in patients with decreased AUC during diuretic therapy, during strict salt-free diet, hemodialysis, as well as during diarrhea or vomiting, or with severe renin-dependent arterial hypertension. Severe arterial hypotension was observed in patients with severe CHF, both in the presence of concomitant renal failure and in its absence. Most often, severe arterial hypotension may develop in patients with more severe CHF who take “loop” diuretics in high doses, as well as against the background of hyponatremia or renal insufficiency. In these patients, close medical supervision at the beginning of therapy and during titration of drug doses is recommended. The same applies to patients with CHD or cerebrovascular disease, in whom excessive BP reduction may lead to myocardial infarction or cerebrovascular complications.

In case of arterial hypotension, the patient should be placed in a horizontal position with elevated legs and, if necessary, intravenous 0.9% sodium chloride solution should be administered to increase the blood pressure. Transient arterial hypotension is not a contraindication for further therapy. After restoration of the RBC and BP, treatment may be continued with careful selection of the drug dosage.

In some patients with CHF and normal or low BP during therapy with Perindopril-Teva, an additional decrease in BP may occur. This effect is expected and is usually not a reason for discontinuation of the drug. If arterial hypotension is accompanied by clinical manifestations, a dose reduction or discontinuation of Perindopril-Teva may be required.

Renal dysfunction

In patients with renal impairment (CKI less than 60 ml/min) the initial dose of Perindopril-Teva should be adjusted according to CKI (see section “Dosage and administration”) and then depending on therapeutic response. Regular monitoring of potassium and serum creatinine concentration is necessary for these patients.

In patients with symptomatic heart failure, arterial hypotension developing during initial therapy with ACE inhibitors may lead to worsening of renal function. Cases of acute renal failure, usually reversible, have occasionally been reported in these patients.

In some patients with bilateral renal artery stenosis or renal artery stenosis of the sole kidney (especially in the presence of renal failure) during therapy with ACE inhibitors, increased serum concentrations of urea and creatinine have been noted, reversible after withdrawal of therapy.

Patients with renovascular hypertension during therapy with ACE inhibitors have an increased risk of severe arterial hypotension and renal failure. Treatment of such patients should be started under close medical supervision, with low doses of the drug and with further adequate dose adjustment. During the first weeks of therapy with Perindopril-Teva it is necessary to cancel diuretics and regularly monitor renal function.

In some patients with arterial hypertension with previously undetected renal insufficiency, especially with concomitant therapy with diuretics, a slight and temporary increase in serum urea and creatinine concentrations has been noted. In this case, it is recommended to reduce the dose of Perindopril-Teva and/or discontinue the diuretic.

Patients on hemodialysis

In patients on dialysis using high-flow membranes and taking ACE inhibitors simultaneously, there have been several cases of persistent, life-threatening anaphylactic reactions. A different type of membrane should be used if hemodialysis is necessary.

Kidney transplantation

There is no experience with Perindopril-Teva in patients after recent kidney transplantation.

Ensensitivity, angioedema

In rare cases, patients who took ACE inhibitors, including perindopril, developed angioedema of the face, limbs, lips, tongue, vocal folds and/or larynx. Patients taking mTOR inhibitors concomitantly may have an increased risk of angioedema. This condition can develop at any time during treatment. If angioedema develops, treatment should be discontinued immediately and the patient should be under medical observation until symptoms have completely disappeared. Angioedema of the lips and face usually does not require treatment; antihistamines may be used to reduce the severity of the symptoms. Angioedema of the tongue, vocal folds or larynx may be fatal. If angioedema develops, epinephrine (adrenaline) should be given immediately by subcutaneous injection and the airway should be secured.

Patients with a history of angioedema not associated with ACE inhibitor use may be at high risk of developing angioedema when taking an ACE inhibitor.

In rare cases, angioedema of the intestine develops during therapy with ACE inhibitors. Patients have abdominal pain as an isolated symptom or in combination with nausea and vomiting, in some cases without preceding angioedema of the face and with normal C1-esterase levels. The diagnosis was established by abdominal computed tomography, ultrasound or surgery. Symptoms disappeared after discontinuation of ACE inhibitors; when making a differential diagnosis, the possibility of angioedema of the bowel should be considered (see section “Side effects”).

Anaphylactoid reactions during low-density lipoprotein apheresis (LDL apheresis)

. In patients receiving ACE inhibitors during LDL apheresis with dextran sulfate, an anaphylactic reaction may occur in rare cases. Temporary withdrawal of ACE inhibitor before each apheresis procedure is recommended.

Anaphylactic reactions during desensitization

In patients receiving ACE inhibitors during desensitization (e.g., by hymenopteran venom), in very rare cases, life-threatening anaphylactic reactions may develop. It is recommended that the ACE inhibitor be temporarily withdrawn prior to each desensitization procedure.

Help failure

An ACE inhibitor therapy may sometimes develop a syndrome that begins with cholestatic jaundice and then progresses to fulminant liver necrosis, sometimes with a fatal outcome. The mechanism of this syndrome is unclear. If jaundice or increased hepatic enzyme activity occurs while taking an ACE inhibitor, the ACE inhibitor should be stopped immediately and the patient should be closely monitored. Appropriate testing should also be performed.

Neutropenia, agranulocytosis, thrombocytopenia, anemia

. Cases of neutropenia, agranulocytosis, thrombocytopenia and anemia have been reported in patients on ACE inhibitor therapy. Neutropenia is rare in normal renal function in the absence of other complications. Perindopril-Teva should be used with great caution in patients with systemic connective tissue diseases (e.g., SLE, scleroderma) who simultaneously receive immunosuppressive therapy, allopurinol or procainamide, as well as in combination of all these factors, especially in existing renal impairment. These patients may develop severe infections that are not amenable to intensive antibiotic therapy. During therapy with Perindopril-Teva in patients with the above factors, it is recommended to periodically monitor the number of leukocytes in blood and warn the patient to inform the physician about the appearance of any symptoms of infection.

In patients with congenital deficiency of glucose-6-phosphate dehydrogenase, there have been isolated cases of hemolytic anemia.

Negroid race

Like other ACE inhibitors, perindopril is less effective in reducing BP in patients of the non-human race, possibly because of the higher prevalence of low-renin states in this patient population with arterial hypertension.

Cough

In therapy with ACE inhibitors, persistent, nonproductive cough may develop, which ceases after drug withdrawal. This should be considered in the differential diagnosis of cough.

Surgery and general anesthesia

. In patients whose condition requires extensive surgery or general anesthesia with drugs that cause arterial hypotension, ACE inhibitors, including perindopril, may block angiotensin II formation with compensatory renin release. The day before surgery, ACE inhibitor therapy should be discontinued. If ACE inhibitor cannot be abolished, arterial hypotension developing according to the described mechanism can be corrected by increasing the RBC.

Hyperkalemia

With ACE inhibitor therapy, including perindopril, blood potassium levels may increase in some patients. The risk of hyperkalemia is increased in patients with renal and/or heart failure, elderly (>70 years), decompensated diabetes mellitus, hypoaldosteronism, metabolic acidosis, dehydration and in patients using potassium-saving diuretics, potassium drugs or other drugs that cause hyperkalemia (eg, heparin, Co-trimoxazole (trimethoprim + sulfamethoxazole). If concomitant administration of these drugs is necessary, it is recommended to monitor serum potassium levels regularly, since hyperkalemia can lead to arrhythmias, sometimes fatal.

Diabetes mellitus

In diabetic patients receiving oral hypoglycemic agents or insulin, blood glucose concentrations should be monitored carefully during the first few months of therapy with ACE inhibitors.

Lactose

Perindopril-Teva tablets contain lactose. Therefore, patients with hereditary lactose intolerance, lactase deficiency or malabsorption syndrome should not take this drug.

Double blockade of the RAAS

. Cases of arterial hypotension, syncope, stroke, hyperkalemia, and renal dysfunction (including acute renal failure) have been reported in susceptible patients, especially when used concomitantly with medications that affect this system. Therefore, dual blockade of the RAAS as a result of combining an ACE inhibitor with ARAII or aliskiren is not recommended. Concomitant use of ACE inhibitors with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or with moderate or severe renal insufficiency (FFR less than 60 ml/min/1.73 m2 body surface area) and is not recommended in other patients.

Mitral stenosis/aortic stenosis/hypertrophic obstructive cardiomyopathy

. Perindopril, like other ACE inhibitors, should be prescribed with caution in patients with left ventricular outflow tract obstruction (aortic stenosis, hypertrophic obstructive cardiomyopathy) and in patients with mitral stenosis.

The concomitant use of ACE inhibitors with APA II is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Influence on driving and operating ability

The possibility of arterial hypotension or dizziness must be considered, which may affect the ability to drive vehicles and operate machinery requiring increased concentration and rapid psychomotor reactions.

Synopsis

Contraindications

Hypersensitivity to perindopril or other components of the drug, as well as to other ACE inhibitors; pregnancy; breastfeeding period; history of angioedema (hereditary, idiopathic or angioedema due to ACE inhibitors); hereditary lactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome; age less than 18 years (efficacy and safety not established); concomitant use with aliskiren and drugs containing aliskiren in patients with diabetes and/or moderate to severe renal function impairment (glomerular filtration rate (GFR) < 60 ml/min/1.73 m2 body surface area); concomitant use with ARA II in patients with diabetic nephropathy.

With caution

Renovascular hypertension, bilateral renal artery stenosis, presence of one functioning kidney, artery stenosis of the single kidney – risk of severe arterial hypotension and renal failure; chronic heart failure (CHF) in decompensation stage, arterial hypotension; chronic renal failure (creatinine clearance (CK) less than 60 ml/min); hypovolemia and hyponatremia (due to a salt-free diet and/or prior therapy with diuretics, dialysis, vomiting, diarrhea), cerebrovascular disease (including cerebrovascular insufficiency, CHD, coronary artery disease) risk of developing excessive BP reduction aortic or mitral valve stenosis, hypertrophic obstructive cardiomyopathy (HCMP), hemodialysis using high-flow polyacrylonitrile membranes – risk of anaphylactoid reactions; conditions after kidney transplantation – no clinical experience; before low-density lipoprotein (LDL) apheresis procedure, simultaneous desensitization therapy with allergens (e.g., Hymenoptera venom) – risk of anaphylactoid reactions; connective tissue diseases (including systemic lupus erythematosus (SLE), scleroderma), inhibition of bone marrow hematopoiesis while taking immunosuppressants, allopurinol or procainamide – risk of agranulocytosis and neutropenia; congenital deficiency of glucose-6-phosphate dehydrogenase – single cases of hemolytic anemia; use in representatives of the Negro race; surgical intervention (general anesthesia) – risk of excessive decrease of BP; diabetes (control of blood glucose concentration); hyperkalemia; old age.

Side effects

The incidence of adverse reactions below was determined in accordance with the recommendations of the World Health Organization: very common – at least 10%; common – at least 1%, but less than 10%; infrequent – at least 0.1%, but less than 1%; rare – at least 0.01%, but less than 0.1%; very rare – less than 0.01%, including individual reports; frequency is unknown (cannot be calculated from the available data).

Central and peripheral nervous system disorders:often, headache, dizziness, paresthesia, vertigo; infrequently, sleep disturbances, mood lability, somnolence, fainting; very rarely, confusion.

VIight organ disorders: often – visual disturbances.

Hearing organ: frequently – tinnitus.

Cardiovascular system disorders: frequent – marked decrease in BP; infrequent* – tachycardia, palpitations, vasculitis; very rare – arrhythmias, angina, myocardial infarction or stroke, possibly secondary, due to severe arterial hypotension in high-risk patients.

Respiratory organs: frequent – cough, dyspnea; infrequent – bronchospasm; very rare – eosinophilic pneumonia, rhinitis.

From the digestive tract: frequent – nausea, vomiting, abdominal pain, dyspepsia, dyspepsia, diarrhea, constipation; infrequent – dry mouth mucosa; rare – pancreatitis; very rare – cytolytic or cholestatic hepatitis (see. section “Special indications”), angioedema of the intestine.

Csides of the skin: frequent – skin rash, itching; infrequent – angioedema of the face, upper and lower extremities, mucous membranes, tongue, vocal folds and/or larynx, photosensitization, vesicles, urticaria; rare – worsening of the course of psoriasis; very rare – erythema multiforme.

Musculoskeletal system: frequently – muscle cramps; infrequently – arthralgia, myalgia.

Side of the urinary tract: infrequent – renal failure, erectile dysfunction; very rare – acute renal failure.

General disorders: frequent – asthenia; infrequent – increased sweating, chest pain, peripheral edema, weakness, fever, falls.

Hematopoietic and lymphatic system disorders: infrequent* – eosinophilia, very rare – decrease in hemoglobin and hematocrit, thrombocytopenia, leukopenia/neutropenia, agranulocytosis, pancytopenia – hemolytic anemia (in patients with congenital deficiency of glucose-6-phosphate dehydrogenase).

Laboratory findings: infrequent* – increased concentration of urea and plasma creatinine, hyperkalemia, reversible after drug withdrawal (especially in patients with renal failure, severe CHF and renovascular hypertension), hyponatremia, hypoglycemia; rarely – increased activity of “liver” enzymes and serum bilirubin.

*Evaluation of the incidence of adverse reactions, identified by spontaneous reports, was carried out on the basis of the results of clinical trials.

Overdose

Symptoms:A marked decrease in BP, shock, stupor, bradycardia, water-electrolyte imbalance (hyperkalemia, hyponatremia), renal failure, hyperventilation, tachycardia, palpitations, dizziness, anxiety, cough.

Treatment:Emergency measures are limited to elimination of the drug from the body: gastric lavage and/or intake of activated charcoal, followed by restoration of water-electrolyte balance.

In case of marked BP decrease – put the patient in a horizontal position with elevated legs, and take measures to replenish the circulating blood volume (RBC). If marked bradycardia develops and is not amenable to drug therapy (including atropine), a pacemaker is indicated. Vital functions and serum creatinine and electrolyte concentrations should be monitored. Perindoprilat, the active metabolite of perindopril, can be removed from the systemic blood stream by hemodialysis. High-flow polyacrylonitrile membranes should be avoided.

Pregnancy use

Pregnancy

Pregnancy the use of Perindopril-Teva is contraindicated. The drug should not be used in the first trimester of pregnancy, so if pregnancy is planned or diagnosed, Perindopril-Teva should be discontinued as soon as possible and other hypotensive therapy should be carried out. No relevant controlled studies on the use of ACE inhibitors in pregnant women have been conducted. The limited data available on the effects of the drug in the first trimester of pregnancy indicate that the use of ACE inhibitors does not lead to fetotoxicity related fetal malformations. Perindopril-Teva is contraindicated in II-III trimesters of pregnancy, because it may cause fetotoxic effects in fetus (decreased renal function, scarcity of water, delayed ossification of fetal skull bones) and neonatal toxic effects (renal failure, arterial hypotension, hyperkalemia). If the drug was still used in the II-III trimesters of pregnancy, an ultrasound examination of the kidneys and fetal skull bones should be performed.

Breast-feeding period

The use of the drug Perindopril-Teva during breast-feeding is not recommended due to the lack of data on its possible excretion into the breast milk. If it is necessary to use the drug during lactation, breastfeeding must be stopped.

Fertility

Preclinical studies have shown no effect of perindopril on fertility in rats of either sex.

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