Indapen

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT INDAPEN (INDAPEN)

Composition:

active substance: indapamide;

1 coated tablet contains 2.5 mg of indapamide;

excipients: microcrystalline cellulose, crospovidone, magnesium stearate;

coating: microcrystalline cellulose, hypromellose, stearic acid, titanium dioxide (E 171).

Pharmaceutical form. Coated tablets.

Basic physico-chemical properties: white colored tablets, round, biconvex, with a rough surface.

Pharmacotherapeutic group. Non-thiazide diuretics with moderate diuretic activity. Sulfonamides, plain agents. 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 effect persists even in hypertensive patients undergoing hemodialysis.

Indapamide has high lipophilicity and acts at the level of the vascular wall, specifically:

• alters transmembrane ion flux (primarily calcium), leading to reduced contractility of smooth muscle in blood vessels; stimulates synthesis of prostaglandin PGE2 and prostacyclin PGI2, which are vasodilators and inhibitors of platelet aggregation. All of these effects lead to a reduction in total peripheral vascular and arteriolar resistance, resulting in decreased arterial pressure.

Indapamide reduces left ventricular hypertrophy.

In short-term, medium-term, and long-term observations of patients with arterial hypertension, it has been shown that indapamide:

• does not affect lipid metabolism: triglycerides, LDL cholesterol, or HDL cholesterol;
• does not affect carbohydrate metabolism, even in patients with arterial hypertension associated with diabetes mellitus.

Pharmacokinetics.

After oral administration, indapamide is rapidly and completely absorbed, reaching peak blood concentration within 1–2 hours. Indapamide accumulates in erythrocytes and is 71–79% bound to plasma and erythrocyte proteins. The elimination half-life (t_1/2) is approximately 15 hours. Steady-state conditions are achieved within 4 days. Due to its high lipid solubility, the drug penetrates through membranes into vascular smooth muscle fibers.

Renal clearance accounts for 60–80% of total clearance. The majority of indapamide is metabolized, with only 5–7% of the substance excreted unchanged in urine. Approximately 20–30% of the administered dose is excreted in feces.

Clinical characteristics.

Indications.

Essential arterial hypertension in adults.

Contraindications.

Hypersensitivity to indapamide, to any other component of the medicinal product or to other sulfonamides. Severe renal impairment. Hepatic encephalopathy and severe hepatic dysfunction. Hypokalemia.

Interaction with other medicinal products and other forms of interaction.

Combinations not recommended:

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

Combinations requiring caution:

Medicinal products that may induce torsades de pointes (paroxysmal ventricular tachycardia of the "twisting of points" type):

• 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 vincaamine.

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

Before initiating such combination therapy, potassium levels should be checked and corrected if necessary. Clinical status, plasma electrolytes, and ECG should be monitored. If hypokalemia is present, medicinal products that do not induce torsades de point es should be prescribed.

Non-steroidal anti-inflammatory drugs (for systemic use), including selective COX-2 inhibitors, high-dose salicylates (>3 g/day):

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

ACE inhibitors: Sudden arterial hypotension and/or acute renal failure may occur in patients with hyponatremia (particularly in patients with renal artery stenosis). In patients with arterial hypertension in whom prior diuretic therapy has led to hyponatremia, either diuretic therapy should be discontinued three days before starting ACE inhibitor treatment and then resumed if necessary, or ACE inhibitor therapy should be initiated at a low starting dose with gradual dose escalation.

In patients with congestive heart failure, ACE inhibitor therapy should be initiated at the lowest possible dose, possibly after reducing the dose of concomitant potassium-wasting diuretic.

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

Medicinal products whose concomitant use may lead to 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. Particular attention should be paid when concomitant therapy with cardiac glycosides is used. Non-stimulant laxatives are recommended.

Cardiac glycosides

Hypokalemia and hypomagnesemia favor digitalis toxicity. Monitoring of plasma potassium and magnesium levels and ECG control are recommended, with treatment adjustment if necessary.

Baclofen enhances the antihypertensive effect of the drug. At the beginning of therapy, the patient's 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, particularly in patients with diabetes or renal impairment, or hyperkalemia. Monitoring of plasma potassium levels and ECG is recommended, with therapy adjustment if necessary.

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

Iodinated contrast agents: Dehydration caused by diuretic use increases the risk of acute renal failure, particularly with high doses of iodinated contrast agents. Fluid balance should be restored before administering iodinated contrast agents.

Imipramine-like antidepressants, neuroleptics: Increased risk of orthostatic hypotension (additive effect).

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

Cyclosporine, tacrolimus: Increased plasma creatinine levels may occur without affecting circulating cyclosporine levels, even in the absence of water and sodium deficiency.

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

Special precautions for use.

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

Photosensitivity. Cases of photosensitivity reactions have been reported in patients taking thiazide and thiazide-like diuretics. If such reactions occur, diuretic treatment should be discontinued. If re-administration of diuretics is necessary, protection of susceptible areas from sunlight or artificial ultraviolet sources is recommended.

Water and electrolyte balance:

Plasma sodium levels

Plasma sodium levels should be measured before starting treatment and regularly thereafter. Decreased plasma sodium levels may initially be asymptomatic; therefore, regular monitoring is recommended. In elderly patients and patients with liver cirrhosis, sodium levels should be measured more frequently. Diuretic therapy may cause hyponatremia, sometimes with very serious consequences. Hyponatremia with hypovolemia may lead to dehydration and orthostatic hypotension. Concomitant chloride ion loss may lead to secondary compensatory metabolic alkalosis (this phenomenon occurs infrequently and is usually mild).

Plasma potassium levels

Reduction in plasma potassium levels leading to hypokalemia is a major risk during treatment with thiazide and thiazide-like diuretics. The risk of developing hypokalemia (< 3.4 mmol/L) should be anticipated in certain high-risk groups, particularly in elderly, debilitated and/or poly-medicated patients, patients with cirrhosis of the liver associated with edema and ascites, and patients with ischemic heart disease and heart failure. In these patients, hypokalemia increases the cardiotoxicity of cardiac glycosides and increases the risk of arrhythmias.

Patients with prolonged QT interval are also at risk, regardless of whether this condition is congenital or drug-induced. In such cases, hypokalemia, as well as bradycardia, may trigger severe arrhythmias, including potentially fatal torsades de pointes. In all the above cases, more frequent monitoring of plasma potassium levels is recommended. The first measurement of plasma potassium should be performed within the first week of treatment initiation. If hypokalemia is detected, it should be corrected. Hypokalemia associated with low serum magnesium concentration may be difficult to treat unless serum magnesium levels are also corrected.

Plasma magnesium

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

Plasma calcium levels

Thiazide and thiazide-like diuretics may reduce urinary calcium excretion and may cause a slight, transient increase in plasma calcium levels. Marked hypercalcemia may indicate previously undiagnosed hyperparathyroidism. Before investigating parathyroid function, diuretic treatment should be discontinued.

Blood glucose levels

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

Uric acid

In patients with hyperuricemia, there may be an increased frequency of gout attacks.

Renal function and diuretics

Thiazide and thiazide-like diuretics are effective only with normal renal function or minimal renal impairment (plasma creatinine below 25 mg/L, i.e., below 220 µmol/L in adults). In elderly patients, plasma creatinine levels should be appropriate for age, body weight, and sex.

Secondary hypovolemia due to water and sodium loss induced by diuretics during the initial phase of treatment may lead to a decrease in glomerular filtration rate. This may result in increased blood urea and plasma creatinine levels. In patients with normal renal function, transient functional renal insufficiency is not clinically significant; however, it may exacerbate pre-existing renal impairment.

Athletes

Use of the drug may lead to a positive result in doping controls.

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

Drugs 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 initiating the drug.

Untreated acute angle-closure glaucoma may lead to permanent vision loss. The primary treatment is prompt discontinuation of the medication. 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 thiazide diuretics 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 any direct or indirect toxic effects on reproduction. As a precautionary measure, indapamide use during pregnancy should be avoided.

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 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 animals. No effect on human fertility is expected.

Effect on ability to drive and use machines.

Indapen does not affect reaction speed; however, during treatment, individual reactions related to decreased blood pressure may occur, especially at the beginning of therapy or when combined with another antihypertensive agent. As a result, ability to drive vehicles or operate machinery may be impaired.

Dosage and Administration

For oral use: one tablet (2.5 mg) once daily, preferably in the morning. The tablet should be swallowed whole, without chewing, with water.

Higher doses of the drug do not lead to an increase in antihypertensive effect, but the diuretic effect increases.

Special Patient Groups

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

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 appropriate for age, body weight, and gender. Indapene can be prescribed to elderly patients if renal function is normal or only slightly impaired.

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

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

Children

Indapene is not recommended for use in children and adolescents due to insufficient data on safety and efficacy in this patient group.

Overdose

No toxic effects of indapamide have been confirmed at doses up to 40 mg, which is 16 times higher than the therapeutic dose.

Symptoms

Signs of acute poisoning include water and electrolyte disturbances such as hyponatremia and hypokalemia. Overdose with indapamide may be accompanied by nausea, vomiting, arterial hypotension, seizures, dizziness, drowsiness, confusion, polyuria or oliguria, which may progress to anuria caused by hypovolemia.

Treatment

Initial management includes rapid removal of ingested substances by gastric lavage and/or administration of activated charcoal, followed by restoration of water and electrolyte balance under hospital conditions.

Adverse Reactions

The most commonly reported adverse reactions were hypokalemia, and hypersensitivity reactions, primarily dermatological, in patients predisposed to allergic and asthmatic reactions, as well as maculopapular rashes.

Most of the adverse effects observed, both clinically and laboratory-confirmed, are dose-dependent.

The adverse events observed during treatment with indapamide are listed below by frequency of occurrence: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders

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

Metabolism and nutrition disorders

Common: hypokalemia (see section "Special precautions and warnings").

Uncommon: hyponatremia (see section "Special precautions and warnings").

Rare: hypochloremia, hypomagnesemia.

Very rare: hypercalcemia.

Nervous system disorders

Rare: 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 "Interaction with other medicinal products and other forms of interaction", "Special precautions and warnings").

Vascular disorders

Very rare: arterial hypotension.

Gastrointestinal disorders

Uncommon: vomiting.

Rare: nausea, constipation, dry mouth.

Very rare: pancreatitis.

Hepatobiliary disorders

Very rare: impaired liver function.

Frequency not known: hepatic encephalopathy and hepatitis may occur in patients with pre-existing liver insufficiency.

Skin and subcutaneous tissue disorders

Common: hypersensitivity reactions, maculopapular rashes.

Uncommon: purpura.

Very rare: angioneurotic edema, urticaria, toxic epidermal necrolysis, Stevens-Johnson syndrome.

Frequency not known: possible exacerbation of existing systemic lupus erythematosus, photosensitivity reactions (see section "Special precautions and warnings").

Renal and urinary disorders

Very rare: renal failure.

Investigations

Frequency not known: QT interval prolongation on electrocardiogram (see sections "Interaction with other medicinal products and other forms of interaction", "Special precautions and warnings"), increased blood glucose levels (see section "Special precautions and warnings"), increased serum uric acid levels (see section "Special precautions and warnings"), elevated liver enzymes.

Reproductive system and breast disorders

Uncommon: erectile dysfunction.

Description of selected adverse reactions

During Phase II and III clinical trials comparing indapamide doses of 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 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

3 years.

Do not use the medicinal product after the expiry date.

Storage conditions

Store at temperatures not exceeding 25°C, in the original packaging.

Keep out of reach and sight of children.

Packaging

10 tablets per blister; 2, 3, or 6 blisters per cardboard box.

Prescription status

Prescription only.

Manufacturer

Pharmaceutical Works «Polpharma» S.A.

Manufacturer's address

Pelplinska 19, 83-200 Starogard Gdanski, Poland.