Indapamide-teva sr

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

Composition:

Active substance: indapamide;

1 tablet contains 1.5 mg of indapamide;

Excipients: lactose monohydrate, hypromellose, colloidal anhydrous silicon dioxide, magnesium stearate, glycerin, titanium dioxide (E 171).

Pharmaceutical form. Prolonged-release film-coated tablets.

Main physicochemical properties: white or almost white, round, biconvex, film-coated tablets.

Pharmacotherapeutic group. Cardiovascular drugs. Non-thiazide diuretics with moderately pronounced activity. Indapamide. ATC code C03BA11.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Indapamide is a sulfonamide diuretic with an indole ring, pharmacologically related to thiazide diuretics, and is used for the treatment of arterial hypertension. Indapamide acts at the level of the kidneys and blood vessels.

Indapamide inhibits sodium reabsorption in the cortical segment of the kidneys. This increases urinary excretion of sodium and chlorides, and to a lesser extent, potassium and magnesium, thereby enhancing diuresis.

Pharmacodynamic effects

Phase II-III clinical studies using indapamide in monotherapy have demonstrated that the antihypertensive effect of indapamide lasts for 24 hours. The diuretic effect was moderate. The antihypertensive action of indapamide is associated with improved arterial elasticity and reduced arteriolar resistance and total peripheral vascular resistance.

Indapamide reduces left ventricular hypertrophy.

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

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),
• does not affect carbohydrate metabolism, even in patients with diabetes mellitus and arterial hypertension.

Indapamide acts at the vascular level by:

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

Pharmacokinetics.

Active substance – 1.5 mg of indapamide is contained in a prolonged-release tablet based on a matrix system. The distribution of indapamide within the matrix ensures its uniform release from the tablet.

Absorption

The released fraction of indapamide is rapidly and completely absorbed in the gastrointestinal tract. Food intake slightly increases the rate of absorption but does not affect the total amount of drug absorbed.

Maximum plasma concentration after a single dose is reached approximately 12 hours after administration. Continued use reduces fluctuations in plasma indapamide levels during the interdose interval. Individual variations exist.

Distribution

Plasma protein binding – 79%.

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

Steady-state concentration is achieved within 7 days. Regular administration does not lead to accumulation.

Excretion

Indapamide is excreted in urine (70% of the dose) and feces (22%) as inactive metabolites.

High-risk patients

Pharmacokinetic parameters are not altered in patients with renal impairment.

Clinical characteristics.

Indications.

Essential hypertension in adults.

Contraindications.

• Hypersensitivity to indapamide, other sulfonamides, or to any of the excipients;
• severe renal impairment;
• hepatic encephalopathy or severe hepatic dysfunction;
• hypokalemia.

Interaction with other medicinal products and other forms of interaction.

Not recommended combinations

Lithium. Possible increase in plasma lithium levels and occurrence of lithium toxicity symptoms, as with a low-sodium diet (reduced urinary lithium excretion). If concomitant diuretic therapy is necessary, careful monitoring of plasma lithium levels and lithium dose adjustment are required.

Diuretics. Concomitant use of indapamide with diuretics that may cause hypokalemia (bumetanide, furosemide, piretanide, thiazides, and xipamide) is not recommended.

Combinations requiring caution

Medicinal products that may induce torsade de pointes-type ventricular tachycardia:

• Class Ia antiarrhythmics (quinidine, hydroquinidine, disopyramide);
• Class III antiarrhythmics (amiodarone, sotalol, dofetilide, ibutilide);
• certain antipsychotics:
  • phenothiazines (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine);
  • benzamides (amisulpride, sulpiride, sultopride, tiapride);
  • butyrophenones (droperidol, haloperidol);
• other medicinal products: bepridil, cisapride, difemanil, intravenous erythromycin, halofantrine, mizolastine, pentamidine, sparfloxacin, moxifloxacin, intravenous vinpocetine.

When indapamide is used concomitantly with the above-mentioned medicinal products, the risk of ventricular arrhythmias, including torsades de pointes – a form of torsade-type ventricular tachycardia – increases (hypokalemia being a risk factor).

Plasma potassium levels should be checked before initiating such combination therapy and corrected if necessary. Clinical status, plasma electrolytes, and ECG should be monitored. In the presence of hypokalemia, use of agents not associated with torsades de pointes is recommended.

Non-steroidal anti-inflammatory drugs (systemic use), including selective cyclooxygenase-2 inhibitors, and high-dose salicylates (≥3 g/day):

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

ACE inhibitors. Risk of sudden arterial hypotension and/or acute renal failure may occur in patients with low sodium levels (especially in patients with renal artery stenosis).

Hypertension. If prior diuretic therapy has caused sodium depletion, diuretic treatment should be discontinued 3 days before starting angiotensin-converting enzyme (ACE) inhibitor therapy. Thereafter, if necessary, therapy with a potassium-wasting diuretic may be resumed or ACE inhibitor therapy initiated at a low starting dose with gradual dose escalation.

In congestive heart failure, ACE inhibitor therapy should be initiated at the lowest dose, possibly after reducing the dose of a previously prescribed potassium-wasting diuretic.

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

MEDICINAL PRODUCTS THAT MAY INDUCE HYPOKALEMIA: systemic glucocorticoids and mineralocorticoids, intravenous amphotericin B, tetracosactide, stimulant laxatives — increase the risk of hypokalemia (additive effect). Plasma potassium levels should be monitored and corrected if necessary. Particular attention should be paid when concomitantly administering cardiac glycosides. Use of non-stimulant laxatives is recommended.

Cardiac glycosides. Hypokalemia and/or hypomagnesemia predispose to cardiac glycoside cardiotoxicity. Monitoring of plasma potassium and magnesium levels, ECG monitoring, and treatment adjustment if necessary are recommended.

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 attention

Potassium-sparing diuretics (amiloride, spironolactone, triamterene). If combination therapy is considered appropriate for certain patients, the possibility of developing hypokalemia or hyperkalemia (especially in patients with diabetes mellitus or renal impairment) cannot be excluded. Monitoring of plasma potassium levels, ECG monitoring, and treatment adjustment if necessary are recommended.

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

Iodinated contrast agents. Due to diuretic-induced dehydration, the risk of acute renal failure increases, especially with high doses of iodinated contrast agents. Fluid balance should be restored prior to administration of iodinated contrast agents.

Imipramine-like antidepressants, neuroleptics. Enhanced antihypertensive effect and increased risk of orthostatic hypotension due to additive effects.

Calcium salts. Hypercalcemia may occur due to reduced renal calcium excretion.

Cyclosporine, tacrolimus. Risk of increased plasma creatinine levels without affecting circulating cyclosporine levels, even in the absence of reduced water/sodium levels.

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

Special precautions for use.

Patients with impaired liver function

In patients with impaired liver function, the use of thiazide-like diuretics may lead to the development of hepatic encephalopathy, particularly in the presence of electrolyte imbalances. 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 "Adverse reactions"). If such reactions occur, diuretic treatment should be discontinued. If re-administration of diuretics is necessary, vulnerable areas should be protected from sunlight or artificial ultraviolet sources.

Excipients

The medicinal product contains lactose and therefore should not be administered to patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption syndrome.

Water and electrolyte balance

Plasma sodium

Plasma sodium levels should be monitored before initiating 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 with hypovolemia may lead to dehydration and orthostatic hypotension; concomitant chloride loss may lead to secondary compensatory metabolic alkalosis (this phenomenon is of low frequency and severity).

Plasma potassium

Reduction in plasma potassium levels leading to hypokalemia is a major risk associated with the use of thiazide and thiazide-like diuretics. The risk of developing hypokalemia (<3.4 mmol/L) should be anticipated in certain high-risk patient groups, such as elderly patients, poorly nourished patients and/or those taking multiple medications, patients with cirrhosis of the liver associated with edema and ascites, patients with ischemic heart disease, and patients with heart failure. In these cases, hypokalemia increases the cardiotoxicity of cardiac glycosides and the risk of arrhythmias.

Patients with prolonged QT interval, whether congenital or drug-induced, also belong to the risk group. Hypokalemia, as well as bradycardia, may predispose to severe cardiac rhythm disturbances, including paroxysmal ventricular tachycardia of the "torsades de pointes" type, which may be fatal.

In all the above-mentioned cases, more frequent monitoring of serum 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 refractory to treatment unless serum magnesium levels are also corrected.

Plasma magnesium

Thiazide and thiazide-like diuretics, including indapamide, may increase urinary excretion of magnesium and lead to hypomagnesemia (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

Plasma calcium

Thiazide and thiazide-like diuretics may reduce urinary excretion of calcium and lead to a slight and transient increase in plasma calcium levels. Marked hypercalcemia may be due to previously undiagnosed hyperparathyroidism. In such cases, treatment should be discontinued and parathyroid function should be investigated.

Blood glucose

In patients with diabetes mellitus, blood glucose levels should be closely monitored, particularly in the presence of hypokalemia.

Uric acid

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

Kidney function and diuretics

Thiazide and thiazide-like diuretics are most effective when kidney function is normal or only slightly impaired (plasma creatinine <25 mg/L, i.e., <220 µmol/L in adults). In elderly patients, plasma creatinine levels should be within the range corresponding to age, body weight, and sex. Hypovolemia due to water and sodium loss at the beginning of diuretic therapy may lead to a reduction in glomerular filtration. This may result in increased blood urea and creatinine levels. This transient functional renal insufficiency has no consequences in individuals with normal kidney function, but may worsen pre-existing renal impairment.

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

Sulfonamide medicinal products 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 initiating treatment. Untreated acute angle-closure glaucoma may lead to permanent vision loss. Initial management includes immediate discontinuation of the medicinal product. If intraocular pressure remains uncontrolled, prompt medical or surgical intervention may be required. Risk factors for developing acute angle-closure glaucoma may include a history of allergy to sulfonamides or penicillin.

In athletes, indapamide may lead to a positive doping test.

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 leading to fetoplacental ischemia and delayed fetal development. Animal studies have not revealed direct or indirect toxic effects on reproductive toxicity. 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 occur. 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 contraindicated during breastfeeding.

Fertility

Reproductive toxicity studies showed no effects on fertility in male and female rats. Effects on human fertility are not expected.

Ability to influence the ability to drive and use machines.

Indapamide has a negligible or moderate influence on the ability to drive vehicles or operate machinery. Indapamide does not affect alertness. However, if adverse reactions occur (see section "Adverse reactions"), including symptoms related to decreased blood pressure, particularly at the beginning of treatment or in combination with other antihypertensive agents, the ability to drive or operate machinery may be impaired.

Method of Administration and Dosage

Method of Administration

For oral use.

Dosage

1 tablet per day, preferably in the morning. The tablet should be swallowed whole, without chewing, with water.

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

Special Patient Groups

Renal Impairment (see sections "Special Warnings and Precautions for Use" and "Contraindications")

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 Patients (see section "Special Warnings and Precautions for Use")

In elderly patients, plasma creatinine levels should be within the range corresponding to age, body weight, and sex. Indapamide-Teva SR may be prescribed to elderly patients if renal function is not impaired or only slightly impaired.

Patients with Hepatic Impairment (see sections "Special Warnings and Precautions for Use" and "Contraindications")

Treatment with the drug is contraindicated in cases of severe hepatic impairment.

Children

The safety and efficacy of Indapamide-Teva SR in children have not been established. Data are lacking.

Overdose

Indapamide has not shown toxicity when administered at doses up to 40 mg, i.e., a dose 27 times higher than the therapeutic dose.

Symptoms of overdose are primarily manifestations of water-electrolyte disturbances (hyponatremia, hypokalemia). Clinically, nausea, vomiting, arterial hypotension, seizures, drowsiness, dizziness (vertigo), confusion, polyuria, or oliguria up to anuria (caused by hypovolemia) may occur.

First aid measures include rapid elimination of the drug by gastric lavage and/or administration of activated charcoal, followed by restoration of water-electrolyte balance under hospital conditions.

Adverse Reactions

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

Most of the adverse effects, both clinical and laboratory, are dose-dependent.

The following adverse events have been observed during treatment with indapamide, listed below according to the following frequency categories: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000), frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders

Very rare – thrombocytopenia, leukopenia, agranulocytosis, aplastic anemia, hemolytic anemia.

Metabolism and nutrition disorders

Common – hypokalemia (see section "Special precautions");

Uncommon – hyponatremia (see section "Special precautions");

Rare – hypochloremia, hypomagnesemia;

Very rare – hypercalcemia.

Nervous system disorders

Rare – dizziness (vertigo), fatigue, headache, paresthesia;

Frequency not known – loss of consciousness.

Eye disorders

Frequency not known – myopia, blurred vision, visual disturbances, choroidal effusion.

Cardiac disorders

Very rare – arrhythmia;

Frequency not known – paroxysmal ventricular tachycardia of the torsades de pointes type, which may lead to fatal outcomes (see sections "Special precautions", "Interaction with other medicinal products and other forms of interaction").

Vascular disorders

Very rare – arterial hypotension.

Gastrointestinal disorders

Uncommon – vomiting;

Rare – nausea, constipation, dry mouth;

Very rare – pancreatitis.

Renal and urinary disorders

Very rare – renal failure.

Reproductive system and breast disorders

Uncommon – erectile dysfunction.

Hepatobiliary disorders

Very rare – hepatic function abnormalities;

Frequency not known – in patients with hepatic insufficiency, hepatic encephalopathy may occur (see sections "Special precautions", "Contraindications"), hepatitis.

Skin and subcutaneous tissue disorders

Hypersensitivity reactions, mainly affecting the skin, in patients predisposed to allergic and asthmatic reactions:

Common – maculopapular rash;

Uncommon – purpura;

Very rare – angioneurotic edema and/or urticaria, toxic epidermal necrolysis, Stevens–Johnson syndrome;

Frequency not known – possible exacerbation of pre-existing systemic lupus erythematosus. Cases of photosensitivity reactions have been reported (see section "Special precautions").

Investigations

Frequency not known – QT interval prolongation on electrocardiogram (see sections "Special precautions", "Interaction with other medicinal products and other forms of interaction"); increased plasma levels of uric acid and glucose during diuretic therapy, the appropriateness of which should be carefully evaluated before prescribing to patients with gout or diabetes mellitus; elevated liver enzymes.

Description of selected adverse reactions

In Phase II and III clinical trials comparing indapamide 1.5 mg and 2.5 mg, a dose-dependent effect of indapamide on plasma potassium levels was observed:

• 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 therapy, the mean decrease in serum potassium level 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 therapy, the mean decrease in serum potassium level was 0.41 mmol/L.

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 30 °C, in a place inaccessible to children.

Packaging.

10 tablets per blister; 3 blisters per carton.

Prescription status.

Prescription only.

Manufacturer.

Merkle GmbH.

Manufacturer's address and location of business activity.

Ludwig-Merckle-Straße 3, 89143 Blaubeuren, Germany.