Indapamide/Perindopril-Teva, 1.25mg+5 mg 30 pcs

Pharmacotherapeutic group: hypertensive combined (diuretic + angiotensin-converting enzyme inhibitor)

Code ATX: C09BA04

Pharmacological properties.

Pharmacodynamics

Indapamide/Perindopril-Teva, a combined antihypertensive drug containing perindopril, angiotensin-converting enzyme (ACE) inhibitor and indapamide, thiazide-like diuretic. The synergistic action of perindopril and indapamide determines the pharmacological properties of the drug.

Indapamide with regard to the chemical structure belongs to the group of sulfonamides, and with regard to pharmacological properties is similar to thiazide diuretics. Indapamide inhibits sodium reabsorption in the cortical segment of the renal tubules, increasing renal excretion of sodium, chlorine and, to a lesser extent, potassium and magnesium, increasing diuresis and reducing blood pressure (BP).

Perindopril is an ACE inhibitor whose mechanism of action is associated with inhibition of ACE activity, resulting in reduction of angiotensin II, which has a vasoconstrictor effect, and which also breaks down bradykinin, which has a vasoconstrictor effect, to an inactive heptapeptide.

As a result, perindopril decreases aldosterone secretion and increases plasma renin activity by the principle of feedback; with long-term use it reduces total peripheral vascular resistance (PPR), which is mainly due to the effect on the vessels in the muscles and kidneys. These effects are not accompanied by retention of salts and fluids or development of reflex tachycardia.

Perindopril has therapeutic effects due to its active metabolite, perindoprilat. Its other metabolites are not active.

Perindopril normalizes heart function by promoting vein dilation (decreased preload) through changes in prostaglandin metabolism and decreased RPS (decreased postload).

In chronic heart failure (CHF), perindopril reduces filling pressures in the left and right ventricles of the heart, decreases PPS, increases cardiac output and increases cardiac index, and increases peripheral blood flow in the muscles.

Antihypertensive effect

. The indapamide/perindopril combination has dose-dependent antihypertensive effects on both diastolic and systolic BP in standing and lying positions. Antihypertensive effect is maintained for 24 hours. Stable therapeutic effect occurs in less than 1 month from the start of treatment and is not accompanied by tachyphylaxis. Discontinuation of treatment does not cause “withdrawal” syndrome. Moreover, combination indapamide/perindopril decreases degree of left ventricular hypertrophy (LVH), improves arterial elasticity, decreases RPS, does not influence lipid metabolism (total cholesterol, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C), triglycerides).

In patients with type 2 diabetes mellitus (mean age 66 years, body mass index 28 kg/m², glycosylated hemoglobin (HbA1c) 7.5%, BP 145/81 mm Hg.) the effect of a fixed perindopril/indapamide combination on major micro- and macrovascular complications was studied in addition to both standard therapy for glycemic control and an intensive glycemic control (IGC) strategy (target HbA1c < 6.5%). At the same time, 83% of patients had arterial hypertension, 32% and 10% had macrovascular and microvascular complications, and 27% had microalbuminuria. Most patients were receiving hypoglycemic therapy at the time of inclusion in the study. As concomitant therapy, patients received hypotensive agents (75%), as well as hypolipidemic agents (28%) and antiplatelet agents (47%).

After a 6-week introductory period during which patients received indapamide/perindopril therapy, they were allocated to the standard glycemic control group or to the IGC group (gliclazide with the possibility of increasing the dose to a maximum of 120 mg/day or the addition of another hypoglycemic agent).

The IGC group (mean duration of follow-up 4.8 years, mean HbA1c 6.5%) compared with the standard control group (mean HbA1c 7.3%) showed a 10% significant reduction in the relative risk of combined incidence of macrovascular and microvascular complications. The benefit was achieved by a significant reduction in the relative risk of: major microvascular complications by 14%, the occurrence and progression of nephropathy by 21%, microalbuminuria by 9%, macroalbuminuria by 30%, and the development of renal complications by 11%. The benefits of hypotensive therapy were independent of the benefits achieved on IGC.

Indapamide in monotherapy has an antihypertensive effect within 24 hours at doses with minimal diuretic effect. Indapamide improves elasticity of large arteries, reduces PPS, reduces congestion. Increasing dose of indapamide does not increase antihypertensive effect, but increases risk of adverse events.

Indapamide has no effect on lipid metabolism (total cholesterol, HDL-C and LDL-C, triglycerides) and carbohydrate metabolism.

Perindopril is effective in the therapy of arterial hypertension of any severity. Antihypertensive effect reaches its maximum 4-6 hours after a single dose and lasts for 24 hours. 24 hours after perindopril administration there is a clear (about 80%) residual ACE inhibition. Perindopril shows antihypertensive effect both in patients with low and normal plasma renin activity.

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

The concomitant use of thiazide diuretics enhances the antihypertensive effect of perindopril.

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

. There is evidence from clinical studies of combination 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, as well as 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 interactions between ACE inhibitors and ARA II classes.

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

There are data from a clinical trial investigating the beneficial effects of adding the direct renin inhibitor drug aliskiren to standard therapy with an ACE inhibitor or ARA II in patients with type 2 diabetes and chronic kidney disease or cardiovascular disease, or with a combination of these conditions. The study was terminated early due to an increased risk of adverse outcomes. Cardiovascular death and stroke occurred more frequently in the group of patients receiving aliskiren compared to the placebo group. Also adverse events and serious adverse events (hyperkalemia, arterial hypotension and renal dysfunction) were reported more frequently in the aliskiren group than in the placebo group.

Pharmacokinetics

The combined use of perindopril and indapamide does not change the pharmacokinetic characteristics of these drugs compared to their separate administration.

Indapamide is rapidly and completely absorbed from the gastrointestinal tract. Maximum plasma concentration (C_max) of indapamide is reached after 1 hour. Binding to plasma proteins is 79%. The elimination half-life (T_1/2) is 14-24 hours (average 18 hours). Repeated administration of indapamide does not lead to its cumulation in the body. It is excreted mainly by the kidneys (70%) and through the intestine (22%) in the form of inactive metabolites.

The pharmacokinetics of indapamide is not altered in patients with renal insufficiency.

Perindopril after oral administration is rapidly absorbed in the gastrointestinal tract (GIT) and reaches maximum plasma concentration (C_max) within 1 hour. Perindopril has no pharmacological activity. Approximately 27% of the total amount of perindopril taken orally enters the bloodstream as the active metabolite perindoprilat. In addition to perindoprilat, 5 other metabolites without pharmacological activity are formed. C_max of perindoprilat is reached after 3-4 hours.

The intake of perindopril with meals is accompanied by a decrease in the conversion of perindopril to perindoprilate, and its bioavailability is correspondingly reduced. Therefore, perindopril should be taken once daily, before meals.

There is a linear dependence of plasma concentration of perindopril on its dose. The volume of distribution of free perindoprilat is 0.2 l/kg. Binding to plasma proteins is insignificant, the binding of perindoprilat, mainly to ACE, is less than 20% and depends on its concentration.

Perindopril is excreted by the kidneys. The “effective” half-life (T_1/2) of the free fraction is about 17 hours, so the equilibrium state is reached within 4 days.

The excretion of perindopril is slower in the elderly and in patients with cardiac and renal insufficiency.

The dialysis clearance of perindopril is 70 ml/min.

In patients with cirrhosis, the “hepatic” clearance of perindopril is reduced by half, while the total amount of perindoprilate produced is not reduced, and no dosing adjustment is required.

Indications

Active ingredient

Composition

1 tablet contains:

acting ingredients:indapamide 0.625 mg/1.25 mg; perindopril tosylate 2.50 mg/5.00 mg, corresponding to perindopril 1.7 mg/3.4 mg;

complementary substances: lactose monohydrate 74.056 mg/148.112 mg; corn starch 2.70 mg/5.40 mg; sodium hydrogen carbonate 0.793 mg/1.586 mg; pregelatinized corn starch 7.20 mg/14.40 mg; Povidone-K30 1.80 mg/3.60 mg; magnesium stearate 0.90 mg/1.80 mg;

coating for tablets 0.625 mg + 2.5 mg; 1.25 mg + 5 mg: Opadray II white 85F18422 (polyvinyl alcohol partially hydrolyzed 1.800 mg/3.600 mg; titanium dioxide (E171) 1.125 mg/2.250 mg; macrogol-3350 (polyethylene glycol-3350) 0.909 mg/1.818 mg; talc 0.666 mg/1.332 mg).

How to take, the dosage

Orally, preferably in the morning, before meals.

Essential hypertension

1 tablet once daily.

If possible, the drug should be started with a single-component dose selection. If clinically necessary, consideration may be given to prescribing combination therapy with the drug immediately after monotherapy.

In patients with arterial hypertension and type 2 diabetes mellitus to reduce the risk of microvascular complications (from the kidneys) and macrovascular complications from cardiovascular disease.

It is recommended to start therapy with the combination indapamide/perindopril at a dose of 0.625 mg/2.5 mg once daily. After 3 months of therapy, if tolerated well, the dose can be increased to 1 tablet at a dose of 1.25 mg/5 mg once daily.

Patient Special Groups

Patients in the elderly

The drug should be started after monitoring renal function and BP.

Renal failure

The drug is contraindicated in patients with severe renal impairment (CKR < 30 ml/min). For patients with moderate renal insufficiency (CKR 30 – 60 ml/min) it is recommended to start therapy with the required doses of drugs (in monotherapy) included in the drug.

Patients with CK equal to or greater than 60 ml/min do not require dose adjustment. Regular monitoring of plasma creatinine and potassium concentrations is required during therapy.

Hepatic insufficiency (see sections “Contraindications”, “Special indications” and “Pharmacokinetics”). The drug is contraindicated in patients with severe hepatic insufficiency. No dose adjustment is required in moderately severe hepatic insufficiency.

Children and adolescents

The drug should not be administered to children and adolescents under 18 years of age due to lack of data on the effectiveness and safety of the drug in patients in this age group.

Interaction

Common for perindopril and indapamide

.Combinations not recommended for use

When lithium drugs and ACE inhibitors are used together, reversible increases in plasma lithium and associated toxic effects have been reported. Co-administration of perindopril and indapamide with lithium preparations is not recommended. Plasma lithium levels should be monitored regularly if such therapy is necessary (see section “Special Precautions”).

Drugs with which combination requires special attention and caution

Baclofen

Augment the antihypertensive effect. BP and renal function should be monitored and, if necessary, doses of antihypertensive drugs should be adjusted.

Non-steroidal anti-inflammatory drugs (NSAIDs), including high doses of acetylsalicylic acid (≥3 g/day)

. When concomitant use of ACE inhibitors and NSAIDs (acetylsalicylic acid in a dose with anti-inflammatory effect, cyclooxygenase-2 inhibitors (COX-2) and non-selective NSAIDs) a decrease in antihypertensive effect may be observed. 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 using 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)

Special Instructions

In common to perindopril and indapamil

. The use of Indapamide/Perindopril-Teva is not associated with a significant decrease in the incidence of side effects, with the exception of hypokalemia, when compared to the use of the individual components of the drug at the lowest authorized doses (see section “Side effects”). At the beginning of therapy with two hypotensive drugs that the patient has not received before, it is impossible to rule out an increased incidence of idiosyncrasy. Close patient monitoring helps to minimize this risk.

Lithium preparations

The combination of perindopril and indapamide with lithium preparations is not recommended (see section “Interaction with other medicinal products”).

Renal dysfunction

The therapy is contraindicated in patients with severe renal dysfunction (CKG less than 30 ml/min). In some patients with arterial hypertension without previous obvious impairment of renal function during the therapy, laboratory signs of functional renal failure may appear. In this case, the treatment should be discontinued. In the future, the combination therapy can be resumed using low doses of drugs, or only one of the drugs can be used. Such patients require regular monitoring of potassium and creatinine blood concentrations – 2 weeks after the start of therapy and then every 2 months during the period when the dose of drug is adjusted. Renal failure occurs more frequently in patients with severe heart failure or initial renal insufficiency, including renal artery stenosis.

The drug Indapamide/Perindopril-Teva is not recommended for use in cases of bilateral renal artery stenosis or in cases of a single functioning kidney.

Hypotension and water-electrolyte imbalance

In case of initial hyponatremia, there is a risk of sudden development of arterial hypotension, particularly in patients with renal artery stenosis. Therefore, systematic evaluation of symptoms of dehydration and decreased plasma electrolytes, such as after diarrhea or vomiting, is necessary. These patients need regular monitoring of plasma electrolytes.

In severe arterial hypotension, intravenous administration of isotonic saline solution may be required.

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

Potassium

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

Excipients

. The medicinal product Indapamide/Perindopril-Teva contains the excipient lactose monohydrate and is contraindicated in patients with hereditary galactose intolerance, lactase deficiency and glucose-galactose malabsorption.

Sodium content

The drug Indapamide/Perindopril-Teva contains less than 1 mmol of sodium (less than 23 mg) per tablet, which means it is virtually “sodium-free.”

Children

The drug Indapamide/Perindopril-Teva is contraindicated in children and adolescents under 18 years of age due to the lack of data on the efficacy and safety of perindopril and indapamide, both separately and together, in patients in this age group.

Indapamide

Hepatic encephalopathy

. In patients with hepatic impairment, administration of thiazide and thiazide-like diuretics may lead to hepatic encephalopathy. In this situation, the diuretic should be stopped immediately.

Photosensitivity

Photosensitivity reactions have been reported with thiazide and thiazide-like diuretics (see section “Adverse effects”). In case of photosensitivity reactions during the drug administration, the 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.

Water-electrolyte balance

Plasma sodium ion concentration

. The concentration of sodium ions in blood plasma should be determined before starting treatment, and then regularly monitored against the background of the drug. Decrease in concentration of sodium ions at the initial stage may not be accompanied by clinical symptoms, therefore regular laboratory control is necessary. More frequent monitoring of sodium ions content is indicated in patients with liver cirrhosis and elderly patients (see sections “Side effects” and “Overdose”). Treatment with any diuretics may cause hyponatremia, sometimes with very serious consequences. Hyponatremia accompanied by hypovolemia may lead to dehydration and orthostatic hypotension. Concomitant reduction of chlorine ions may lead to secondary compensatory metabolic alkalosis: the frequency of its occurrence and degree of severity are insignificant.

Potassium ion concentration in plasma

Decreased potassium concentration with hypokalemia is a major risk associated with therapy with thiazide and thiazide-like diuretics.

Potassium ion concentrations (less than 3.4 mmol/l) should be prevented in the following high-risk patient categories: elderly patients and/or emaciated patients receiving or not receiving combined drug therapy, patients with cirrhosis with edema and ascites, coronary heart disease, heart failure. Hypokalemia in these patients increases the toxic effects of cardiac glycosides and increases the risk of rhythm disturbances.

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

Hypokalemia, like bradycardia, contributes to severe heart rhythm disturbances, especially pirouette-type polymorphic ventricular tachycardia, 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.

Concentration of plasma calcium ions

Thiazide and thiazide-like diuretics may decrease renal excretion of calcium ions, resulting in a slight and temporary increase in plasma calcium concentration. A marked increase in calcium ion concentration may be associated with undiagnosed hyperparathyroidism. Before the study of parathyroid gland function, diuretics should be cancelled.

Blood glucose concentrations

Blood glucose concentrations should be monitored in patients with diabetes, especially when potassium ion concentrations are low.

Ureic acid

Patients with elevated plasma concentrations of uric acid tend to have an increased incidence of gout attacks.

Diuretics and renal function

Thiazide and thiazide-like diuretics are fully effective only in patients with normal or mildly impaired renal function (creatinine concentration in adult patients 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 xplasma creatinine concentration,

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

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

At the start of diuretic treatment, patients may experience a transient 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 has no adverse effects on patients with baseline normal renal function, but may exacerbate pre-existing renal impairment.

Athletes

Athletes should note that the drug contains an active ingredient that may give a positive result in a doping test.

Acute myopia and secondary closed angle glaucoma

Sulfonamides and their derivatives may cause an idiosyncrasic reaction leading to temporary myopia and acute closed angle glaucoma. Without proper therapy, acute closed-angle 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 can lead to the development of acute closed angle glaucoma include allergy to sulfonamide or penicillin.

Perindopril

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

. There is evidence of an increased risk of arterial hypotension, hyperkalemia, and decreased renal function (including acute renal failure) when ACE inhibitors are coadministered with ARA II or aliskiren. Therefore, dual blockade of the RAAS by combining an ACE inhibitor with ARA II or aliskiren is not recommended (see sections “Pharmacodynamics”, “Interaction with other medicinal products”). If dual blockade is absolutely necessary, it should be performed under the strict supervision of a specialist 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 (see sections Contraindications and Interaction with other drugs).

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

The combined use of perindopril and potassium-saving diuretics as well as potassium preparations, potassium-containing salt substitutes and dietary supplements is not recommended (see “Interaction with other medicinal products”). see section “Interaction with other medicinal products”).

Neutropenia/agranulocytosis/thrombocytopenia/anemia

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 against the background of systemic connective tissue diseases, as well as against the background of 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 about any signs of infectious diseases (e.g., sore throat, fever) (see sections “Side effects” and “Interaction with other medicinal products”).

Anemia may develop in patients after kidney transplantation or in patients on hemodialysis. The greater the decrease in hemoglobin, the higher the initial hemoglobin level. 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 of treatment, then it remains stable and completely recovers after discontinuation of the drug. Treatment may be continued in these patients, but hematologic tests should be performed regularly.

Renovascular Hypertension

In patients with bilateral renal artery stenosis or artery stenosis of the only functioning kidney, the risk of hypotension and renal failure increases with ACE inhibitor use (see section “Contraindications”). Taking diuretics may be an additional risk factor (see section “Contraindications”). Deterioration of renal function may be observed even with minor changes in serum creatinine concentration, even in patients with unilateral renal artery stenosis.

The method of treatment of renovascular hypertension is revascularization. However, ACE inhibitors may be beneficial in this category of patients, whether awaiting surgery or where surgery is not feasible.

If therapy with indapamide/perindopril combination is indicated for patients with established or suspected renal artery stenosis, it should be started at a low dose in a hospital setting with monitoring of renal function and potassium levels, as some patients have developed functional renal failure which resolved with withdrawal.

Ensensitivity/angioneurotic edema

In rare cases, angioedema of the face, extremities, lips, tongue, vocal folds and/or larynx may occur when taking ACE inhibitors, including perindopril (see section “Side effects”). See section “Side effects”). This may occur at any time during therapy. If symptoms occur, perindopril should be discontinued immediately and the patient should be observed until the signs of edema have completely disappeared. If only the face and lips are affected, the swelling usually resolves on its own, and antihistamines may be used as a symptomatic treatment.

Synopsis

Contraindications

– Hypersensitivity to the active substances, other ACE inhibitors, sulfonamide derivatives, excipients included in the drug (see section “Composition”).

– History of angioedema (Quincke’s edema) with other ACE inhibitors (see section “Special Indications”).

– Hereditary/idiopathic angioedema.

– Pregnancy and breastfeeding (see section “Administration during pregnancy and breastfeeding”).

– Concomitant use with aliskiren and drugs containing aliskiren in patients with diabetes mellitus and/or moderate to severe renal function impairment (glomerular filtration rate (GFR) less than 60 ml/min/1.73 m2 body surface area) (see. Pharmacodynamics” and “Interaction with other medicinal products”).

– Concomitant use with ARA II in patients with diabetic nephropathy (see section “Special Precautions”).

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

– Severe renal failure (creatinine clearance (CK) less than 30 ml/min).

– Hepatic encephalopathy.

– Hypokalemia.

– Severe hepatic insufficiency.

– Concomitant use with non-antiarrhythmic drugs that can cause pirouette-type polymorphic ventricular tachycardia (see section “Interaction with other medicinal products”).

– Severe bilateral stenosis of the renal arteries or stenosis of the artery of the only functioning kidney.

– Due to lack of sufficient clinical experience, the drug Indapamide/Perindopril-Teva should not be used in patients on hemodialysis and in patients with untreated decompensated heart failure.

– Presence of lactase deficiency, galactosemia or glucose-galactose malabsorption syndrome (the drug contains lactose).

– Concomitant use with neutral endopeptidase inhibitors (e.g., with drugs containing Sacubitril) due to the high risk of angioedema.

With caution

Systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma); immunosuppressant therapy (risk of neutropenia, agranulocytosis); concomitant therapy with lithium drugs; gold drugs, nonsteroidal anti-inflammatory drugs (NSAIDs), baclofen, corticosteroids; drugs that may cause QT interval prolongation, drugs that may cause pirouette-type polymorphic ventricular tachycardia, except non-antiarrhythmic medications (see section “Contraindications”); bone marrow hematopoiesis inhibition; decreased circulating blood volume (taking diuretics, salt-free diet, vomiting, diarrhea, hemodialysis); angina pectoris; cerebrovascular diseases; renovascular hypertension; diabetes mellitus; chronic heart failure (functional class IV according to NYHA classification); liver failure; hyperuricemia (especially accompanied with gout and urate nephrolithiasis); labile BP; advanced age; hemodialysis with high-flow membranes or desensitization, before LDL apheresis procedure; condition after kidney transplantation; anesthesia; aortic valve stenosis/hypertensive 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 preparations or in patients with increased plasma potassium content; hyperkalemia; hyponatremia; history of severe allergic diseases.

Side effects

The frequency of adverse reactions that may occur during therapy is given as the following gradation: Very common (≥1/10); common (≥1/100, but < 1/10); infrequent (≥1/1000, but < 1/100); rare (≥1/10000, but < 1/1000); very rare (< 1/10000); unknown frequency (frequency of development cannot be calculated from available data).

MedDRA

classes and organ systems

Side effects

Frequency

Reactions of hypersensitivity (mostly dermatological reactions, in patients with predisposition to allergic and bronchoobstructive reactions)

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Often

–

Metabolic and nutritional disorders

Hypoglycemia

(see “Special Indications”).

–

Infrequent*

Hyperkalemia, reversible when the drug is discontinued (see Special Indications)

–

Infrequent*

Hyponatremia

(see “Special Indications. Special Indications)

Frequency unknown

Infrequent*

Hypercalcemia

Very rare

–

Decreased potassium and hypokalemia, especially significant in patients at risk (see “Special Indications. Special Indications)

Frequency unknown

–

Psychiatric disorders

Mood lability

–

Infrequent

Sleep disturbance

–

Infrequent

Confusion

–

Very rarely

Nervous system disorders

Dizziness

–

Often

Headache

Rarely

Often

Parasthesias

Rarely

Often

Dysgeusia

–

often

Overdose

Symptoms:A marked decrease in BP, nausea, vomiting, muscle cramps, dizziness, drowsiness, confusion, oliguria turning into anuria (reduction of the BOD), violation of the water-electrolyte balance (hypokalemia, hyponatremia).

Treatment:Gastric lavage and/or use of activated charcoal, restoration of water-electrolyte balance. If there is a significant decrease in BP, the patient should be transferred to the “lying” position with elevated legs, if necessary, measures to replenish the blood circulation (e.g., intravenous (IV) injection of 0.9% sodium chloride solution) should be taken. Perindoprilat can be removed from the body by dialysis.

Pregnancy use

Pregnancy

The use of Indapamide/Perindopril-Teva is contraindicated in pregnancy.

The significance of therapy for the mother must be evaluated and a decision must be made whether to stop breastfeeding or to discontinue the drug.

Indapamide

There are no or limited data on the use of indapamide in pregnant women (less than 300 cases). Prolonged use of thiazide diuretics in the third trimester of pregnancy may cause hypovolemia in the mother and decreased uteroplacental blood flow, resulting in fetoplacental ischemia and delayed fetal development.

Animal studies have shown no direct or indirect toxic effects on reproduction.

In rare cases, hypoglycemia and thrombocytopenia have developed in newborns when taking diuretics shortly before delivery.

If the patient received Indapamide/Perindopril-Teva during the second or third trimester of pregnancy, an ultrasound examination of the newborn is recommended to evaluate the skull and renal function.

As a precautionary measure, it is recommended to avoid the use of indapamide during pregnancy.

Perindopril

There have been no relevant controlled studies on the use of ACE inhibitors in pregnant women. There is currently no conclusive epidemiologic data on teratogenic risk when taking ACE inhibitors in the first trimester of pregnancy, but some increased risk of fetal abnormalities cannot be excluded. If pregnancy is planned, the drug should be discontinued and other hypotensive agents approved for use in pregnancy should be prescribed. If pregnancy is detected, therapy with ACE inhibitors should be stopped immediately and other therapy should be prescribed if necessary.

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

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

In newborns whose mothers received therapy with ACE inhibitors may have arterial hypotension, and therefore, newborns should be closely monitored medically.

Breastfeeding period

Indapamide/Perindopril-Teva is contraindicated during breastfeeding.

Indapamide

There is currently no reliable information about excretion of indapamide or its metabolites with breast milk. The newborn may develop hypersensitivity to sulfonamide derivatives and hypokalemia.

Risk to newborns/infants cannot be ruled out.

Indapamide is similar in structure to thiazide diuretics, administration of which causes reduction of breast milk or suppression of lactation.

Indapamide is contraindicated during breastfeeding.

Perindopril

At this time, it is not known whether perindopril is excreted into breast milk. Because of the lack of information regarding the use of perindopril during breastfeeding, its use is not recommended; other drugs with a better studied safety profile are preferable, especially when feeding newborns and premature infants.

Fertility

General information for perindopril and indapamide

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Reproductive toxicity studies have shown no effect on fertility in rats of either sex. There is presumably no effect on fertility in humans.

Similarities