Indopres

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT INDOPRES (Indopres)

Composition:

Active substance: indapamide;

1 tablet contains 2.5 mg of indapamide, calculated as 100% anhydrous substance;

Excipients: lactose monohydrate, sodium lauryl sulfate, calcium stearate; film-coating: hydroxypropylcellulose, lactose monohydrate, titanium dioxide (E 171), polyethylene glycol 3000, triacetin.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated tablets, white in color, with a biconvex surface. In cross-section, two layers of different structure are visible.

Pharmacotherapeutic group.

Agents affecting the cardiovascular system. Non-thiazide diuretics with moderately expressed activity. Simple sulfonamides. Indapamide. ATC Code C03BA11.

Pharmacological Properties.

Pharmacodynamics.

Indapamide is a sulfonamide diuretic pharmacologically related to thiazide diuretics. Indapamide inhibits sodium reabsorption in the cortical segment of the kidneys. This increases urinary excretion of sodium and chlorides, and to a lesser extent, excretion of potassium and magnesium, thereby enhancing diuresis.

The antihypertensive effect of indapamide is evident at doses where the diuretic effect is minimal. Moreover, its antihypertensive action persists even in patients with arterial hypertension undergoing hemodialysis.

Indapamide acts at the vascular level through:

• reducing the contractility of vascular smooth muscle, associated with changes in transmembrane ion exchange (primarily calcium);
• stimulating the synthesis of prostaglandin PGE₂ and prostacyclin PGI₂ (vasodilators and inhibitors of platelet aggregation).

Indapamide reduces left ventricular hypertrophy.

As demonstrated in studies of varying duration (short, medium, and long-term) involving patients with arterial hypertension, indapamide does not affect:

• lipid metabolism (triglycerides, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol);
• carbohydrate metabolism, even in patients with diabetes mellitus and arterial hypertension.

When the recommended dose is exceeded, the therapeutic effect of thiazide and thiazide-like diuretics does not increase, while the risk of adverse effects rises. If treatment is insufficiently effective, the dose should not be increased.

Pharmacokinetics.

Absorption

Indapamide has high bioavailability – 93%.

Maximum plasma concentration (T_max) after a 2.5 mg dose is reached approximately within 1–2 hours.

Distribution

Protein binding in plasma exceeds 75%.

The elimination half-life ranges from 14 to 24 hours (on average, 18 hours).

With regular administration of indapamide, a higher steady-state plasma concentration (plateau) is achieved compared to the plasma concentration after a single dose. This concentration level remains stable over a prolonged period without accumulation.

Elimination

Renal clearance accounts for 60–80% of total clearance.

Indapamide is primarily excreted in the form of metabolites; the fraction excreted unchanged in the urine is 5%.

Patients with renal impairment: pharmacokinetic parameters are not altered.

Clinical characteristics.

Indications.

Essential hypertension.

Contraindications.

• Hypersensitivity to indapamide, to any component of the medicinal product, other sulfonamides or their derivatives;
• hepatic encephalopathy, severe hepatic impairment;
• severe renal impairment;
• hypokalemia.

Interaction with other medicinal products and other forms of interaction.

The drug may be used both as monotherapy and in combination with other antihypertensive agents.

Not recommended combinations.

Lithium: increased plasma lithium levels (due to reduced excretion) and occurrence of symptoms of lithium overdose. If such combination is necessary, plasma lithium levels should be monitored and the dose adjusted accordingly.

Combinations requiring caution.

Medicinal products that may cause "torsade de pointes":

• Class IA antiarrhythmics (quinidine, hydroquinidine, disopyramide);
• Class III antiarrhythmics (amiodarone, bretylium, sotalol, dofetilide, ibutilide);
• certain antipsychotics:
  • phenothiazines (chlorpromazine, thioproperazine, levomepromazine, thioridazine, trifluoperazine);
  • benzamides (amisulpride, sulpiride, sultopride, tiapride);
  • butyrophenones (droperidol, haloperidol);
  • pimozide, sertindole, zotepine;
• drugs from other groups: astemizole, mizolastine, terfenadine, bepridil, cisapride, difemanil, atomoxetine, arsenic compounds, intravenous erythromycin, clarithromycin, halofantrine, pentamidine, sparfloxacin, moxifloxacin, intravenous vinca alkaloids.

Risk of ventricular arrhythmias, especially "torsade de pointes" (hypokalemia, as well as bradycardia and prolonged QT interval, are risk factors). Hypokalemia must be corrected before initiating such combination therapy. Monitoring of clinical status, ECG (QT interval), and plasma electrolyte levels is mandatory.

Medicinal products that do not induce arrhythmias of the "torsade de pointes" type should be used in the presence of hypokalemia.

Systemic nonsteroidal anti-inflammatory drugs, including COX-2 selective inhibitors, high-dose salicylates (≥ 3 g/day): possible reduction in the antihypertensive effect of indapamide. In dehydrated patients, acute renal failure may occur (due to decreased glomerular filtration). Renal function should be monitored before and during treatment, and fluid imbalance should be corrected.

ACE inhibitors, angiotensin-II receptor antagonists: risk of sudden arterial hypotension and/or acute renal failure at the beginning of treatment with ACE inhibitors or angiotensin-II receptor antagonists in the presence of pre-existing hyponatremia (especially in patients with renal artery stenosis).

In arterial hypertension, when prior diuretic therapy has caused hyponatremia, it is recommended to:

• discontinue diuretic therapy 3 days before starting ACE inhibitors/angiotensin-II receptor antagonists (and subsequently resume if necessary);
• or initiate treatment with low doses of ACE inhibitors/angiotensin-II receptor antagonists, gradually increasing the dose.

In congestive heart failure, treatment should begin with very low doses of ACE inhibitors/angiotensin-II receptor antagonists, with concomitant reduction of the potassium-wasting diuretic dose.

In all cases, monitoring of renal function (plasma creatinine levels) is mandatory during the first weeks of treatment with ACE inhibitors/angiotensin-II receptor antagonists.

Alpha-adrenergic blockers: enhanced antihypertensive effect; increased risk of first-dose hypotension with postsynaptic alpha-blockers such as prazosin.

Diuretics that may cause hypokalemia (e.g., bumetanide, furosemide, piretanide, thiazides, xipamide, acetazolamide): increased risk of hypokalemia. Plasma potassium levels should be closely monitored and corrected if necessary.

Other medicinal products that may cause hypokalemia (amphotericin B (intravenous), high doses of beta2-sympathomimetics, systemic glucocorticoids and mineralocorticoids, tetracosactide, theophylline, stimulant laxatives, reboxetine): increased risk of hypokalemia (additive effect). Plasma potassium levels should be monitored, especially when concomitant therapy with cardiac glycosides is used, and corrected if needed. Use non-stimulant laxatives.

Baclofen: enhanced antihypertensive effect. Patient rehydration is required, and renal function should be monitored at the beginning of treatment.

Cardiac glycosides (digitalis preparations): risk of increased toxicity of cardiac glycosides (due to possible diuretic-induced hypokalemia and/or hypomagnesemia). Monitoring of plasma potassium and magnesium levels and ECG is required; treatment should be reviewed if necessary.

Flecainide: diuretic-induced hypokalemia enhances the cardiotoxicity of flecainide.

Lidocaine, mexiletine: diuretic-induced hypokalemia antagonizes the effects of lidocaine and mexiletine.

Combinations requiring attention.

Potassium-sparing diuretics (amiloride, spironolactone, triamterene): although such combination may be beneficial in some patients, there is a risk of hypokalemia (especially in patients with diabetes mellitus or renal impairment) or hyperkalemia. Plasma potassium levels and ECG should be monitored, and treatment reviewed if necessary.

Metformin: increased risk of metformin-induced lactic acidosis due to diuretic-associated functional renal impairment, particularly with loop diuretics. Metformin should not be used when plasma creatinine levels exceed 15 mg/L (135 mmol/L) in men and 12 mg/L (110 mmol/L) in women.

Iodinated contrast agents: in cases of dehydration caused by diuretic use, the risk of acute renal failure is increased, especially with high doses of iodinated contrast agents. Adequate hydration should be ensured prior to administration.

Calcium salts, vitamin D, toremifene: increased risk of hypercalcemia due to reduced urinary excretion of calcium.

Oxcarbazepine, carbamazepine: increased risk of hyponatremia when used concomitantly with indapamide.

Imipramine-like antidepressants, neuroleptics, anxiolytics and sedatives, MAO inhibitors, alprostadil, aldesleukin, levodopa, general anesthetics: enhanced antihypertensive effect of indapamide and increased risk of orthostatic hypotension.

Other antihypertensive agents (including beta-blockers, calcium channel blockers, nitrates, vasodilators, methyldopa, moxonidine, clonidine): enhanced antihypertensive effect and increased risk of orthostatic hypotension (additive effect).

Ciclosporin, tacrolimus: risk of increased plasma creatinine levels without changes in circulating ciclosporin levels, even in the absence of water-sodium deficit.

Corticosteroids, tetracosactide (systemic action): reduced antihypertensive effect of indapamide due to water and sodium retention induced by glucocorticoids.

Estrogens: possible reduction in antihypertensive effect of the drug due to fluid retention.

Cholestyramine, colestipol: reduced absorption of diuretics. The interval between administration of indapamide and these agents should be at least 2 hours.

Indirect anticoagulants (coumarin or indandione derivatives): reduced anticoagulant effect due to increased concentration of blood coagulation factors resulting from decreased blood volume and increased hepatic production (dose adjustment may be required).

Non-depolarizing muscle relaxants: enhanced neuromuscular blockade.

Allopurinol: concomitant treatment with indapamide may increase the frequency of hypersensitivity reactions to allopurinol.

Gives a positive reaction in doping control.

Special precautions.

Patients with impaired liver function.

In patients with impaired liver function, thiazide-like diuretics may precipitate hepatic encephalopathy, especially in the presence of electrolyte imbalance. In such cases, or if symptoms of worsening renal insufficiency occur, the drug must be discontinued immediately.

Photosensitization.

Cases of photosensitization reactions have been reported with thiazide and thiazide-like diuretics. If photosensitization reactions develop during treatment, the drug should be discontinued immediately. If continued use of the drug is necessary, it is recommended to protect exposed areas of skin from direct sunlight and artificial ultraviolet radiation.

Choroidal effusion, acute myopia, and secondary angle-closure glaucoma.

Drugs containing sulfonamide or sulfonamide derivatives, including indapamide, may cause an idiosyncratic reaction leading to choroidal effusion with visual field defects, acute transient myopia, and acute angle-closure glaucoma. Symptoms include sudden onset of decreased visual acuity or eye pain and usually occur within hours to weeks after initiating treatment.

Untreated acute angle-closure glaucoma can lead to irreversible vision loss. The primary step in management is prompt discontinuation of indapamide. If intraocular pressure remains uncontrolled, urgent medical or surgical intervention should be considered. Risk factors for developing acute angle-closure glaucoma may include a history of allergy to sulfonamides or penicillins.

Excipients.

The drug contains lactose; therefore, patients with rare hereditary disorders such as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this drug.

The drug contains sodium lauryl sulfate, which should be taken into account in patients on a sodium-controlled diet.

Water and electrolyte balance.

Serum sodium. Serum sodium levels should be determined before initiating treatment with Indopres and monitored regularly thereafter. Treatment with any diuretic may lead to hyponatremia, sometimes with very serious consequences. Decreased plasma sodium levels may initially be asymptomatic; therefore, regular monitoring is essential and should be performed more frequently in elderly patients and in patients with liver cirrhosis.

Hyponatremia with hypovolemia may result in dehydration and orthostatic hypotension. Concomitant chloride ion loss may lead to secondary compensatory metabolic alkalosis; the frequency and severity of this effect are low.

Cases of severe hyponatremia in combination with hypokalemia have been reported during treatment with recommended doses, more frequently in elderly women.

Serum potassium. Reduction in plasma potassium levels leading to hypokalemia is a major risk associated with thiazide and thiazide-like diuretics. Hypokalemia (< 3.4 mmol/L) should be prevented, particularly in high-risk patients (elderly patients, patients on multiple medications, patients with unbalanced/inadequate nutrition, patients with hyperaldosteronism, patients with cirrhosis and edema or ascites, patients with ischemic heart disease or heart failure). In such cases, hypokalemia increases the cardiotoxicity of cardiac glycosides and the risk of arrhythmias. Patients with prolonged QT interval (congenital or drug-induced) are also at increased risk.

Hypokalemia, as well as bradycardia, may predispose to severe arrhythmias, including paroxysmal ventricular tachycardia of the "torsade de pointes" type, sometimes with fatal outcome.

In all the above cases, serum potassium levels should be monitored more frequently. Initial measurements should be performed during the first week of treatment. If hypokalemia is detected, it should be corrected. Hypokalemia associated with low serum magnesium levels may be refractory to treatment unless serum magnesium levels are also corrected.

Serum magnesium. Thiazides and related diuretics, including indapamide, increase urinary excretion of magnesium, which may lead to hypomagnesemia (see sections "Interaction with other medicinal products and other forms of interaction" and "Undesirable effects").

Serum calcium. Thiazide and thiazide-like diuretics may reduce urinary calcium excretion and consequently cause a slight, transient increase in plasma calcium levels. Marked hypercalcemia may occur in the presence of previously undiagnosed hyperparathyroidism. Indapamide may reduce plasma parathyroid hormone levels. Indapamide treatment should be discontinued prior to evaluation of parathyroid function.

Since an increase in blood glucose levels may occur during treatment with indapamide, monitoring this parameter is important in patients with diabetes mellitus, especially in the presence of hypokalemia.

Due to possible elevation of serum uric acid levels during treatment, patients with hyperuricemia may experience an increased frequency of gout attacks.

Renal function and diuretics. Thiazide and thiazide-like diuretics are fully effective only when renal function is normal or minimally impaired (plasma creatinine level below 25 mg/L (220 µmol/L) in adults). It should be noted that in elderly patients, this value depends on age, body weight, and sex.

Hypovolemia resulting from water and sodium loss induced by diuretics leads to reduced glomerular filtration, which may cause increased blood levels of urea and creatinine. This transient functional renal insufficiency has no consequences in patients with normal renal function but may worsen pre-existing renal impairment. Use with caution in patients with nephrotic syndrome.

During indapamide use, a positive result in doping control testing in athletes is possible.

Use during pregnancy or breastfeeding.

Pregnancy.

Data on the use of indapamide in pregnant women are lacking or limited (fewer than 300 cases). Prolonged use of diuretics during the third trimester of pregnancy may reduce maternal plasma volume and uteroplacental perfusion, potentially causing fetoplacental ischemia and risk of fetal growth retardation.

Animal studies have not revealed any direct or indirect toxic effects on reproductive function. As a precautionary measure, indapamide should be avoided during pregnancy.

Breastfeeding.

Data on the passage of indapamide/metabolites into breast milk are insufficient. Hypersensitivity to sulfonamide derivatives and hypokalemia may develop. Risk to newborns/infants cannot be excluded. Indapamide belongs to thiazide-like diuretics, the use of which during breastfeeding is associated with reduced or even suppressed lactation. Indapamide is contraindicated during breastfeeding.

Fertility.

Reproductive toxicity studies showed no effect on fertility in male and female rats. An effect on human fertility is not expected.

Ability to affect reaction speed while driving or operating machinery.

The drug does not impair psychomotor function; however, if adverse reactions occur (see section "Undesirable effects"), including symptoms related to sudden drop in blood pressure—especially at the beginning of treatment or in combination with other antihypertensive agents—it may affect the ability to drive or operate machinery.

Administration and Dosage

For oral use. Indopres should be administered at a dose of 2.5 mg (1 tablet) once daily (in the morning), before meals.

The effect of the drug develops gradually. Increasing the dose is not advisable, as antihypertensive action does not significantly increase at higher doses, but diuretic effect becomes more pronounced. If the therapeutic effect is insufficient, combination therapy with other antihypertensive agents is recommended. Combination therapy with diuretics that may cause hypokalemia is not recommended.

Duration of treatment is determined by the course of the disease and therapeutic response.

There is no evidence of rebound arterial hypertension after discontinuation of indapamide.

Renal impairment. The use of the drug is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min). Thiazide and thiazide-like diuretics are most effective when renal function is normal or only minimally impaired (see sections "Special precautions for use" and "Contraindications").

Elderly patients. In elderly patients, plasma creatinine levels should be assessed considering age, body weight, and gender. Indopres should be prescribed to patients in this age group only if renal function is normal or minimally impaired (see section "Special precautions for use").

Hepatic impairment. Treatment with the drug is contraindicated in case of severe hepatic impairment (see sections "Special precautions for use" and "Contraindications").

Children

The drug is not recommended for use in children due to insufficient data on safety and efficacy of indapamide in this patient group.

Overdose

Indopres may cause mild toxic effects when administered at doses exceeding 40 mg. Signs of overdose are primarily manifested as water-electrolyte disturbances (hyponatremia, hypokalemia). Clinical symptoms include nausea, vomiting, dyspepsia, arterial hypotension, muscle weakness, cramps, respiratory depression, dizziness, drowsiness, confusion, polyuria or oliguria (anuria due to hypovolemia may occur).

Treatment. Gastric lavage, activated charcoal, and restoration of water-electrolyte balance should be performed under hospital conditions. Symptomatic therapy.

Adverse reactions.

Treatment with Indopres is generally well tolerated. Most clinical and laboratory adverse effects are dose-dependent. The risk of their occurrence can be significantly reduced by using the minimum effective dose.

The most commonly reported adverse reactions include hypokalemia, hypersensitivity reactions (mainly dermatological), maculopapular rashes, particularly in patients predisposed to allergic and asthmatic reactions.

Metabolic disorders:

• Decreased potassium levels and development of hypokalemia, which may be particularly serious in high-risk patients (see section "Special precautions");
• Hypercalcemia;
• Hyponatremia, which may lead to hypovolemia and dehydration with possible development of orthostatic hypotension. Concomitant loss of chloride ions may cause compensatory metabolic alkalosis; the extent and severity of this effect are generally minor. Warning signs of electrolyte disturbances may include excessive thirst, confusion, muscle cramps, muscle weakness, and cardiac arrhythmias;
• Hypochloremia;
• Hypomagnesemia;
• Hyperuricemia and hyperglycemia during treatment; a slight decrease in glucose tolerance may occur in patients with diabetes mellitus. The use of this drug in patients with gout or diabetes mellitus should be carefully considered.

Hematological disorders: thrombocytopenia, leukopenia, agranulocytosis, hemolytic anemia, aplastic anemia.

Neurological disorders: dizziness (vertigo), fatigue, paresthesia, headache, syncope.

Cardiovascular disorders: QT interval prolongation on ECG, arrhythmias including potentially life-threatening types such as "torsade de pointes", arterial hypotension.

Gastrointestinal disorders: vomiting, nausea, constipation, dry mouth, pancreatitis.

Hepatobiliary disorders: liver function abnormalities, including increased liver transaminase activity, hepatitis. In patients with pre-existing liver insufficiency, hepatic encephalopathy may develop.

Urinary system disorders: renal failure. Abnormal renal function test results (increased plasma urea and creatinine levels) associated with hypovolemia have been reported.

Immune system, skin and skin appendages: hypersensitivity reactions (mostly dermatological, especially in patients predisposed to allergic and asthmatic reactions) – maculopapular rashes, purpura, angioneurotic edema and/or urticaria, pruritus, toxic epidermal necrolysis, Stevens-Johnson syndrome.

Photosensitivity reactions are possible, as well as exacerbation of pre-existing systemic lupus erythematosus.

Eye disorders: choroidal effusion, reversible acute myopia, secondary acute angle-closure glaucoma, blurred vision, visual disturbances.

Reproductive system and breast: erectile dysfunction.

Description of selected adverse reactions

During Phase II and III comparative studies of 1.5 mg and 2.5 mg indapamide, analysis of plasma potassium levels revealed a dose-dependent effect of indapamide:

• Indapamide 1.5 mg: plasma potassium level < 3.4 mmol/L was observed in 10% of patients and < 3.2 mmol/L in 4% of patients after 4–6 weeks of treatment. After 12 weeks of treatment, the mean decrease in plasma potassium level was 0.23 mmol/L.
• Indapamide 2.5 mg: plasma potassium level < 3.4 mmol/L was observed in 25% of patients and < 3.2 mmol/L in 10% of patients after 4–6 weeks of treatment. After 12 weeks of treatment, the mean decrease in plasma potassium level was 0.41 mmol/L.

Shelf life. 4 years.

Do not use the medication after the expiry date stated on the packaging!

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging. 10 tablets in a blister; 3 blisters per carton.

Prescription category. Prescription only.

Manufacturer. Public Joint-Stock Company "Scientific and Production Center "Boryspil Chemical-Pharmaceutical Plant".

Manufacturer's address and place of business.

17 Myru Street, Kyiv, 03134, Ukraine.