INDAPAMIDE-ASTRAFARM

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT INDAPAMIDE-ASTRAPHARM (INDAPAMIDE-ASTRAPHARM)

Composition:

active substance: indapamide;

1 tablet contains 2.5 mg of indapamide;

excipients: maize starch; lactose monohydrate; povidone; magnesium stearate; sodium lauryl sulfate; coating: hypromellose 2910, 5 cPs; PEG 6000; titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, round, biconvex film-coated tablets. Two layers are visible in the cross-section.

Pharmacotherapeutic group.

Non-thiazide diuretics with moderately pronounced activity. Simple sulfonamides.

ATC code C03B A11.

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, thus enhancing diuresis. The antihypertensive effect of indapamide is evident at doses producing only a slight diuretic effect. Moreover, its antihypertensive action persists even in hypertensive patients undergoing hemodialysis.

Indapamide acts at the vascular level by:

• reducing the contractile capacity of vascular smooth muscle, associated with changes in transmembrane ion exchange (primarily calcium);
• stimulating the synthesis of prostaglandin PGE2 and prostacyclin PGI2 (a vasodilator and inhibitor of platelet aggregation).

Indapamide reduces left ventricular hypertrophy.

Furthermore, studies of varying duration (short-, medium-, and long-term) involving patients with arterial hypertension have shown that indapamide:

• does not affect lipid metabolism: triglycerides, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol;
• does not affect carbohydrate metabolism, even in patients with arterial hypertension and diabetes mellitus.

When the recommended dose is exceeded, the therapeutic effect of thiazides and thiazide-like diuretics does not increase, while the incidence of adverse effects rises. If treatment proves insufficiently effective, increasing the dose is not recommended.

Pharmacokinetics.

Absorption. Indapamide has high bioavailability – 93%. Maximum plasma concentration is reached within 1–2 hours after a 2.5 mg dose.

Distribution. Plasma protein binding exceeds 75%. Elimination half-life ranges from 14 to 24 hours (average 18 hours). With regular administration, a stable plasma concentration plateau of indapamide is achieved, higher than the concentration observed after a single dose. This plasma concentration level remains stable over time without accumulation.

Elimination. Renal clearance accounts for 60–80% of total clearance. Indapamide is primarily excreted as metabolites; the fraction excreted unchanged in the urine is 5%. Pharmacokinetic parameters are not altered in patients with renal insufficiency.

Clinical characteristics.

Indications.

Essential hypertension.

Contraindications.

Hypersensitivity to indapamide, other sulfonamides, or to any of the other components of the medicinal product. Severe renal impairment, hepatic encephalopathy, or severe hepatic dysfunction, hypokalemia.

Interaction with other medicinal products and other forms of interactions.

Combinations not recommended

Lithium. Possible increase in plasma lithium levels and appearance of lithium toxicity symptoms, as may occur with a low-salt diet (reduced urinary lithium excretion). If a diuretic must be co-administered, careful monitoring of plasma lithium levels is required and lithium dosage should be adjusted accordingly.

Combinations requiring caution

Medicinal products that may induce torsades de pointes-type ventricular tachycardia, such as, but not limited to:

• Class Ia antiarrhythmics (e.g., quinidine, hydroquinidine, disopyramide);
• Class III antiarrhythmics (e.g., amiodarone, sotalol, dofetilide, ibutilide, bretylium);
• Certain antipsychotics:
  • phenothiazines (e.g., chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine);
  • benzamides (e.g., amisulpride, sulpiride, sultopride, tiapride);
  • butyrophenones (e.g., droperidol, haloperidol);
• other antipsychotics (e.g., pimozide);
• other medicinal products (e.g., bepridil, cisapride, diphemanil, intravenous erythromycin, halofantrine, mizolastine, pentamidine, sparfloxacin, moxifloxacin, intravenous vinca alkaloids, methadone, astemizole, terfenadine).

Concomitant use of indapamide with the above-mentioned medicinal products increases the risk of ventricular arrhythmias, including torsades de pointes – a form of polymorphic ventricular tachycardia (hypokalemia being a risk factor).

Before initiating such combination therapy, serum potassium levels should be checked and corrected if necessary. Clinical status, plasma electrolytes, and ECG should be monitored. In the presence of hypokalemia, medicinal products not associated with torsades de pointes are recommended.

Non-steroidal anti-inflammatory drugs (NSAIDs) (for systemic use), including selective COX-2 inhibitors, high-dose acetylsalicylic acid (more than 3 g/day):

• may reduce the antihypertensive effect of indapamide;
• in dehydrated patients, increased risk of acute renal failure (due to reduced glomerular filtration rate). Fluid balance should be restored and renal function assessed before starting treatment.

ACE inhibitors. Possible occurrence of sudden arterial hypotension and/or acute renal failure in patients with low sodium levels (particularly in patients with renal artery stenosis).

Arterial hypertension. In patients with arterial hypertension who have previously received diuretic therapy resulting in low sodium levels, either discontinue the diuretic 3 days before initiating ACE inhibitor therapy and, if necessary, resume diuretic therapy later; or initiate ACE inhibitor therapy at a low initial dose with gradual dose escalation.

Congestive heart failure. In patients with congestive heart failure, ACE inhibitor therapy should be initiated at the lowest dose and possibly after reducing the dose of previously prescribed potassium-wasting diuretics.

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

Medicinal products that may cause hypokalemia: glucocorticoids and mineralocorticoids (for systemic use), intravenous amphotericin B, tetracosactide, stimulant laxatives – increase the risk of hypokalemia (additive effect). Plasma potassium levels should be monitored and corrected if necessary, especially during concomitant therapy with cardiac glycosides. Non-stimulant laxatives are recommended.

Cardiac glycosides: Hypokalemia and/or hypomagnesemia may predispose to digitalis toxicity. Monitoring of plasma potassium and magnesium levels and ECG monitoring are recommended, with treatment adjustment if necessary.

Baclofen enhances the antihypertensive effect of the drug. At the beginning of therapy, fluid and electrolyte balance should be restored and renal function monitored.

Combinations requiring special attention

Allopurinol. Concomitant use with indapamide may increase the frequency of hypersensitivity reactions to allopurinol.

Combinations requiring attention

Potassium-sparing diuretics (amiloride, spironolactone, triamterene)

This combination does not exclude the possibility of hypokalemia (especially in patients with diabetes mellitus or renal impairment) or hyperkalemia. Monitoring of plasma potassium levels and ECG monitoring are required, with treatment adjustment if necessary.

Metformin: Risk of lactic acidosis increases if functional renal impairment develops due to diuretic therapy, particularly loop diuretics. Metformin should not be prescribed if plasma creatinine exceeds 15 mg/L (135 µmol/L) in men or 12 mg/L (110 µmol/L) in women.

Iodinated contrast agents: Dehydration caused by diuretics increases the risk of acute renal failure, especially with high doses of iodinated contrast agents. Fluid balance should be restored prior to administration of iodinated contrast agents.

Tricyclic antidepressants, neuroleptics: Increased risk of orthostatic hypotension due to additive antihypertensive effects.

Calcium salts: Hypercalcemia may occur due to reduced renal elimination of calcium.

Cyclosporine, tacrolimus: Possible increase in plasma creatinine without affecting circulating cyclosporine levels, even in the absence of water/sodium depletion.

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

Special precautions for use.

Special warnings

In patients with impaired liver function, the use of thiazide-like diuretics, especially in the presence of electrolyte imbalance, may lead to the development of hepatic encephalopathy, which can progress to hepatic coma. In such cases, diuretic therapy should be discontinued immediately.

Photosensitivity. Cases of photosensitivity reactions have been reported in patients taking thiazide and thiazide-like diuretics (see section "Side effects"). If such reactions occur, diuretic treatment should be discontinued. If re-initiation of diuretic therapy is necessary, protection of exposed skin areas from sunlight or artificial ultraviolet sources is recommended.

Excipients

Patients with rare hereditary conditions such as galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

The product contains less than 1 mmol of sodium (23 mg) per tablet, i.e. it is essentially "sodium-free".

Precautionary measures

Water and electrolyte balance

Plasma sodium

Plasma sodium levels should be monitored before starting treatment and regularly during therapy. Hyponatremia may initially be asymptomatic; therefore, regular monitoring is essential. Monitoring should be performed more frequently in elderly patients and in patients with liver cirrhosis. Any diuretic may cause hyponatremia, which can sometimes have serious consequences. Hyponatremia associated with hypovolemia may lead to dehydration and orthostatic hypotension; concomitant chloride ion loss may lead to secondary compensatory metabolic alkalosis (the frequency and severity of this phenomenon are low).

Plasma potassium levels. Reduction in plasma potassium levels leading to hypokalemia is the main risk associated with the use of thiazide and thiazide-like diuretics. Hypokalemia may cause muscle disorders. Cases of rhabdomyolysis have been reported, predominantly in association with severe hypokalemia. The risk of hypokalemia (< 3.4 mmol/L) should be prevented in certain high-risk patient groups, such as elderly patients, poorly nourished patients and/or those taking multiple medications, patients with cirrhosis and associated edema and ascites, patients with ischemic heart disease, and patients with heart failure. In these patients, hypokalemia increases the cardiotoxicity of cardiac glycosides and the risk of arrhythmias.

Patients with congenital or drug-induced prolonged QT interval also belong to high-risk groups. In such patients, hypokalemia, as well as bradycardia, may trigger severe cardiac rhythm disturbances, including torsade de pointes ventricular tachycardia, which may be fatal.

In all the above cases, more frequent monitoring of blood potassium levels is required. The first test should be performed within the first week of treatment. If hypokalemia is detected, it should be corrected.

Hypokalemia associated with low serum magnesium levels may be difficult to treat unless serum magnesium levels are also corrected.

Serum magnesium

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

Serum calcium levels. Thiazide and thiazide-like diuretics may reduce urinary calcium excretion and lead to a slight and transient increase in serum calcium levels. Marked hypercalcemia may be due to previously undiagnosed hyperparathyroidism. Treatment should be discontinued and parathyroid function should be investigated.

Blood glucose levels. In patients with diabetes mellitus, blood glucose monitoring is particularly important when hypokalemia is present.

Uric acid

In patients with elevated uric acid levels, there may be a tendency towards increased frequency of gout attacks.

Kidney function and diuretics. The use of this medicinal product is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 mL/min). Thiazide and thiazide-like diuretics are most effective when kidney function is normal or only slightly impaired (plasma creatinine below 25 mg/L, i.e. 220 µmol/L in adults). In elderly patients, plasma creatinine levels should be appropriate for age, body weight, and sex. Hypovolemia caused by loss of water and sodium due to diuretic therapy at the beginning of treatment may lead to decreased glomerular filtration. This may result in increased blood urea and plasma creatinine levels. This transient functional renal impairment has no consequences in individuals with normal kidney function, but may worsen pre-existing renal impairment.

In athletes, indapamide may lead to a positive result in doping tests.

Choroidal effusion, acute myopia, and secondary angle-closure glaucoma. Medicinal products containing sulfonamide or sulfonamide derivatives may cause an idiosyncratic reaction leading to choroidal effusion with visual field defects, transient myopia, and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or eye pain and usually occur within hours to weeks after starting treatment. Untreated acute angle-closure glaucoma may lead to permanent vision loss. The primary treatment is prompt discontinuation of the drug. If intraocular pressure remains uncontrolled, medical or surgical interventions may be necessary. Risk factors for developing acute angle-closure glaucoma may include a history of allergy to sulfonamides or penicillin.

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 a thiazide diuretic during the third trimester of pregnancy may reduce the pregnant woman's circulating blood volume and uteroplacental perfusion, potentially causing fetoplacental ischemia and fetal growth retardation. Animal studies have not revealed any direct or indirect toxic effects on reproductive performance. As a precautionary measure, it is advisable to avoid the use of indapamide during pregnancy.

Breastfeeding period

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 the group of thiazide-like diuretics, the use of which during breastfeeding has been associated with reduced or even suppressed lactation.

Indapamide is not recommended 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 when driving or operating machinery.

The medicinal product does not impair attention. However, if symptoms related to decreased blood pressure occur, especially at the beginning of treatment or when combined with another antihypertensive agent, the ability to drive or operate machinery may be affected.

Dosage and Administration.

For oral use: 1 tablet per day, preferably in the morning. The tablet should be swallowed whole, without chewing, with water. The tablet must not be divided.

Maximum daily dose – 1 tablet.

Administration of higher doses of the drug does not lead to an increase in the antihypertensive effect, but the diuretic effect increases.

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 slightly impaired.

Elderly

In elderly patients, plasma creatinine levels should be appropriate for age, body weight, and gender. Indapamide-Astrafarm may be prescribed to elderly patients if renal function is normal or only slightly impaired.

Patients with hepatic impairment

The use of the drug is contraindicated in cases of severe hepatic impairment.

Children

The drug is not administered to children due to insufficient data on safety and efficacy in this patient group.

Overdose.

Primarily, symptoms of fluid and electrolyte disturbances occur (hyponatremia, hypokalemia). Nausea, vomiting, arterial hypotension, seizures, dizziness, drowsiness, confusion, polyuria, or oliguria up to anuria (caused by hypovolemia) may also occur.

Treatment. Emergency measures include rapid removal of the drug by gastric lavage and/or administration of activated charcoal, followed by restoration of fluid and electrolyte balance under hospital conditions.

Adverse reactions.

The most frequently reported adverse reactions are hypokalemia, hypersensitivity reactions, predominantly dermatological, in individuals predisposed to allergic and asthmatic reactions, and maculopapular rashes.

The following adverse reactions have been observed during treatment with indapamide, with the frequency of occurrence as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), frequency not known (cannot be estimated according to available information).

Description of individual adverse reactions.

During phase II and III studies comparing 1.5 mg and 2.5 mg of indapamide, analysis of plasma potassium showed a dose-dependent effect of indapamide:

• Indapamide 1.5 mg: plasma potassium < 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 was 0.23 mmol/L.
• Indapamide 2.5 mg: plasma potassium < 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 was 0.41 mmol/L.

Reporting of suspected adverse reactions. Reporting suspected adverse reactions for the medicinal product during the post-marketing period is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are obliged to report any suspected adverse reactions through the national reporting system.

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

30 tablets in a blister, 1 blister in a box.

Prescription status. Prescription only.

Manufacturer.

LLC "ASTRAFARM".

Manufacturer's address and address of its business location.

6 Kyivska Street, city of Vyshneve, Kyiv-Sviatoshyn district, Kyiv region, 08132, Ukraine.