Indapamid + Perindopril Canon (Tablets) Instructions for Use

Marketing Authorization Holder

Canonpharma Production, CJS (Russia)

ATC Code

C09BA04 (Perindopril and diuretics)

Active Substances

Indapamide (Rec.INN registered by WHO)

Perindopril (Rec.INN registered by WHO)

Dosage Forms

	Indapamide + Perindopril Canon	Film-coated tablets 1.25 mg+5 mg: 7, 10, 14, 20, 28, 30, 56, 60 or 90 pcs.
		Film-coated tablets 2.5 mg+10 mg: 7, 10, 14, 20, 28, 30, 56, 60 or 90 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white or almost white, round, biconvex; white or almost white on the cross-section.

Excipients: sodium starch glycolate, colloidal silicon dioxide, lactose monohydrate, magnesium stearate, maltodextrin, microcrystalline cellulose, Opadry 20A28380 white, incl.: hypromellose, hydroxypropyl cellulose, talc, titanium dioxide.

7 pcs. – contour cell packaging (1) – cardboard packs with leaflet.
7 pcs. – contour cell packaging (2) – cardboard packs with leaflet.
7 pcs. – contour cell packaging (4) – cardboard packs with leaflet.
7 pcs. – contour cell packaging (8) – cardboard packs with leaflet.
10 pcs. – contour cell packaging (1) – cardboard packs with leaflet.
10 pcs. – contour cell packaging (2) – cardboard packs with leaflet.
10 pcs. – contour cell packaging (3) – cardboard packs with leaflet.
10 pcs. – contour cell packaging (6) – cardboard packs with leaflet.
14 pcs. – contour cell packaging (1) – cardboard packs with leaflet.
14 pcs. – contour cell packaging (2) – cardboard packs with leaflet.
14 pcs. – contour cell packaging (4) – cardboard packs with leaflet.
30 pcs. – contour cell packaging (1) – cardboard packs with leaflet.
30 pcs. – contour cell packaging (2) – cardboard packs with leaflet.
60 pcs. – polymer jars (1) – cardboard packs with leaflet.
90 pcs. – polymer jars (1) – cardboard packs with leaflet.

Film-coated tablets white or almost white, round, biconvex; white or almost white on the cross-section.

Excipients: sodium starch glycolate, colloidal silicon dioxide, lactose monohydrate, magnesium stearate, maltodextrin, microcrystalline cellulose, Opadry 20A28380 white, incl.: hypromellose, hydroxypropyl cellulose, talc, titanium dioxide.

7 pcs. – contour cell packaging (1) – cardboard packs with leaflet.
7 pcs. – contour cell packaging (2) – cardboard packs with leaflet.
7 pcs. – contour cell packaging (4) – cardboard packs with leaflet.
7 pcs. – contour cell packaging (8) – cardboard packs with leaflet.
10 pcs. – contour cell packaging (1) – cardboard packs with leaflet.
10 pcs. – contour cell packaging (2) – cardboard packs with leaflet.
10 pcs. – contour cell packaging (3) – cardboard packs with leaflet.
10 pcs. – contour cell packaging (6) – cardboard packs with leaflet.
14 pcs. – contour cell packaging (1) – cardboard packs with leaflet.
14 pcs. – contour cell packaging (2) – cardboard packs with leaflet.
14 pcs. – contour cell packaging (4) – cardboard packs with leaflet.
30 pcs. – contour cell packaging (1) – cardboard packs with leaflet.
30 pcs. – contour cell packaging (2) – cardboard packs with leaflet.
60 pcs. – polymer jars (1) – cardboard packs with leaflet.
90 pcs. – polymer jars (1) – cardboard packs with leaflet.

Clinical-Pharmacological Group

Antihypertensive combination drug (diuretic + ACE inhibitor)

Pharmacotherapeutic Group

Agents acting on the renin-angiotensin system; angiotensin-converting enzyme (ACE) inhibitors, combinations; ACE inhibitors and diuretics

Pharmacological Action

Antihypertensive combination drug.

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 an increased excretion of sodium, chloride ions and, to a lesser extent, potassium and magnesium ions by the kidneys, thereby enhancing diuresis and reducing blood pressure.

The antihypertensive effect is manifested when the drug 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 vascular resistance.

Perindopril is an ACE inhibitor.

ACE, or kininase II, is an exopeptidase that carries out both the conversion of angiotensin I to the vasoconstrictor substance angiotensin II and the degradation of bradykinin, which has a vasodilatory effect, to an inactive heptapeptide.

As a result, perindopril reduces the secretion of aldosterone; by the principle of negative feedback increases plasma renin activity; with long-term use reduces total peripheral vascular resistance, which is mainly due to the 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, reducing preload and afterload.

When studying hemodynamic parameters in patients with chronic heart failure, the following was revealed: a decrease in filling pressure in the left and right ventricles of the heart; reduction of total peripheral vascular resistance; increased cardiac output; increased muscle peripheral blood flow.

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

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

24 hours after administration, a pronounced (about 80%) residual inhibition of ACE is observed.

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

Simultaneous use 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.

The combination drug has a dose-dependent antihypertensive effect on both diastolic and systolic blood pressure, both in the standing and lying positions.

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

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.

Pharmacokinetics

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

Indapamide is rapidly and completely absorbed from the gastrointestinal tract.

C_max of the drug in blood plasma is observed 1 hour after oral administration.

Plasma protein binding is 79%.

T_1/2 is 14-24 hours (average 19 hours).

Repeated administration of the drug 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.

When taken orally, perindopril is rapidly absorbed.

Bioavailability is 65-70%.

Approximately 20% of the total amount of absorbed perindopril is converted to perindoprilat, an active metabolite.

Taking the drug with food is accompanied by a decrease in the metabolism of perindopril to perindoprilat (this effect has no significant clinical significance).

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

Plasma protein binding is less than 30% and depends on the concentration of perindopril in plasma.

The dissociation of perindoprilat bound to ACE is slowed.

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, equilibrium is reached after 4 days.

Perindopril crosses the placental barrier.

Perindoprilat is excreted from the body by the kidneys.

The T_1/2 of the metabolite is 3-5 hours.

The excretion of perindoprilat is slowed in the elderly, as well as in patients with cardiac 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 2 times.

Nevertheless, the amount of perindoprilat formed does not decrease, so no dose adjustment is required.

Indications

Essential arterial hypertension.

ICD codes

Dosage Regimen

For oral administration. A single dose is taken once a day.

For patients with moderate renal impairment (creatinine clearance 30-60 ml/min), it is recommended to start therapy with the necessary doses of single-component drugs. The maximum recommended dose of the perindopril/Indapamide combination is 0.625 mg/2 mg once a day.

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.

Adverse Reactions

Perindopril has an inhibitory effect on the renin-angiotensin-aldosterone system and reduces the renal excretion of potassium ions during indapamide administration.

From the hematopoietic system very rarely – thrombocytopenia, leukopenia/neutropenia, agranulocytosis, aplastic anemia, hemolytic anemia.

From the nervous system often – paresthesia, headache, dizziness, asthenia, vertigo; infrequently – sleep disorder, mood lability; very rarely – confusion; frequency unknown – syncope.

From the organ of vision often – visual impairment.

From the organ of hearing often – tinnitus.

From the cardiovascular system often – marked decrease in blood pressure, including orthostatic hypotension; very rarely – 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 often – during the use of ACE inhibitors, a dry cough may occur (persisting for a long time during the use of drugs of this group and disappearing after their withdrawal), dyspnea; infrequently – bronchospasm; very rarely – eosinophilic pneumonia, rhinitis.

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

From the skin and subcutaneous tissues often – skin rash, pruritus, maculopapular rash; infrequently – 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, a worsening of the disease course is possible; very rarely – erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome; cases of photosensitivity reactions have been noted.

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

From the urinary system infrequently – renal failure; very rarely – acute renal failure.

From the reproductive system infrequently – impotence.

General reactions often – asthenia; infrequently – increased sweating.

Laboratory parameters rarely – hypercalcemia; frequency unknown – QT interval prolongation on ECG; increased 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

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 insufficiency; hypokalemia; simultaneous use of drugs that prolong the QT interval; simultaneous use of drugs that can cause polymorphic ventricular tachycardia of the “torsades de pointes” type; simultaneous use with drugs containing aliskiren in patients with diabetes mellitus or renal impairment (GFR less than 60 ml/min/1.73 m²); pregnancy; lactation period (breastfeeding); age under 18 years; hypersensitivity to perindopril or other ACE inhibitors, indapamide and other sulfonamide derivatives.

Due to insufficient clinical experience, this combination 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 or low-sodium diet); 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 cerebrovascular insufficiency), chronic heart failure (NYHA functional class IV), hepatic insufficiency, elderly age, labile blood pressure, representatives of the black race (reduced effectiveness), 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

Contraindicated for use during pregnancy and during the lactation period (breastfeeding).

Use in Hepatic Impairment

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

In moderate hepatic insufficiency, no dose adjustment is 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

The drug is contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

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

Special Precautions

In some patients with arterial hypertension without prior obvious renal impairment, laboratory signs of functional renal failure may appear during therapy.

In this case, treatment should be discontinued.

When resuming combination therapy, the components should be used in low doses or only one of them should 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.

In case of pre-existing hyponatremia, there is a risk of a sudden development of arterial hypotension, especially in patients with renal artery stenosis.

Therefore, when dynamically monitoring patients, attention should be paid to possible symptoms of dehydration and a decrease in plasma electrolyte levels, for example, after diarrhea or vomiting.

Such patients require regular monitoring of plasma electrolyte levels.

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.

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

In patients with normal renal function and no concomitant risk factors, neutropenia occurs rarely.

Perindopril should be used with particular caution against the background of systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma), as well as against the background of taking 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 number of leukocytes in the blood.

Patients should report any signs of infectious diseases (e.g., sore throat, fever) to their doctor.

When taking ACE inhibitors, including perindopril, the development of angioedema of the face, extremities, lips, tongue, vocal folds, and/or larynx may rarely occur. This can happen at any time during treatment. If symptoms appear, the drug should be discontinued immediately, and the patient should be monitored 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 involving laryngeal edema can be fatal. Swelling of the tongue, vocal folds, or larynx can lead to airway obstruction. If such symptoms occur, appropriate therapy should be initiated immediately, for example, subcutaneous administration of epinephrine (adrenaline) in a 1:1000 dilution (0.3-0.5 ml) and/or ensuring airway patency.

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

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of its development when taking drugs of this class.

In patients with abdominal pain receiving ACE inhibitors, the possibility of intestinal angioedema should be considered during 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. ACE inhibitors should be avoided in patients receiving immunotherapy with hymenoptera venom. However, an anaphylactoid reaction can be avoided by temporarily discontinuing

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

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

In some pathological conditions, significant activation of the RAAS may be noted, especially in cases of marked hypovolemia and reduced plasma electrolyte levels (due to a salt-free diet or long-term diuretic use), 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 blocks 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 during therapy. In such cases, when resuming therapy, it is recommended to use the drug at a lower dose and then gradually increase it.

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

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.

Treatment of patients with diagnosed or suspected renal artery stenosis with the perindopril/indapamide combination should be started with a low dose of the drug in a hospital setting, monitoring kidney function and plasma potassium levels. In some patients, functional renal failure may develop, which disappears upon discontinuation of this combination.

In individuals 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.

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

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

Performing general anesthesia while taking ACE inhibitors can lead to a significant decrease in blood pressure, especially when using general anesthetic 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 informed that the patient is taking ACE inhibitors.

If jaundice or a significant increase in liver enzyme activity occurs while taking ACE inhibitors, the drug should be discontinued and a doctor should be consulted.

Hyperkalemia may develop during treatment with ACE inhibitors, including perindopril. Hyperkalemia can lead to serious, sometimes fatal, cardiac arrhythmias. Risk factors for hyperkalemia are renal failure, worsening kidney function, age over 70 years, diabetes mellitus, certain 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 a number of other medicinal products. In such cases, treatment should be carried out with caution under regular monitoring of serum potassium levels.

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

Therapy with thiazide and thiazide-like diuretics is associated with a risk of hypokalemia. Hypokalemia (less than 3.4 mmol/L) should be avoided in the following high-risk patient categories: elderly patients, debilitated patients (both receiving and not receiving combination 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, contributes to 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.

Thiazide and thiazide-like diuretics can 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.

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

If the concentration of uric acid in the blood plasma increases during therapy, the frequency of gout attacks may increase.

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).

At the beginning of diuretic treatment, a temporary decrease in GFR and an increase in plasma urea and creatinine concentrations may be observed in patients 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.

Indapamide may give a positive reaction during doping control.

Effect on the ability to drive vehicles and 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 therapy. In this case, the ability to drive a car or operate machinery may be reduced.

Drug Interactions

Lithium preparations: simultaneous use of lithium preparations and ACE inhibitors may cause a reversible increase in plasma lithium concentration and associated toxic effects. Additional prescription of thiazide diuretics may contribute to a further increase in lithium concentration and increase the risk of toxicity manifestations. Simultaneous 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.

Baclofen: enhancement 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): simultaneous use of ACE inhibitors with NSAIDs (acetylsalicylic acid at a dose that has an anti-inflammatory effect, COX-2 inhibitors, and non-selective NSAIDs) may lead to a reduction in the antihypertensive effect.

Simultaneous 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 this combination 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.

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 antihypertensive effect (fluid and sodium ion retention as a result of corticosteroid action).

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

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

ACE inhibitors can cause angioedema. The risk of angioedema may increase with simultaneous 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 simultaneously with ACE inhibitors.

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

Oral hypoglycemic agents (sulfonylurea derivatives) and insulin: the effects described below have been reported 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).

Antihypertensive agents and vasodilators: simultaneous 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: simultaneous use with ACE inhibitors may be associated with an increased risk of leukopenia.

General anesthetics: simultaneous 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: when using ACE inhibitors, including perindopril, in patients receiving intravenous gold preparation (sodium aurothiomalate), nitrate-like reactions have been described, including: facial flushing, nausea, vomiting, arterial hypotension.

Drugs that can cause 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 that can cause 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; QT interval should be monitored.

Drugs that can cause hypokalemia: amphotericin B (IV), 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 simultaneously receiving cardiac glycosides. Non-stimulant laxatives should be used.

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

Metformin: functional renal failure, which can occur while taking diuretics, 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 while taking diuretic drugs 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: when prescribed concomitantly, hypercalcemia may develop due to reduced renal excretion of calcium ions.

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

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.