Perindopril PLUS (Indapamin, perindopril)

1 tablet contains:

Active substances:

Indapamide 

Perindopril erbumine 

Excipients:

Microcrystalline cellulose - 70.375 mg;

Pregelatinized corn starch - 15 mg;

Crospovidone - 10 mg;

Magnesium stearate - 1 mg;

Colloidal silicon dioxide - 1 mg.

A combined antihypertensive drug containing an angiotensin-converting enzyme (ACE) inhibitor - perindopril and a thiazide-like diuretic - indapamide. The drug has an antihypertensive, diuretic and vasodilating effect.

Perindopril PLUS Indapamide has a pronounced dose-dependent antihypertensive effect, independent of the age and position of the patient's body and is not accompanied by reflex tachycardia. Does not affect lipid metabolism (total cholesterol, low density lipoproteins (LDL), very low density lipoproteins (VLDL), high density lipoproteins (HDL), triglycerides (TG) and carbohydrates), incl. in patients with diabetes mellitus. Reduces the risk of hypokalemia caused by diuretic monotherapy.

The antihypertensive effect persists for 24 hours.

A stable decrease in blood pressure (BP) is achieved within 1 month with the use of the drug Perindopril PLUS Indapamide without an increase in the heart rate (HR). Discontinuation of treatment does not lead to withdrawal syndrome.

Perindopril is an ACE inhibitor, the mechanism of action of which is associated with inhibition of ACE activity, leading to a decrease in the formation of angiotensin II, eliminates the vasoconstrictor effect of angiotensin II, and reduces the secretion of aldosterone. The use of perindopril does not lead to sodium and fluid retention, does not cause reflex tachycardia during long-term treatment. The antihypertensive effect of perindopril develops in patients with low or normal blood plasma renin activity. Perindopril acts through its main active metabolite, perindoprilat. Its other metabolites are inactive.

The action of perindopril leads to varicose veins (reduced preload on the heart) due to changes in prostaglandin metabolism; decrease in total peripheral vascular resistance (OPSS) (decrease in afterload on the heart).

In patients with heart failure, perindopril reduces the filling pressure of the left and right ventricles; increased cardiac output and cardiac index; increased regional blood flow in the muscles.

Perindopril is effective for hypertension of any severity: mild, moderate and severe.

The maximum hypotensive effect develops 4-6 hours after a single oral administration and lasts for a day.

Discontinuation of therapy does not lead to the development of a withdrawal syndrome.

It has vasodilating properties and restores the elasticity of large arteries. The addition of a thiazide-like diuretic enhances the hypotensive (additive) effect of perindopril.

Indapamide is a sulfonamide derivative and is a diuretic. Inhibits sodium reabsorption in the cortical segment of the renal tubules, increasing the excretion of sodium and chlorine by the kidneys, thus leading to increased urine output. Increases the excretion of potassium and magnesium to a lesser extent. Possessing the ability to selectively block slow calcium channels, indapamide increases the elasticity of the arterial walls and reduces the systemic vascular resistance. It has an antihypertensive effect in doses that do not have a pronounced diuretic effect. An increase in the dose of indapamide does not entail an increase in the hypotensive effect, but increases the risk of developing adverse events. Indapamide in patients with arterial hypertension does not affect the metabolism of lipids - TG, LDL and HDL; on the metabolism of carbohydrates, even in patients with diabetes mellitus and arterial hypertension.

Pharmacokinetics:

The combined use of perindopril and indapamide does not change their pharmacokinetic parameters, compared with the separate administration of these drugs.

Perindopril

Suction

After oral administration, perindopril is rapidly absorbed from the gastrointestinal tract (GIT). Bioavailability is 65-70%. The maximum concentration (Cmax) in blood plasma is reached 3-4 hours after oral administration.

Food intake reduces the conversion of perindopril to perindoprilat and the bioavailability of perindopril, so it should be taken 1 time / day in the morning, before breakfast. When taking perindopril 1 time / day. Equilibrium concentration (Css) is reached within 4 days.

Distribution

Plasma protein binding of perindoprilat is dose-dependent and amounts to 20%. Perindoprilat easily crosses the histohematological barriers, excluding the blood-brain barrier (BBB). Does not cumulate.

Metabolism

In the liver, it is metabolized to form the active metabolite of perindoprilat. In addition, 5 more inactive metabolites are formed.

Withdrawal

The half-life (T1 / 2) of perindopril from blood plasma is 1 hour. T1 / 2 of perindoprilat is about 17 hours. It is excreted by the kidneys.

Pharmacokinetics in special patient groups

In elderly patients, in patients with renal and heart failure, the excretion of perindoprilat is slowed down.

The dialysis clearance of perindoprilat is 70 ml / min.

The kinetics of perindopril is altered in patients with liver cirrhosis: hepatic clearance is reduced by half. However, the amount of perindoprilat formed does not decrease, which does not require dose adjustment.

Indapamide

Suction

After oral administration, it is rapidly and almost completely absorbed from the gastrointestinal tract. Food intake slows down the absorption somewhat, but does not significantly affect the amount of indapamide absorbed. After oral administration in a single dose, Cmax in blood plasma is reached after 1 hour.

Distribution

Plasma protein binding is 79%. Does not cumulate.

Metabolism

Metabolized in the liver.

Withdrawal

T1 / 2 ranges from 14 to 24 hours (average 18 hours). It is excreted by the kidneys (70%) mainly in the form of metabolites (the fraction of the unchanged drug is about 5%) and by the intestines with bile in the form of inactive metabolites (22%).

Pharmacokinetics in special clinical situations

In patients with renal insufficiency, the pharmacokinetic parameters of indapamide do not change significantly.

Arterial hypertension.

• Hypersensitivity to excipients that make up the drug;

• Severe renal failure (CC <30 ml / min);

• Simultaneous reception with potassium-sparing diuretics, potassium and lithium preparations, and in patients with hyperkalemia;

• Simultaneous intake of drugs that lengthen the QT interval;

• Due to the lack of sufficient clinical experience, the drug Perindopril plus Indapamide should not be used in patients on hemodialysis, as well as in patients with untreated heart failure in the stage of decompensation;

• Age up to 18 years (efficacy and safety have not been established).

Carefully:

• The drug should be used in case of systemic diseases of the connective tissue (including systemic lupus erythematosus, scleroderma);

• Against the background of immunosuppressive therapy (risk of developing neutropenia, agranulocytosis); with oppression of bone marrow hematopoiesis;

• Decrease in circulating blood volume (BCC) (due to taking diuretics, diet restricting table salt, vomiting, diarrhea);

• With ischemic heart disease (CHD);

• Cerebrovascular diseases;

• Renovascular hypertension;

• Chronic heart failure (NYHA functional class IV);

• With hyperuricemia (especially accompanied by gout and urate nsfrolithiasis);

• Lability of blood pressure;

• During hemodialysis using high-flow polyacrylonitrile membranes (risk of developing anaphylactoid reactions);

• Before the procedure of LDL apheresis with dextrin sulfate;

• Simultaneously with desensitizing therapy with allergens (for example, hymenoptera venom);

• With a condition after kidney transplantation;

• Stenosis of the aortic and / or mitral valve, hypertrophic obstructive cardiomyopathy;

• In elderly patients.

In patients with a history of Quincke's edema, which is not associated with the use of ACE inhibitors, the risk of its development may be increased when taking drugs of this group.

In patients of the Negroid race, angioedema develops more often than in patients of other races.

Classification of the incidence of side effects (WHO): very often (> 1/10). often (from> 1/100 to <1/10), infrequently (from> 1/1000 to <1/100), rarely (from> 1/10 000 to <1/1000). very rare (from <1/10 000), the frequency is unknown (the frequency cannot be calculated from the available data).

From the hematopoietic system:  infrequently - eosinophilia, hyponatremia, very rarely - thrombocytopenia, leukopeia / neutropenia, agranulocytosis, aplastic anemia, hemolytic anemia. In certain clinical situations (patients after kidney transplantation, patients on hemodialysis), ACE inhibitors can cause anemia.

From the side of the central nervous system:  often - paresthesia, headache, dizziness, vertigo; infrequently - sleep disturbance, mood lability; very rarely - confusion of consciousness; frequency unknown - syncope.

From the side of the organ of vision:  often - visual impairment.

From the organ of hearing:  often - tinnitus.

From the side of the cardiovascular system:  infrequently - a marked decrease in blood pressure (including orthostatic hypotension), palpitations; very rarely - cardiac arrhythmias (including bradycardia, ventricular tachycardia, atrial fibrillation), angina pectoris and myocardial infarction, possibly due to an excessive decrease in blood pressure in high-risk patients; frequency unknown - arrhythmias of the "pirouette" type (possibly fatal), an increase in the QT interval on the ECG.

On the part of the respiratory system:  often - against the background of the use of ACE inhibitors, a dry cough may occur, which persists for a long time while taking drugs of this group and disappears after their withdrawal, shortness of breath; infrequently - bronchospasm; very rarely - eosiophilic pneumonia, rhinitis.

On the part of the digestive system:  often - dryness of the oral mucosa, nausea, vomiting, abdominal pain, epigastric pain, impaired taste, loss of appetite, dyspepsia, constipation, diarrhea: very rarely - pancreatitis, angioedema of the intestines, cholestatic jaundice; frequency unknown - hepatic encephalopathy in patients with hepatic insufficiency, increased activity of "hepatic" transaminases.

From the side of the skin:  often - skin rash, itching, maculopapular rash; infrequently - angioedema of the face, lips, extremities, mucous membrane of the tongue, vocal folds and / or larynx, urticaria, hypersensitivity reactions in patients predisposed to bronchial obstruction and allergic reactions, hemorrhagic vasculitis. In patients with an acute form of systemic lupus erythematosus, the course of the disease may worsen; very rarely - erythema multiforme, toxic epidermal necrolysis. Stevens-Johnson syndrome. Cases of photosensitivity reactions have been reported.

From the musculoskeletal system:  often - muscle spasms.

From the urinary system:  infrequently - renal failure; very rarely - acute renal failure, the frequency is unknown - hepatitis.

On the part of the reproductive system:  infrequently - erectile dysfunction.

Laboratory indicators:  rarely - hypercalcemia; the frequency is unknown - hypocatia, especially significant for patients at risk; hyponatremia and gynovolemia, leading to dehydration and orthostatic hypotension; an increase in the concentration of uric acid and glucose in the blood while taking the drug: a slight increase in the concentration of creatinine in the urine and in the blood plasma, which takes place after discontinuation of therapy, more often in patients with renal artery stenosis, in the treatment of arterial hypertension with diuretics and in case of renal failure; hyperkalemia, often transient.

Others:  often - asthenia; infrequently - increased sweating.

With the use of ACE inhibitors, the syndrome of impaired secretion of aitidiuretic hormone was rarely observed.

Simultaneous use is not recommended

Lithium preparations: Cases of a reversible increase in serum lithium concentration have been reported. The risk of its toxic effect increases while taking an ACE inhibitor.

The simultaneous administration of a combination of perindopril and indapamide with lithium preparations is not recommended.

In the case of therapy, it is necessary to control the concentration of lithium in the blood plasma.

With simultaneous use, special care is required

Baclofen: potentiates the antihypertensive effect (control of blood pressure, renal function and, if necessary, dose adjustment of Perindopril PLUS Indapamide is required).

The combination of ACE inhibitors with non-steroidal anti-inflammatory drugs (NSAIDs) (including selective inhibitors of cyclooxygenase-2 (COX-2) and non-selective NSAIDs, acetylsalicylic acid in doses that have an anti-inflammatory effect) reduces the antihypertensive effect of ACE inhibitors; increases the risk of impaired renal function, up to the development of acute renal failure; increases serum potassium in patients with pre-existing renal impairment.

This combination is recommended to be used with caution, especially in elderly patients.

Patients need to compensate for the BCC, as well as monitor renal function before and after starting treatment with Perindopril PLUS Indapamide.

With simultaneous use, caution is required

Tricyclic antidepressants, antipsychotics (antipsychotics) increase the antihypertensive effect and increase the risk of orthostatic hypotension (additive effect).

Glucocorticosteroids (GCS), tetracosactide reduce the antihypertensive effect (fluid retention).

With simultaneous use with other antihypertensive drugs, it is possible to enhance the antihypertensive effect of the drug.

Perindopril

Simultaneous use is not recommended

ACE inhibitors reduce the loss of potassium by the kidneys caused by a diuretic.

With the combined use of potassium-sparing diuretics (spironolactone, triamterene, amiloride, eplerenone), potassium preparations or potassium-containing salt substitutes with ACE inhibitors, it is possible to increase the potassium content in the blood serum up to death.

If the combined use of an ACE inhibitor and the above drugs is necessary (in the case of confirmed hypokalemia), care should be taken and regular monitoring of plasma potassium and ECG parameters should be carried out.

The simultaneous use of ACE inhibitors and angiotensin II receptor antagonists with aliskiren in patients with diabetes mellitus and patients with moderate renal insufficiency (CC less than 60 ml / min) is contraindicated.

With simultaneous use with estramustine, the risk of developing angioedema increases.

With simultaneous use, special care is required

The use of ACE inhibitors can enhance the hypoglycemic effect of oral hypoglycemic agents (sulfonylurea derivatives) and insulin in patients with diabetes mellitus; when used together, it is possible to increase glucose tolerance, which may require adjusting the doses of hypoglycemic agents for oral administration and insulin.

Baclofen enhances the antihypertensive effect of ACE inhibitors.

With the simultaneous use of potassium-non-sparing diuretics, gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin) - the risk of developing angioedema due to suppression of the activity of dipeptidyl peptidase IV by gliptin.

When used simultaneously with sympathomimetics, it enhances the antihypertensive effect of ACE inhibitors.

There are reports that in patients with established atherosclerotic disease, heart failure, or diabetes mellitus with target organ damage, concomitant therapy with an ACE inhibitor and ARAII is associated with a higher incidence of arterial hypotension, syncope, hyperkalemia, and deterioration of renal function (including acute renal insufficiency) but compared with the use of only one drug that affects the RAAS.

Double blockade (for example, when an ACE inhibitor is combined with ARAII) should be limited to individual cases with careful monitoring of renal function, potassium content and blood pressure.

With simultaneous use, caution is required

With the simultaneous use of allopurinol, cytostatics, immunosuppressants, GCS (for systemic use), procainamide with ACE inhibitors, the risk of leukopenia may increase.

In patients whose condition requires extensive surgery or general anesthesia with drugs that cause arterial hypotension, ACE inhibitors, including perindopril, can block the formation of angiotensin II during compensatory renin release.

The day before surgery or therapy with ACE inhibitors must be canceled.

If it is impossible to cancel an ACE inhibitor, then arterial hypotension, which develops according to the described mechanism, can be corrected by an increase in the BCC.

With the use of diuretics in high doses, hypovolemia is possible (due to a decrease in the BCC), and the addition of perindopril to therapy leads to a pronounced decrease in blood pressure.

When prescribing ACE inhibitors, including perindopril. patients receiving a gold preparation (sodium aurothiomalate) intravenously, were noted nitrate-like reactions (nausea, vomiting, a marked decrease in blood pressure, hyperemia of the skin of the face).

Indapamide

With simultaneous use, special care is required

Due to the risk of hypokalemia, indapamide should be used with caution in conjunction with drugs that cause ventricular arrhythmias of the "pirouette" type, such as antiarrhythmics (quinidine, hydroquinidine, disopyramide, amiodarone, dofetilide, ibutilide, bretilium tosylate, sotalol), some antipsychotics ( chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine), benzamides (amisulpride, sulpiride, sultopride, tiapride), butyrophenone (droperidol, haloperidol), other antipsychotics (pimozide); other substances such as bepridil, cisapride, diphemanil methyl sulfate, erythromycin (i.v.), halofantrine, mizolastine, moxifloxacin, pentamidine, sparfloxacin, vincamine i.v., methadone, astemizole, terfenadine.

It is necessary to control the potassium content in order to avoid hypokalemia, with the development of which it is necessary to carry out its correction, to control the QT interval on the ECG.

With the simultaneous use of indapamide with amphotericin  (i / v), gluco- and mineralocorticoids (for systemic administration), tetracosactide. laxatives that stimulate gastrointestinal motility, the risk of hypokalemia increases (additive effect).

It is necessary to control the content of potassium in the blood plasma, if necessary, to correct it.

Particular attention should be paid to patients concomitantly receiving cardiac glycosides.

Use laxatives that do not stimulate gastrointestinal motility.

Hypokalemia enhances the toxic effect of cardiac glycosides.

With the simultaneous use of indapamide and cardiac glycosides, the content of potassium in the blood plasma, ECG parameters should be monitored and, if necessary, the dose of cardiac glycosides should be adjusted.

With simultaneous use, caution is required

When metformin is used with diuretics, renal failure may develop.

With simultaneous use with metformin, the risk of developing lactic acidosis increases.

Do not use metformin if the serum creatinine concentration exceeds 15 mg / l in men and 12 mg / l in women.

Against the background of taking diuretics, the BCC decreases, the risk of acute renal failure increases, especially when using iodine-containing contrast agents in high doses.

Before using iodine-containing contrast media, it is necessary to compensate for the BCC.

With simultaneous use with calcium preparations, hypercalcemia may develop due to a decrease in calcium excretion by the kidneys.

With simultaneous use with cyclosporine, the risk of developing renal dysfunction (hypercreatininemia) increases.

Assign inside 1 time / day. preferably in the morning before breakfast with plenty of fluids.

Doses are given for the ratio of perindopril / indapamide.

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

Patients with renal insufficiency (CC 60 ml / min or more) do not require dose adjustment. For patients with CC 30-60 ml / min, the maximum dose of Perindopril plus Indapamide is 0.625 mg / 2 mg (1 tablet) 1 time / day, treatment should begin with the selection of doses of perindopril and indapamide in monotherapy mode. When CC is less than 30 ml / min, the use of the drug Perindopril plus Indapamide is contraindicated (see section "Contraindications").

No dose adjustment is required in patients with moderate hepatic impairment. The use of the drug Perindopril plus Indapamide is contraindicated in patients with severely impaired liver function.

For elderly patients, the initial dose of the drug Perindopril plus Indapamide is 0.625 mg / 2 mg (1 tablet) 1 time / day.

In elderly patients, before taking the drug Perindopril plus Indapamide, renal function and plasma potassium should be assessed. The initial dose of the drug Perindopril plus Indapamide is selected depending on the degree of decrease in blood pressure, especially with a decrease in BCC and chronic heart failure (NYHA functional class IV). Such measures allow you to avoid a sharp decrease in blood pressure.

The risk of arterial hypotension exists in all patients, however, special care should be taken when using the drug Perindopril plus Indapamide in patients with coronary artery disease and cerebrovascular accident. In such patients, drug treatment should be started with a dose of 0.625 mg / 2 mg (initial dose). In patients with diagnosed or suspected renal artery stenosis, treatment with Perindopril plus Indapamide should be started in a hospital setting with a dose of 0.625 mg / 2 mg under the control of renal function and plasma potassium. Some patients may develop acute renal failure, which is reversible after discontinuation of the drug.

In patients with chronic heart failure (NYHA functional class IV), treatment with Perindopril plus Indapamide should be started with an initial dose of 0.625 mg / 2 mg under medical supervision.

It is not recommended to use the drug simultaneously with lithium preparations.

Therapy with Perindopril PLUS Indapamide is contraindicated in patients with severe renal insufficiency (CC less than 30 ml / min).

In some patients with arterial hypertension without previous impairment of renal function during therapy with the drug, symptoms of acute renal failure may appear. In this case, treatment with this drug should be discontinued. In the future, you can resume combination therapy using low doses of Perindopril PLUS Indapamide, or use perindopril and indapamide as monotherapy. Such patients need regular monitoring of potassium and serum creatinine concentrations every 2 weeks after the start of therapy and every subsequent 2 months of therapy with Perindopril PLUS Indapamide.

Acute renal failure is more common in patients with severe chronic heart failure or underlying renal impairment, including bilateral renal artery stenosis or arterial stenosis of a single functioning kidney.

The drug is not recommended for patients with bilateral renal artery stenosis or arterial stenosis of a single functioning kidney. Hyponatremia is associated with the risk of a sudden decrease in blood pressure (especially in patients with bilateral renal artery stenosis or arterial stenosis of a single functioning kidney). 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 prolonged diarrhea or vomiting. Such patients need regular monitoring of plasma electrolytes.

With a pronounced decrease in blood pressure, intravenous administration of 0.9% sodium chloride solution may be required.

Transient arterial hypotension is not a contraindication for further continuation of therapy. After the restoration of BCC and blood pressure, you can resume therapy with Perindopril PLUS Indapamide, using low doses of the drug, or using perindopril and indapamide in monotherapy. The combined use of perindopril and indapamide does not prevent the development of hypokalemia, especially in patients with diabetes mellitus or renal failure. As in the case of the combined use of antihypertensive drugs and a diuretic, regular monitoring of the potassium content in the blood plasma is necessary.

Perindopril

In patients taking ACE inhibitors, cases of neutropenia / agranulocytosis, thrombocytopenia and anemia are possible.

In patients with normal renal function in the absence of other complications, neutropenia rarely develops and resolves spontaneously after discontinuation of ACE inhibitors.

Perindopril should be used with extr