Perindopril-Indapamide Richter (Tablets) Instructions for Use

Marketing Authorization Holder

Gedeon Richter, Plc. (Hungary)

Manufactured By

Gedeon Richter Poland, Co. Ltd. (Poland)

ATC Code

C09BA04 (Perindopril and diuretics)

Active Substances

Indapamide (Rec.INN registered by WHO)

Perindopril (Rec.INN registered by WHO)

Dosage Forms

	Perindopril-Indapamide Richter	Tablets 0.625 mg+2 mg: 30 pcs.
		Tablets 1.25 mg+4 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Tablets white, round, flat-cylindrical with a bevel; engraved with “C63” on one side.

Excipients: microcrystalline cellulose (type 102), lactose monohydrate 200 mesh, lactose monohydrate 80 mesh, colloidal silicon dioxide, magnesium stearate.

10 pcs. – double-sided aluminum blisters (3) – cardboard packs.

Tablets white, round, flat-cylindrical with a bevel; engraved with “C64” on one side.

Excipients: microcrystalline cellulose (type 102), lactose monohydrate 200 mesh, lactose monohydrate 80 mesh, colloidal silicon dioxide, magnesium stearate.

10 pcs. – double-sided aluminum blisters (3) – cardboard packs.

Clinical-Pharmacological Group

Antihypertensive drug

Pharmacotherapeutic Group

Antihypertensive agent, combination (diuretic + ACE inhibitor)

Pharmacological Action

Perindopril-Indapamide Richter is a combined preparation containing perindopril erbumine and Indapamide. The pharmacological properties of Perindopril-Indapamide Richter combine the individual properties of each of the components.

Mechanism of action of the preparation

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

Perindopril

Perindopril is an inhibitor of the enzyme that converts angiotensin I to angiotensin II (ACE inhibitor). ACE, or kininase II, is an exopeptidase that both converts angiotensin I to the vasoconstrictor angiotensin II and degrades bradykinin, which has vasodilatory action, to an inactive heptapeptide.

As a result, Perindopril:

• Reduces aldosterone secretion;
• Increases plasma renin activity by negative feedback;
• With long-term use, reduces total peripheral resistance, which is mainly due to its effect on blood vessels in muscles and kidneys. These effects are not accompanied by sodium and fluid retention or the development of reflex tachycardia.

Perindopril normalizes myocardial function by reducing preload and afterload.

When studying hemodynamic parameters in patients with chronic heart failure (CHF), the following was revealed:

• Decrease in filling pressure in the left and right ventricles of the heart;
• Decrease in total peripheral resistance;
• Increase in cardiac output;
• Enhancement of muscular peripheral blood flow.

Indapamide

Indapamide belongs to the sulfonamide group and is pharmacologically close to thiazide diuretics. Indapamide inhibits the reabsorption of sodium ions in the cortical segment of the loop of Henle, which leads to increased renal excretion of sodium and chloride ions and, to a lesser extent, potassium and magnesium ions, thereby enhancing diuresis and reducing blood pressure.

Antihypertensive action

The preparation Perindopril-Indapamide Richter has a dose-dependent antihypertensive effect on both diastolic and systolic blood pressure, both in the “standing” and “lying” positions. The antihypertensive effect persists for 24 hours. A stable therapeutic effect develops in less than 1 month from the start of therapy and is not accompanied by tachyphylaxis. Discontinuation of treatment does not cause a “withdrawal” syndrome.

The preparation Perindopril-Indapamide Richter reduces the degree of left ventricular hypertrophy, improves arterial elasticity, reduces total peripheral resistance, and does not affect lipid metabolism (total cholesterol, HDL and LDL cholesterol, triglycerides).

The effect of using the combination of perindopril and indapamide on left ventricular hypertrophy compared to enalapril has been proven. In patients with arterial hypertension and left ventricular hypertrophy receiving therapy with perindopril erbumine 2 mg/indapamide 0.625 mg or enalapril at a dose of 10 mg once daily, and with an increase in the dose of perindopril erbumine to 8 mg and indapamide to 2.5 mg, or enalapril to 40 mg once daily, a more significant reduction in the left ventricular myocardial mass index (LVMMI) was noted in the Perindopril/Indapamide group compared to the enalapril group. The most significant effect on LVMMI was noted with the use of perindopril erbumine 8 mg/indapamide 2.5 mg.

A more pronounced antihypertensive effect was also noted with combination therapy with perindopril and indapamide compared to enalapril.

Perindopril

Perindopril is effective for the treatment of arterial hypertension of any severity.

The antihypertensive effect of the preparation reaches its maximum 4-6 hours after a single oral dose and persists for 24 hours. 24 hours after taking the preparation, a pronounced residual inhibition of ACE (about 80%) is observed.

Perindopril has an antihypertensive effect in patients with both low and normal plasma renin activity.

Concomitant administration of thiazide diuretics enhances the severity of the antihypertensive effect. In addition, the combination of an ACE inhibitor and a thiazide diuretic also leads to a reduction in the risk of hypokalemia during diuretic therapy.

Dual blockade of the RAAS

There is data from clinical studies on combination therapy using an ACE inhibitor with an angiotensin II receptor antagonist (AIIRA).

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

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

Given the similar intragroup pharmacodynamic properties of ACE inhibitors and AIIRAs, these results can be expected for the interaction of any other drugs, representatives of the classes of ACE inhibitors and AIIRAs.

Therefore, ACE inhibitors and AIIRAs should not be used simultaneously in patients with diabetic nephropathy. There is data from a clinical study on the effect of adding aliskiren to standard therapy with an ACE inhibitor or AIIRA in patients with type 2 diabetes mellitus and chronic kidney disease or cardiovascular disease, or a combination of these conditions. The study was terminated prematurely 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.

Indapamide

The antihypertensive effect is manifested when the preparation is used in doses that have a minimal diuretic effect.

The antihypertensive effect of indapamide is associated with an improvement in the elastic properties of large arteries and a decrease in total peripheral resistance.

Indapamide reduces left ventricular hypertrophy, does not affect plasma lipid concentrations (triglycerides, total cholesterol, LDL, HDL), carbohydrate metabolism (including in patients with concomitant diabetes mellitus).

Pharmacokinetics

The combination of perindopril and indapamide does not change their pharmacokinetic characteristics compared to the separate administration of these preparations.

Perindopril

Absorption, distribution, metabolism

When taken orally, Perindopril is rapidly absorbed. Bioavailability is 65-70%.

Approximately 20% of the total amount of absorbed perindopril is converted to perindoprilat, the active metabolite. Taking the preparation with food is accompanied by a reduction in the metabolism of perindopril to perindoprilat (this effect has no significant clinical significance).

C_max of perindoprilat in plasma is reached 3-4 hours after oral administration.

Binding to plasma proteins is less than 30% and depends on the concentration of perindopril in plasma.

The dissociation of perindoprilat bound to ACE is slow. As a result, the “effective” T_1/2 is 25 hours. Repeated administration of perindopril does not lead to its accumulation, and the T_1/2 of perindoprilat upon repeated administration corresponds to its period of activity, thus, a steady state is reached after 4 days.

Perindopril crosses the placenta.

Excretion

Perindoprilat is excreted from the body by the kidneys. The T_1/2 of the metabolite is 3-5 hours.

Pharmacokinetics in special clinical cases

The excretion of perindoprilat is slowed in the elderly, as well as in patients with heart and renal failure.

The dialysis clearance of perindoprilat is 70 ml/min.

The pharmacokinetics of perindopril are altered in patients with liver cirrhosis: its hepatic clearance is reduced by half. However, the amount of perindoprilat formed does not decrease, so no dose adjustment of the preparation is required.

Indapamide

Absorption and distribution

Indapamide is rapidly and completely absorbed from the gastrointestinal tract. C_max of the preparation in plasma is observed 1 hour after oral administration.

Binding to plasma proteins is 79%.

Metabolism and excretion

T_1/2 is 14-24 hours (average 19 hours). Repeated administration of the preparation does not lead to its accumulation in the body. It is excreted mainly by the kidneys (70% of the administered dose) and through the intestines (22%) in the form of inactive metabolites.

The pharmacokinetics of the preparation do not change in patients with renal failure.

Indications

• Essential arterial hypertension.

ICD codes

Dosage Regimen

Orally, preferably in the morning, before meals, 1 tablet of Perindopril-Indapamide Richter once daily.

Arterial hypertension

The dose of the preparation is selected individually for each patient, depending on the patient’s condition and individual response to treatment.

Administration of the preparation begins with the selection of doses of single-component preparations. If clinically necessary, the possibility of prescribing combination therapy with Perindopril-Indapamide Richter immediately after monotherapy can be considered.

Elderly patients

It is recommended to start therapy with a dosage of 0.625 mg + 2 mg once daily.

Renal insufficiency

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

For patients with moderate renal insufficiency (creatinine clearance 30-60 ml/min), it is recommended to start therapy with the necessary doses of single-component preparations. The maximum recommended dose of Perindopril-Indapamide Richter is 0.625 mg+2 mg once daily.

For patients with creatinine clearance equal to or greater than 60 ml/min, no dose adjustment is required, provided that plasma creatinine and potassium levels are regularly monitored.

Hepatic insufficiency

The preparation is contraindicated in patients with severe hepatic insufficiency. In moderate hepatic insufficiency, no dose adjustment is required.

Children and adolescents

Perindopril-Indapamide Richter should not be prescribed to children and adolescents under 18 years of age due to the lack of data on efficacy and safety in patients of this age group.

Adverse Reactions

Perindopril has an inhibitory effect on the RAAS and reduces the renal excretion of potassium ions during indapamide administration. Hypokalemia (potassium level less than 3.4 mmol/l) develops in 2% of patients during the use of Perindopril-Indapamide Richter.

The frequency of adverse reactions that may occur during therapy is presented using the following gradation: common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10,000); frequency unknown (frequency cannot be calculated from available data).

From the hematopoietic system very rare – thrombocytopenia, leukopenia/neutropenia, agranulocytosis, aplastic anemia, hemolytic anemia. Anemia: in certain clinical situations (patients after kidney transplantation, patients on hemodialysis) ACE inhibitors can cause anemia.

From the nervous system common – paresthesia, headache, dizziness, asthenia, vertigo; uncommon – sleep disorder, mood lability; very rare – confusion; frequency unknown – syncope.

From the organ of vision common – visual impairment.

From the organ of hearing common – tinnitus.

From the cardiovascular system common – pronounced decrease in blood pressure, including orthostatic hypotension; very rare – cardiac arrhythmias, incl. bradycardia, ventricular tachycardia, atrial fibrillation, as well as angina pectoris and myocardial infarction, possibly due to excessive blood pressure reduction in high-risk patients; frequency unknown – polymorphic ventricular tachycardia of the “torsades de pointes” type (possibly fatal).

From the respiratory system common – during the use of ACE inhibitors, a dry cough may occur (persisting for a long time during the use of preparations of this group and disappearing after their discontinuation), dyspnea; uncommon – bronchospasm; very rare – eosinophilic pneumonia, rhinitis.

From the digestive system common – dry oral mucosa, nausea, vomiting, abdominal pain, epigastric pain, taste perversion, decreased appetite, dyspepsia, constipation, diarrhea; very rare – intestinal angioedema, cholestatic jaundice, pancreatitis, cytolytic or cholestatic hepatitis; frequency unknown – hepatic encephalopathy in patients with hepatic insufficiency.

From the skin and subcutaneous tissues common – skin rash, pruritus, maculopapular rash; uncommon – angioedema of the face, lips, extremities, tongue mucosa, vocal folds and/or larynx, urticaria, hypersensitivity reactions in patients predisposed to bronchospastic and allergic reactions, purpura; in patients with acute systemic lupus erythematosus, worsening of the disease is possible; very rare – erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome; cases of photosensitivity reactions have been noted.

From the musculoskeletal system and connective tissue common – muscle cramps.

From the urinary system uncommon – renal failure; very rare – acute renal failure.

From the reproductive system uncommon – impotence.

General reactions common – asthenia; uncommon – increased sweating.

Laboratory parameters rare – hypercalcemia; frequency unknown – prolongation of the QT interval on ECG; increase in plasma uric acid and glucose levels; increased activity of liver enzymes; hypokalemia, especially significant for patients at risk; hyponatremia and hypovolemia leading to dehydration and orthostatic hypotension. Simultaneous hypochloremia can lead to compensatory metabolic alkalosis (the likelihood and severity of this effect is low); hyperkalemia, often transient; a slight increase in the concentration of creatinine in urine and plasma, which resolves after discontinuation of therapy, more often in patients with renal artery stenosis, during the treatment of arterial hypertension with diuretics and in case of renal failure.

Contraindications

• Hypersensitivity to perindopril or other ACE inhibitors, indapamide and other sulfonamide derivatives, other components of the preparation;
• History of angioedema (including while taking other ACE inhibitors);
• Hereditary/idiopathic angioedema;
• Severe renal failure (creatinine clearance less than 30 ml/min);
• Bilateral renal artery stenosis or presence of a single functioning kidney;
• Hepatic encephalopathy;
• Severe hepatic failure;
• Hypokalemia;
• Concomitant use of preparations that prolong the QT interval;
• Concomitant use of preparations that can cause polymorphic ventricular tachycardia of the “torsades de pointes” type;
• Concomitant use with preparations containing aliskiren in patients with diabetes mellitus or renal impairment (GFR) less than 60 ml/min/1.73 m²);
• The preparation contains lactose monohydrate. Perindopril-Indapamide Richter is contraindicated in lactase deficiency, galactosemia or glucose-galactose malabsorption syndrome;
• Pregnancy;
• Breastfeeding period;
• Age under 18 years.

Due to insufficient clinical experience, Perindopril-Indapamide Richter should not be used:

• In patients on hemodialysis;
• In patients with untreated decompensated heart failure.

With caution

Aortic valve stenosis/hypertrophic obstructive cardiomyopathy; renovascular hypertension, hyponatremia (increased risk of arterial hypotension in patients who are on a salt-free diet or a diet with reduced sodium content); hypovolemia (including diarrhea, vomiting); systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma); therapy with immunosuppressants (risk of neutropenia, agranulocytosis); diabetes mellitus, gout, bone marrow depression, hyperuricemia (especially accompanied by gout and urate nephrolithiasis), hyperkalemia, angina pectoris, cerebrovascular diseases (including cerebral circulatory insufficiency), chronic heart failure (NYHA functional class IV), hepatic insufficiency, old age, labile blood pressure, representatives of the black race (reduced efficacy), athletes (possible positive reaction in doping control), hemodialysis using high-flux membranes or desensitization before LDL apheresis procedure, condition after kidney transplantation, therapy with lithium preparations, anesthesia.

Use in Pregnancy and Lactation

The drug is contraindicated during pregnancy.

Perindopril-Indapamide Richter is contraindicated during lactation. The significance of therapy for the mother should be assessed and a decision should be made to discontinue breastfeeding or to discontinue the drug.

Pregnancy

Perindopril

Appropriate controlled studies on the use of ACE inhibitors in pregnant women have not been conducted. The available limited data on the effects of ACE inhibitors in the first trimester of pregnancy indicate that the use of ACE inhibitors did not lead to fetal malformations associated with fetotoxicity, but the fetotoxic effect of the drug cannot be completely ruled out.

When planning a pregnancy or if pregnancy occurs while taking Perindopril-Indapamide Richter, the drug should be discontinued immediately and another antihypertensive therapy approved for use during pregnancy should be prescribed.

It is known that exposure to ACE inhibitors on the fetus in the second and third trimesters of pregnancy can lead to impaired development (decreased renal function, oligohydramnios, delayed skull bone ossification) and the 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, it is recommended to perform a fetal ultrasound to assess the skull and renal function.

Newborns whose mothers received ACE inhibitor therapy may experience arterial hypotension, therefore newborns should be under close medical supervision.

Indapamide

Long-term use of thiazide diuretics in the third trimester of pregnancy can cause hypovolemia in the mother and a decrease in uteroplacental blood flow, leading to fetoplacental ischemia and fetal growth retardation. In rare cases, hypoglycemia and thrombocytopenia have been observed in newborns following the use of diuretics shortly before delivery.

Lactation period (breastfeeding)

Perindopril-Indapamide Richter is contraindicated during lactation.

Perindopril

It is not known whether Perindopril passes into breast milk. Due to the lack of information regarding the use of perindopril during breastfeeding, its use is not recommended; it is preferable to use other drugs with a more established safety profile, especially when feeding newborns and premature infants.

Indapamide

Indapamide passes into breast milk. The use of thiazide diuretics causes a decrease in the amount of breast milk or suppression of lactation. The newborn may develop increased sensitivity to sulfonamide derivatives, hypokalemia, and “nuclear” jaundice.

Use in Hepatic Impairment

In severe liver dysfunction, treatment with this drug is contraindicated.

In moderate hepatic insufficiency, dose adjustment is not required.

Use in Renal Impairment

In severe renal failure (creatinine clearance less than 30 ml/min), treatment with Perindopril-Indapamide Richter is contraindicated. In moderate renal failure (creatinine clearance 30-60 ml/min), it is recommended to start therapy with the combination drug depending on blood pressure. For patients with creatinine clearance greater than 60 ml/min, no dose adjustment is required with regular monitoring of creatinine and potassium levels.

Pediatric Use

Perindopril-Indapamide Richter should not be taken by children and adolescents because the efficacy and safety of perindopril and indapamide in this age group, both separately and in combination with other active substances, have not been studied.

Geriatric Use

Treatment in elderly patients should be initiated taking into account the decrease in blood pressure and renal function.

Special Precautions

Perindopril-Indapamide Richter

The use of Perindopril-Indapamide Richter is not accompanied by a significant reduction in the frequency of side effects, with the exception of hypokalemia, compared with perindopril and indapamide prescribed in the minimum necessary doses. At the start of therapy with two antihypertensive drugs that the patient has not previously received, an increased risk of idiosyncrasy cannot be excluded. Careful monitoring of the patient allows minimizing this risk.

Renal impairment

Therapy is contraindicated in patients with severe renal failure (creatinine clearance less than 30 ml/min). In some patients with arterial hypertension without prior apparent renal impairment, laboratory signs of functional renal failure may appear during therapy. In this case, treatment should be discontinued. Subsequently, combination therapy can be resumed using low doses of the drugs, or only one of the drugs can be used. Such patients require regular monitoring of serum potassium and creatinine levels – 2 weeks after the start of therapy and every 2 months thereafter. Renal failure occurs more often in patients with severe chronic heart failure or pre-existing renal impairment, including renal artery stenosis.

Arterial hypotension and water-electrolyte imbalance

In case of pre-existing hyponatremia, there is a risk of sudden development of arterial hypotension, especially in patients with renal artery stenosis. Therefore, during dynamic observation of patients, attention should be paid to possible symptoms of dehydration and decreased plasma electrolyte levels, for example, after diarrhea or vomiting. Such patients require regular monitoring of plasma electrolyte levels.

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 continuing therapy. After restoration of circulating blood volume and blood pressure, therapy can be resumed using low doses of the drugs, or only one of the drugs can be used.

Potassium content

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

Excipients

It should be taken into account that the excipients of the drug include lactose monohydrate. Perindopril-Indapamide Richter should not be prescribed to patients with hereditary galactose intolerance, lactase deficiency, and glucose-galactose malabsorption.

Lithium preparations

Concomitant use of the combination of perindopril and indapamide with lithium preparations is not recommended.

Children and adolescents

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

Perindopril

Dual blockade of the RAAS

There is evidence of an increased risk of arterial hypotension, hyperkalemia, and renal impairment (including acute renal failure) with the simultaneous use of ACE inhibitors with ARBs or aliskiren. Therefore, dual blockade of the RAAS by combining an ACE inhibitor with an ARB or aliskiren is not recommended. If dual blockade is necessary, it should be performed under strict specialist supervision with regular monitoring of renal function, plasma potassium levels, and blood pressure. ACE inhibitors should not be used simultaneously with ARBs in patients with diabetic nephropathy.

Potassium-sparing diuretics, potassium preparations, potassium-containing salt substitutes and dietary supplements

Simultaneous administration of perindopril and potassium-sparing diuretics, as well as potassium preparations, potassium-containing salt substitutes and dietary supplements, is not recommended.

Neutropenia/agranulocytosis/thrombocytopenia/anemia

There are reports of the development of neutropenia/agranulocytosis, thrombocytopenia and anemia during the use of ACE inhibitors. In patients with normal renal function and no concomitant risk factors, neutropenia occurs rarely. Perindopril should be used with particular caution in the context of systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma), as well as during the use of immunosuppressants, allopurinol or procainamide, or a combination of these factors, especially in patients with pre-existing impaired renal function.

Some of these patients developed severe infections, in some cases resistant to intensive antibiotic therapy. When prescribing perindopril to such patients, it is recommended to periodically monitor the white blood cell count. Patients should report any signs of infectious diseases (e.g., sore throat, fever) to their doctor.

Hypersensitivity/angioedema

When taking ACE inhibitors, including perindopril, in rare cases, the development of angioedema of the face, extremities, lips, tongue, vocal folds and/or larynx may be observed. This can occur at any time during treatment. If symptoms appear, the drug should be discontinued immediately and the patient should be observed until the signs of edema completely disappear. If the edema affects only the face and lips, it usually resolves on its own, although antihistamines may be used as symptomatic therapy. Angioedema accompanied by laryngeal edema can be fatal. Swelling of the tongue, vocal folds, or larynx can lead to airway obstruction. If such symptoms appear, appropriate therapy should be started immediately, for example, subcutaneous administration of epinephrine (adrenaline) in a dilution of 1:1000 (0.3-0.5 ml) and/or ensuring airway patency.

A higher risk of developing angioedema has been reported in patients of the Black race.

Patients with a history of angioedema not associated with ACE inhibitor use may have an increased risk of its development when taking drugs of this group. In rare cases, intestinal angioedema develops during therapy with ACE inhibitors. In this case, patients experienced abdominal pain as an isolated symptom or in combination with nausea and vomiting, in some cases without preceding facial angioedema and with normal C1-esterase levels. The diagnosis was established using computed tomography of the abdomen, ultrasound, or at the time of surgery. Symptoms resolved after discontinuation of ACE inhibitors. Therefore, in patients with abdominal pain receiving ACE inhibitors, the possibility of intestinal angioedema should be considered in the differential diagnosis.

mTOR inhibitors (sirolimus, everolimus, temsirolimus). The risk of developing angioedema (swelling of the airways or tongue with or without respiratory distress) is increased in patients taking mTOR inhibitors.

Racecadotril. ACE inhibitors can cause angioedema. The risk of angioedema may increase with simultaneous use with racecadotril (used for acute diarrhea).

Anaphylactoid reactions during desensitization

There are isolated reports of the development of prolonged, life-threatening anaphylactoid reactions in patients receiving ACE inhibitors during desensitizing therapy with hymenoptera venom (bees, wasps). ACE inhibitors should be used with caution in patients prone to allergic reactions undergoing desensitization procedures. The prescription of an ACE inhibitor should be avoided in patients receiving immunotherapy with hymenoptera venom. However, an anaphylactoid reaction can be avoided by temporarily discontinuing the ACE inhibitor at least 24 hours before the procedure.

Anaphylactoid reactions during LDL apheresis

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

Hemodialysis

Anaphylactoid reactions have been observed in patients receiving ACE inhibitors during hemodialysis using high-flux membranes (e.g., AN69^®). Therefore, it is advisable to use a different type of membrane or use an antihypertensive agent of another pharmacotherapeutic group.

Cough

During therapy with an ACE inhibitor, a dry persistent cough may be noted, which disappears after discontinuation of the drug. If a patient develops a dry cough, the possible iatrogenic nature of this symptom should be remembered. If the attending physician believes that ACE inhibitor therapy is necessary for the patient, it is possible to continue taking the drug.

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

In some pathological conditions, significant activation of the RAAS may be noted, especially in severe hypovolemia and decreased plasma electrolyte levels (against the background of a salt-free diet or long-term use of diuretics), in patients with initially low blood pressure, renal artery stenosis, chronic heart failure or liver cirrhosis with edema and ascites. The use of an ACE inhibitor causes blockade of this system and therefore may be accompanied by a sharp decrease in blood pressure and/or an 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 or during the first two weeks of therapy. Sometimes these conditions develop acutely at other times of therapy. In such cases, when resuming therapy, it is recommended to use the drug at a lower dose and then gradually increase it.

Elderly age

Before starting the drug, renal function and plasma potassium levels should be assessed. At the beginning of therapy, the dose of the drug is selected taking into account the degree of blood pressure reduction, especially in case of dehydration and electrolyte loss. Such measures help to avoid a sharp decrease in blood pressure.

Atherosclerosis

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

Renovascular hypertension

The method of treatment for renovascular hypertension is revascularization. Nevertheless, the use of ACE inhibitors has a beneficial effect in this category of patients, both those awaiting surgery and in cases where surgery is not possible.

Treatment of patients with diagnosed or suspected renal artery stenosis with Perindopril-Indapamide Richter should be started with a low dose of the drug in a hospital setting, monitoring renal function and plasma potassium levels. In some patients, functional renal failure may develop, which disappears after discontinuation of the drug.

Heart failure

In persons with severe heart failure (NYHA functional class IV) and patients with type 1 diabetes (risk of spontaneous increase in potassium levels), treatment should be started with a low dose of the drug and under careful medical supervision.

Patients with arterial hypertension and coronary artery disease should not stop taking beta-blockers: ACE inhibitors should be used together with beta-blockers.

Diabetes mellitus

During the first month of therapy with ACE inhibitors, plasma glucose levels should be carefully monitored in patients with diabetes mellitus receiving treatment with oral hypoglycemic drugs or insulin.

Ethnic differences

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

Anemia

Anemia may develop in patients after kidney transplantation or in persons on hemodialysis. In this case, the decrease in hemoglobin is greater the higher its initial level was. This effect does not appear to be dose-dependent but may be related to the mechanism of action of ACE inhibitors. A slight decrease in hemoglobin occurs during the first 6 months, then it remains stable and is completely restored after discontinuation of the drug. In such patients, treatment can be continued, but hematological tests should be performed regularly.

Surgery/General anesthesia

General anesthesia while taking ACE inhibitors can lead to a pronounced decrease in blood pressure, especially when using general anesthesia agents that have a hypotensive effect.

It is recommended, if possible, to discontinue long-acting ACE inhibitors, including perindopril, one day before surgery. The anesthesiologist must be warned that the patient is taking ACE inhibitors.

Aortic or mitral stenosis/Hypertrophic obstructive cardiomyopathy

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

Hepatic insufficiency

In rare cases, cholestatic jaundice occurs while taking ACE inhibitors. With the progression of this syndrome, the development of fulminant liver necrosis, sometimes with a fatal outcome, is possible. The mechanism of development of this syndrome is unclear. If jaundice or a significant increase in the activity of “liver” enzymes occurs while taking ACE inhibitors, the drug should be discontinued and a doctor should be consulted.

Hyperkalemia

Hyperkalemia may develop during treatment with ACE inhibitors, including perindopril. Risk factors for hyperkalemia are renal failure, worsening renal function, age over 70 years, diabetes mellitus, some concomitant conditions (dehydration, acute decompensation of heart failure, metabolic acidosis), simultaneous use of potassium-sparing diuretics (such as spironolactone and its derivative eplerenone, triamterene, amiloride), as well as potassium preparations or potassium-containing salt substitutes, and the use of other drugs that contribute to an increase in plasma potassium levels (for example, heparin, ACE inhibitors, ARBs, acetylsalicylic acid (3 g/day and more), COX-2 inhibitors and non-selective NSAIDs, immunosuppressants such as cyclosporine or tacrolimus, trimethoprim). The use of potassium preparations, potassium-sparing diuretics, potassium-containing salt substitutes can lead to a significant increase in blood potassium levels, especially in patients with reduced renal function. Hyperkalemia can lead to serious, sometimes fatal, cardiac arrhythmias. If simultaneous use of the above drugs is necessary, treatment should be carried out with caution with regular monitoring of serum potassium levels.

Indapamide

Hepatic encephalopathy

In the presence of liver dysfunction, the use of thiazide and thiazide-like diuretics can lead to the development of hepatic encephalopathy. In this case, the drug should be discontinued immediately.

Water-Electrolyte Balance

Plasma sodium ion levels. Plasma sodium ion levels must be determined before starting treatment. This parameter should be monitored regularly during drug administration. All diuretic drugs can cause hyponatremia, which sometimes leads to serious complications. Hyponatremia may not be accompanied by clinical symptoms in the initial stage, so regular laboratory monitoring is necessary. More frequent monitoring of sodium ion levels is indicated for patients with liver cirrhosis and elderly patients.

Plasma potassium ion levels. Therapy with thiazide and thiazide-like diuretics is associated with a risk of hypokalemia. Hypokalemia (less than 3.4 mmol/L) must be avoided in the following high-risk patient categories: elderly patients, debilitated patients (whether receiving or not receiving concomitant drug therapy), patients with liver cirrhosis (with edema and ascites), coronary artery disease, heart failure. Hypokalemia in these patients enhances 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, promotes the development of severe cardiac arrhythmias, particularly polymorphic ventricular tachycardia of the ‘torsades de pointes’ type, which can be fatal. In all the cases described above, more regular monitoring of plasma potassium ion levels is necessary. The first measurement of potassium ion levels should be performed within the first week of starting therapy. If hypokalemia is detected, appropriate treatment should be prescribed.

Plasma calcium ion levels. Thiazide and thiazide-like diuretics may reduce the renal excretion of calcium ions, leading to a slight and temporary increase in plasma calcium concentration. Marked hypercalcemia may be a consequence of previously undiagnosed hyperparathyroidism. Diuretic drugs should be discontinued before testing parathyroid function.

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

Uric acid. An increase in plasma uric acid levels during therapy may increase the frequency of gout attacks.

Diuretics and Renal Function

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

In elderly patients, the normative plasma creatinine concentration should be adjusted for age, weight, and sex, according to the Cockcroft formula.

The formula is suitable for elderly men; for elderly women, the result should be multiplied by a coefficient of 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 and hyponatremia. This transient functional renal failure is not dangerous for patients with initially normal renal function, but its severity may increase in patients with renal insufficiency.

Photosensitivity

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

Athletes

Indapamide may give a positive reaction during doping control.

Effect on Ability to Drive and Operate Machinery

The action of indapamide and perindopril, both separately and in combination, does not lead to impairment of psychomotor reactions. However, some individuals may develop various individual reactions in response to decreased blood pressure, especially at the beginning of treatment or when other antihypertensive drugs are added to the ongoing therapy. In this case, the ability to drive a car or operate other machinery may be impaired.

Overdose

Symptoms most likely pronounced decrease in blood pressure, sometimes combined with nausea, vomiting, convulsions, dizziness, drowsiness, confusion, and oliguria, which may progress to anuria (due to hypovolemia). Electrolyte disturbances (hyponatremia, hypokalemia) may also occur.

Treatment emergency measures involve removing the drug from the body – gastric lavage and/or administration of activated charcoal followed by restoration of water-electrolyte balance. In case of a significant decrease in blood pressure, the patient should be placed in a ‘lying’ position with legs elevated. If necessary, correct hypovolemia (e.g., intravenous infusion of 0.9% sodium chloride solution). Perindoprilat, the active metabolite of perindopril, can be removed from the body by dialysis.

Drug Interactions

Combinations not recommended for use

Lithium preparations : concurrent use of lithium preparations and ACE inhibitors may cause a reversible increase in plasma lithium concentration and related toxic effects. Additional prescription of thiazide diuretics may contribute to a further increase in lithium concentration and increase the risk of toxicity manifestations. Concurrent use of the perindopril and indapamide combination with lithium preparations is not recommended. If such therapy is necessary, plasma lithium levels should be monitored regularly.

Drugs requiring special attention and caution when combined

Baclofen : potentiation of the antihypertensive effect is possible. Blood pressure and renal function should be monitored; adjustment of the dose of antihypertensive drugs may be required.

NSAIDs, including high doses of acetylsalicylic acid (≥ 3 g/day): concurrent use of ACE inhibitors with NSAIDs (acetylsalicylic acid at a dose exerting an anti-inflammatory effect, COX-2 inhibitors and non-selective NSAIDs) may lead to a reduction of the antihypertensive effect.

Concurrent use of ACE inhibitors and NSAIDs may lead to an increased risk of worsening renal function, including the development of acute renal failure, and an increase in serum potassium levels, especially in patients with pre-existing reduced renal function. Caution should be exercised when prescribing the combination of the drug and NSAIDs, especially in elderly patients: patients should receive adequate amounts of fluid, and it is recommended to monitor renal function both at the start of combination therapy and periodically during treatment.

Drug combinations requiring attention

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

Corticosteroids, tetracosactide : reduction of the antihypertensive effect (fluid and sodium ion retention as a result of corticosteroid action).

Other antihypertensive agents: potentiation of the antihypertensive effect is possible.

Perindopril

Clinical trial data show that dual blockade of the RAAS due to simultaneous use of ACE inhibitors, ARBs or aliskiren leads to an increased frequency of adverse events such as arterial hypotension, hyperkalemia and impaired renal function (including acute renal failure), compared to situations where only one drug affecting the RAAS is used.

Racecadotril

ACE inhibitors can cause angioedema. The risk of angioedema may increase with concurrent use of racecadotril (used for acute diarrhea).

Mammalian target of rapamycin inhibitors (mTOR) (sirolimus, everolimus, temsirolimus)

The risk of developing angioedema is increased in patients taking mTOR inhibitors concurrently with ACE inhibitors.

Combinations not recommended for use

Potassium-sparing diuretics (amiloride, spironolactone, triamterene) and potassium preparations : ACE inhibitors reduce potassium loss caused by the diuretic. Potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, amiloride), potassium preparations and potassium-containing salt substitutes can lead to a significant increase in serum potassium levels, even to a fatal outcome. If concurrent use of an ACE inhibitor and the aforementioned drugs is necessary (in case of confirmed hypokalemia), caution should be exercised and regular monitoring of plasma potassium levels and ECG parameters should be performed.

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

Drug combinations requiring special attention

Oral hypoglycemic agents (sulfonylurea derivatives) and insulin : the effects listed below have been described for captopril and enalapril. ACE inhibitors may enhance the hypoglycemic effect of insulin and sulfonylurea derivatives in patients with diabetes mellitus. The development of hypoglycemia is observed very rarely (due to increased glucose tolerance and reduced insulin requirement).

Drug combinations requiring attention

Antihypertensive agents and vasodilators : concurrent use of these drugs may enhance the antihypertensive effect of perindopril. When used concomitantly with nitroglycerin, other nitrates or other vasodilators, an additional decrease in blood pressure is possible.

Allopurinol, cytotoxic and immunosuppressive agents, corticosteroids (for systemic use) and procainamide : concurrent use with ACE inhibitors may be associated with an increased risk of leukopenia.

General anesthetics : concurrent use of ACE inhibitors and general anesthetics may lead to an enhancement of the antihypertensive effect.

Diuretics (thiazide and ‘loop’): use of diuretics in high doses can lead to hypovolemia, and the addition of perindopril to therapy can lead to arterial hypotension.

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

Sympathomimetics : may weaken the antihypertensive effect of ACE inhibitors.

Gold preparations : nitrate-like reactions, including facial flushing, nausea, vomiting, and arterial hypotension, have been described in patients receiving intravenous gold preparation (sodium aurothiomalate) while taking ACE inhibitors, including perindopril.

Indapamide

Drug combinations requiring special attention

Drugs capable of causing polymorphic ventricular tachycardia of the ‘torsades de pointes’ type: due to the risk of hypokalemia, caution should be exercised when using indapamide concomitantly with drugs capable of causing polymorphic ventricular tachycardia of the ‘torsades de pointes’ type, for example, class IA antiarrhythmic agents (quinidine, hydroquinidine, disopyramide) and class III (amiodarone, dofetilide, ibutilide, bretylium tosylate), sotalol; some antipsychotics (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine); benzamides (amisulpride, sulpiride, sultopride, tiapride); butyrophenones (droperidol, haloperidol); other antipsychotics (pimozide); other drugs such as bepridil, cisapride, difemanil methyl sulfate, intravenous erythromycin, halofantrine, mizolastine, moxifloxacin, pentamidine, sparfloxacin, intravenous vincamine, methadone, astemizole, terfenadine. Plasma potassium levels should be monitored and corrected if necessary; monitor the QT interval.

Drugs capable of causing hypokalemia : amphotericin B (intravenous), gluco- and mineralocorticoids (for systemic use), tetracosactide, stimulant laxatives: increased risk of hypokalemia (additive effect). Monitoring of plasma potassium levels is necessary, with correction if needed. Particular attention should be paid to patients concurrently receiving cardiac glycosides. Non-stimulant laxatives should be used.

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

Drug combinations requiring attention

Metformin: functional renal failure, which can occur during diuretic therapy, especially ‘loop’ diuretics, when prescribed concomitantly with metformin increases the risk of lactic acidosis. Metformin should not be used if plasma creatinine concentration exceeds 15 mg/L (135 µmol/L) in men and 12 mg/L (110 µmol/L) in women.

Iodinated contrast agents : dehydration of the body during diuretic therapy increases the risk of acute renal failure, especially when using high doses of iodinated contrast agents. Before using iodinated contrast agents, patients must compensate for fluid loss.

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

Cyclosporine : an increase in plasma creatinine concentration may occur without changes in plasma cyclosporine concentration, even with normal water and sodium ion levels.

Storage Conditions

The drug should be stored out of the reach of children, protected from light, at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 2 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.