Ekvapress^® (Capsules) Instructions for Use

Marketing Authorization Holder

Gedeon Richter, Plc. (Hungary)

Manufactured By

Gedeon Richter, Plc. (Hungary)

Labeled By

GEDEON RICHTER, Plc. (Hungary)

Or

GEDEON RICHTER ROMANIA, S.A. (Romania)

Or

GEDEON RICHTER-RUS, AO (Russia)

Quality Control Release

GEDEON RICHTER, Plc. (Hungary)

Or

GEDEON RICHTER-RUS, AO (Russia)

Contact Information

GEDEON RICHTER OJSC (Hungary)

ATC Code

C09BX (ACE inhibitors in combination with other drugs)

Active Substances

Indapamide (Rec.INN registered by WHO)

Lisinopril (Rec.INN registered by WHO)

Amlodipine (Rec.INN registered by WHO)

Dosage Forms

	Ekvapress®	Modified-release capsules 5 mg+1.5 mg+10 mg: 56 pcs.
		Modified-release capsules 5 mg+1.5 mg+20 mg: 28 pcs.
		Modified-release capsules 10 mg+1.5 mg+20 mg: 28 pcs.

Dosage Form, Packaging, and Composition

Modified-release capsules hard gelatin, yellow, size No. 1; capsule contents – 1 round, biconvex white tablet, engraved “CF4” on one side (contains amlodipine and lisinopril) and 1 oval, biconvex film-coated white tablet, engraved “CP3” on one side and with a score on the other side (contains Indapamide).

Excipients : lactose monohydrate, hypromellose, calcium hydrogen phosphate dihydrate, mannitol, corn starch, microcrystalline cellulose, croscarmellose sodium, talc, magnesium stearate, colloidal silicon dioxide, Opadry II white (contains: polyvinyl alcohol, titanium dioxide, macrogol-3350, talc), hard gelatin capsule (contains: yellow iron oxide, titanium dioxide, water, gelatin).

14 pcs. – blisters (4) – cardboard packs.

Modified-release capsules hard gelatin, light orange, size No. 1; capsule contents – 2 round, biconvex white tablets, engraved “CF4” on one side (contain amlodipine and lisinopril) and 1 oval, biconvex film-coated white tablet, engraved “CP3” on one side and with a score on the other side (contains Indapamide).

Excipients : lactose monohydrate, hypromellose, calcium hydrogen phosphate dihydrate, mannitol, corn starch, microcrystalline cellulose, croscarmellose sodium, talc, magnesium stearate, colloidal silicon dioxide, Opadry II white (contains: polyvinyl alcohol, titanium dioxide, macrogol-3350, talc), hard gelatin capsule (contains: yellow iron oxide, red iron oxide, titanium dioxide, water, gelatin).

14 pcs. – blisters (2) – cardboard packs.

Modified-release capsules hard gelatin, dark orange, size No. 0; capsule contents – 2 round, biconvex white tablets, engraved “CF1” on one side (contain amlodipine and lisinopril) and 1 oval, biconvex film-coated white tablet, engraved “CP3” on one side and with a score on the other side (contains Indapamide).

Excipients : lactose monohydrate, hypromellose, calcium hydrogen phosphate dihydrate, mannitol, corn starch, microcrystalline cellulose, croscarmellose sodium, talc, magnesium stearate, colloidal silicon dioxide, Opadry II white (contains: polyvinyl alcohol, titanium dioxide, macrogol-3350, talc), hard gelatin capsule (contains: yellow iron oxide, red iron oxide, water, gelatin).

14 pcs. – blisters (2) – cardboard packs.

Clinical-Pharmacological Group

Combined antihypertensive drug

Pharmacotherapeutic Group

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

Pharmacological Action

Ekvapress^® is a fixed combination of the antihypertensive components amlodipine, indapamide, and lisinopril, which have complementary mechanisms of action, allowing for blood pressure control, and also synergistically exert a cardioprotective effect.

The combination of amlodipine, indapamide, and lisinopril helps prevent the possible development of side effects that occur when prescribing the individual components of the drug. For example, by dilating arterioles, slow calcium channel blockers (CCBs) can cause sodium and fluid retention in the body, leading to activation of the RAAS. The ACE inhibitor blocks this process and normalizes the body’s response to salt load.

ACE inhibitors significantly reduce hypokalemia caused by diuretics.

Amlodipine

A dihydropyridine derivative – a slow calcium channel blocker, which has antihypertensive and antianginal effects. It blocks slow calcium channels, reduces the transmembrane transition of calcium ions into the cell (more in vascular smooth muscle cells than in cardiomyocytes). The antianginal effect is due to the dilation of coronary and peripheral arteries and arterioles

• In angina, it reduces the severity of myocardial ischemia; by dilating peripheral arterioles, it reduces total peripheral vascular resistance, reduces cardiac afterload, and reduces myocardial oxygen demand;
• By dilating coronary arteries and arterioles in unchanged and ischemic areas of the myocardium, it increases oxygen supply to the myocardium (especially in vasospastic angina); prevents spasm of the coronary arteries (including that caused by smoking).

In patients with stable angina, a single daily dose increases exercise tolerance, delays the development of angina attacks and ST-segment depression, and reduces the frequency of angina attacks and the consumption of nitroglycerin and other nitrates.

It has a long-term, dose-dependent antihypertensive effect. The antihypertensive effect is due to a direct vasodilatory effect on vascular smooth muscles. In arterial hypertension, a single dose provides a clinically significant reduction in blood pressure for 24 hours (in lying and standing positions).

Orthostatic hypotension is quite rare when using amlodipine. Amlodipine does not cause a decrease in exercise tolerance or left ventricular ejection fraction. It reduces the degree of left ventricular myocardial hypertrophy. It does not affect myocardial contractility and conductivity, does not cause a reflex increase in heart rate, inhibits platelet aggregation, increases glomerular filtration rate, and has a weak natriuretic effect. In diabetic nephropathy, it does not increase the severity of microalbuminuria. It does not have any adverse effect on metabolism and plasma lipid concentrations and can be used in the treatment of patients with bronchial asthma, diabetes mellitus, and gout. A significant decrease in blood pressure is observed after 6-10 hours, the duration of the effect is 24 hours.

In patients with cardiovascular diseases (including coronary atherosclerosis with single-vessel disease and up to stenosis of 3 or more arteries, carotid artery atherosclerosis), who have had myocardial infarction, percutaneous transluminal coronary angioplasty (PTCA), or in patients with angina, the use of amlodipine prevents the development of intima-media thickening of the carotid arteries, reduces mortality from myocardial infarction, stroke, PTCA, coronary artery bypass grafting; leads to a reduction in the number of hospitalizations for unstable angina and progression of chronic heart failure (CHF); reduces the frequency of interventions aimed at restoring coronary blood flow.

It does not increase the rate of mortality or the development of complications and fatal outcomes in patients with CHF (NYHA functional class III-IV) on therapy with digoxin, diuretics, and ACE inhibitors. In patients with CHF (NYHA functional class III-IV) of non-ischemic etiology, there is a possibility of pulmonary edema when using amlodipine.

Indapamide

Indapamide belongs to sulfonamide derivatives with an indole ring and is close in pharmacological properties to thiazide diuretics, which inhibit the reabsorption of sodium ions in the cortical segment of the nephron loop. This increases the renal excretion of sodium, chloride ions and, to a lesser extent, potassium and magnesium ions, which is accompanied by an increase in diuresis and an antihypertensive effect. In clinical studies, when indapamide was used in monotherapy at doses that did not have a pronounced diuretic effect, a 24-hour antihypertensive effect was demonstrated.

The antihypertensive activity of indapamide is associated with an improvement in the elastic properties of large arteries and a reduction in arteriolar and total peripheral vascular resistance.

Indapamide reduces left ventricular hypertrophy.

Thiazide and thiazide-like diuretics reach a plateau of therapeutic effect at a certain dose, while the frequency of side effects continues to increase with a further increase in the drug dose. Therefore, the drug dose should not be increased if the therapeutic effect is not achieved at the recommended dose.

In short-term, medium-term, and long-term studies involving patients with arterial hypertension, it was shown that Indapamide

• Does not affect lipid metabolism parameters, including the concentration of triglycerides, cholesterol, LDL, and HDL;
• Does not affect carbohydrate metabolism, including in patients with diabetes mellitus.

Lisinopril

An ACE inhibitor, it suppresses the conversion of angiotensin I to angiotensin II. The decrease in angiotensin II concentration leads to a direct reduction in aldosterone secretion. Lisinopril inhibits the degradation of bradykinin and increases the synthesis of prostaglandins. It reduces total peripheral vascular resistance, blood pressure, preload, and pulmonary capillary pressure. In patients with CHF, it increases cardiac output and increases myocardial tolerance to stress. It dilates arteries more than veins. Some effects are explained by its action on the tissue renin-angiotensin system. With long-term use, it reduces hypertrophy of the myocardium and walls of resistive-type arteries.

Lisinopril improves blood supply to the ischemic myocardium.

In patients with CHF, ACE inhibitors increase life expectancy; in patients with a history of myocardial infarction without clinical manifestations of heart failure, lisinopril slows the progression of left ventricular dysfunction.

In patients with CHF, lisinopril begins to act within 1 hour after oral administration. The maximum effect is achieved within 6-7 hours; the duration of the effect is 24 hours. In patients with arterial hypertension, the effect appears within the first days after starting treatment; effect stabilization occurs within 1-2 months of treatment. Cases of a marked increase in blood pressure after abrupt withdrawal of the drug have not been registered. Lisinopril provides both a reduction in blood pressure and a decrease in albuminuria. In patients with hyperglycemia, the drug promotes the restoration of the function of the damaged glomerular endothelium. In patients with diabetes mellitus, lisinopril does not affect plasma glucose concentration; taking the drug does not lead to an increase in the incidence of hypoglycemia.

Pharmacokinetics

Amlodipine

Absorption

After oral administration, amlodipine is well absorbed from the gastrointestinal tract. The mean absolute bioavailability is 64-80%, C_max in serum is observed after 6-12 hours. C_ss is achieved after 7-8 days of therapy. Food intake does not affect the absorption of amlodipine.

Distribution

The mean V_d is 21 L/kg of body weight, indicating that most of the drug is in the tissues, and a smaller part is in the blood. Most of the amlodipine in the blood (97.5%) is bound to plasma proteins. Amlodipine penetrates the BBB.

Metabolism and excretion

Amlodipine undergoes slow but active metabolism in the liver in the absence of a significant first-pass effect through the liver. Metabolites do not have significant pharmacological activity. T_1/2 from plasma varies from 35 to 50 hours, which allows the drug to be taken once a day. T_1/2 with repeated use is approximately 45 hours. About 60% of the orally administered dose is excreted by the kidneys mainly as metabolites, 10% unchanged, and 20-25% through the intestine with bile. The total clearance of amlodipine is 0.116 ml/s/kg (7 ml/min/kg, 0.42 L/h/kg). Amlodipine is not removed from plasma by hemodialysis.

Pharmacokinetics in special patient groups

Elderly patients (over 65 years). In elderly patients (over 65 years), the elimination of amlodipine is slowed (T_1/2 – 65 hours) compared to young patients, but this difference is not clinically significant.

Patients with hepatic insufficiency. Prolongation of T_1/2 in patients with hepatic insufficiency suggests that with long-term use, the accumulation of the drug in the body will be higher (T_1/2 – up to 60 hours).

Patients with renal insufficiency. Renal insufficiency does not significantly affect the kinetics of amlodipine.

Indapamide

The active substance is in a special matrix-carrier that provides slow controlled release of indapamide in the gastrointestinal tract.

Absorption

The released Indapamide is rapidly and completely absorbed from the gastrointestinal tract. Food intake slightly increases the absorption time of the drug, without affecting the completeness of absorption. C_max is reached 12 hours after a single oral dose. With repeated administration, fluctuations in indapamide plasma concentrations are smoothed out. There is individual variability in the drug absorption parameters.

Distribution

About 79% of the drug is bound to plasma proteins. C_ss is achieved 7 days after the start of therapy. Repeated administration does not lead to drug accumulation.

Excretion

T_1/2 is 14-24 hours (average, 18 hours). Indapamide is excreted mainly as inactive metabolites by the kidneys (70% of the administered dose) and through the intestine (22%).

Pharmacokinetics in special patient groups

The pharmacokinetics of indapamide does not change in patients with renal insufficiency.

Lisinopril

Absorption

When taken orally, about 25% of lisinopril is absorbed from the gastrointestinal tract. Food intake does not affect absorption. Absorption averages 30%, bioavailability is 29%. C_max is reached 6-8 hours after oral administration.

Distribution

The degree of binding to plasma proteins is low. Lisinopril poorly penetrates the BBB.

Metabolism

Lisinopril does not undergo biotransformation in the human body.

Excretion

T_1/2 is 12 hours.

Pharmacokinetics in special patient groups

Patients with CHF. In patients with CHF, the absorption and clearance of lisinopril are reduced. In this category of patients, the absolute bioavailability of lisinopril decreases by approximately 16%.

Patients with renal insufficiency. Impaired renal function leads to an increase in the AUC and T_1/2 of lisinopril, but these changes become clinically significant only when the glomerular filtration rate (GFR) falls below 30 ml/min/1.73 m². In mild and moderate renal insufficiency (CC from 30 to 80 ml/min), the mean AUC value increases by 13%, while in severe renal insufficiency (CC from 5 to 30 ml/min), an increase in the mean AUC value by 4.5 times is observed.

Patients with hepatic insufficiency. In patients with liver cirrhosis, the absorption of lisinopril is reduced (by approximately 30%), but the exposure to the drug is increased (by approximately 50%) compared to healthy volunteers due to reduced clearance.

Elderly patients (over 65 years). In elderly patients, the plasma concentration and AUC of lisinopril are 2 times higher than in young patients.

Indications

The drug Ekvapress^® is indicated for use in adults over 18 years of age

• Arterial hypertension (patients requiring combination therapy).

ICD codes

Dosage Regimen

The drug is taken orally, regardless of meals.

Fixed-dose combination drugs are not recommended for initial therapy. The drug Ekvapress^® is prescribed to adult patients who have achieved adequate blood pressure control while taking lisinopril, amlodipine, and indapamide, which the patient takes simultaneously in the same doses as in the combination drug: amlodipine 5 mg, Indapamide 1.5 mg, lisinopril 10 mg (Ekvapress^® 5 mg + 1.5 mg + 10 mg), amlodipine 10 mg, Indapamide 1.5 mg, lisinopril 20 mg (Ekvapress^® 10 mg + 1.5 mg + 20 mg), amlodipine 5 mg, Indapamide 1.5 mg, lisinopril 20 mg (Ekvapress^® 5 mg + 1.5 mg + 20 mg).

The recommended dose is 1 capsule/day, preferably in the morning at the same time every day. The maximum daily dose is 1 capsule.

If symptomatic arterial hypotension develops at the beginning of treatment with Ekvapress^®, the patient should lie on their back, discontinue the drug, and consult a doctor. Transient arterial hypotension usually does not require drug withdrawal, but the need for dose reduction should be assessed.

If dose titration is necessary, the drugs amlodipine, indapamide, and lisinopril should be used separately.

Missed Dose

If a patient forgets to take a capsule of Ekvapress^®, the next dose should be taken at the usual time. Two capsules should not be taken at the same time to compensate for a missed dose.

Special Patient Groups

In patients with renal insufficiency during therapy with Ekvapress^®, monitoring of renal function, as well as serum potassium and sodium levels, is necessary. If renal function deteriorates, Ekvapress^® should be discontinued and replaced with individually selected therapy from separate components.

In patients with impaired liver function, the elimination of amlodipine may be slowed. For such cases, precise recommendations are not available, so Ekvapress^® should be used with caution in these patients.

The safety and efficacy of Ekvapress^® in children and adolescents (<18 years) have not been established.

This drug should be used with caution in elderly patients (>65 years).

Plasma creatinine concentration should be monitored according to age, body weight, and sex.

Clinical studies have not found age-dependent changes in the efficacy and safety profile of amlodipine or lisinopril.

Adverse Reactions

The most frequent adverse reactions reported during treatment with amlodipine, indapamide, and lisinopril as monotherapy were: dizziness, headache, drowsiness, visual disturbances, tinnitus, palpitations, flushing, decreased blood pressure (and effects associated with arterial hypotension), cough, dyspnea, gastrointestinal disorders (abdominal pain, constipation, diarrhea, nausea, dyspepsia, vomiting), maculopapular rash, muscle cramps, ankle swelling, asthenia, edema, and fatigue.

The following adverse drug reactions (ADRs) were reported during separate use of amlodipine, indapamide, and lisinopril.

Frequency is defined as follows: very common – ≥1/10 (≥10%), common – ≥1/100 to <1/10 (≥1% and <10%), uncommon – ≥1/1,000 to <1/100 (≥0.1% and <1%), rare – ≥1/10,000 to <1/1,000 (≥0.01% and <0.1%), very rare – <1/10,000 (<0.01%), frequency not known (cannot be estimated from the available data). Within each frequency group, adverse reactions are presented in order of decreasing seriousness.

* A symptom complex has been reported which may include one or more of the following symptoms: fever, vasculitis, myalgia, arthralgia/arthritis, positive antinuclear antibody (ANA) test, increased erythrocyte sedimentation rate (ESR), eosinophilia and leukocytosis, skin rash, photosensitivity, or other skin changes.

Contraindications

• Hypersensitivity to amlodipine or other dihydropyridine derivatives;
• Hypersensitivity to lisinopril or other ACE inhibitors;
• Hypersensitivity to indapamide or other sulfonamide derivatives;
• Hypersensitivity to the excipients of the drug;
• Severe arterial hypotension (systolic BP below 90 mm Hg);
• History of angioedema, including that associated with ACE inhibitor use;
• Hereditary or idiopathic angioedema;
• Severe renal failure (CrCl <30 ml/min);
• Hepatic encephalopathy or severe liver dysfunction;
• Hypokalemia;
• Hemodynamically significant left ventricular outflow tract obstruction (e.g., severe aortic stenosis, hypertrophic obstructive cardiomyopathy), hemodynamically significant mitral stenosis;
• Hemodynamically unstable heart failure after myocardial infarction;
• Shock (including cardiogenic);
• Unstable angina (except for Prinzmetal’s angina);
• Concomitant use of Ekvapress^® and drugs containing aliskiren in patients with diabetes mellitus and/or moderate or severe renal impairment (glomerular filtration rate (GFR) less than 60 ml/min/1.73 m² body surface area).
• Concomitant use with angiotensin II receptor antagonists (AIIRAs) in patients with diabetic nephropathy;
• Concomitant use with neutral endopeptidase inhibitors (e.g., drugs containing sacubitril) due to the high risk of angioedema;
• Pregnancy;
• Breastfeeding period;
• Age under 18 years (efficacy and safety not established);
• Hereditary lactose intolerance, galactosemia, glucose-galactose malabsorption syndrome.

With caution

Aortic stenosis, mitral stenosis, hypertrophic obstructive cardiomyopathy, Prinzmetal’s angina, arterial hypotension, cerebrovascular diseases (including cerebral circulatory insufficiency), coronary artery disease, coronary insufficiency, non-ischemic CHF class III-IV, acute myocardial infarction (and within 1 month after myocardial infarction), sick sinus syndrome, severe autoimmune systemic connective tissue diseases (including SLE, scleroderma), myelosuppression, diabetes mellitus, hyperkalemia, bilateral renal artery stenosis, stenosis of the artery to a single kidney, status after kidney transplantation, renal failure, azotemia, primary aldosteronism, salt-restricted diet, conditions associated with reduced blood volume (including vomiting and diarrhea), elderly patients, hepatic insufficiency; history of allergic reaction to penicillin; debilitated patients or patients receiving combined therapy with drugs that prolong the QT interval on ECG (see section “Drug Interactions”); concomitant use with drugs containing aliskiren or angiotensin II receptor antagonists (AIIRAs) (increased risk of arterial hypotension, hyperkalemia, and renal failure with dual blockade of the RAAS); water-electrolyte imbalance; prolongation of the QT interval on ECG; hyperuricemia (especially accompanied by gout and urate nephrolithiasis); hyperparathyroidism; in patients of Black race.

Use in Pregnancy and Lactation

Pregnancy

The use of Ekvapress^® during pregnancy is contraindicated.

Adequately controlled clinical studies on the use of the drug Ekvapress^® during pregnancy have not been conducted. When pregnancy is established, the use of the drug Ekvapress^® should be stopped immediately. Patients planning pregnancy should switch to another antihypertensive drug with an established safety profile during pregnancy.

Amlodipine

The safety of amlodipine during pregnancy has not been established, therefore its use during pregnancy is possible only if the expected benefit to the mother outweighs the potential risk to the fetus.

Indapamide

As a rule, diuretics are contraindicated during pregnancy. It is prohibited to use these drugs to reduce physiological edema during pregnancy. Diuretics can lead to fetoplacental insufficiency and impaired intrauterine development.

Lisinopril

The use of ACE inhibitors by pregnant women in the II-III trimesters can lead to fetal or neonatal death. Careful monitoring of the condition of newborns and infants whose mothers took ACE inhibitors in the prenatal period is indicated to identify possible pronounced arterial hypotension, oliguria and hyperkalemia. The development of oligohydramnios, as well as hypoplasia of the facial bones, deformation of the facial and skull bones, pulmonary hypoplasia and impaired renal development in newborns is possible. Women of childbearing age should use reliable methods of contraception. Lisinopril crosses the placental barrier. Lisinopril is contraindicated during pregnancy.

Breastfeeding period

The use of the drug Ekvapress^® is contraindicated during breastfeeding.

Amlodipine

The safety of amlodipine use during breastfeeding has not been established. Experience with the drug shows that amlodipine is excreted in human breast milk. The mean milk/plasma ratio for amlodipine concentration was 0.85 among 31 breastfeeding women who had pregnancy-induced hypertension and received amlodipine at an initial dose of 5 mg/day. The drug dose was adjusted if necessary (depending on the mean daily dose and body weight: 6 mg and 98.7 mcg/kg, respectively). The estimated daily dose of amlodipine received by the infant through breast milk is 4.17 mcg/kg.

The use of amlodipine during breastfeeding is contraindicated. If it is necessary to use the drug during lactation, breastfeeding should be discontinued.

Indapamide

Not recommended for nursing mothers (Indapamide passes into breast milk).

Lisinopril

There are no data on the passage of lisinopril into breast milk. Breastfeeding should be discontinued during treatment with lisinopril.

Use in Hepatic Impairment

Contraindicated in hepatic encephalopathy or severe liver dysfunction.

Use with caution: hepatic insufficiency.

Use in Renal Impairment

Contraindicated in severe renal failure (creatinine clearance <30 ml/min).

Use with caution: bilateral renal artery stenosis, stenosis of the artery to a single kidney, condition after kidney transplantation, renal failure.

Pediatric Use

Contraindicated for use under the age of 18 years (efficacy and safety have not been established).

Geriatric Use

The drug should be prescribed with caution to elderly patients.

Special Precautions

In case of hospitalization, the patient must inform the attending physician about taking the drug Ekvapress^®.

When using the drug Ekvapress^®, special instructions regarding the individual components of the drug must be taken into account.

Related to amlodipine

Maintenance of dental hygiene and observation by a dentist is necessary (to prevent soreness, bleeding and gingival hyperplasia).

In elderly patients, the T_1/2 of amlodipine may increase and clearance may decrease. Dose adjustment is not required, but more careful monitoring of patients in this category is necessary.

The efficacy and safety of amlodipine in hypertensive crisis have not been established.

Although calcium channel blockers do not have a withdrawal syndrome, discontinuation of amlodipine treatment is desirable by gradually reducing the dose of the drug.

During the use of amlodipine in patients with NYHA class III and IV CHF of non-ischemic origin, an increased incidence of pulmonary edema was noted, despite the absence of signs of worsening heart failure.

Effect on fertility

Some patients receiving calcium channel blockers have been found to have reversible biochemical changes in the sperm head, which may be clinically significant during in vitro fertilization (IVF). However, there is currently insufficient clinical data regarding the potential effect of amlodipine on fertility. A preclinical study revealed adverse effects on fertility in males.

Related to indapamide

Liver dysfunction

When prescribing thiazide and thiazide-like diuretics to patients with impaired liver function, the development of hepatic encephalopathy is possible, especially in the presence of electrolyte imbalance. In this case, it is necessary to stop the use of diuretics.

Photosensitivity

Cases of photosensitivity have been reported with the use of thiazide and thiazide-like diuretics (see section “Adverse Reactions”). If photosensitivity develops, these drugs should be discontinued. If it is necessary to continue treatment, protection of the skin from sunlight or artificial UV radiation is recommended.

Water and electrolyte balance

Plasma sodium content. Plasma sodium levels should be determined before starting treatment and this indicator should be monitored regularly. All diuretics can cause hyponatremia, which can lead to extremely serious consequences. Constant monitoring of plasma sodium levels is necessary, because its decrease may initially have no clinical manifestations. Control of sodium levels should be carried out especially carefully in patients with liver cirrhosis and in the elderly (see sections “Adverse Reactions” and “Overdose”).

All diuretic drugs can cause hyponatremia, sometimes leading to extremely serious consequences. Hyponatremia and hypovolemia can lead to dehydration and orthostatic hypotension. A concomitant decrease in chloride ions can lead to secondary compensatory metabolic alkalosis: the frequency and severity of this effect are insignificant.

Plasma potassium content. During therapy with thiazide and thiazide-like diuretics, a sharp decrease in plasma potassium levels, as well as the development of hypokalemia, is possible. It is necessary to prevent the risk of developing hypokalemia (<3.4 mmol/l) in the following groups of patients: the elderly, debilitated patients and/or those receiving combined drug therapy, patients with liver cirrhosis, peripheral edema and ascites, coronary artery disease, heart failure. In such patients, hypokalemia enhances the toxic effects of cardiac glycosides and increases the risk of arrhythmias. In addition, patients with a prolonged QT interval are at high risk, regardless of whether this increase is caused by congenital causes or the action of drugs.

Hypokalemia, like bradycardia, contributes to the development of severe arrhythmias, especially cardiac arrhythmias, which can be fatal. The first measurement of plasma potassium levels should be performed within the first week of starting treatment. If hypokalemia is detected, appropriate therapy is indicated.

Plasma calcium content. Thiazide and thiazide-like diuretics reduce the excretion of calcium in the urine, which leads to a slight temporary increase in plasma calcium levels. Hypercalcemia with clinical manifestations may be the result of previously undiagnosed hyperparathyroidism. Diuretics should be discontinued before testing parathyroid function.

Blood plasma glucose

Monitoring of glucose concentration is indicated in patients with diabetes mellitus, especially in the presence of hypokalemia.

Uric acid

In patients suffering from gout, an increase in the frequency of gout attacks or an exacerbation of its course is possible.

Diuretics and renal function

Thiazide and thiazide-like diuretics are most effective in patients with normal or slightly reduced renal function (plasma creatinine in adults <25 mg/l or 220 µmol/l). The plasma creatinine concentration in elderly patients is assessed depending on age, body weight and gender.

At the beginning of treatment, patients may experience a decrease in glomerular filtration rate due to hypovolemia, which may be associated with the loss of water and sodium due to the action of diuretics. This may be associated with an increase in the concentration of uric acid and creatinine in the blood plasma. With preserved renal function, such transient functional renal failure usually resolves without complications. However, in the presence of renal failure, the general condition of patients may worsen.

Choroidal effusion/Acute myopia/Secondary angle-closure glaucoma

Sulfonamides and their derivatives can cause an idiosyncratic reaction leading to the development of choroidal effusion with visual field defects, acute myopia and an acute attack of secondary angle-closure glaucoma. Symptoms include: sudden decrease in visual acuity or eye pain, which usually appear within several hours or weeks of starting therapy with a thiazide/thiazide-like diuretic. If left untreated, acute angle-closure glaucoma can lead to irreversible vision loss. If symptoms appear, the thiazide/thiazide-like diuretic should be discontinued as soon as possible. If intraocular pressure remains uncontrolled, emergency medical treatment or surgery may be required. Risk factors for the development of acute angle-closure glaucoma include a history of an allergic reaction to sulfonamide derivatives or penicillin.

Athletes

Indapamide may give a positive doping control result in athletes.

Related to lisinopril

Symptomatic arterial hypotension

Most often, a pronounced decrease in blood pressure is associated with hypovolemia caused by the use of diuretics, a decrease in salt in the diet, dialysis, diarrhea or vomiting (see sections “Drug Interactions”, “Adverse Reactions”). In patients with CHF, regardless of whether it is associated with renal failure, the development of arterial hypotension is possible. It has been found that in patients with severe heart failure, this condition occurs more often in connection with the prescription of high doses of diuretics, hyponatremia or impaired renal function. Such patients require careful medical supervision (it is necessary to carefully select the doses of lisinopril and diuretics). The same instructions apply to patients with coronary artery disease and cerebrovascular insufficiency, in whom a sharp decrease in blood pressure can lead to myocardial infarction or stroke.

If blood pressure decreases significantly, the patient should be placed in a supine position and, if necessary, 0.9% sodium chloride solution should be administered intravenously.

A transient hypotensive reaction is not a contraindication for taking the next dose of lisinopril.

In patients with CHF but with normal or low blood pressure, the use of lisinopril may lead to a decrease in blood pressure; this usually does not serve as a reason for discontinuing the drug. If arterial hypotension becomes symptomatic, it is necessary to reduce the dose of the drug or discontinue treatment with the drug. In patients at risk of developing symptomatic arterial hypotension (with a low-salt or salt-free diet), regardless of the presence of hyponatremia, as well as in patients receiving diuretics in high doses, it is necessary to compensate for hypovolemia or sodium deficiency before starting treatment.

Blood pressure should be monitored when taking the first dose of lisinopril.

Renal dysfunction

In patients with CHF, a significant decrease in blood pressure while taking ACE inhibitors can lead to increased renal dysfunction. Cases of acute renal failure have been reported.

In patients with bilateral renal artery stenosis or stenosis of the renal artery of a single kidney, while taking ACE inhibitors, an increase in the concentration of urea and serum creatinine was noted; usually such disorders were transient and stopped after discontinuation of therapy. They were more common in patients with renal failure.

Lisinopril should not be prescribed to patients with acute myocardial infarction and severe renal impairment (serum creatinine concentration >177 µmol/l and/or proteinuria >500 mg/day). If renal dysfunction develops during treatment (serum creatinine concentration >265 µmol/l or doubling compared to the baseline), lisinopril should be discontinued.

Hypersensitivity, angioedema

In rare cases, during the use of ACE inhibitors, including lisinopril, the development of angioedema of the face, extremities, lips, tongue, epiglottis and/or larynx has been observed. In such cases, immediate withdrawal of lisinopril is required; monitoring of the patient’s condition until the symptoms completely resolve is indicated. Usually, angioedema of the face and lips is temporary and does not require treatment; however, antihistamines may be prescribed.

Laryngeal angioedema can be fatal. Edema of the tongue, epiglottis, or larynx can lead to secondary airway obstruction. In this case, it is necessary to immediately inject 0.3-0.5 ml of 1:1000 adrenaline solution subcutaneously, as well as ensure airway patency.

In rare cases, intestinal angioedema has developed during therapy with ACE inhibitors. In this case, patients experienced abdominal pain as an isolated symptom or in combination with nausea or vomiting, in some cases without preceding facial angioedema and with normal C1-esterase levels. The diagnosis was made using computed tomography of the abdominal organs, ultrasound, or during surgery. The symptoms disappeared 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.

In patients with a history of angioedema not associated with ACE inhibitor use, the risk of its development when using ACE inhibitors is higher (see “Contraindications”).

Anaphylactic reactions associated with desensitization to hymenoptera insects

In very rare cases, patients taking ACE inhibitors may develop life-threatening anaphylactic reactions during desensitization to hymenoptera insects, so it is necessary to temporarily discontinue ACE inhibitors before desensitization.

Patients on hemodialysis

Anaphylactic reactions have also occurred in patients undergoing hemodialysis using high-flux dialysis membranes (e.g., AN69) while receiving ACE inhibitors. Such patients are advised to use other dialysis membranes or other antihypertensive drugs.

Cough

ACE inhibitor therapy may cause cough, which should be considered in the differential diagnosis. A persistent dry cough usually resolves after discontinuation of ACE inhibitors.

Surgical interventions/general anesthesia

The use of antihypertensive drugs during major surgery or during general anesthesia can lead to suppression of angiotensin II formation due to compensatory renin secretion.

A significant decrease in blood pressure associated with this effect can be prevented by increasing the circulating blood volume.

Patients taking ACE inhibitors should inform the surgeon/anesthesiologist about this before surgery (including dental procedures).

Serum potassium

Cases of hyperkalemia have been reported. Risk factors for hyperkalemia include renal failure, diabetes mellitus, therapy with potassium-sparing diuretics (spironolactone, triamterene and amiloride), the use of potassium preparations and potassium-based salt substitutes, especially in patients with impaired renal function.

If combined use of lisinopril and these drugs is necessary, regular monitoring of serum potassium concentration is indicated.

Dual blockade of the RAAS

It has been proven that simultaneous administration of ACE inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of arterial hypotension, hyperkalemia and impaired renal function (including acute renal failure). Thus, combined administration of ACE inhibitors, angiotensin II receptor blockers or aliskiren for dual blockade of the RAAS is not recommended.

If there are absolute indications for dual blockade of the RAAS, it should be carried out under the careful supervision of a specialist with frequent monitoring of renal function, electrolyte levels and blood pressure.

Simultaneous use of ACE inhibitors with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or with moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m² body surface area) and is not recommended in other patients.

Simultaneous use of ACE inhibitors with angiotensin II receptor antagonists is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Neutropenia/agranulocytosis/thrombocytopenia/anemia

Neutropenia/agranulocytosis, thrombocytopenia and anemia may occur during the use of ACE inhibitors. In patients with normal renal function and in the absence of other aggravating factors, neutropenia rarely develops. The drug Ekvapress^® should be prescribed with particular caution to patients with systemic connective tissue diseases, while taking immunosuppressants, allopurinol or procainamide, or when these risk factors are combined, especially to patients with impaired renal function. Some patients developed severe infections, in some cases resistant to intensive antibiotic therapy. When prescribing the drug Ekvapress^® to such patients, it is recommended to periodically monitor the number of leukocytes in the blood plasma. Patients should report any signs of infectious diseases (e.g., sore throat, fever) to their doctor.

Mitral stenosis/aortic stenosis/hypertrophic cardiomyopathy

ACE inhibitors should be prescribed with caution to patients with mitral stenosis, as well as to patients with left ventricular outflow tract obstruction (aortic stenosis, hypertrophic cardiomyopathy).

Hepatic insufficiency

Very rarely, cholestatic jaundice occurs during the use of ACE inhibitors. With the progression of this syndrome, fulminant liver necrosis develops, sometimes with a fatal outcome. The mechanism of development of this syndrome is unclear. If jaundice or a significant increase in liver enzyme activity occurs during the use of ACE inhibitors, the drug Ekvapress^® should be discontinued and the patient should be carefully monitored.

Ethnic Differences

Patients of Black race experience angioedema more frequently than patients of other races when taking ACE inhibitors. ACE inhibitors may have a less pronounced antihypertensive effect in patients of Black race compared to patients of other races. This difference may be due to the fact that Black patients with arterial hypertension more frequently have low renin activity.

Excipients

The drug Ekvapress^® contains lactose monohydrate. Patients with rare hereditary conditions such as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

The drug Ekvapress^® contains mannitol. It may have a mild laxative effect.

Effect on Ability to Drive and Use Machines

There are no data on the effect of the drug Ekvapress^® on the ability to drive vehicles and operate machinery. Considering the possibility of a decrease in blood pressure, the risk of dizziness, drowsiness, and similar adverse effects, patients should exercise caution when engaging in potentially hazardous activities requiring special attention and rapid reactions (driving, operating moving machinery, working as a dispatcher or operator, etc.).

Overdose

Amlodipine Overdose

Symptoms marked decrease in blood pressure with possible development of reflex tachycardia and excessive peripheral vasodilation (there is a risk of significant and persistent hypotension, with the development of shock and fatal outcome).

Treatment gastric lavage, administration of activated charcoal (especially within the first 2 hours after overdose), placing the patient in a supine position with legs elevated, active support of cardiovascular function, monitoring of heart and lung function parameters, monitoring of circulating blood volume and diuresis. If there are no contraindications, the administration of vasoconstrictors may be useful to restore vascular tone and blood pressure. Intravenous injections of calcium gluconate may help reverse the effects of calcium channel blockade. Since amlodipine is highly bound to serum proteins, hemodialysis is not effective in the treatment of amlodipine overdose.

Indapamide Overdose

Toxic effects of indapamide have not been observed in cases of overdose even at very high doses (up to 40 mg, i.e., 27 times the therapeutic dose).

Signs of acute indapamide poisoning are primarily associated with disturbances in water-electrolyte balance (hyponatremia, hypokalemia). Clinical symptoms of overdose may include nausea, vomiting, decreased blood pressure, convulsions, dizziness, drowsiness, confusion, polyuria or oliguria leading to anuria (due to hypovolemia).

Treatment emergency measures include removal of the drug from the body, gastric lavage and/or administration of activated charcoal with restoration of water-electrolyte balance.

Lisinopril Overdose

Symptoms marked decrease in blood pressure, dry mouth, drowsiness, urinary retention, constipation, anxiety, increased irritability.

Treatment symptomatic therapy, intravenous administration of 0.9% sodium chloride solution and, if possible, vasopressors, blood pressure monitoring, monitoring of water-electrolyte balance. Hemodialysis may be performed.

Drug Interactions

Amlodipine

Contraindicated Drug Combinations

Dantrolene (intravenous administration)

Cases of fatal ventricular fibrillation and collapse have been observed in laboratory animals with the use of verapamil and intravenous dantrolene, accompanied by hyperkalemia. Due to the risk of hyperkalemia, concomitant use of the drug Ekvapress^®, containing amlodipine, a slow calcium channel blocker, should be avoided in patients susceptible to malignant hyperthermia, as well as during the treatment of malignant hyperthermia.

Not Recommended Drug Combinations

Grapefruit Juice

Concomitant administration of amlodipine with grapefruit or grapefruit juice is not recommended, as it may increase the bioavailability of amlodipine in some patients, leading to enhanced blood pressure-lowering effects.

Drug Combinations Requiring Special Caution

Inducers of CYP3A4 isoenzyme

Data on the effect of CYP3A4 isoenzyme inducers on the pharmacokinetics of amlodipine are lacking. Concomitant administration of CYP3A4 isoenzyme inducers (e.g., rifampicin, St. John’s wort preparations) and amlodipine may lead to a decrease in the plasma concentration of amlodipine. Caution should be exercised when using the drug Ekvapress^® concomitantly with inducers of the CYP3A4 isoenzyme.

Inhibitors of CYP3A4 isoenzyme

Concomitant administration of amlodipine and strong or moderate CYP3A4 inhibitors (protease inhibitors, e.g., ritonavir, azole antifungals, macrolides, e.g., erythromycin or clarithromycin, verapamil or diltiazem) may lead to a significant increase in amlodipine concentration. The clinical manifestations of these pharmacokinetic deviations may be more pronounced in elderly patients. Therefore, monitoring of clinical status and dose adjustment of the drug Ekvapress^® may be required.

Drug Combinations Requiring Caution

Simvastatin

Multiple administration of amlodipine 10 mg in combination with simvastatin 80 mg resulted in a 77% increase in simvastatin exposure compared to simvastatin monotherapy. Thus, patients receiving amlodipine should take simvastatin at a daily dose not exceeding 20 mg.

Calcium Preparations

May reduce the effect of calcium channel blockers.

Lithium Preparations

When calcium channel blockers are used concomitantly with lithium preparations (no data for amlodipine), an increase in the manifestation of their neurotoxicity (nausea, vomiting, diarrhea, ataxia, tremor, or tinnitus) is possible.

Baclofen

Enhancement of the antihypertensive effect. Blood pressure and renal function should be monitored, and the dose of amlodipine should be adjusted if necessary.

Amifostine

Enhancement of the antihypertensive effect of amlodipine is possible.

Corticosteroids

Reduction of the antihypertensive effect (fluid and sodium retention caused by corticosteroids).

Tricyclic antidepressants, antipsychotics, isoflurane

There is an increased risk of orthostatic hypotension and enhancement of the antihypertensive effect (additive effect).

Tacrolimus

When used concomitantly with amlodipine, there is a risk of increased plasma concentration of tacrolimus. To avoid tacrolimus toxicity when used concomitantly with amlodipine, plasma tacrolimus concentration should be monitored in patients and the tacrolimus dose should be adjusted if necessary.

Tasonermin

When used concomitantly, amlodipine may increase the systemic exposure of tasonermin in plasma. In such cases, regular monitoring of blood tasonermin levels and dose adjustment if necessary is required.

mTOR inhibitors

MTOR inhibitors such as sirolimus, temsirolimus, and everolimus are substrates of the CYP3A isoenzyme. Amlodipine is a weak inhibitor of the CYP3A isoenzyme. When used concomitantly with mTOR inhibitors, amlodipine may increase their exposure.

Other types of interactions with amlodipine

For the treatment of arterial hypertension, amlodipine can be safely used with thiazide diuretics, alpha-blockers, beta-blockers, and ACE inhibitors. In patients with stable angina pectoris, amlodipine can be used concomitantly with other antianginal drugs, such as long-acting and short-acting nitrates, beta-blockers.

Enhancement of the antianginal and antihypertensive effects of calcium channel blockers is likely when used concomitantly with thiazide and loop diuretics, ACE inhibitors, beta-blockers, and nitrates, as well as enhancement of their antihypertensive effect when co-administered with alpha₁-blockers and antipsychotics.

Amlodipine does not cause a negative inotropic effect. Nevertheless, some calcium channel blockers may increase the severity of the negative inotropic effect of antiarrhythmic drugs that cause QT interval prolongation (e.g., amiodarone and quinidine).

Unlike other calcium channel blockers, no significant interaction has been identified between amlodipine (3rd generation calcium channel blocker) and NSAIDs, including indomethacin.

It is safe to prescribe amlodipine with oral hypoglycemic drugs.

A single dose of sildenafil 100 mg in patients with essential arterial hypertension did not affect the pharmacokinetics of amlodipine.

Concomitant multiple administration of amlodipine 10 mg and atorvastatin 80 mg resulted in no significant change in the pharmacokinetic parameters of atorvastatin at steady state.

Ethanol (beverages containing alcohol) amlodipine does not have a significant effect on the pharmacokinetics of ethanol after single and multiple administration at a dose of 10 mg.

Interaction studies of cyclosporine and amlodipine have not been conducted in healthy volunteers and in special patient groups, except for patients after kidney transplantation. Various studies of the interaction between amlodipine and cyclosporine in patients after kidney transplantation show that the use of this combination may either have no effect or increase the minimum concentration of cyclosporine to varying degrees up to 40%. Cyclosporine concentration should be monitored in patients after kidney transplantation.

When amlodipine and digoxin are used concomitantly, renal clearance and serum digoxin concentration do not change.

When warfarin is used concomitantly with amlodipine, prothrombin time does not change.

When used concomitantly with cimetidine, the pharmacokinetics of amlodipine do not change.

Amlodipine does not affect the degree of protein binding of digoxin, phenytoin, warfarin, and indomethacin in plasma in vitro.

Aluminum- and magnesium-containing antacids a single dose of such antacids with amlodipine does not have a significant effect on the pharmacokinetics of amlodipine.

Indapamide

Contraindicated Drug Combinations

Lithium Preparations

When indapamide and lithium preparations are used concomitantly, as well as when a salt-free diet is followed, an increase in plasma lithium concentration may be observed due to a decrease in its excretion, accompanied by signs of overdose. If necessary, diuretic drugs may be used in combination with lithium preparations, while plasma lithium levels should be carefully monitored and the drug dose should be adjusted accordingly.

Drug Combinations Requiring Special Caution

Drugs that can cause polymorphic ventricular tachycardia of the "torsades de pointes" type

• Class IA antiarrhythmic drugs (quinidine, hydroquinidine, disopyramide, procainamide) and Class IC (flecainide).
• Class III antiarrhythmic drugs (amiodarone, sotalol, dofetilide, ibutilide, bretylium tosilate, dronedarone).
• Antipsychotics: phenothiazines (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine, fluphenazine), benzamides (amisulpride, sulpiride, sultopride, tiapride), butyrophenones (droperidol, haloperidol); pimozide, sertindole.
• Antidepressants: tricyclic antidepressants, selective serotonin reuptake inhibitors (citalopram, escitalopram).
• Antibacterial agents: fluoroquinolones (levofloxacin, moxifloxacin, sparfloxacin, ciprofloxacin); macrolides (erythromycin with intravenous administration, azithromycin, clarithromycin, roxithromycin, spiramycin), co-trimoxazole.
• Azole antifungals (voriconazole, itraconazole, ketoconazole, fluconazole).
• Antimalarial agents (quinine, chloroquine, mefloquine, halofantrine, lumefantrine).
• Antianginal agents (ranolazine, bepridil).
• Antineoplastic agents and immunomodulators (vandetanib, arsenic trioxide, oxaliplatin, tacrolimus, anagrelide).
• Antiemetics (ondansetron).
• Drugs affecting gastrointestinal motility (cisapride, domperidone).
• Antihistamines (astemizole, terfenadine, mizolastine).
• Others: pentamidine, diphemanil, vincamine with intravenous administration, vasopressin, terlipressin, ketanserin, probucol, propofol, sevoflurane, terodiline, cilostazol.

Increased risk of ventricular arrhythmias, especially polymorphic ventricular tachycardia of the "torsades de pointes" type (risk factor – hypokalemia).

Before prescribing combined therapy with indapamide and the drugs listed above, an investigation should be conducted to detect hypokalemia and correction should be performed if necessary. Monitoring of the patient’s clinical condition, plasma electrolyte levels, and ECG parameters is necessary.

In patients with hypokalemia, drugs that do not cause polymorphic ventricular tachycardia of the "torsades de pointes" type should be used.

NSAIDs (for systemic use), including selective COX-2 inhibitors, high doses of salicylic acid (>3 g/day)

Possible reduction of the antihypertensive effect of indapamide.

There is a risk of acute renal failure due to decreased glomerular filtration. Patients should be compensated for fluid loss and renal function should be carefully monitored at the beginning of treatment.

ACE Inhibitors

Prescription of ACE inhibitors to patients with initially decreased blood sodium concentration (especially patients with renal artery stenosis) is associated with the risk of sudden arterial hypotension and/or acute renal failure. Patients with arterial hypertension and possibly decreased plasma sodium levels due to diuretic use must

• Discontinue the diuretic 3 days before starting treatment with an ACE inhibitor. Subsequently, if necessary, the non-potassium-sparing diuretic can be resumed;
• Or start therapy with an ACE inhibitor at low doses with a subsequent gradual increase in dose if necessary.

In chronic heart failure, treatment with ACE inhibitors should be started at the lowest possible doses, with a possible preliminary reduction in diuretic doses.

In all cases, during the first weeks of ACE inhibitor use, renal function (plasma creatinine level) should be monitored in patients.

Other drugs that can cause hypokalemia: amphotericin B (with intravenous administration), glucocorticoids and mineralocorticoids (for systemic use), tetracosactide, stimulant laxatives

Increased risk of hypokalemia (additive effect).

Constant monitoring of plasma potassium concentration is necessary, with correction if needed. Particular attention should be paid to patients simultaneously receiving cardiac glycosides. The use of non-stimulant laxatives is recommended.

Baclofen

Enhancement of the antihypertensive effect is noted.

Patients should be compensated for fluid loss and renal function should be carefully monitored at the beginning of treatment.

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 should be adjusted if necessary.

Allopurinol

Concomitant use with indapamide may increase the risk of hypersensitivity during treatment with allopurinol.

Drug Combinations Requiring Caution

Potassium-sparing diuretics (amiloride, spironolactone, triamterene, eplerenone)

Combined therapy with indapamide and potassium-sparing diuretics is appropriate in some patients; however, the possibility of hypokalemia or hyperkalemia is not excluded (especially in patients with diabetes mellitus or in patients with renal failure).

Plasma potassium concentration and ECG parameters should be monitored, and therapy should be adjusted if necessary.

Metformin

Functional renal failure, which can occur during the use of diuretics, especially loop diuretics, when metformin is prescribed concomitantly, increases the risk of lactic acidosis.

Metformin should not be used if plasma creatinine levels exceed 15 mg/l (135 µmol/l) in men and 12 mg/l (110 µmol/l) in women.

Iodine-containing contrast agents

With dehydration caused by diuretics, the risk of acute renal failure increases, especially when high doses of iodine-containing contrast agents are used.

Before using iodine-containing contrast agents, patients must be compensated for fluid loss.

Tricyclic antidepressants, antipsychotic drugs (neuroleptics)

Drugs of these classes enhance the antihypertensive effect of indapamide and increase the risk of orthostatic hypotension (additive effect).

Calcium Salts

When used concomitantly, the risk of hypercalcemia increases due to decreased renal excretion of calcium ions.

Cyclosporine, tacrolimus

An increase in plasma creatinine levels is possible without a change in the concentration of circulating cyclosporine, even with normal circulating blood volume and plasma sodium levels.

Corticosteroids, tetracosactide (for systemic use)

Reduction of the antihypertensive effect (fluid and sodium retention caused by corticosteroids).

Lisinopril

Contraindicated Drug Combinations

Aliskiren

Concomitant use of ACE inhibitors with aliskiren and aliskiren-containing drugs is contraindicated in patients with diabetes mellitus and/or moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m² body surface area).

Prescription of ACE inhibitors with angiotensin II receptor antagonists is contraindicated in patients with diabetic nephropathy.

Not Recommended Drug Combinations

Angiotensin II Receptor Antagonists (ARBs)

The literature has reported that in patients with established atherosclerotic disease, chronic heart failure, or diabetes mellitus with target organ damage, simultaneous therapy with an ACE inhibitor and an ARB is associated with a higher incidence of arterial hypotension, syncope, hyperkalemia, and worsening of renal function (including acute renal failure) compared to the use of only one drug affecting the RAAS. Dual blockade (e.g., combining an ACE inhibitor with an ARB) should be limited to individual cases with careful monitoring of renal function, potassium levels, and blood pressure.

Potassium preparations, potassium-sparing diuretics (spironolactone, triamterene, amiloride, eplerenone) or potassium-containing salt substitutes

The development of hyperkalemia (with a possible fatal outcome) is possible, especially in cases of impaired renal function (additional effects associated with hyperkalemia). ACE inhibitors should not be used simultaneously with substances that increase plasma potassium levels, except in cases of hypokalemia. The combination of lisinopril and the aforementioned agents is not recommended. If, however, concurrent use is indicated, they should be used with precautions and regular monitoring of serum potassium levels.

Lithium preparations

With the simultaneous use of lithium preparations and ACE inhibitors, a reversible increase in serum lithium concentration and associated toxic effects may be noted. The simultaneous use of lisinopril and lithium preparations is not recommended. If such therapy is necessary, regular monitoring of serum lithium concentration should be performed.

Drug combinations requiring special caution during use

Insulin and oral hypoglycemic agents

Epidemiological studies have shown that the concomitant use of ACE inhibitors and hypoglycemic agents (insulins, oral hypoglycemic agents) may enhance their hypoglycemic effect, up to the development of hypoglycemia. This effect is most likely to be observed during the first weeks of concurrent therapy, as well as in patients with impaired renal function.

Baclofen

It enhances the antihypertensive effect of ACE inhibitors. Blood pressure levels should be carefully monitored and, if necessary, the dose of antihypertensive drugs should be adjusted.

Diuretics

In patients taking diuretics, especially those excreting fluid and/or salts, a significant decrease in blood pressure may be observed at the beginning of therapy with an ACE inhibitor. The risk of developing antihypertensive effects can be reduced by discontinuing the diuretic agent, replenishing fluid or salt loss before starting ACE inhibitor therapy. In arterial hypertension in patients with prior diuretic therapy, which could have led to excessive excretion of fluid and/or salts, diuretics should be discontinued before starting the drug Ekvapress^®.

Renal function (creatinine concentration) must be monitored during the first weeks of using the drug Ekvapress^®.

NSAIDs, including acetylsalicylic acid at a dose of ≥3 g/day

Concomitant 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 in the antihypertensive effect of ACE inhibitors. Concurrent use of ACE inhibitors and NSAIDs may lead to worsening of renal function, including the development of acute renal failure and an increase in serum potassium levels, especially in patients with reduced renal function. Caution should be exercised when prescribing this combination, especially in elderly patients. Patients need to compensate for fluid loss and carefully monitor renal function both at the beginning of treatment and during the course of treatment.

Estramustine, mTOR inhibitors (sirolimus, everolimus, temsirolimus)

Concomitant use of estramustine with ACE inhibitors is associated with an increased risk of angioedema.

Neutral endopeptidase inhibitors

An increased risk of angioedema has been reported with the concurrent use of ACE inhibitors and racecadotril (an enkephalinase inhibitor).

When ACE inhibitors are used concurrently with medicinal products containing sacubitril (a neprilysin inhibitor), the risk of angioedema increases, therefore the simultaneous use of these drugs is contraindicated. ACE inhibitors should be prescribed no earlier than 36 hours after discontinuation of drugs containing sacubitril. The administration of drugs containing sacubitril is contraindicated in patients receiving ACE inhibitors, as well as within 36 hours after discontinuation of ACE inhibitors.

DPP-4 inhibitors (gliptins)

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

Drug combinations requiring caution during use

Other antihypertensive agents (e.g., beta-blockers, slow calcium channel blockers, diuretics) and vasodilators

Enhancement of the antihypertensive effect of the drug is possible. Caution should be exercised when co-administering with nitroglycerin, other nitrates, or other vasodilators, as this may lead to an additional decrease in blood pressure.

Antacids and cholestyramine

Concomitant use with antacids and cholestyramine leads to suppression of gastrointestinal absorption.

Tricyclic antidepressants, antipsychotics, general anesthetics, barbiturates, phenothiazine, ethanol

Concomitant administration may enhance the effect of lisinopril.

Sympathomimetics

Sympathomimetics may weaken the antihypertensive effect of ACE inhibitors.

Muscle relaxants

Concomitant use of muscle relaxants with ACE inhibitors may lead to a pronounced decrease in blood pressure.

Gold preparations

Rare cases of nitritoid reactions (a symptom complex including facial skin flushing, nausea, vomiting, and arterial hypotension) have been described in patients receiving ACE inhibitors, including lisinopril, who were receiving intravenous gold preparation (sodium aurothiomalate).

Co-trimoxazole (sulfamethoxazole and trimethoprim)

Increased risk of hyperkalemia.

Selective serotonin reuptake inhibitors (SSRIs: escitalopram, paroxetine, fluoxetine, sertraline)

Concomitant use with SSRIs may lead to the development of severe hyponatremia.

Allopurinol, procainamide, cytostatics (5-fluorouracil, vincristine, docetaxel)

The development of leukopenia is possible.

Tissue plasminogen activators

Observational studies have revealed an increased incidence of angioedema in patients taking ACE inhibitors after the use of alteplase for thrombolytic therapy of ischemic stroke.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

Shelf life is 3 years. Do not use after the expiration date stated on the packaging.

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.