Perindopril PLUS, tablets 1.25mg+4 mg 30 pcs

Name: Perindopril PLUS, tablets 1.25mg+4 mg 30 pcs
SKU: 355192
Availability: InStock

€8.83

EAN: 4690655020049 SKU: 355192 Categories: Cardiovascular, High pressure, Medicine

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

Mechanism of Action

Perindopril PLUS

The combination of indapamide and perindopril enhances the antihypertensive effects of each.

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 vasoconstrictor angiotensin II and the degradation of bradykinin, which has a vasodilatory effect, to an inactive heptapeptide.

The result is perindopril:

reduces aldosterone secretion;
by the principle of negative feedback, it increases plasma renin activity;

with long-term use reduces total peripheral vascular resistance (TPRR), which is mainly due to the effect on the vessels in the muscles and kidneys. These effects are not accompanied by retention of sodium ions and fluid or development of reflex tachycardia.

Perindopril normalizes myocardial function by reducing preload and postload.

In a study of hemodynamic parameters in patients with chronic heart failure (CHF), it was found:

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

Indapamide

Indapamide belongs to the group of sulfonamides and has pharmacological properties similar to thiazide diuretics.

Indapamide inhibits reabsorption of sodium ions in the cortical segment of the Genle loop, which leads to increased renal excretion of sodium ions, chloride ions and to a lesser extent sodium and magnesium ions, thereby increasing diuresis and reducing blood pressure (BP).

Antihypertensive effects

Perindopril PLUS

The drug Perindopril PLUS has dose-dependent antihypertensive effects on both diastolic and systolic BP in both standing and lying positions.

The antihypertensive effect lasts for 24 h. Stable therapeutic effect develops in less than 1 month from the beginning of therapy and is not accompanied by tachyphylaxis. Discontinuation of therapy does not cause “withdrawal” syndrome.

The drug Perindopril PLUS reduces the degree of left ventricular hypertrophy (LVH), improves arterial elasticity, decreases PEEP, has no effect on lipid metabolism (total cholesterol, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, triglycerides).

The combination of perindopril and indapamide has been shown to have an effect on HLV compared with enalapril. In patients with arterial hypertension and HLV treated with perindopril erbumin 2 mg/indapamide 0.625 mg or enalapril at a dose of 10 mg once daily and when the perindopril erbumin dose was increased to 8 mg and indapamide to 2,5 mg, or enalapril to 40 mg once daily, there was a more significant reduction in left ventricular mass index (LVMI) of the perindopril/indapamide group compared with the enalapril group. The most significant effect on BMI was noted with perindopril erbumin 8 mg/indapamide 2.5 mg.

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

Perindopril

Perindopril is effective in therapy of arterial hypertension of any severity. Its antihypertensive effect reaches its maximum 4-6 hours after a single oral dose and lasts for 24 hours. Twenty-four hours after the drug administration there is a significant (about 80%) residual inhibition of ACE.

Perindopril has antihypertensive effect in patients with both low and normal plasma renin activity. Concomitant administration of thiazide diuretics increases the severity of antihypertensive effect. In addition, combination of ACE inhibitor and thiazide diuretic also leads to decrease of risk of hypokalemia during diuretic therapy.

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

There are data from clinical studies of combined therapy with ACE inhibitor with angiotensin II receptor antagonists (ARA 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, and studies involving patients with type 2 diabetes and diabetic nephropathy.

These studies found no significant positive effect on the occurrence of renal and/or cardiovascular events and 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.

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

The use of ACE inhibitors in combination with angiotensin II receptor antagonists is therefore contraindicated in patients with diabetic nephropathy.

There are data from a clinical trial examining the beneficial effects of 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 who have a combination of these conditions.

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

Indapamide

The antihypertensive effect is seen when the drug is used in doses that have minimal diuretic effect. The antihypertensive effect of indapamide is associated with improvement of elastic properties of large arteries, reduction of PPS.

Indapamide decreases VLDL, does not influence plasma lipid concentrations: triglycerides, total cholesterol, LDL, HDL; carbohydrate metabolism (including in patients with concomitant diabetes).

Indications

Stenocardia, Heart Failure, Dyspnea, Edema, Cardialgia (pain in the heart area), Hypertension (high blood pressure), Prevention of heart attacks and strokesEssential hypertension.

Active ingredient

Indapamide, Perindopril

Composition

1 tablet contains:

active ingredients:

indapamide – 1.25 mg,

perindopril erbumin – 4.0 mg;

excipients: microcrystalline cellulose 102 – 70.75 mg; croscarmellose sodium (primellose) – 3.0 mg; corn starch pregelatinized (starch 1500) – 15.0 mg; sodium hydrocarbonate – 4.0 mg; magnesium stearate – 1.0 mg; colloidal silicon dioxide anhydrous (aetherless) – 1.0 mg.

How to take, the dosage

Overly, once daily, preferably in the morning before breakfast, with plenty of fluid.

If possible, the drug should be started with a selection of single-component doses. If clinically necessary, combined therapy with Perindopril PLUS may be prescribed immediately after monotherapy with one of the components of the drug (perindopril and indapamide).

Doses are given for the indapamide/perindapril ratio.

The starting dose is 1 tablet of Perindopril PLUS (0.625 mg/2mg) once daily. If adequate BP control is not achieved after 1 month of therapy, the dose should be increased to 1 tablet of Perindopril PLUS (1.25 mg/4 mg) once daily.

If necessary to achieve a more significant hypotensive effect, the dose of Perindopril PLUS may be increased to maximum daily dose of 1 tablet (2.5 mg/8 mg) once daily.

Perindopril PLUS elderly patients

The starting dose is 1 tablet of 0.625 mg/2 mg of Perindopril PLUS once daily.

The therapy with the drug should be started under monitoring of renal function and BP.

Patients with impaired renal function

Perindopril PLUS is contraindicated in patients with severe renal impairment (CKG less than 30 ml/min).

Patients with moderate renal impairment (CKD 30-60 ml/min) are recommended to start therapy with the required doses of Perindopril PLUS (in monotherapy); the maximum daily dose of Perindopril PLUS is 1.25 mg/4 mg.

Patients with a CK of 60 ml/min or more do not require dose adjustment. Creatinine and serum potassium concentrations should be monitored regularly during therapy.

Patients with impaired liver function

The drug is contraindicated in patients with severe hepatic impairment.

There is no need to adjust doses in moderately severe hepatic impairment.

Children and adolescents

Perindopril PLUS should not be used in children and adolescents less than 18 years of age because of insufficient data on efficacy and safety.

Interaction

General for perindopril and indapamide

Combinations not recommended

Lithium drugs: Concomitant use of lithium drugs and ACE inhibitors has reported a reversible increase in plasma lithium concentration and associated toxic effects. Concomitant use of the combination of perindopril and indapamide with lithium preparations is not recommended. Plasma lithium levels should be monitored regularly if such therapy is necessary.

Combinations of drugs requiring special attention and caution

Baclofen: Increased antihypertensive effect. BP should be monitored and, if necessary, doses of hypotensive drugs should be adjusted.

Non-steroidal anti-inflammatory drugs (NSAIDs), including high doses of acetylsalicylic acid (≥3 g/day): Simultaneous use of ACE inhibitors with NSAIDs (acetylsalicylic acid in a dose with anti-inflammatory effect, cyclooxygenase-2 (COX-2) inhibitors and non-selective NSAIDs) may lead to decreased antihypertensive effect. Concomitant use of ACE inhibitors and NSAIDs may lead to an increased risk of worsening of renal function, including the development of acute renal failure, and increased 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 adequate fluid intake and it is recommended to monitor renal function both at the beginning of co-therapy and periodically during treatment.

Combinations of drugs requiring attention

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

Perindopril

. Data from clinical studies demonstrate that dual RAAS blockade resulting from concomitant use of ACE inhibitors, ARA II or aliskiren leads to an increased incidence of adverse events such as arterial hypotension, hyperkalemia and renal dysfunction (including acute renal failure) compared to situations where only one RAAS-acting medication is used.

Drugs that cause hyperkalemia

Some drugs or classes of drugs can increase the incidence of hyperkalemia: Aliskiren, potassium salts, potassium-saving diuretics, ACE inhibitors, ARA II, NSAIDs, heparins, immunosuppressants (such as cyclosporine or tacrolimus), drugs containing trimethoprim, including a fixed combination of trimethoprim and sulfometoxazole.

The combination of these drugs 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 dysfunction (GFR < 60 ml/min/1.73 m2 body surface area). There is an increased risk of hyperkalemia, impaired renal function, cardiovascular morbidity and mortality.

Combinations not recommended for use

Aliskiren: In patients without diabetes mellitus or renal dysfunction, there is an increased risk of hyperkalemia, impaired renal function, and increased incidence of cardiovascular morbidity and mortality.

Combination of therapy with ACE inhibitors and ARA II: In patients with established atherosclerotic disease, heart failure, or diabetes mellitus with target organ damage, concomitant administration of ACE inhibitors and ARA II has been reported in the literature to increase the incidence of arterial hypotension, syncope, hyperkalemia, and renal function impairment (including acute renal failure), compared with situations in which only one drug acting on RA AC is used. The use of dual ACE RA blockade (e.g., concomitant administration of an ACE inhibitor and ARA II) should be limited to single cases with strict monitoring of renal function, plasma potassium, and BP.

Estramustine: Simultaneous use may increase the risk of side effects such as angioedema.

Kalium-saving diuretics (e.g., triamterene, amiloride) and potassium salts: hyperkalemia (possibly fatal), especially in impaired renal function (additional effects associated with hyperkalemia).

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

The specifics of spironolactone use in chronic heart failure are described in the sub-section “Drug combinations requiring special attention”.

Combinations of drugs requiring special attention

Hypoglycemic oral agents and insulin: Epidemiologic studies have shown that the combined use of ACE inhibitors and hypoglycemic agents (insulin, oral hypoglycemic agents) may increase the hypoglycemic effect of insulin and oral hypoglycemic agents to the point of developing hypoglycemia. This effect is most likely to be observed during the first weeks of concomitant therapy, as well as in patients with impaired renal function.

Potassium-saving diuretics: In patients receiving diuretics, especially in patients with hypovolemia and/or reduced salt concentration, an excessive decrease in BP may be observed at the beginning of perindopril therapy. The risk of hypotension can be reduced by withdrawal of the diuretic, by replenishing fluid or salt loss before starting perindopril therapy, and by prescribing perindopril at a low dose with further gradual increase.

In patients with arterial hypertension with hypovolemia or reduced salt concentration on diuretic therapy, diuretics should either be discontinued before starting an ACE inhibitor, (and the potassium-intolerant diuretic may be prescribed again later), or the ACE inhibitor should be given at a low dose with further gradual increase in dose.

When diuretics are used in cases of chronic heart failure, the ACE inhibitor should be prescribed at a very low dose, possibly after reducing the dose of a concomitantly used potassium-uncontaining diuretic.

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

Kaliberating 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 therapy of chronic heart failure 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 (with possible fatal outcome), especially if recommendations regarding this drug combination are not followed.

Before using this drug combination, it is necessary to ensure that hyperkalemia and renal dysfunction are absent. We recommend regular monitoring of creatinine and potassium concentrations in blood: weekly in the first month of treatment and monthly thereafter.

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

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

Racecadotril

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

Combinations of drugs requiring attention

Hypotensive agents and vasodilators: concomitant use of these drugs may increase the antihypertensive effect of perindopril. When concomitant administration with nitroglycerin, other nitrates or other vasodilators, additional BP reduction is possible.

Allopurinol, cytostatic and immunosuppressive agents, corticosteroids for systemic use and procainamide: concomitant use with ACE inhibitors may be accompanied by an increased risk of leukopenia.

Medications for general anesthesia: ACE inhibitors may increase the antihypertensive effect of a number of agents for general anesthesia.

Glyptins (linagliptin, saxagliptin, sitagliptin, vildagliptin): co-administration with ACE inhibitors increases the risk of angioedema due to inhibition of dipeptide dilpeptidase-4 (DPP-IV) activity by griptin.

Sympathomimetics: may impair the antihypertensive effect of ACE inhibitors.

Gold preparations: when using ACE inhibitors, including perindopril, patients receiving intravenous gold (sodium aurothiomalate) have been described with nitrite reactions manifested by facial hyperemia, nausea, vomiting, arterial hypotension.

Indapamide

Combinations of drugs requiring special attention

Drugs that can cause pirouette-type polymorphic ventricular tachycardia: Because of the risk of hypokalemia, caution should be exercised when concomitant use of indapamide with drugs that can cause polymorphic pirouette-type ventricular tachycardia, such as Class IA antiarrhythmic agents (quinidine, hydroquinidine, disopyramide), and Class III (amiodarone, dofetilide, ibutilide, bretylium, sotalol); some neuroleptics (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine); benzamides (amisulpride, sulpiride, sultopride, thiapride); butyrophenones (droperidol, haloperidol) other neuroleptics (pimozide); other drugs such as bepridil, cisapride, difemanil, erythromycin IV, halofantrine, misolastin, moxifloxacin, pentamidine, sparfloxacin, vincamine IV, methadone, astemizole, terfenadine. Plasma potassium should be monitored and corrected if necessary; monitor the QT interval.
Drugs that may cause hypokalemia: amphotericin B (IV), gluco- and mineralocorticosteroids (when used systemically), tetracosactide, intestinal motility stimulants: increased risk of hypokalemia (additive effect). Control of plasma potassium is necessary, and its correction, if necessary. Particular attention should be paid to patients concomitantly receiving cardiac glycosides. Laxatives that do not stimulate intestinal motility should be used.

Cardiac glycosides: hypokalemia increases toxic effects of cardiac glycosides. In concomitant use of indapamide and cardiac glycosides, plasma potassium and ECG parameters should be monitored and, if necessary, therapy should be adjusted.

Combinations of drugs requiring attention

Potassium-saving diuretics (amiloride, spironolactone, triamterene): this combination is reasonably used in some patients. Hypokalemia or hyperkalemia may be observed (especially in patients with renal insufficiency or diabetes mellitus). If concomitant use of indapamide and potassium-saving diuretics is necessary, plasma potassium and ECG parameters should be monitored. The treatment regimen may be reconsidered if necessary.

Metformin: functional renal insufficiency, which may occur against the background of taking diuretics, especially loop diuretics, when concomitant administration of metformin increases the risk of lactic acidosis. Metformin should not be used if plasma creatinine concentrations exceed 15 mg/L (135 µmol/L) in men and 12 mg/L (110 µmol/L) in women.

Iodine-containing contrast agents: dehydration of the body against the background of diuretic drugs increases the risk of acute renal failure, especially when using high doses of iodine-containing contrast agents. Patients should compensate for fluid loss before using iodine-containing contrast agents.

Calcium salts: concomitant use may lead to hypercalcemia due to reduced renal excretion of calcium ions.

Cyclosporine, tacrolimus: increased plasma creatinine concentration is possible without changing the plasma concentration of cyclosporine, even when water and sodium ion levels are normal.

Corticosteroids, tetracosactide (when used systemically): reduction of antihypertensive effect (salt and water retention with corticosteroids).

Special Instructions

Kidney function impairment

The therapy is contraindicated in patients with moderate to severe renal impairment (CKI less than 60 ml/min). In some patients with arterial hypertension without previous obvious impairment of renal function during the therapy, laboratory signs of functional renal insufficiency may appear. In this case, the treatment should be discontinued. Subsequently, combination therapy may be resumed with a low-dose combination of indapamide and perindopril, or only one of the drugs may be used.

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

Arterial hypotension and water-electrolyte imbalance

In cases 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 decreased plasma electrolyte content, e.g., after diarrhea or vomiting. These patients require regular monitoring of plasma electrolytes.

In case of severe arterial hypotension, intravenous administration of 0.9% sodium chloride solution may be required.

Transient arterial hypotension is not a contraindication for continuation of therapy. After recovery of circulating blood volume and BP, therapy may be resumed using lower doses of the drugs, or only one of the drugs may be used.

Potassium content

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

Auxiliary substances

Please note that the excipients of the drug include lactose monohydrate. Perindopril PLUS should not be used in patients with hereditary galactose intolerance, lactase deficiency and glucose-galactose malabsorption.

Lithium preparations

The concomitant use of Perindopril PLUS with lithium preparations is not recommended.

Perindopril PLUS should not be used in children and adolescents less than 18 years of age because of lack of data about the effectiveness and safety of indapamide and perindopril, either alone or together, in this age group of patients.

Perindopril

Double blockade of the angiotensin-aldosterone system (RAAS)

. There is evidence for an increased risk of arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure) when ACE inhibitors are used concomitantly 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 dual blockade is absolutely necessary, it should be performed under close professional supervision with regular monitoring of renal function, plasma electrolytes and BP.

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-saving diuretics, potassium preparations, potassium salt substitutes, and dietary supplements

Perindopril should not be used with potassium-saving diuretics or with potassium preparations, potassium salt substitutes, or dietary supplements.

Neutropenia / agranulocytosis / thrombocytopenia

There have been reports of neutropenia/ agranulocytosis, thrombocytopenia and anemia with ACE inhibitors. Neutropenia is rare in patients with normal renal function and without concomitant risk factors. Perindopril should be used with extreme caution during systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma), as well as during taking immunosuppressants, allopurinol or procainamide, or in combination of these factors, especially in patients with initially impaired renal function.

Some patients had 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 leukocytes in the blood. Patients should inform the physician of any signs of infectious diseases (e.g., sore throat, fever).

Anemia may develop in patients after kidney transplantation or in those on hemodialysis. The greater the decrease in hemoglobin, the greater the initial hemoglobin decrease. This effect does not seem 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. Treatment may continue in these patients, but hematologic tests should be performed regularly.

Hypersensitivity / angioedema

In rare cases, angioedema of the face, extremities, lips, tongue, vocal folds and/or larynx may occur when taking ACE inhibitors, including perindopril. This may occur during any period of therapy. If symptoms occur, administration of Perindopril PLUS should be stopped immediately and the patient should be observed until the signs of edema disappear completely. If the swelling only affects the face and lips, it usually resolves on its own, although antihistamines may be used as symptomatic therapy. A higher risk of angioedema has been reported in patients of non-highland race.

In patients with a history of angioedema not associated with ACE inhibitors, there may be an increased risk of developing it when taking this group of drugs.

In rare cases, angioedema of the intestine has developed during therapy with ACE inhibitors. Patients reported 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 C-1 esterase levels. The diagnosis was established by abdominal computed tomography, ultrasound, or at the time of surgery. Symptoms went away after discontinuation of ACE inhibitors. Therefore, in patients with abdominal pain receiving ACE inhibitors, the possibility of angioedema of the bowel should be considered in the differential diagnosis.

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

In patients receiving concomitant therapy with mTOR inhibitors may increase the risk of angioedema (including airway or tongue edema with/without respiratory dysfunction).

Anaphylactoid reactions during desensitization

There have been isolated reports of long-term, life-threatening anaphylactoid reactions in patients receiving ACE inhibitors during desensitization therapy with venom from hymenopteran insects (bees, wasps). ACE inhibitors should be used with caution in patients prone to allergic reactions undergoing desensitization procedures. Prescription of ACE inhibitor should be avoided in patients receiving immunotherapy with venom of hymenopterous insects. However, an anaphylactoid reaction can be avoided by temporarily withdrawing the ACE inhibitor at least 24 hours before the desensitization procedure.

Anaphylactoid reactions during LDL apheresis

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

Hemodialysis

In patients receiving ACE inhibitors, anaphylactoid reactions have been reported when hemodialysis is performed using high-flow membranes (e.g., AN69®). Therefore, it is advisable to use a different type of membrane or to use a hypotensive agent from a different pharmacotherapeutic group.

Cough

Dry, persistent cough may occur with ACE inhibitor therapy and disappear after discontinuation of the drugs of this group. If a patient has a dry cough, you should be aware of the possible iatrogenic nature of this symptom. If the attending physician considers that therapy with ACE inhibitor is necessary for the patient, continuation of therapy with ACE inhibitor is possible.

The risk of arterial hypotension and/or renal failure (in patients with heart failure, electrolyte balance disorders, etc.

In some pathological states there may be significant activation of the RAAS, especially with significant hypovolemia and decrease of plasma electrolyte content (due to salt-free diet or long-term use of diuretics), in patients with baseline low blood pressure, renal artery stenosis, chronic heart failure or cirrhosis with edemas and ascites.

The use of ACE inhibitors causes RAAS blockade and therefore may be accompanied by a sharp decrease in BP and/or increase in plasma creatinine concentration 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 in other terms of therapy. In such cases, it is recommended to resume therapy at a lower dose and then gradually increase the dose.

Elderly age

Before starting perindopril therapy, renal functional activity and plasma content of potassium ions should be assessed. At the start of therapy, the dose of the drug should be adjusted to the degree of BP decrease, especially in cases of dehydration and electrolyte loss. Such measures allow to avoid a sharp decrease in BP.

Atherosclerosis

The risk of arterial hypotension exists in all patients, but special caution should be exercised when using the drug in patients with ischemic heart disease and cerebrovascular insufficiency. In such patients, treatment should be started with low doses of the drug.

Renovascular hypertension

The method of treatment of renovascular hypertension is revascularization. However, the use of ACE inhibitors may be beneficial in this category of patients both awaiting surgery and when surgery is not feasible.

Perindopril PLUS is not indicated in patients with diagnosed or suspected renal artery stenosis, because therapy should be initiated in the 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 be initiated with lower doses of indapamide and perindopril combination and under close medical supervision.

Patients with arterial hypertension and coronary heart disease should not discontinue beta-adrenoblocker therapy: the ACE inhibitor should be added to beta-adrenoblocker therapy.

Diabetes mellitus

Patients with type 1 diabetes may have spontaneous increase of potassium in blood. The treatment with Perindopril PLUS is not indicated in these patients, since it should be started with minimal doses and under constant medical monitoring.

In the first month of therapy with ACE inhibitors, plasma glucose concentrations should be monitored closely in patients with diabetes mellitus treated with oral hypoglycemic agents or insulin.

Ethnic differences

Perindopril, like other ACE inhibitors, has a markedly less pronounced antihypertensive effect in patients of the Negro race compared with other races. It is possible that this difference is due to the fact that patients with arterial hypertension of the non-human race are more likely to have low renin activity.

Surgery/general anesthesia

The administration of general anesthesia with ACE inhibitors may result in a significant decrease in BP, especially with the use of general anesthesia agents that have antihypertensive effects.

The use of long-acting ACE inhibitors, including perindopril, should be discontinued if possible a day before surgery. The anesthesiologist should be advised that the patient is taking ACE inhibitors.

Aortic or mitral stenosis/Hypertrophic obstructive cardiomyopathy

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

Hepatic failure

In rare cases, cholestatic jaundice occurs with ACE inhibitors. If this syndrome progresses, fulminant liver necrosis develops, sometimes with a fatal outcome. The mechanism of this syndrome is unclear. If jaundice or significant increase in liver enzymes activity occurs with ACE inhibitor therapy, the patient should discontinue ACE inhibitor therapy and consult a physician.

Hyperkalemia

Hyperkalemia may develop during treatment with ACE inhibitors, including perindopril. Risk factors for hyperkalemia include renal insufficiency, impaired renal function, age older than 70 years, diabetes mellitus, certain concomitant conditions (dehydration, acute decompensation of cardiac activity, metabolic acidosis), concomitant use of potassium-saving diuretics (such as spironolactone and its derivatives eplerenone, triamterene, amiloride) as well as potassium preparations or potassium-containing meal salt substitutes, as well as the use of other drugs that contribute to increased plasma potassium levels (e.g., 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 preparations, potassium-saving diuretics, and potassium-containing salt substitutes may lead to a significant increase in blood potassium content, especially in patients with reduced renal function.

Hyperkalemia can lead to serious, sometimes fatal heart rhythm disturbances. If concomitant administration of the above drugs is necessary, treatment should be undertaken with caution with regular monitoring of serum potassium.

Indapamide

Hepatic encephalopathy

The use of thiazide and thiazide-like diuretics may lead to hepatic encephalopathy if liver function is impaired. In this situation, the diuretic should be stopped immediately.

Water-electrolyte balance

The content of sodium ions in blood plasma

The content of sodium ions in blood plasma should be determined before starting treatment, and then regularly monitored against the background of the drug.

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

The simultaneous reduction of chlorine ions may lead to the development of secondary compensatory metabolic alkalosis: the frequency of its occurrence and the degree of manifestation are small.

Potassium ion content in plasma

The therapy with thiazide and thiazide-like diuretics is associated with risk of hypokalemia. Hypokalemia (less than 3.4 mmol/l) should be avoided in the following high-risk patients: elderly patients, malnourished patients (both receiving and not receiving combined drug therapy), patients with cirrhosis (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 arrhythmias.

Patients with prolonged QT interval, both congenital and drug-induced, are also at increased risk.

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

If hypokalemia is detected, appropriate correction should be performed.

Plasma calcium ion content

Thiazide and thiazide-like diuretics may decrease renal excretion of calcium ions, resulting in a slight and temporary increase in plasma calcium content. Severe hypercalcemia may result from previously undiagnosed hyperparathyroidism. Diuretics should be discontinued prior to parathyroid function study.

Plasma glucose concentrations

Blood glucose concentrations in patients with diabetes mellitus should be monitored, especially in the presence of hypokalemia.

Uric acid

The incidence of gout attacks may increase with increasing plasma uric acid concentrations during therapy.

Diuretics and renal function

The thiazide and thiazide-like diuretics are only fully effective in patients with normal or mildly impaired renal function (creatinine plasma concentrations in adults below 25 mg/l or 220 µmol/L).

In elderly patients, plasma creatinine levels should be assessed taking into account age, weight and sex, according to the Cockroft formula:

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

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

The formula is appropriate for older men; for older women multiply the result by 0.85.

At the beginning of diuretic treatment, patients may experience a temporary decrease in glomerular filtration rate and an increase in plasma urea and creatinine concentrations due to hypovolemia (due to water and sodium ion excretion). This transient functional renal failure is not dangerous in patients with baseline normal renal function, but in patients with renal insufficiency, its severity may worsen.

Photosensitivity

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

Athletes

Indapamide may react positively in doping controls.

Acute myopia and secondary closed angle glaucoma

Sulfonamides and their derivatives may cause idiosyncratic reactions leading to temporary (transient) myopia and acute closed angle glaucoma. Without proper therapy, acute angle closure glaucoma can lead to vision loss. The first step is to stop taking the medication as soon as possible. If intraocular pressure continues to be high, immediate therapeutic or surgical treatment may be necessary. Risk factors that may lead to the development of acute closed angle glaucoma include a history of allergy to sulfonamides or penicillin.

Influence on ability to drive vehicles and machinery:

Caution should be exercised when driving motor vehicles and other technical devices that require increased attention and rapid psychomotor reactions.

Contraindications

Perindopril

High sensitivity to perindopril and other ACE inhibitors;
An history of angioedema (Quincke’s edema) with other ACE inhibitorsHistory of angioedema (Quincke’s edema) with other ACE inhibitors;
Hereditary/ idiopathic angioedema;
Pregnancy and breastfeedingPregnancy and breastfeeding period;
Simultaneous use with aliskiren and drugs containing aliskiren in patients with diabetes and/or moderate to severe renal function impairment (glomerular filtration rate (GFR) less than 60 ml/min/1.73 m2 body surface area.
Simultaneous use with angiotensin II receptor antagonists (ARA II) in patients with diabetic nephropathy.
Age under 18 years (effectiveness and safety not established).

Indapamide

High sensitivity to indapamide and other sulfonamides;

Severe hepatic impairment;

Hepatic encephalopathy;

Hypokalemia;

Simultaneous use with non antiarrhythmic drugs that can cause pirouette-type polymorphic ventricular tachycardia;

Breastfeeding period;

Age under 18 years of age (efficacy and safety not established).

Perindopril PLUS

High sensitivity to the excipients in the drug;
.Because of insufficient clinical experience Perindopril PLUS should not be used in patients on hemodialysis or in patients with untreated decompensated heart failure;
Age below 18 years of age (efficacy and safety not established);
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-administration with lithium drugs, gold drugs, nonsteroidal anti-inflammatory drugs (NSAIDs), baclofen, corticosteroids, drugs that may cause QT interval prolongation, drugs that may cause polymorphic ventricular tachycardia of the “pirouette” type, except non antiarrhythmic drugs inhibition of bone marrow hematopoiesis; reduced circulating blood volume (taking diuretics, salt-free diet, vomiting, diarrhea); coronary heart disease; cerebrovascular disease; hepatic and renal disorders; renovascular hypertension; diabetes mellitus; chronic heart failure (NYHA functional class IV); hyperuricemia (especially accompanied with gout and urate nephrolithiasis); labile BP; advanced age; hemodialysis with high-flow membranes (e.g., AN69®) or desensitization, LDL apheresis; conditions after kidney transplantation; planned anesthesia aortic valve stenosis/hypertrophic obstructive cardiomyopathy; atherosclerosis; members of the Negro race (less pronounced effect of use); athletes (possible positive reaction in doping control), bilateral renal artery stenosis or presence of only one functioning kidney, concomitant therapy with potassium-saving diuretics, potassium drugs or in patients with high plasma potassium levels.

Side effects

The incidence of side effects is estimated on the basis of: often – 1-10%; rarely – 0.1-1%; extremely rare, including isolated reports – less than 0.1%.

Cardiovascular system: often – excessive decrease in blood pressure and related symptoms, rarely – arrhythmia, angina pectoris, myocardial infarction and stroke.

Urinary system disorders: decreased renal function and acute renal failure.

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

Gastrointestinal system: frequently – nausea, vomiting, abdominal pain, change in taste, diarrhea or constipation, dry mouth, decreased appetite, cholestatic jaundice, pancreatitis, intestinal edema.

The central nervous system: often – headache, asthenia, fatigue, dizziness, tinnitus, visual disturbances, muscle cramps, paresthesias; rarely – decreased mood, insomnia; extremely rare – confusion.

Allergic reactions: common – skin rash, itching, rarely – urticaria, angioedema; very rare – erythema multiforme.

Laboratory indices: frequent – hypercreatininemia, proteinuria, hyperkalemia; hyperuricemia; rare (with prolonged use in high doses) – neutropenia, leukopenia, hypogemoglobinemia, thrombocytopenia, decreased hematocrit; Very rarely – agranulocytosis, pancytopenia, increased “liver” enzymes activity, hyperbilirubinemia, hemolytic anemia (with glucose-6-phosphate dehydrogenase deficiency).

Others: increased sweating, impaired sexual function.

Overdose

Symptoms: marked BP decrease, nausea, vomiting, muscle cramps, dizziness, drowsiness, confusion, oliguria up to anuria (due to reduction of the blood circulation); disorders of water-electrolyte balance (low plasma levels of sodium and potassium) are possible.

Treatment: gastric lavage and/or administration of activated charcoal, restoration of water-electrolyte balance in hospital. With a pronounced BP decrease the patient should be transferred to the “supine” position with elevated legs; then measures should be taken to increase the blood circulation (intravenous injection of 0.9% sodium chloride solution). Perindoprilat, the active metabolite of perindopril, can be eliminated from the body by dialysis.

Similarities

Co-Perineva, Noliprel A Bi-forte, Noliprel A, Noliprel A forte, Perindopril-Indapamide , Perindopril, Indapamide / Perindopril-Teva

Additional information