Indapamide Renewal 2.5 mg 90 tablets, film-coated

Indications

Arterial hypertension in adults.

Method of administration and doses

Orally.
The recommended dose is 1 tablet per day, preferably in the morning.
In the treatment of patients with arterial hypertension, the dose of the drug should not exceed 2.5 mg/day (increased risk of side effects without enhancing the antihypertensive effect).
Special patient groups
Patients with impaired kidney function (see sections "Contraindications" and "Special instructions")
Use is contraindicated in patients with severe renal insufficiency (creatinine clearance less than 30 ml/min). Thiazide and thiazide-like diuretics are fully effective only in patients with normal kidney function or minimal impairments.
Patients with impaired liver function (see sections "Contraindications" and "Special instructions")
Use is contraindicated in patients with severe liver insufficiency.
Elderly patients (see section "Special instructions")
In elderly patients, plasma creatinine levels should be monitored considering age, body weight, and sex. The drug can be prescribed to elderly patients with normal kidney function or only with minimal impairments.
Children and adolescents under 18 years of age
The safety and efficacy of indapamide in children and adolescents have not been established. Data are lacking.

Composition per tablet
Active ingredient: indapamide - 2.50 mg;
excipients: lactose monohydrate, corn starch, povidone K30, talc, magnesium stearate; coating composition: hypromellose, titanium dioxide, glycerol, magnesium stearate, macrogol 6000, sodium lauryl sulfate

Description of the dosage form

Round biconvex tablets coated with a film, white or almost white in color. Surface roughness is acceptable. The core is white or almost white in color when cut in cross-section.

Contraindications

• Increased sensitivity to the active substance, other sulfonamide derivatives, or any of the excipients of the drug (see the section "Composition per tablet");

• Severe renal insufficiency (creatinine clearance less than 30 ml/min);

• Hepatic encephalopathy or severe liver dysfunction;

• Hypokalemia;

• Patients with galactose intolerance, lactase deficiency, glucose-galactose malabsorption;

• Pregnancy and breastfeeding;

• Children under 18 years of age.

With Caution

Disorders of liver and kidney function of mild or moderate severity, disturbances in water-electrolyte balance, use in patients with prolonged QT interval on ECG, use in depleted patients, in patients receiving concomitant therapy with drugs that may prolong the QT interval, use with drugs capable of causing polymorphic ventricular tachycardia of the "Torsades de Pointes" type, lithium drugs, drugs that may cause hypokalemia, cardiac glycosides (see the section "Interaction with other medicinal products"), peripheral edema or ascites, ischemic heart disease, heart failure, hyperparathyroidism, diabetes mellitus, hyperuricemia, and gout.

Use During Pregnancy and Breastfeeding

Pregnancy

Currently, there is insufficient data on the use of indapamide during pregnancy (less than 300 cases reported). Prolonged use of thiazide diuretics in the third trimester of pregnancy may cause hypovolemia in the mother and reduced uteroplacental blood flow, leading to fetal placental ischemia and developmental delay of the fetus. Animal studies have not shown direct or indirect toxic effects on reproductive function. As a precaution, it is recommended to avoid the use of indapamide during pregnancy.

Breastfeeding

There is insufficient data on the penetration of indapamide or its metabolites into human breast milk. The newborn may develop increased sensitivity to sulfonamide derivatives and hypokalemia. Therefore, the risk to the newborn/infant cannot be excluded. Indapamide is similar to thiazide diuretics, the use of which causes a decrease in breast milk production or even suppression of lactation. Indapamide should not be used during breastfeeding.

Fertility

Reproductive toxicity studies have shown no effect on the fertility of female and male rats. It is presumed that there is no effect on fertility in humans.

Special instructions

Liver function disorders
When prescribing thiazide and thiazide-like diuretics to patients with liver function disorders, especially in cases of water-electrolyte imbalance, hepatic encephalopathy may develop, which can progress to hepatic coma. In this case, the intake of diuretics should be immediately discontinued.
Photosensitivity reactions
Cases of photosensitivity reactions have been reported during the use of thiazide and thiazide-like diuretics (see the "Side Effects" section).
If photosensitivity reactions develop during treatment with the drug, it is recommended to discontinue therapy. If re-prescribing the diuretic is deemed necessary, it is recommended to protect exposed areas from sunlight or artificial ultraviolet type A rays.
Water-electrolyte balance
• Sodium ion levels in plasma
Before starting treatment, the concentration of sodium ions in plasma should be determined.
During treatment with the drug, this parameter should be monitored regularly. Continuous monitoring of sodium ion concentration is necessary, as initial decreases in sodium concentration in plasma may be asymptomatic. More frequent monitoring of sodium ion concentration is indicated for patients with liver cirrhosis and elderly individuals (see the "Side Effects" and "Overdose" sections).
Any diuretic can cause hyponatremia, which can sometimes lead to extremely severe consequences.
Hyponatremia combined with hypovolemia can lead to dehydration and orthostatic hypotension.
Accompanying decreases in chloride ion concentration in plasma may lead to secondary compensatory metabolic alkalosis: the frequency and severity of this effect are minor.
• Potassium ion levels in plasma
When treating with thiazide and thiazide-like diuretics, the main risk is the decrease in potassium concentration in plasma and the development of hypokalemia. It is necessary to prevent the development of hypokalemia (< 3.4 mmol/L) in high-risk patients: elderly patients, those who are malnourished and/or receiving combined drug therapy, patients with liver cirrhosis, peripheral edema, and ascites, patients with ischemic heart disease, and heart failure. Hypokalemia in these patients enhances the cardiotoxicity of cardiac glycosides and increases the risk of arrhythmias. Patients with a prolonged QT interval, whether congenital or drug-induced, are at risk. Hypokalemia, as well as bradycardia, is a condition that promotes the development of severe arrhythmias, particularly polymorphic ventricular tachycardia (Torsades de Pointes), which can lead to fatal outcomes. In all the cases described above, potassium concentration in plasma should be monitored more frequently than usual. The first measurement of potassium ion concentration in blood should be performed within the first week of treatment. If hypokalemia occurs, appropriate treatment should be initiated. • Calcium levels in plasma Thiazide and thiazide-like diuretics may reduce calcium excretion by the kidneys and lead to a slight and temporary increase in calcium levels in plasma. True hypercalcemia may be a consequence of previously undiagnosed hyperparathyroidism. Diuretic therapy should be discontinued before testing parathyroid function. • Glucose levels in plasma It is important to monitor blood glucose concentration in patients with diabetes, especially in the presence of hypokalemia. • Uric acid In patients with hyperuricemia, the risk of gout attacks may increase. • Diuretic drugs and kidney function Thiazide and thiazide-like diuretics are fully effective only in patients with normal or slightly impaired kidney function (plasma creatinine levels in adults below 25 mg/L or 220 µmol/L). In elderly patients, normal plasma creatinine levels are calculated considering age, body weight, and sex. It should be noted that at the beginning of treatment, patients may experience a decrease in glomerular filtration rate due to hypovolemia, which, in turn, is caused by the loss of water and sodium ions during diuretic therapy. As a result, plasma concentrations of urea and creatinine may increase. This transient functional renal failure is of no clinical significance in patients with normal kidney function but may exacerbate pre-existing renal insufficiency. • Choroidal effusion/acute myopia/acute angle-closure glaucoma Sulfonamides and their derivatives may cause an idiosyncratic reaction leading to choroidal effusion with visual field disturbances, acute transient myopia, and acute angle-closure glaucoma. Symptoms include a sudden onset of decreased visual acuity or eye pain and usually occur within a few hours or weeks after starting the medication. Without treatment, an acute attack of angle-closure glaucoma may lead to permanent vision loss. It is essential to discontinue the medication as soon as possible. If intraocular pressure remains uncontrolled, emergency medical treatment or surgical intervention may be required. Risk factors for developing an acute attack of angle-closure glaucoma include allergic reactions to sulfonamide derivatives and penicillins in the medical history. • Athletes Athletes should be aware that the active substance contained in the drug Indapamide may yield a positive result in doping control.Effect on the ability to drive vehicles and operate machinery Indapamide does not affect attention impairment, but in some cases, reactions related to decreased blood pressure may occur, especially at the beginning of therapy or when adding other antihypertensive agents to ongoing therapy. As a result, the ability to drive vehicles or operate other machinery may be impaired.

Section: Side Effects

General information about the safety profile
The most common adverse reactions reported were: hypersensitivity reactions, mainly dermatological, in patients predisposed to allergic and asthmatic reactions, as well as maculopapular rash.
In clinical studies, hypokalemia (plasma potassium concentration less than 3.4 mmol/L) was observed in 25% of patients, and plasma potassium concentration less than 3.2 mmol/L was observed in 10% of patients 4-6 weeks after the start of therapy. After 12 weeks of therapy, the average decrease in plasma potassium concentration was 0.41 mmol/L.
Most adverse reactions (laboratory and clinical indicators) are dose-dependent.
The frequency of adverse reactions is presented according to the MedDRA classification: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10000, < 1/1000); very rare (< 1/10000); frequency unknown (frequency cannot be calculated from available data). MedDRA classes and organ systems Adverse reactions Frequency Disorders of the blood and lymphatic system Agranulocytosis Very rare Aplastic anemia Very rare Hemolytic anemia Very rare Leukopenia Very rare Thrombocytopenia Very rare Disorders of metabolism and nutrition Hypercalcemia Very rare Decrease in potassium concentration and development of hypokalemia, especially significant for patients in the risk group (see "Special Precautions" section) Frequency unknown Hyponatremia (see "Special Precautions" section) Frequency unknown Disorders of the nervous system Vertigo Rare Increased fatigue Rare Headache Rare Paresthesia Rare Syncope Frequency unknown Disorders of the eye Myopia Frequency unknown Blurred vision Frequency unknown Visual impairment Frequency unknown Choroidal effusion Frequency unknown Disorders of the heart Arrhythmia Very rare Polymorphic ventricular tachycardia type "Torsades de Pointes" (possibly fatal) (see "Special Precautions" and "Interactions with Other Medicinal Products" sections) Frequency unknown Disorders of the vascular system Arterial hypotension Very rare Disorders of the gastrointestinal tract Vomiting Uncommon Nausea Rare Constipation Rare Dryness of the oral mucosa Rare Pancreatitis Very rare Disorders of the liver and biliary tract Impaired liver function Very rare Possible development of hepatic encephalopathy in case of liver failure (see "Contraindications" and "Special Precautions" sections) Frequency unknown Hepatitis Frequency unknown Disorders of the skin and subcutaneous tissue Hypersensitivity reactions Common Maculopapular rash Common Hemorrhagic vasculitis Uncommon Angioedema and/or urticaria Very rare Toxic epidermal necrolysis Very rare Stevens-Johnson syndrome Very rare Possible exacerbation of pre-existing acute systemic lupus erythematosus Frequency unknown Photosensitivity reactions (see "Special Precautions" section) Frequency unknown Disorders of the kidneys and urinary tract Renal failure Very rare Laboratory indicators Prolongation of the QT interval on ECG (see "Interactions with Other Medicinal Products" and "Special Precautions" sections) Frequency unknown Increase in blood glucose concentration (see "Special Precautions" section) Frequency unknown Increase in blood uric acid concentration (see "Special Precautions" section) Frequency unknown Increase in liver enzyme activity Frequency unknownSection: OverdoseIndapamide, even in very high doses (up to 40 mg, which is 16 times the therapeutic dose), does not have a toxic effect. Symptoms of acute poisoning are associated with disturbances in water-electrolyte balance (hyponatremia, hypokalemia). Nausea, vomiting, significant decrease in blood pressure, seizures, dizziness, drowsiness, confusion, polyuria, or oliguria up to anuria (due to hypovolemia) may also be observed. Treatment: emergency measures consist of removing the drug from the body: gastric lavage and/or administration of activated charcoal, followed by restoration of water-electrolyte balance.Combinations not recommended for use • Lithium preparations: When indapamide is used simultaneously with lithium preparations, as well as during a salt-free diet, an increase in lithium concentration in the plasma may be observed due to decreased excretion, accompanied by signs of overdose. If necessary, diuretic preparations can be used in combination with lithium preparations, while monitoring lithium levels in the plasma and adjusting the drug dosage accordingly. Combinations requiring caution • Preparations that can cause polymorphic ventricular tachycardia type "Torsades de Pointes":• Class IA antiarrhythmic drugs (quinidine, hydroquinidine, disopyramide, procainamide) and class IC (flecainide);• Class III antiarrhythmic drugs (amiodarone, sotalol, dofetilide, ibutilide, bretylium tosylate, dronedarone);• Neuroleptics: phenothiazines (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine), 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 when administered intravenously, azithromycin, clarithromycin, roxithromycin, spiramycin), co-trimoxazole; Antifungal agents of the azole group (voriconazole, itraconazole, ketoconazole, fluconazole);• Antimalarial agents (quinine, chloroquine, mefloquine, halofantrine, lumefantrine);• Antianginal agents (ranolazine, bepridil);• Antineoplastic drugs and immunomodulators (vandetanib, arsenic trioxide, oxaliplatin, tacrolimus, anagrelide);• Antiemetic agents (ondansetron);• Agents affecting gastrointestinal motility (cisapride, domperidone);• Antihistamines (astemizole, terfenadine, mizolastine)• Others: pentamidine, difemanil, vincamine (IV), vasopressin, terlipressin, ketanserin, probucol, profonol, sevoflurane, terodiline, cilostazol. Before prescribing combination therapy with indapamide and the above-mentioned preparations, it is necessary to conduct a study to identify hypokalemia and, if necessary, perform correction. Continuous monitoring of the patient's clinical condition, plasma electrolyte levels, and ECG indicators is required. In patients with hypokalemia, it is necessary to use preparations that do not cause Torsades de Pointes arrhythmia. • Non-steroidal anti-inflammatory drugs of systemic action, including selective cyclooxygenase-2 (COX-2) inhibitors, high doses of acetylsalicylic acid (≥ 3 g/day): There may be a decrease in the antihypertensive effect of indapamide. In dehydrated patients, there is a risk of acute renal failure due to decreased glomerular filtration rate. Patients need to compensate for fluid loss and carefully monitor kidney function at the beginning of therapy. • Angiotensin-converting enzyme (ACE) inhibitors: The use of ACE inhibitors in patients with low sodium levels in the blood (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 reduced sodium ion levels in the plasma due to diuretic use need to:• stop taking the diuretic 3 days before starting therapy with an ACE inhibitor. If necessary, the diuretic can be resumed later;• or start therapy with an ACE inhibitor at low doses, with subsequent gradual dose increases if necessary. In cases of chronic heart failure, therapy with ACE inhibitors should begin with low doses, possibly with a preliminary reduction in diuretic doses. In all cases, during the first week of taking ACE inhibitors, patients need to monitor kidney function (plasma creatinine levels). • Other drugs that can cause hypokalemia: amphotericin B (IV), glucocorticoids and mineralocorticoids when used systemically, tetracosactide, laxatives that stimulate intestinal motility: Increased risk of developing hypokalemia (additive effect). Continuous monitoring of potassium levels in the plasma and, if necessary, correction is required. It is recommended to use laxatives that do not stimulate intestinal motility. • Baclofen: Increased hypotensive effect is noted. Patients need to compensate for fluid loss and carefully monitor kidney function at the beginning of treatment. • Cardiac glycosides: Hypokalemia enhances the toxic effects of cardiac glycosides. When indapamide and cardiac glycosides are used simultaneously, potassium levels in the plasma, ECG indicators, and therapy may need to be adjusted. Combinations requiring special attention • Potassium-sparing diuretics (amiloride, spironolactone, triamterene): Combination therapy with indapamide and potassium-sparing diuretics is appropriate in some patients; however, the possibility of developing hypokalemia or hyperkalemia (especially in patients with renal insufficiency or diabetes) cannot be excluded. Potassium levels in the plasma, ECG indicators, and therapy may need to be adjusted. • Metformin: Functional renal insufficiency, which may occur against the background of diuretics, especially loop diuretics, when metformin is prescribed simultaneously increases the risk of lactic acidosis. Metformin should not be used if creatinine levels exceed 15 mg/l (135 μmol/l) in men and 12 mg/l (110 μmol/l) in women. • Iodine-containing contrast agents: In cases of dehydration due to diuretic use, the risk of acute renal failure increases, especially when using high doses of iodine-containing contrast agents. Before using iodine-containing contrast agents, patients need to compensate for fluid loss. • Tricyclic antidepressants, antipsychotic agents (neuroleptics): Drugs in these classes enhance the antihypertensive effect of indapamide and increase the risk of orthostatic hypotension (additive effect). • Calcium (salts): When used simultaneously, hypercalcemia may develop due to decreased excretion of calcium ions by the kidneys. • Cyclosporine, tacrolimus: There may be an increase in plasma creatinine levels without changes in circulating cyclosporine concentration, even with normal fluid and sodium ion levels. • Corticosteroid preparations, tetracosactide (when used systemically): Decreased hypotensive effect (fluid and sodium ion retention due to the action of corticosteroids).

Pharmacodynamics

Mechanism of action
Indapamide belongs to the sulfonamide derivatives with an indole ring and is pharmacologically similar to thiazide diuretics, which inhibit the reabsorption of sodium ions in the cortical segment of the nephron loop.
This increases the excretion of sodium, chloride, and to a lesser extent, potassium and magnesium ions by the kidneys, which is accompanied by an increase in diuresis and a hypotensive effect.
Pharmacodynamic effects
In clinical studies of phases II and III, the use of indapamide in a monotherapy regimen at doses that do not produce a pronounced diuretic effect demonstrated a 24-hour hypotensive effect.
The antihypertensive activity of indapamide is associated with the improvement of the elastic properties of large arteries, 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 further dose escalation. Therefore, the dose of the drug should not be increased if the therapeutic effect is not achieved with the recommended dose.
In short, medium-duration, and long-term studies involving patients with arterial hypertension, it has been shown that indapamide:
• does not affect lipid metabolism parameters, including levels of triglycerides, cholesterol, low-density lipoproteins, and high-density lipoproteins;
• does not affect carbohydrate metabolism parameters, including in patients with diabetes mellitus.

Pharmacokinetics

Absorption

The bioavailability of indapamide is 93%. The maximum concentration in plasma (Tmax) is reached 1-2 hours after a single oral dose of 2.5 mg.

Distribution

About 75% of the drug binds to plasma proteins. The half-life of the drug is 14-24 hours (on average 18 hours). With regular use of the drug, the steady-state concentration of indapamide in plasma increases (compared to a single dose). At the same time, the achieved steady state is maintained for a long period, indicating that repeated administration of the drug does not lead to accumulation of indapamide in the body.

Excretion

Indapamide is excreted as inactive metabolites mainly in the urine (60-80% of the administered dose). No more than 5% of indapamide is excreted unchanged in the urine. In patients with renal insufficiency, the pharmacokinetic properties of indapamide do not change.