Perindopril PLUS pills 1.25mg + 4mg, 30pcs

Composition

1 tablet contains: active ingredients:  indapamide – 1.25 mg of perindopril erbumin – 4.0 mg;

excipients: microcrystalline cellulose 102 – 70,75 mg; croscarmellose sodium (Primerose) – 3.0 mg; pregelatinized corn starch (starch 1500) and 15.0 mg; sodium bicarbonate – 4.0 mg; magnesium stearate – 1.0 mg; silicon dioxide colloidal anhydrous (Aerosil anhydrous) – 1,0 mg.

Pharmacological action

The drug Perindopril PLUS is a combined drug containing indapamide and perindopril erbumin Pharmacological properties of the drug Perindopril PLUS combine the individual properties of each of its active components.

Mechanism of action

Perindopril PLUS

The combination of indapamide and perindopril enhances the antihypertensive effect of each of them.

Perindopril

Perindopril is an inhibitor of the enzyme that converts angiotensin I to angiotensin II (angiotensin-converting enzyme (ACE) inhibitor). ACE, or kininase II, is an exopeptidase that performs both the conversion of angiotensin I to the vasoconstrictor substance angiotensin II, and the destruction of bradykinin, which has a vasodilating effect, to an inactive heptapeptide.

As a result, perindopril:

• reduces the secretion of aldosterone;
• increases the activity of renin in the blood plasma according to the negative feedback principle;
• with prolonged use, it reduces the total peripheral vascular resistance( OPSS), which is mainly due to the effect on the vessels in the muscles and kidneys. These effects are not accompanied by retention of sodium and fluid ions or the development of reflex tachycardia.

Perindopril normalizes myocardial function, reducing preload and afterload.

The study of hemodynamic parameters in patients with chronic heart failure (CHF) revealed:

• reduced filling pressure in the left and right ventricles of the heart;
• reduced OPSS;
• increased cardiac output and increased cardiac index;
• increased muscle peripheral blood flow.

Indapamide

Indapamide belongs to the group of sulfonamides, and its pharmacological properties are similar to those of thiazide diuretics.

Indapamide inhibits the reabsorption of sodium ions in the cortical segment of the Henle loop, which leads to an increase in the excretion of sodium, chlorine and, to a lesser extent, sodium and magnesium ions by the kidneys, thereby increasing diuresis and lowering blood pressure (BP).

Antihypertensive effect

Perindopril PLUS

The drug Perindopril PLUS has a dose-dependent antihypertensive effect on both diastolic and systolic blood pressure both in the “standing” and “lying” positions.

The antihypertensive effect persists for 24 hours. A stable therapeutic effect develops less than 1 month after the start of therapy and is not accompanied by tachyphylaxis. Discontinuation of treatment does not cause withdrawal symptoms.

The drug Perindopril PLUS reduces the degree of left ventricular hypertrophy (LVH), improves the elasticity of the arteries, reduces OPSS, does not affect the metabolism of lipids (total cholesterol, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, triglycerides).

The effect of using a combination of perindopril and indapamide on LVH in comparison with enalapril was proved. In patients with hypertension and LVH treated with perindopril erbumin 2 mg/indapamide 0.625 mg or enalapril 10 mg once daily, and with an increase in the dose of perindopril erbumin to 8 mg and indapamide to 2.5 mg, or enalapril to 40 mg once daily, there was a more significant decrease in the left ventricular mass index (LVMI) in the perindopril/indapamide group compared to the enalapril group. At the same time, the most significant effect on LVMI is observed with the use of perindopril erbumin 8 mg/indapamide 2.5 mg.

There was also a more pronounced antihypertensive effect on the background of combined therapy with perindopril and indapamide compared to enalapril.

Perindopril

Perindopril is effective in the treatment of arterial hypertension of any severity. The antihypertensive effect of the drug reaches a maximum in 4-6 hours after a single oral use and persists for 24 hours. 24 hours after taking the drug, there is a pronounced (about 80%) residual ACE inhibition.

Perindopril has an antihypertensive effect in patients with both low and normal plasma renin activity. Simultaneous use of thiazide diuretics increases the severity of the antihypertensive effect. In addition, the combination of an ACE inhibitor and a thiazide diuretic also reduces the risk of hypokalemia when taking diuretics.

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

There are data from clinical studies of combination therapy with an ACE inhibitor and angiotensin II receptor antagonists (ARA II).

Clinical studies were conducted with the participation of patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by confirmed damage to the target organ, as well as studies with patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies did not show a significant positive effect on the occurrence of renal and/or cardiovascular events and on mortality rates in patients receiving combination therapy, while the risk of hyperkalemia, acute renal failure and/or arterial hypotension increased compared to patients receiving monotherapy.

Taking into account the similar intragroup pharmacodynamic properties of ACE inhibitors and ARA II, these results can be expected for the interaction of any other drugs, representatives of the classes of ACE inhibitors and ARA II.

Therefore, the use of ACE inhibitors in combination with angiotensin II receptor antagonists is contraindicated in patients with diabetic nephropathy.

There is evidence from a clinical trial investigating the beneficial effects of adding aliskiren to standard therapy with an ACE inhibitor or ARA II in patients with type 2 diabetes mellitus and chronic kidney disease or cardiovascular disease, or who have a combination of these diseases.

The study was terminated prematurely due to an increased risk of adverse outcomes. Cardiovascular death and stroke occurred more frequently in the aliskiren-treated group compared to the placebo group. Also, adverse events and serious adverse events of special interest (hyperkalemia, hypotension, and renal dysfunction) were reported more frequently in the aliskiren group than in the placebo group.

Indapamide

Antihypertensive effect is manifested when the drug is used in doses that have a minimal diuretic effect. The antihypertensive effect of indapamide is associated with an improvement in the elastic properties of large arteries, a decrease in OPSS.

Indapamide reduces LVH, does not affect the concentration of lipids in blood plasma: triglycerides, total cholesterol, LDL, HDL; carbohydrate metabolism (including in patients with concomitant diabetes mellitus).

Indications

Essential hypertension.

Contraindications

Perindopril

• Hypersensitivity to perindopril and other ACE inhibitors;
• Angioedema (angioedema) in the anamnesis against the background of taking other ACE inhibitors;
• Hereditary / idiopathic angioedema;
• Pregnancy and breast-feeding period;
• Concomitant use with aliskiren and medicinal products containing aliskiren in patients with diabetes mellitus and / or moderate to severe renal impairment (glomerular filtration rate (GFR) less than 60 ml/min/1.73 m2 of body surface area).
• Concomitant use with angiotensin II receptor antagonists (ARA II) in patients with diabetic nephropathy.
• Age up to 18 years (efficacy and safety have not been established).

Indapamide

• Hypersensitivity to indapamide and other sulfonamides;
• Moderate to severe renal insufficiency (creatinine clearance less than 60 ml / min);
• Severe liver failure;
• Hepatic encephalopathy;
• Hypokalemia;
• Simultaneous use with non-antiarrhythmic drugs that can cause polymorphic ventricular tachycardia of the “pirouette” type;
• Breast-feeding period;
• Age up to 18 years (efficacy and safety have not been established).

Perindopril PLUS

• Hypersensitivity to excipients that are part of the drug;
• Due to the lack of sufficient clinical experience, the drug Perindopril PLUS should not be used in patients undergoing hemodialysis, as well as in patients with untreated decompensated heart failure;
• Age up to 18 years (efficacy and safety have not been established);
• The presence of lactase deficiency, galactosemia or glucose-galactose malabsorption syndrome, lactose intolerance (the drug contains lactose).

With caution:

Systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma); immunosuppressant therapy (risk of neutropenia, agranulocytosis); co-use with lithium preparations, gold preparations, nonsteroidal anti-inflammatory drugs (NSAIDs), baclofen, corticosteroids, drugs that can cause prolongation of the QT interval, drugs that can cause polymorphic ventricular tachycardia of the “pirouette” type other than non-antiarrhythmic medications; inhibition of bone marrow hematopoiesis; reduced circulating blood volume (taking diuretics, salt-free diet, vomiting, diarrhea); coronary heart disease; cerebrovascular diseases; impaired liver and kidney function; renovascular hypertension; diabetes mellitus; chronic heart failure (NYHA functional class IV); hyperuricemia (especially accompanied by gout and urate nephrolithiasis lability of blood pressure; advanced age; hemodialysis with high-flow membranes (for example, AN69®) or desensitization, LDL apheresis; condition after kidney transplantation; planned anesthesia; aortic valve stenosis/hypertrophic obstructive cardiomyopathy; atherosclerosis; representatives of the black race (less pronounced effect from the use); athletes (possible positive reaction during doping control), bilateral renal artery stenosis or the presence of only one functioning kidney, concomitant therapy with potassium-sparing diuretics, potassium preparations, or in patients with elevated plasma potassium levels.

Side effects

The frequency of side effects is estimated based on: often-1-10%; rarely-0.1-1%; extremely rare, including individual reports-less than 0.1%.

From the cardiovascular system: often-excessive lowering of blood pressure and associated symptoms, rarely-arrhythmia, angina pectoris, myocardial infarction and stroke.

From the urinary system: decreased renal function, acute renal failure.

Respiratory system disorders: often – ” dry ” cough, difficulty breathing; rarely-bronchospasm, rhinorrhea.

From the digestive system: often – nausea, vomiting, abdominal pain, taste changes, diarrhea or constipation, dry mouth, decreased appetite, cholestatic jaundice, pancreatitis, intestinal edema.

From the central nervous system: often – headache, asthenia, increased fatigue, dizziness, ringing in the ears, visual disturbances, muscle cramps, paresthesia; rarely-decreased mood, insomnia; extremely rarely-confusion.

Allergic reactions: often-skin rash, pruritus; rarely-urticaria, angioedema; extremely rarely-erythema multiforme.

Laboratory parameters: often – hypercreatininemia, proteinuria, hyperkalemia; hyperuricemia; rarely (with prolonged use in high doses) – neutropenia, leukopenia, hypohemoglobinemia, thrombocytopenia, decreased hematocrit; extremely rarely – agranulocytosis, pancytopenia, increased activity of “liver” enzymes, hyperbilirubinemia, hemolytic anemia (against the background of glucose-6 deficiency-phosphate dehydrogenase).

Other services: increased sweating, impaired sexual function.

Interaction

Common to perindopril and indapamide

Combinations not recommended for use

Lithium preparations: When lithium preparations are co-administered with ACE inhibitors, reversible increases in plasma lithium concentrations and associated toxic effects have been reported. Concomitant use of a combination of perindopril and indapamide with lithium preparations is not recommended. If such therapy is necessary, the lithium content in the blood plasma should be regularly monitored.

A combination of drugs that requires special attention and caution

Baclofen: Increased antihypertensive effect. Blood pressure should be monitored and, if necessary, the dose of antihypertensive drugs should be adjusted.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including high doses of acetylsalicylic acid (≥3 g / day): concomitant use of ACE inhibitors with NSAIDs (acetylsalicylic acid at a dose that has an anti-inflammatory effect, cyclooxygenase-2 (COX-2) inhibitors and non-selective NSAIDs) may lead to a decrease in the antihypertensive effect. Concomitant use of ACE inhibitors and NSAIDs may increase the risk of worsening renal function, including acute renal failure, and increase serum potassium, especially in patients with initially reduced renal function. Caution should be exercised when prescribing a combination of the drug and NSAIDs, especially in elderly patients.

Patients should receive an adequate amount of fluid and it is recommended to monitor renal function both at the beginning of co-therapy and periodically during treatment.

A combination of medications that requires attention

Tricyclic antidepressants, antipsychotic drugs (neuroleptics): drugs of these classes enhance the antihypertensive effect and increase the risk of orthostatic hypotension (additive effect).

Perindopril

Data from clinical studies show that double blockade of the RAAS as a result of simultaneous use of ACE inhibitors, ARA II or aliskiren leads to an increased incidence of adverse events such as hypotension, hyperkalemia and impaired renal function (including acute renal failure), compared to situations when only one drug is used that affects the RAAS.

Medications that cause hyperkalemia

Certain medications or classes of medications may increase the incidence of hyperkalemia: aliskiren, potassium salts, potassium-sparing diuretics, ACE inhibitors, ARA II, NSAIDs, heparins, immunosuppressants (such as cyclosporine or tacrolimus), medications containing trimethoprim, including a fixed combination of trimethoprim and sulfomethoxazole.

The combination of these medications increases the risk of hyperkalemia.

Simultaneous use is contraindicated

Aliskiren and medicinal products containing aliskiren

Concomitant use of ACE inhibitors with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus and / or moderate to severe renal impairment (GFR The risk of hyperkalemia, deterioration of kidney function, cardiovascular morbidity and mortality increases.

Combinations not recommended for use

Aliskiren: Patients who do not have diabetes mellitus or impaired renal function have an increased risk of hyperkalemia, impaired renal function, and increased incidence of cardiovascular morbidity and mortality.

Combination of therapy with ACE and ARA II inhibitors: According to the available literature, in patients with established atherosclerotic disease, heart failure, or diabetes mellitus with target organ damage, concomitant use of ACE inhibitors and ARA II leads to an increased incidence of hypotension, syncope, hyperkalemia, and impaired renal function (including acute renal failure), compared to situations when only one drug is used that affects RA AS. The use of double blockade of RA AS (for example, simultaneous use of an ACE inhibitor and ARA II) should be limited to isolated cases with strict monitoring of renal function, blood potassium content and blood pressure.

Estramustine: concomitant use may lead to an increased risk of side effects, such as angioedema.

Potassium-sparing diuretics (e. g. triamterene, amiloride) and potassium salts: hyperkalemia (potentially fatal), especially in patients with impaired renal function (additional effects associated with hyperkalemia).

The combination of perindopril with the above-mentioned medications is not recommended. However, if concomitant use is indicated, they should be used with caution and regular monitoring of serum potassium levels.

Features of spironolactone use in patients with chronic heart failure are described in the subsection “Combination of medications requiring special attention”.

A combination of drugs that requires special attention

Hypoglycemic agents for oral use and insulin: epidemiological studies have shown that the combined use of ACE inhibitors and hypoglycemic agents (insulins, hypoglycemic agents for oral use) can increase the hypoglycemic effect of insulin and hypoglycemic agents for oral use up to the development of hypoglycemia. This effect is most likely observed during the first weeks of concomitant therapy, as well as in patients with impaired renal function.

Potassium-sparing diuretics: in patients receiving diuretics, especially in patients with hypovolemia and/or reduced salt concentrations, an excessive decrease in blood pressure may occur at the beginning of perindopril therapy. The risk of developing hypotension can be reduced by discontinuing the diuretic, replacing fluid or salt loss before starting perindopril therapy, and prescribing perindopril at a low dose with a further gradual increase.

In hypertensive patients with hypovolemia or reduced salt concentrations during diuretic therapy, diuretics should either be discontinued before starting the use of an ACE inhibitor (while a potassium-sparing diuretic may later be re-prescribed), or an ACE inhibitor should be prescribed at a low dose with a further gradual increase.

When using diuretics in the case of chronic heart failure, an ACE inhibitor should be prescribed at a very low dose, possibly after reducing the dose of the potassium-sparing diuretic used simultaneously.

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 treatment of NYHA functional class II-IV chronic heart failure with left ventricular ejection fraction

Before using this combination of medications, it is necessary to make sure that there is no hyperkalemia and impaired renal function. It is recommended to regularly monitor the concentration of creatinine and potassium in the blood: weekly in the first month of treatment and monthly thereafter.

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

Patients receiving concomitant therapy with mTOR inhibitors may have an increased risk of developing angioedema.

Racecadotril

ACE inhibitors (including perindopril) may cause the development of angioedema. The risk of angioedema may increase with concomitant use of racecadotril (an enkephalinase inhibitor used to treat acute diarrhea).

A combination of medications that requires attention

Antihypertensive agents and vasodilators: concomitant use of these drugs may increase the antihypertensive effect of perindopril. Allopurinol, cytostatic and immunosuppressive agents, systemic corticosteroids, and procainamide may be used concomitantly with nitroglycerin, other nitrates, or other vasodilators.

: concomitant use with ACE inhibitors may be associated with an increased risk of leukopenia.

General anesthesia products: ACE inhibitors may enhance the antihypertensive effect of a number of general anaesthetic agents.

Gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin): when combined with ACE inhibitors, the risk of angioedema increases due to the suppression of dipeptidyl peptidase – 4 (DPP-IV) activity by gliptin.

Sympathomimetics: may weaken the antihypertensive effect of ACE inhibitors.

Gold preparations: when using ACE inhibitors, including perindopril, patients receiving intravenous gold preparation (sodium aurothiomalate), nitritoid reactions were described, manifested by facial hyperemia, nausea, vomiting, and arterial hypotension.

Indapamide

A combination of drugs that requires special attention

Drugs that can cause polymorphic ventricular tachycardia of the “pirouette”type: due to the risk of hypokalemia, caution should be exercised when using indapamide concomitantly with drugs that can cause polymorphic ventricular tachycardia of the “pirouette” type, for example, Class IA antiarrhythmics (quinidine, hydroquinidine, disopyramide) and Class III (amiodarone, dofetilide, ibutilide, bretilium, sotalol); some neuroleptics (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine); benzamides (amisulpride, sulpiride, sultopride, tiapride); butyrophenones (droperidol, haloperidol); other neuroleptics (pimozide); other drugs such as bepridil, cisapride, difemanil, intravenous erythromycin, halofantrin, mizolastine, moxifloxacin, pentamidine, sparfloxacin, vincamine iv, methadone, astemizole, terfenadine. The potassium content in the blood plasma should be monitored and corrected if necessary; the QT interval should be monitored. Drugs that can cause hypokalemia: amphotericin B (IV), gluco-and mineralocorticosteroids (with systemic use), tetracosactide, laxatives that stimulate intestinal motility: increased risk of hypokalemia (additive effect). It is necessary to monitor the content of potassium in the blood plasma, if necessary – its correction. Special attention should be paid to patients receiving concomitant cardiac glycosides. Laxatives that do not stimulate intestinal motility should be used.

Cardiac glycosides: hypokalemia increases the toxic effect of cardiac glycosides. When indapamide and cardiac glycosides are used concomitantly, the blood plasma potassium content and ECG parameters should be monitored and, if necessary, therapy should be adjusted.

A combination of medications that requires attention

Potassium-sparing diuretics (amiloride, spironolactone, triamterene): this combination is reasonably used in some patients. Hypokalemia or hyperkalemia may occur (especially in patients with renal insufficiency or diabetes mellitus). If the simultaneous use of indapamide and potassium-sparing diuretics is necessary, monitoring of the potassium content in the blood plasma and ECG parameters should be carried out. If necessary, the treatment regimen can be revised. Metformin: functional renal failure, which may occur during the use of diuretics, especially “loop”, with simultaneous use of metformin increases the risk of lactic acidosis. Metformin should not be used if the plasma creatinine concentration exceeds 15 mg / l (135 mmol/l) in men and 12 mg/l (110 mmol/l) for women.

Iodine-containing contrast agents: dehydration of the body while taking diuretics increases the risk of acute renal failure, especially when using high doses of iodine-containing contrast agents. Before using iodine-containing contrast agents, patients need to compensate for fluid loss.

Calcium salts: with simultaneous use, hypercalcemia may develop due to a decrease in the excretion of calcium ions by the kidneys.

Cyclosporine, tacrolimus: it is possible to increase the concentration of creatinine in blood plasma without changing the concentration of cyclosporine in blood plasma, even with a normal content of water and sodium ions.

Corticosteroids, tetracosactide (for systemic use): reduction of the antihypertensive effect (salt and water retention during the use of corticosteroids).

How to take, course of use and dosage

Inside, once a day, preferably in the morning hours before breakfast, with a sufficient amount of liquid.

If possible, the use of the drug should begin with the selection of doses of single-component drugs. If clinically necessary, it is possible to prescribe combination therapy with Perindopril PLUS immediately after monotherapy with one of the components of the drug (perindopril and indapamide).

Doses are given for the indapamide/perindopril ratio.

The initial dose is 1 tablet of Perindopril PLUS (0.625 mg / 2 mg) once a day. If after 1 month of taking the drug it is not possible to achieve adequate blood pressure control, the dose of the drug should be increased to 1 tablet of Perindopril PLUS (1.25 mg/4 mg) once a day.

If necessary, to achieve a more pronounced antihypertensive effect, it is possible to increase the dose of the drug to the maximum daily dose of Perindopril PLUS – 1 tablet (2.5 mg/8 mg) once a day.

Elderly patients

The initial dose is 1 tablet of 0.625 mg/2 mg of Perindopril PLUS 1 time per day.

Start therapy with the drug should be under the control of renal function and blood pressure.

Patients with impaired renal function

Perindopril PLUS is contraindicated in patients with severe renal insufficiency (creatinine clearance less than 30 ml / min).

Patients with moderate renal insufficiency (creatinine clearance 30-60 ml/min) are recommended to start therapy with the necessary doses of drugs (in monotherapy) that are part of the drug Perindopril PLUS; the maximum daily dose of Perindopril PLUS is 1.25 mg/4 mg.

In patients with creatinine clearance of 60 ml/min or more, no dose adjustment is required. During therapy, it is necessary to regularly monitor the concentration of creatinine and potassium in the blood serum.

Patients with impaired liver function

The drug is contraindicated in patients with severe hepatic insufficiency.

No dose adjustment is required for moderate hepatic insufficiency.

Children and teenagers

Perindopril PLUS should not be used in children and adolescents under 18 years of age, as data on efficacy and safety are insufficient.

Overdose

Symptoms: marked decrease in blood pressure, nausea, vomiting, muscle cramps, dizziness, drowsiness, confusion, oliguria up to anuria (due to a decrease in BCC); possible violations of the water-electrolyte balance (low content of sodium and potassium in blood plasma).

Treatment: gastric lavage and / or use of activated charcoal, restoration of water and electrolyte balance in a hospital setting. With a marked decrease in blood pressure, it is necessary to transfer the patient to the “lying” position on his back with his legs raised up; then measures should be taken to increase the BCC (use of 0.9% sodium chloride solution intravenously). Perindoprilate, the active metabolite of perindopril, can be eliminated from the body by dialysis.

Special instructions

Impaired renal function

Therapy is contraindicated in patients with moderate to severe renal insufficiency (creatinine clearance less than 60 ml / min). Some patients with arterial hypertension without previous apparent renal impairment may develop laboratory signs of functional renal failure during therapy. In this case, treatment should be discontinued. In the future, you can resume combination therapy using a low-dose combination of indapamide and perindopril, or use only one of the drugs.

Such patients need regular monitoring of the potassium content and serum creatinine concentration-2 weeks after the start of therapy and every 2 months thereafter. Renal failure occurs more frequently in patients with severe chronic heart failure or underlying renal dysfunction, including renal artery stenosis. The drug Perindopril PLUS is not recommended in cases of bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney.

Arterial hypotension and impaired water-electrolyte balance

In the case of initial hyponatremia, there is a risk of sudden development of arterial hypotension, especially in patients with renal artery stenosis. Therefore, during dynamic monitoring of patients, attention should be paid to possible symptoms of dehydration and a decrease in the content of electrolytes in the blood plasma, for example, after diarrhea or vomiting. Such patients need regular monitoring of blood plasma electrolyte levels.

Severe hypotension may require intravenous use of 0.9% sodium chloride solution.

Transient arterial hypotension is not a contraindication for continuing therapy. After restoring the volume of circulating blood and blood pressure, you can resume therapy using low doses of drugs, or use only one of the drugs.

Potassium content

The combined use of perindopril and indapamide does not prevent the development of hypokalemia, especially in patients with diabetes mellitus or renal insufficiency. As with the use of any antihypertensive drug and diuretic, regular monitoring of the potassium content in the blood plasma is necessary.

Auxiliary substances

It should be borne in mind that the excipients of the drug include lactose monohydrate. Perindopril PLUS should not be prescribed to patients with hereditary problems of galactose intolerance, lactase deficiency, and glucose-galactose malabsorption.

Lithium preparations

Concomitant use of the drug Perindopril PLUS with lithium preparations is not recommended.

Children’s age

The drug should not be prescribed to children and adolescents under 18 years of age due to the lack of data on the effectiveness and safety of indapamide and perindopril, both separately and together, in patients of this age group.

Perindopril

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

There is evidence of an increased risk of hypotension, hyperkalemia, and impaired renal function (including acute renal failure) when ACE inhibitors are co-administered with ARA II or aliskiren. Therefore, dual blockade of the RAAS by combining an ACE inhibitor with ARA II or aliskiren is not recommended.

If a double blockade is absolutely necessary, it should be performed under the strict supervision of a specialist with regular monitoring of kidney function, blood plasma electrolytes and blood pressure.

The use of ACE inhibitors in combination with ARA II receptor antagonists is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Potassium-sparing diuretics, potassium preparations, potassium-containing salt substitutes and food additives

Simultaneous use of perindopril and potassium-sparing diuretics, as well as potassium preparations, potassium-containing salt substitutes and food additives is not recommended.

Neutropenia / agranulocytosis / thrombocytopenia

Neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported with ACE inhibitors. Neutropenia is rare in patients with normal renal function and no concomitant risk factors. With extreme caution, perindopril should be used against the background of systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma), as well as against the background of taking immunosuppressants, allopurinol or procainamide, or with a combination of these factors, especially in patients with initially impaired renal function.

Some patients developed severe infectious diseases, in some cases resistant to intensive antibiotic therapy. When prescribing perindopril to such patients, it is recommended to periodically monitor the number of white blood cells in the blood. Patients should inform the doctor about any signs of infectious diseases (for example, sore throat, fever).

Anemia

Anemia can develop in patients after a kidney transplant or in people on hemodialysis. At the same time, the decrease in hemoglobin is greater, the higher its initial indicator was. This effect does not appear to be dose-dependent, but may be related to the mechanism of action of ACE inhibitors.

A slight decrease in hemoglobin occurs during the first 6 months, then it remains stable and completely recovers after discontinuation of the drug. In such patients, treatment can be continued, but hematological tests should be performed regularly.

Hypersensitivity / angioedema

When taking ACE inhibitors, including perindopril, in rare cases, angioedema of the face, limbs, lips, tongue, vocal folds and/or larynx may develop. This can happen during any period of therapy. If symptoms appear, Perindopril PLUS should be discontinued immediately, and the patient should be monitored until the signs of edema disappear completely. If the swelling affects only the face and lips, it usually goes away on its own, although antihistamines can be used as symptomatic therapy.

Angioedema accompanied by laryngeal edema can be fatal. Swelling of the tongue, vocal folds, or larynx can lead to airway obstruction. If such symptoms occur, appropriate therapy should be initiated immediately, for example, subcutaneously administer epinephrine (epinephrine) in a dilution of 1: 1000 (0.3-0.5 ml) and / or ensure airway patency.

A higher risk of angioedema has been reported in black patients.

Patients with a history of angioedema that is not associated with ACE inhibitors may have an increased risk of developing angioedema when taking this group of drugs.

In rare cases, angioedema of the intestine develops during therapy with ACE inhibitors. At the same time, patients experienced abdominal pain as an isolated symptom or in combination with nausea and vomiting, in some cases without previous angioedema of the face and with normal levels of C-1 esterase. The diagnosis was made using computed tomography of the abdominal cavity, ultrasound, or at the time of surgery. Symptoms resolved after discontinuation of ACE inhibitors. Therefore, in patients with abdominal pain treated with ACE inhibitors, the possibility of developing angioedema of the intestine should be taken into account during differential diagnosis.

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

Patients receiving concomitant therapy with mTOR inhibitors may have an increased risk of developing angioedema (including edema of the airway or tongue with or without respiratory function disorders).

Anaphylactoid reactions during desensitization

There are isolated reports of long-term, life-threatening anaphylactoid reactions in patients receiving ACE inhibitors during desensitizing therapy with hymenopteran venom (bees, wasps). ACE inhibitors should be used with caution in allergic patients undergoing desensitization procedures. Avoid prescribing an ACE inhibitor to patients receiving hymenopteran venom immunotherapy. However, an anaphylactoid reaction can be avoided by temporarily stopping the ACE inhibitor at least 24 hours before the start of the desensitization procedure.

Anaphylactoid reactions during LDL apheresis

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

Hemodialysis

Anaphylactoid reactions have been reported in patients receiving ACE inhibitors during hemodialysis using high-flow membranes (for example, AN69®). Therefore, it is desirable to use a different type of membrane or use a hypotensive agent of a different pharmacotherapeutic group.

Cough

Against the background of ACE inhibitor therapy, a dry persistent cough may occur, which disappears after the withdrawal of drugs of this group and disappears after their withdrawal. If a patient has a dry cough, you should be aware of the possible iatrogenic nature of this symptom. If the attending physician believes that therapy with an ACE inhibitor is necessary for the patient, it is possible to continue taking the drug.

Risk of hypotension and / or renal failure (in patients with heart failure, impaired water-electrolyte balance, etc. )

In some pathological conditions, significant activation of the RAAS may occur, especially with severe hypovolemia and a decrease in the content of electrolytes in blood plasma (against the background of a salt-free diet or long-term use of diuretics), in patients with initially low blood pressure, renal artery stenosis, chronic heart failure or cirrhosis of the liver with edema and ascites.

The use of ACE inhibitors causes blockade of the RAAS and, therefore, may be accompanied by a sharp decrease in blood pressure and / or an increase in the concentration of creatinine in blood plasma, indicating the development of functional renal failure. These phenomena are more often observed when taking the first dose of the drug and during the first two weeks of therapy. In rare cases, these conditions develop acutely and during other periods of therapy. In such cases, it is recommended to resume therapy at a lower dose and then gradually increase the dose.

Advanced age

Before starting perindopril, it is necessary to evaluate the functional activity of the kidneys and the content of potassium ions in the blood plasma. At the beginning of therapy, the dose of the drug is selected, taking into account the degree of reduction in blood pressure, especially in the case of dehydration and loss of electrolytes. Such measures can avoid a sharp decrease in blood pressure.

Atherosclerosis

The risk of hypotension exists in all patients, but special care should be taken when using the drug in patients with coronary heart disease and cerebral circulatory insufficiency. In such patients, treatment should begin with low doses of the drug.

Renovascular hypertension

The method of treating renovascular hypertension is revascularization. However, the use of ACE inhibitors can have a positive effect in this category of patients, both waiting for surgery and in cases where surgical intervention is impossible.

Treatment with Perindopril PLUS is not indicated in patients with diagnosed or suspected renal artery stenosis, as therapy should be initiated in a hospital setting with lower doses of the combination of indapamide and perindopril.

Heart Failure /Severe heart failure

In patients with chronic heart failure (NYHA functional class IV), treatment should begin with lower doses of the combination of indapamide and perindopril and under close medical supervision.

Patients with arterial hypertension and coronary heart disease should not stop taking beta-blockers: an ACE inhibitor should be added to beta-blocker therapy.

Diabetes mellitus

In patients with type 1 diabetes mellitus, a spontaneous increase in the blood potassium content is possible. Treatment of such patients with Perindopril PLUS is not indicated, as it should begin with minimal doses and take place under constant medical supervision.

During the first month of ACE inhibitor therapy, plasma glucose concentrations should be carefully monitored in patients with diabetes mellitus treated with oral hypoglycemic drugs or insulin.

Ethnic differences

Perindopril, like other ACE inhibitors. it has a clearly less pronounced antihypertensive effect in patients of the black race compared to representatives of other races. Perhaps this difference is due to the fact that patients with arterial hypertension of the black race are more likely to have low renin activity.

Surgical intervention / General anesthesia

General anesthesia with ACE inhibitors can lead to a marked decrease in blood pressure, especially when using general anesthesia products that have an antihypertensive effect.

If possible, it is recommended to stop taking long-acting ACE inhibitors, including perindopril, one day before surgery. The anaesthetist should be advised that the patient is taking ACE inhibitors.

Aortic or mitral stenosis / Hypertrophic obstructive cardiomyopathy

ACE inhibitors should be used with caution in patients with left ventricular outflow tract obstruction.

Liver failure

In rare cases, cholestatic jaundice occurs while taking ACE inhibitors. With the progression of this syndrome, fulminant liver necrosis develops, sometimes with a fatal outcome. The mechanism of development of this syndrome is unclear. If jaundice occurs or if there is a significant increase in the activity of liver enzymes while taking ACE inhibitors, the patient should stop taking an ACE inhibitor and consult a doctor.

Hyperkalemia

Hyperkalemia may develop during treatment with ACE inhibitors, including perindopril. Risk factors for hyperkalemia include renal failure, impaired renal function, age over 70 years, diabetes mellitus, certain concomitant conditions (dehydration, acute decompensation of heart activity, metabolic acidosis), concomitant use of potassium-sparing diuretics (such as spironolactone and its derivative eplerenone, triamterene, amiloride), as well as potassium preparations or potassium-containing salt substitutes, as well as the use of other drugs that increase the potassium content in blood plasma (for example, heparins, ACE inhibitors, angiotensin II receptor antagonists, acetylsalicylic acid at a dose of 3 g/day or more, cyclooxygenase-2 (COX-2) inhibitors and non-selective NSAIDs, immunosuppressants such as cyclosporine or tacrolimus, trimethoprim).

The use of potassium supplements, potassium-sparing diuretics, and potassium-containing salt substitutes can lead to a significant increase in blood potassium, especially in patients with reduced renal function.

Hyperkalemia can lead to serious, sometimes fatal, cardiac arrhythmias. If concomitant use of the above drugs is necessary, treatment should be carried out with caution against the background of regular monitoring of the potassium content in the blood serum.

Indapamide

Hepatic encephalopathy

In the presence of impaired liver function, taking thiazide and thiazide-like diuretics can lead to the development of hepatic encephalopathy. In such a situation, you should immediately stop taking the diuretic.

Water-electrolyte balance

Sodium ion content in blood plasma

The level of sodium ions in the blood plasma should be determined before starting treatment, and then regularly monitored while taking the drug.

Hyponatremia at the initial stage may not be accompanied by clinical symptoms, so regular laboratory monitoring is necessary. More frequent monitoring of sodium ions is indicated in patients with cirrhosis of the liver and elderly patients. Treatment with any diuretics can cause hyponatremia, sometimes with very serious consequences. Hyponatremia, accompanied by hypovolemia, can lead to the development of dehydration and orthostatic hypotension.

A simultaneous decrease in the content of chlorine ions can lead to the development of secondary compensatory metabolic alkalosis: its frequency and severity are insignificant.

Potassium ion content in blood plasma

Therapy with thiazide and thiazide-like diuretics is associated with the risk of hypokalemia. Hypokalemia (less than 3.4 mmol) should be avoided. /k) in the following categories of patients from the high-risk group: elderly patients, emaciated patients (both receiving and not receiving combined drug therapy), patients with cirrhosis of the liver (with edema and ascites), coronary heart disease, heart failure. Hypokalemia in these patients increases the toxic effect of cardiac glycosides and increases the risk of arrhythmia.

The increased risk group also includes patients with an extended QT interval, both congenital and caused by the action of drugs.

Hypokalemia, like bradycardia, contributes to the development of severe cardiac arrhythmias, especially pirouette-type arrhythmias, which can be fatal. In all the cases described above, more frequent monitoring of the content of potassium ions in the blood plasma is necessary. The first measurement of the potassium ion content should be carried out within the first week after the start of therapy.

If hypokalemia is detected, appropriate correction should be performed.

Content of calcium ions in blood plasma

Thiazide and thiazide-like diuretics can reduce the excretion of calcium ions by the kidneys, leading to a slight and temporary increase in the content of calcium in the blood plasma. Severe hypercalcemia may be a consequence of previously undiagnosed hyperparathyroidism. Before studying the function of the parathyroid glands, you should stop taking diuretics.

Concentration of glucose in blood plasma

It is necessary to monitor the concentration of glucose in the blood in patients with diabetes mellitus, especially in the presence of hypokalemia.

Uric acid

With an increase in the concentration of uric acid in the blood plasma against the background of therapy, the frequency of gout attacks may increase.

Diuretics and renal function

Thiazide and thiazide-like diuretics are fully effective only in patients with normal or slightly impaired renal function (adult plasma creatinine concentrations below 25 mg / l or 220 mmol / L).

In elderly patients, plasma creatinine levels should be evaluated based on age, weight, and gender, according to the Cockcroft formula:

Creatinine clearance (CC)=(140 – age) x weight / 0.814 x plasma creatinine concentration

where: age in years, weight in kg, plasma creatinine concentration in mmol/L.

The formula is suitable for older men; for older women, multiply the result by a factor of 0.85.

At the beginning of diuretic treatment, patients with hypovolemia (due to the elimination of water and sodium ions) may experience a temporary decrease in glomerular filtration rate and an increase in the concentration of urea and creatinine in blood plasma. This transient functional renal insufficiency is not dangerous for patients with initially normal renal function, but its severity may increase in patients with renal insufficiency.

Photosensitivity

Photosensitivity reactions have been reported with thiazide and thiazide-like diuretics. If photosensitivity reactions develop while taking the drug, treatment should be discontinued. If it is necessary to continue diuretic therapy, it is recommended to protect the skin from exposure to sunlight or artificial ultraviolet rays.

Athletes

Indapamide can give a positive reaction during doping control.

Acute myopia and secondary angle-closure glaucoma

Sulfonamides and their derivatives can cause the development of idiosyncratic reactions, leading to temporary myopia and acute angle-closure glaucoma. Without proper treatment, acute angle-closure glaucoma can lead to vision loss. First of all, it is necessary to stop taking the drug as soon as possible. If intraocular pressure continues to be high, immediate therapeutic or surgical treatment may be required. Risk factors that can lead to the development of acute angle-closure glaucoma include a history of allergy to sulfonamides or penicillin.

Influence on the ability to drive vehicles and mechanisms:

Care should be taken when driving vehicles and other technical devices that require increased attention and speed of psychomotor reactions.

Active ingredient

Indapamide, Perindopril

Conditions of release from pharmacies

By prescription

Dosage form

Tablets

Purpose

For adults as directed by your doctor

Indications

Prevention of heart attacks and strokes, Hypertension, Heart failure, Angina Pectoris