Perindopril Plus Indapamide (Tablets) Instructions for Use

Marketing Authorization Holder

Izvarino Pharma LLC (Russia)

ATC Code

C09BA04 (Perindopril and diuretics)

Active Substances

Indapamide (Rec.INN registered by WHO)

Perindopril (Rec.INN registered by WHO)

Dosage Forms

	Perindopril Plus Indapamide	Film-coated tablets, 0.625 mg+2 mg: 10, 30, 60 or 90 pcs.
		Film-coated tablets, 1.25 mg+4 mg: 10, 30, 60 or 90 pcs.
		Film-coated tablets, 2.5 mg+8 mg: 10, 30, 60 or 90 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets from gray-green to green with a grayish tint, round, biconvex; on the cross-section – a core of white or almost white color.

Excipients: microcrystalline cellulose – 70.375 mg, pregelatinized corn starch – 15 mg, crospovidone – 10 mg, magnesium stearate – 1 mg, colloidal silicon dioxide – 1 mg.

Film coating composition Opadry II green (85F21738), including polyvinyl alcohol – 40%, titanium dioxide – 24.345%, macrogol-3350 – 20.2%, talc – 14.8%, indigo carmine aluminum lake – 0.54%, quinoline yellow – 0.115%.

10 pcs. – blister packs (aluminum/PVC) (1) – cardboard packs.
10 pcs. – blister packs (aluminum/PVC) (3) – cardboard packs.
10 pcs. – blister packs (aluminum/PVC) (6) – cardboard packs.
10 pcs. – blister packs (aluminum/PVC) (9) – cardboard packs.

Film-coated tablets from light yellow with a pinkish tint to yellow with a pinkish tint, round, biconvex; on the cross-section – a core of white or almost white color.

Excipients: microcrystalline cellulose – 67.75 mg, pregelatinized corn starch – 15 mg, crospovidone – 10 mg, magnesium stearate – 1 mg, colloidal silicon dioxide – 1 mg.

Film coating composition Opadry II yellow (85F38201), including polyvinyl alcohol – 40%, titanium dioxide – 24.48%, macrogol-3350 – 20.2%, talc – 14.8%, iron oxide yellow 0.5%, iron oxide red 0.02%.

10 pcs. – blister packs (aluminum/PVC) (1) – cardboard packs.
10 pcs. – blister packs (aluminum/PVC) (3) – cardboard packs.
10 pcs. – blister packs (aluminum/PVC) (6) – cardboard packs.
10 pcs. – blister packs (aluminum/PVC) (9) – cardboard packs.

Film-coated tablets white or almost white, round, biconvex; on the cross-section – a core of white or almost white color.

Excipients: microcrystalline cellulose – 62.5 mg, pregelatinized corn starch – 15 mg, crospovidone – 10 mg, magnesium stearate – 1 mg, colloidal silicon dioxide – 1 mg.

Film coating composition Opadry II white (85F48105), including polyvinyl alcohol – 46.9%, macrogol-3350 – 23.6%, talc – 17.4%, titanium dioxide – 12.1%.

10 pcs. – blister packs (aluminum/PVC) (1) – cardboard packs.
10 pcs. – blister packs (aluminum/PVC) (3) – cardboard packs.
10 pcs. – blister packs (aluminum/PVC) (6) – cardboard packs.
10 pcs. – blister packs (aluminum/PVC) (9) – cardboard packs.

Clinical-Pharmacological Group

Antihypertensive drug

Pharmacotherapeutic Group

Antihypertensive combination agent (ACE inhibitor + diuretic)

Pharmacological Action

Combined antihypertensive drug containing an angiotensin-converting enzyme (ACE) inhibitor – perindopril and a thiazide-like diuretic – Indapamide. The drug has antihypertensive, diuretic and vasodilating effects.

Perindopril plus Indapamide has a pronounced dose-dependent antihypertensive effect, independent of the patient’s age and body position and not accompanied by reflex tachycardia. It does not affect the metabolism of lipids (total cholesterol, low-density lipoproteins (LDL), very low-density lipoproteins (VLDL), high-density lipoproteins (HDL), triglycerides (TG) and carbohydrates), including in patients with diabetes mellitus. It reduces the risk of hypokalemia caused by diuretic monotherapy. The antihypertensive effect lasts for 24 hours.

Stable reduction of blood pressure (BP) is achieved within 1 month of using the drug Perindopril plus Indapamide without increasing the heart rate (HR). Discontinuation of treatment does not lead to the development of a “withdrawal” syndrome.

Perindopril is an ACE inhibitor, the mechanism of action of which is associated with the 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 plasma renin activity. Perindopril acts through its main active metabolite – perindoprilat. Its other metabolites are inactive.

The action of perindopril leads to the expansion of veins (reduction of cardiac preload), due to a change in prostaglandin metabolism; reduction of total peripheral vascular resistance (TPVR) (reduction of cardiac afterload). In patients with heart failure, perindopril helps to reduce the filling pressure of the left and right ventricles; increase in cardiac output and cardiac index; increase in regional blood flow in the muscles. Perindopril is effective in arterial hypertension of any severity: mild, moderate and severe.

The maximum antihypertensive effect develops 4-6 hours after a single oral dose and persists for 24 hours.

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 antihypertensive (additive) effect of perindopril.

Indapamide belongs to the sulfonamide derivatives, is a diuretic. It inhibits the reabsorption of sodium in the cortical segment of the renal tubules, increasing the excretion of sodium and chlorine by the kidneys, thus leading to an increase in diuresis. To a lesser extent, it increases the excretion of potassium and magnesium. Having the ability to selectively block slow calcium channels, Indapamide increases the elasticity of arterial walls and reduces TPVR. It has an antihypertensive effect in doses that do not have a pronounced diuretic effect. Increasing the dose of indapamide does not lead to an increase in the antihypertensive effect, but increases the risk of adverse events. Indapamide in patients with arterial hypertension does not affect lipid metabolism – TG, LDL and HDL; on carbohydrate metabolism, even in patients with diabetes mellitus and arterial hypertension.

Pharmacokinetics

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

Perindopril

Absorption

After oral administration, perindopril is rapidly absorbed from the gastrointestinal tract. Bioavailability is 65 – 70%. C_max 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 once a day in the morning, before breakfast. When taking perindopril once a day, the equilibrium concentration (C_ss) is reached within 4 days.

Distribution

The binding to plasma proteins of perindoprilat is dose-dependent and is 20%. Perindoprilat easily passes through histohematic barriers, excluding the blood-brain barrier (BBB). Does not accumulate.

Metabolism

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

Excretion

T_1/2 of perindopril from blood plasma is 1 hour. T_1/2 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

Absorption

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

Distribution

Binding to plasma proteins is 79%. Does not accumulate.

Metabolism

It is metabolized in the liver.

Excretion

T_1/2 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 unchanged drug is about 5%) and through the intestine with bile in the form of inactive metabolites (22%).

Pharmacokinetics in special clinical cases

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

Indications

• Arterial hypertension.

ICD codes

Dosage Regimen

It is prescribed orally 1 time/day, preferably in the morning before breakfast, with a sufficient amount of liquid.

Doses are given for the perindopril/Indapamide ratio.

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

For patients with renal insufficiency (creatinine clearance 60 ml/min and above) dose adjustment is not required. For patients with creatinine clearance 30-60 ml/min, the maximum dose of the drug Perindopril plus Indapamide is 0.625mg/2mg (1 tablet) 1 time/day, treatment should be started with dose selection of perindopril and indapamide in monotherapy mode. With creatinine clearance less than 30 ml/min, the use of the drug Perindopril plus Indapamide is contraindicated (see section “Contraindications”).

For patients with moderate hepatic impairment dose adjustment is not required. For patients with severe hepatic impairment, the use of the drug Perindopril plus Indapamide is contraindicated.

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 starting the drug Perindopril plus Indapamide, renal function and plasma potassium levels should be assessed. The initial dose of the drug Perindopril plus Indapamide is selected depending on the degree of BP reduction, especially with a decrease in circulating blood volume and in chronic heart failure (NYHA functional class IV). Such measures help to avoid a sharp decrease in BP.

The risk of arterial hypotension exists in all patients, however, special caution should be exercised when using the drug Perindopril plus Indapamide in patients with coronary artery disease and cerebrovascular insufficiency. In such patients, treatment with the drug 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 the drug Perindopril plus Indapamide should be started in a hospital with a dose of 0.625 mg/2 mg under the control of renal function and plasma potassium levels. In some patients, acute renal failure may develop, which is reversible after discontinuation of the drug.

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

Adverse Reactions

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

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

From the central nervous system common – paresthesia, headache, dizziness, vertigo; uncommon – sleep disturbance, 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 uncommon – marked decrease in BP (including orthostatic hypotension), palpitations; very rare – cardiac arrhythmias (including bradycardia, ventricular tachycardia, atrial fibrillation), angina pectoris and myocardial infarction, possibly due to excessive BP reduction in high-risk patients; frequency unknown – torsades de pointes arrhythmia (possibly fatal), QT interval prolongation on ECG.

From the respiratory system common – against the background of the use of ACE inhibitors, a dry cough may occur, which persists for a long time during the use of drugs of this group and disappears after their withdrawal, dyspnea; uncommon – bronchospasm; very rare – eosinophilic pneumonia, rhinitis.

From the digestive system common – dry mouth, nausea, vomiting, abdominal pain, epigastric pain, taste disturbance, decreased appetite, dyspepsia, constipation, diarrhea: very rare – pancreatitis, intestinal angioedema, cholestatic jaundice; frequency unknown – hepatic encephalopathy in patients with hepatic insufficiency, increased activity of “hepatic” transaminases.

From the skin common – skin rash, itching, 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, hemorrhagic vasculitis. In patients with an acute form of systemic lupus erythematosus, a worsening of the disease may occur; very rare – erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome. Cases of photosensitivity reactions have been noted.

From the musculoskeletal system common – muscle cramps.

From the urinary system uncommon – renal failure; very rare – acute renal failure, frequency unknown – hepatitis.

From the reproductive system uncommon – erectile dysfunction.

Laboratory parameters rare – hypercalcemia; frequency unknown – hypokalemia, especially significant for patients at risk; hyponatremia and hypovolemia, leading to dehydration and orthostatic hypotension; increased concentration of uric acid and glucose in the blood during drug administration: a slight increase in the concentration of creatinine in urine and blood 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; hyperkalemia, more often transient.

Other common – asthenia; uncommon – increased sweating.

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

Contraindications

Perindopril

• Hypersensitivity to perindopril and other ACE inhibitors;
• History of angioedema associated with ACE inhibitor use;
• Hereditary/idiopathic angioedema;
• Bilateral renal artery stenosis or stenosis of the artery of a single kidney;
• Simultaneous use of ACE inhibitors with aliskiren and aliskiren-containing drugs in patients with diabetes mellitus and renal failure (creatinine clearance less than 60 ml/min);
• Pregnancy;
• Breastfeeding period;
• Age under 18 years (efficacy and safety not established).

Indapamide

• Hypersensitivity to indapamide and other sulfonamide derivatives;
• Severe hepatic insufficiency (including with encephalopathy);
• Hypokalemia;
• Concomitant use with drugs that can cause torsades de pointes arrhythmia;
• Pregnancy and breastfeeding period;
• Age under 18 years (efficacy and safety not established).

Perindopril plus Indapamide

• Hypersensitivity to excipients included in the drug;
• Severe renal failure (creatinine clearance <30 ml/min);
• Simultaneous use with potassium-sparing diuretics, potassium and lithium preparations, and in patients with hyperkalemia;
• Simultaneous use of drugs that prolong 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 decompensated heart failure;
• Age under 18 years (efficacy and safety not established).

Use with caution in patients with systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma); during therapy with immunosuppressants (risk of neutropenia, agranulocytosis); with bone marrow depression; with reduced circulating blood volume (CBV) (due to diuretic use, salt-restricted diet, vomiting, diarrhea); with ischemic heart disease (IHD); cerebrovascular diseases; renovascular hypertension; chronic heart failure (NYHA functional class IV); with hyperuricemia (especially accompanied by gout and urate nephrolithiasis); labile blood pressure; during hemodialysis using high-flux polyacrylonitrile membranes (risk of anaphylactoid reactions); before LDL apheresis with dextran sulfate; concurrently with desensitizing therapy with allergens (e.g., hymenoptera venom); in patients with a history of kidney transplantation; stenosis of the aortic and/or mitral valve, hypertrophic obstructive cardiomyopathy; in elderly patients. 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. Angioedema occurs more frequently in Black patients than in patients of other races.

Use in Pregnancy and Lactation

Perindopril plus Indapamide is contraindicated during pregnancy.

If pregnancy is planned or occurs during treatment with the drug, administration of the drug should be discontinued immediately and another antihypertensive therapy should be prescribed. Adequate controlled studies of ACE inhibitors in pregnant women have not been conducted. Available limited data on the drug’s exposure in the first trimester of pregnancy indicate that the drug did not lead to malformations associated with fetotoxicity.

The use of Perindopril plus Indapamide is not recommended in the first trimester of pregnancy. Perindopril plus Indapamide is contraindicated in the second and third trimesters of pregnancy.

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

Long-term use of thiazide diuretics in the third trimester of pregnancy can cause hypovolemia in the mother and reduced uteroplacental blood flow, leading to fetoplacental ischemia and fetal growth retardation. In rare cases, newborns develop hypoglycemia and thrombocytopenia when diuretics are taken shortly before delivery.

If the patient received Perindopril plus Indapamide during the second or third trimester of pregnancy, an ultrasound examination of the fetus is recommended to assess the condition of the skull bones and renal function.

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

Perindopril plus Indapamide is contraindicated during breastfeeding. It is not known whether perindopril is excreted in breast milk.

Indapamide is excreted in breast milk. The use of thiazide diuretics causes a decrease in the amount of breast milk or suppression of lactation. The newborn may develop hypersensitivity to sulfonamide derivatives, hypokalemia, and kernicterus.

If it is necessary to use Perindopril plus Indapamide during breastfeeding, breastfeeding should be discontinued.

Use in Hepatic Impairment

No dose adjustment is required for patients with moderate hepatic impairment. The use of Perindopril plus Indapamide is contraindicated in patients with severe hepatic impairment.

Use in Renal Impairment

No dose adjustment is required for patients with renal failure (creatinine clearance 60 ml/min and above). For patients with creatinine clearance 30-60 ml/min, the maximum dose of Perindopril plus Indapamide is 0.625mg/2mg (1 tablet) once daily; treatment should be started by selecting doses of perindopril and indapamide in monotherapy mode. For creatinine clearance less than 30 ml/min, the use of Perindopril plus Indapamide is contraindicated (see the “Contraindications” section).

Pediatric Use

Perindopril plus Indapamide is contraindicated in children and adolescents under 18 years of age due to the lack of data on its efficacy and safety.

Geriatric Use

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

In elderly patients, renal function and plasma potassium levels should be assessed before starting Perindopril plus Indapamide. The initial dose of Perindopril plus Indapamide should be selected depending on the degree of blood pressure reduction, especially in cases of reduced circulating blood volume and in chronic heart failure (NYHA functional class IV). Such measures help avoid a sharp decrease in blood pressure.

Special Precautions

Perindopril plus Indapamide

Concomitant use of Perindopril plus Indapamide with lithium preparations is not recommended.

Treatment with Perindopril plus Indapamide is contraindicated in patients with severe renal failure (creatinine clearance less than 30 ml/min). In some patients with arterial hypertension without prior renal impairment, symptoms of acute renal failure may appear during therapy with Perindopril plus Indapamide. In this case, treatment with Perindopril plus Indapamide should be discontinued. Subsequently, combination therapy can be resumed using low doses of Perindopril plus Indapamide, or perindopril and Indapamide can be used in monotherapy. Such patients require regular monitoring of serum potassium and creatinine levels every 2 weeks after the start of therapy and every subsequent 2 months of therapy with Perindopril plus Indapamide. Acute renal failure develops more often in patients with severe chronic heart failure or pre-existing renal impairment, including bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney. The use of Perindopril plus Indapamide is not recommended in patients with bilateral renal artery stenosis or stenosis of the artery to 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 stenosis of the artery to a single functioning kidney). Therefore, during dynamic observation of patients, attention should be paid to possible symptoms of dehydration and a decrease in plasma electrolyte levels, for example, after prolonged diarrhea or vomiting. Such patients require regular monitoring of plasma electrolytes.

In case of 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 restoration of circulating blood volume and blood pressure, therapy with Perindopril plus Indapamide can be resumed using low doses of the drug, or using perindopril and Indapamide in monotherapy.

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 combined use of antihypertensive agents and a diuretic, regular monitoring of plasma potassium levels is necessary.

Perindopril

In patients taking ACE inhibitors, cases of neutropenia/agranulocytosis, thrombocytopenia, and anemia may occur. In patients with normal renal function and in the absence of other complications, neutropenia is rare and resolves on its own after discontinuation of ACE inhibitors.

Perindopril should be used with particular caution in patients with connective tissue diseases and simultaneously receiving immunosuppressive therapy, allopurinol, or procainamide, especially in the presence of existing renal impairment. In such patients, severe infections that do not respond to intensive antibiotic therapy may develop. If perindopril is prescribed, it is recommended to periodically monitor the white blood cell count. The patient should be warned that if any signs of an infectious disease appear (sore throat, fever), they should immediately consult a doctor.

When taking ACE inhibitors, including perindopril, in rare cases, angioedema of the face, lips, tongue, uvula, and/or larynx may occur. If these symptoms appear, the drug should be discontinued immediately. The patient’s condition should be monitored until the signs of edema completely disappear.

If angioedema involves only the face and lips, its manifestations usually resolve on their own, or antihistamines can be used to treat the symptoms. Angioedema accompanied by swelling of the tongue or larynx can lead to airway obstruction and be fatal. If symptoms of angioedema appear, subcutaneous epinephrine (adrenaline) 1:1000 (0.3 or 0.5 ml) should be administered immediately and/or airway patency should be ensured.

In patients with a history of angioedema not associated with ACE inhibitor use, the risk of its development may be increased when taking drugs of this group. Angioedema occurs more frequently in Black patients than in patients of other races.

In rare cases, intestinal angioedema develops during therapy with ACE inhibitors. In this case, patients experience 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 is established by computed tomography of the abdomen, ultrasound, or at the time of surgery. Symptoms disappear after discontinuation of ACE inhibitors. In patients with abdominal pain receiving ACE inhibitors, the possibility of intestinal angioedema should be considered in the differential diagnosis. There are isolated reports 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, anaphylactoid reactions can be avoided by temporarily discontinuing the ACE inhibitor at least 24 hours before starting the desensitization procedure.

In rare cases, in patients receiving ACE inhibitors, life-threatening anaphylactoid reactions may develop during LDL apheresis using dextran sulfate. To prevent an anaphylactoid reaction, ACE inhibitor therapy should be discontinued before each LDL apheresis procedure using high-flux membranes.

In patients receiving ACE inhibitors, anaphylactoid reactions have been observed during hemodialysis using high-flux membranes (e.g., AN69^®). Therefore, it is advisable to use a different type of membrane or use an antihypertensive drug of another pharmacotherapeutic group. During therapy with an ACE inhibitor, a dry cough may occur, which disappears after discontinuation of drugs in this group. If a dry cough appears, a possible connection of this symptom with taking an ACE inhibitor should be remembered. If the doctor believes that ACE inhibitor therapy is necessary for the patient, the use of Perindopril plus Indapamide may be continued.

In liver cirrhosis accompanied by edema and ascites, arterial hypotension, chronic heart failure, significant activation of the renin-angiotensin-aldosterone system (RAAS) is possible, especially with severe hypovolemia and decreased plasma electrolyte levels (against the background of a salt-free diet or long-term diuretic use).

The use of an ACE inhibitor causes blockade of the RAAS, therefore a sharp decrease in blood pressure and/or an increase in serum creatinine, indicating the development of acute renal failure, may occur, which is more often observed when taking the first dose of Perindopril plus Indapamide or during the first 2 weeks of therapy.

When prescribing Perindopril plus Indapamide to patients with diabetes mellitus receiving oral hypoglycemic agents or insulin, blood glucose concentration should be regularly monitored during the first month of therapy.

Perindopril (like other ACE inhibitors) has a less pronounced antihypertensive effect in Black patients compared to representatives of other races.

The use of ACE inhibitors in patients undergoing surgery with general anesthesia can lead to a pronounced decrease in blood pressure, especially when using general anesthetic agents that have an antihypertensive effect.

It is recommended to discontinue ACE inhibitors, including perindopril, 12 hours before surgery, informing the anesthesiologist about the use of ACE inhibitors.

ACE inhibitors should be used with caution in patients with left ventricular outflow tract obstruction and with aortic and/or mitral stenosis and HOCM (hypertrophic obstructive cardiomyopathy).

In rare cases, cholestatic jaundice occurs during the use of ACE inhibitors, which may progress to fulminant liver necrosis, sometimes with a fatal outcome. If jaundice or a significant increase in the activity of “liver” transaminases occurs during the use of ACE inhibitors, the use of Perindopril plus Indapamide should be discontinued.

In patients after kidney transplantation or in patients on hemodialysis, anemia may develop.

During treatment with ACE inhibitors, including perindopril, hyperkalemia may develop. Risk factors for hyperkalemia are renal failure, old age, diabetes mellitus, some concomitant conditions (decreased circulating blood volume, decompensated acute heart failure, metabolic acidosis), simultaneous use of potassium-sparing diuretics (such as spironolactone, 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 (e.g., heparin). Hyperkalemia can lead to serious cardiac arrhythmias, sometimes fatal. Combined use of the above-mentioned drugs is not recommended; if their use is necessary, therapy should be conducted with particular caution.

Indapamide

There are reports of cases of increased photosensitivity during the use of thiazide and thiazide-like diuretics. If a photosensitivity reaction develops during the use of Perindopril plus Indapamide, treatment should be discontinued. If it is necessary to resume the use of Perindopril plus Indapamide, exposed areas of the skin should be protected from direct exposure to sunlight and artificial ultraviolet rays.

Before starting treatment with Perindopril plus Indapamide, it is necessary to determine the plasma sodium level and conduct regular monitoring of plasma electrolytes during drug use (especially in elderly patients). All diuretic agents can cause hyponatremia, leading to serious complications.

Therapy with thiazide and thiazide-like diuretics is associated with the risk of developing hypokalemia (less than 3.4 mmol/l) in elderly patients, debilitated patients, patients with liver cirrhosis, patients with peripheral edema, ascites, ischemic heart disease, chronic heart failure. Hypokalemia in these patients enhances the toxic effect of cardiac glycosides and increases the risk of arrhythmia. The high-risk group includes patients with an increased QT interval on the ECG. Hypokalemia, like bradycardia, contributes to the development of severe cardiac arrhythmias, especially ventricular arrhythmia of the “torsades de pointes” type, which can be fatal. In all described cases, regular monitoring of plasma potassium levels is necessary. The first determination of plasma potassium should be carried out within the first week from the start of therapy with Perindopril plus Indapamide.

Thiazide and thiazide-like diuretics reduce the renal excretion of calcium, leading to a slight and temporary increase in plasma calcium levels. Severe hypercalcemia may be a consequence of latent hyperparathyroidism. Before examining parathyroid function, the use of Perindopril plus Indapamide should be discontinued.

Glucose concentration should be monitored in patients with diabetes mellitus. In patients with elevated plasma uric acid levels during therapy with Perindopril plus Indapamide, an increase in the frequency of gout exacerbations is possible.

Hypovolemia resulting from a decrease in circulating blood volume or hyponatremia caused by diuretic use at the beginning of treatment with Perindopril plus Indapamide can lead to a decrease in the glomerular filtration rate and be accompanied by an increase in plasma creatinine and urea levels.

Indapamide may give a false-positive reaction during doping control.

Use in Pediatrics

Perindopril plus Indapamide is contraindicated in children and adolescents under 18 years of age due to the lack of data on its efficacy and safety.

Effect on Ability to Drive and Operate Machinery

Caution should be exercised when driving vehicles and other technical devices requiring increased attention and speed of psychomotor reactions.

Overdose

Symptoms pronounced decrease in blood pressure, nausea, vomiting, muscle cramps, dizziness, drowsiness, confusion, oliguria up to anuria (due to decreased circulating blood volume); disturbances in water-electrolyte balance (low plasma sodium and potassium levels) are possible.

Treatment gastric lavage and/or administration of activated charcoal, restoration of water-electrolyte balance in a hospital setting. In case of a pronounced decrease in blood pressure, the patient should be placed in a supine position with legs elevated; then measures should be taken to increase the circulating blood volume (intravenous administration of 0.9% sodium chloride solution). Perindoprilat, the active metabolite of perindopril, can be removed from the body by dialysis.

Drug Interactions

Perindopril plus Indapamide

Concomitant use is not recommended

Cases of reversible increases in serum lithium concentration have been reported with the concomitant use of lithium preparations and ACE inhibitors. Concurrent use of thiazide diuretics may contribute to an increase in lithium concentration and the risk of its toxic effect during ACE inhibitor use. Concomitant use of the combination of perindopril and indapamide with lithium preparations is not recommended. If therapy is conducted, monitoring of plasma lithium levels is necessary.

Special caution is required during concomitant use

Baclofen potentiates the hypotensive effect (blood pressure control, renal function monitoring, and dose adjustment of Perindopril plus Indapamide if necessary are required).

The combination of ACE inhibitors with non-steroidal anti-inflammatory drugs (NSAIDs) (non-selective cyclooxygenase (COX) inhibitors from the NSAID group, for example, acetylsalicylic acid in doses exerting an anti-inflammatory effect; COX-2 inhibitors) reduces the hypotensive effect of ACE inhibitors; increases the risk of renal function impairment, up to the development of acute renal failure; increases serum potassium levels in patients with pre-existing renal impairment. This combination should be used with caution, especially in elderly patients. Patients need to have their circulating blood volume compensated and renal function monitored before and after starting treatment with Perindopril plus Indapamide.

Caution is required during concomitant use

Tricyclic antidepressants, antipsychotic agents (neuroleptics) enhance the hypotensive effect and increase the risk of orthostatic hypotension (additive effect).

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

Concomitant use with other antihypertensive agents may enhance the hypotensive effect of Perindopril plus Indapamide.

Perindopril

Concomitant use is not recommended

ACE inhibitors reduce potassium loss caused by the diuretic. Concomitant use of potassium-sparing diuretics (spironolactone, triamterene, amiloride, eplerenone), potassium preparations, or potassium-containing salt substitutes with ACE inhibitors may lead to an increase in serum potassium levels, which can be fatal. If concomitant 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.

Concomitant use of ACE inhibitors and angiotensin II receptor antagonists with aliskiren is contraindicated in patients with diabetes mellitus and patients with renal impairment (creatinine clearance less than 60 ml/min).

Special caution is required during concomitant use

The use of ACE inhibitors may enhance the hypoglycemic effect of oral hypoglycemic agents (sulfonylurea derivatives) and insulin in patients with diabetes mellitus; their concomitant use may increase glucose tolerance, which may require dose adjustment of oral hypoglycemic agents and insulin. Baclofen enhances the antihypertensive effect of ACE inhibitors.

Use of potassium-sparing diuretics, gliptins may pose a risk of angioedema when used concomitantly with ACE inhibitors. Concomitant use with sympathomimetics enhances the antihypertensive effect of ACE inhibitors.

Use of an ACE inhibitor causes blockade of the RAAS.

Caution is required during concomitant use

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

In patients whose condition requires extensive surgery or general anesthesia with agents causing arterial hypotension, ACE inhibitors, including perindopril, may block the formation of angiotensin II during compensatory renin release. ACE inhibitor therapy should be discontinued one day before surgery. If the ACE inhibitor cannot be discontinued, arterial hypotension developing via the described mechanism can be corrected by increasing the circulating blood volume.

Use of diuretics in high doses may lead to hypovolemia (due to reduced circulating blood volume), and the addition of perindopril to therapy may lead to a pronounced decrease in blood pressure.

When prescribing ACE inhibitors, including perindopril, to patients receiving gold preparations (sodium aurothiomalate) intravenously, nitratoid-like reactions (nausea, vomiting, pronounced decrease in blood pressure, facial skin flushing) have been observed.

Indapamide

Special caution is required during concomitant use

Due to the risk of hypokalemia, Indapamide should be used with caution concomitantly with medicinal products that can induce torsades de pointes ventricular arrhythmia, such as antiarrhythmic agents (quinidine, hydroquinidine, disopyramide, amiodarone, dofetilide, ibutilide, bretylium tosilate, sotalol), some neuroleptics (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine), benzamides (amisulpride, sulpiride, sultopride, tiapride), butyrophenones (droperidol, haloperidol), other neuroleptics (pimozide); other substances such as bepridil, cisapride, difemanil methyl sulfate, erythromycin (IV), halofantrine, mizolastine, moxifloxacin, pentamidine, sparfloxacin, vincamine when administered IV, methadone, astemizole, terfenadine. Potassium levels should be monitored to avoid hypokalemia; if it develops, correction should be performed, and the QT interval on the ECG should be monitored.

Concomitant use of indapamide with amphotericin B (IV), gluco- and mineralocorticoids (for systemic use), tetracosactide, laxatives stimulating intestinal motility increases the risk of hypokalemia (additive effect). Monitoring of plasma potassium levels is necessary, with correction if needed. Particular attention should be paid to patients simultaneously receiving cardiac glycosides. Laxatives that do not stimulate intestinal motility should be used.

Hypokalemia enhances the toxic effect of cardiac glycosides. During concomitant use of indapamide and cardiac glycosides, plasma potassium levels, ECG parameters should be monitored, and the dose of cardiac glycosides should be adjusted if necessary.

Caution is required during concomitant use

Use of metformin with diuretics may lead to the development of renal failure.

Concomitant use with metformin increases the risk of lactic acidosis. Metformin should not be used if serum creatinine levels exceed 15 mg/l (135 µmol/l) in men and 12 mg/l (110 µmol/l) in women.

During diuretic use, a decrease in circulating blood volume occurs, increasing the risk of acute renal failure, especially when using high doses of iodine-containing contrast agents. Before using iodine-containing contrast agents, circulating blood volume must be compensated.

Concomitant use with calcium preparations may lead to hypercalcemia due to reduced renal calcium excretion.

Concomitant use with cyclosporine increases the risk of renal function impairment (hypercreatininemia).

Storage Conditions

In a light-protected place at a temperature not exceeding 25°C (77°F). Keep out of reach of children.

Shelf Life

Shelf life – 2 years.

Dispensing Status

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.