Indapen sr

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Indapen SR (Indapen® SR)

Composition:

Active substance: indapamide;

1 tablet contains 1.5 mg of indapamide;

Excipients: lactose monohydrate, carbomers, hydroxypropylcellulose, magnesium stearate, colloidal anhydrous silicon dioxide, talc;

Coating Opadry II Pink (33 G24509): hypromellose, titanium dioxide (E 171), lactose monohydrate, macrogol 3000, glycerol triacetate, yellow iron oxide (E 172), red iron oxide (E 172), black iron oxide (E 172).

Pharmaceutical form. Modified-release coated tablets.

Main physicochemical properties: pale pink, round, biconvex, coated tablets.

Pharmacotherapeutic group. Non-thiazide diuretics with moderately expressed activity. Antihypertensive agent. ATC code C03BA11.

Pharmacological properties.

Pharmacodynamics.

Indapamide is a diuretic medicinal agent. It belongs to the group of non-thiazide sulfonamide derivatives and contains an indole ring. Pharmacologically, it is closely related to thiazide diuretics. Like thiazide diuretics, it acts on the proximal portion of the distal convoluted tubules of the nephron, where it induces enhanced excretion of sodium and chlorides, and to a lesser extent, potassium and magnesium, thereby increasing urine volume.

The antihypertensive effect of indapamide lasts for 24 hours. This effect is characteristic of doses with moderate diuretic activity.

The antihypertensive properties of indapamide are due to improved arterial elasticity and reduction of resistance in small arteries and overall peripheral vascular resistance.

Indapamide reduces left ventricular hypertrophy.

For thiazides and thiazide-like diuretics, there is a defined dose above which the therapeutic effect does not increase, while the likelihood of adverse effects increases. Therefore, if treatment has been ineffective, the dose of the medicinal agent should not be increased.

Indapamide also does not affect lipid concentrations (total cholesterol, low-density lipoprotein cholesterol, and triglycerides), and does not impair glucose metabolism in patients with diabetes mellitus and arterial hypertension.

Pharmacokinetics.

Absorption

Indapamide is slowly released from the tablet and is completely absorbed in the gastrointestinal tract. Food slightly accelerates absorption but does not affect the total amount of absorbed drug.

The maximum drug concentration in blood plasma is reached approximately 12 hours after administration.

Repeated dosing reduces the fluctuation in drug plasma concentrations between doses, although individual variations exist.

Distribution

Indapamide is 79% bound to plasma proteins.

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

Steady-state is achieved within 7 days. Repeated dosing does not lead to drug accumulation.

Elimination

Indapamide is primarily excreted from the body via urine (70%) and feces (22%) as inactive metabolites. Only 5–7% of the dose is excreted unchanged in urine.

In patients with renal insufficiency, pharmacokinetic parameters are not significantly altered.

Clinical characteristics.

Indications.

Essential arterial hypertension.

Contraindications.

Hypersensitivity to indapamide and/or to any of the excipients or to other sulfonamides.

Severe renal impairment.

Hepatic encephalopathy or other 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 due to reduced lithium excretion (similar to a low-sodium diet). If diuretic therapy is required, careful monitoring of plasma lithium levels and dose adjustment are necessary.

Medicinal products to be used with caution concomitantly with indapamide

Medicinal products affecting cardiac rhythm and causing torsades de pointes:

• Class Ia antiarrhythmics (quinidine, hydroquinidine, disopyramide);
• Class III antiarrhythmics (amiodarone, sotalol, dofetilide, ibutilide);
• certain antipsychotics:

phenothiazines (chlorpromazine, zuclopenthixol, levomepromazine, thioridazine, trifluoperazine), benzamides (amisulpride, sulpiride, sultopride, tiapride),

butyrophenones (droperidol, haloperidol);

• others: bepridil, cisapride, difemanil, erythromycin – intravenous administration, halofantrine, pentamidine, mizolastine, sparfloxacin, moxifloxacin, vinpocetine – intravenous administration.

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

Before prescribing such a combination, serum potassium levels should be checked and, if necessary, corrected. Clinical status, plasma electrolytes, and ECG should be monitored. In the presence of hypokalemia, medicinal products not inducing torsades de pointes should be prescribed.

Non-steroidal anti-inflammatory drugs (NSAIDs) for oral use, including selective COX-2 inhibitors and high-dose salicylates (≥ 3 g/day)

Possible reduction in the antihypertensive effect of indapamide.

Increased risk of acute renal failure in dehydrated patients (reduced glomerular filtration).

Hydration status should be monitored and renal function observed.

Angiotensin-converting enzyme (ACE) inhibitors

When initiating ACE inhibitors in patients with sodium depletion (particularly in patients with renal artery stenosis), there is a risk of sudden drop in blood pressure and development of acute renal failure.

Since prior diuretic therapy may cause sodium depletion, in patients with primary arterial hypertension, it is necessary to:

• discontinue diuretic therapy three days before starting ACE inhibitors, and then, if needed, resume diuretic therapy, or
• initiate ACE inhibitor therapy with low doses, gradually increasing them.

In patients with chronic heart failure, treatment should be initiated with low doses of ACE inhibitors, preferably after reducing the diuretic dose (if possible).

Renal function (serum creatinine concentration) should be monitored during the first week of ACE inhibitor therapy.

Other medicinal products causing hypokalemia

Intravenous amphotericin B, glucocorticoids and mineralocorticoids (when administered orally), tetracosactide, stimulant laxatives.

Increased risk of hypokalemia. Serum potassium concentration should be monitored, especially during concomitant treatment with cardiac glycosides. Stimulant laxatives should not be taken.

Baclofen

Enhances the antihypertensive effect of indapamide. Adequate hydration should be ensured and renal function monitored.

Cardiac glycosides

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

Combination therapy requiring attention

Potassium-sparing diuretics (amiloride, spironolactone, triamterene)

In certain patients, combination therapy may be indicated; however, the possibility of hypokalemia (especially in patients with diabetes mellitus or renal impairment) or hyperkalemia cannot be excluded. Monitoring of plasma potassium levels and ECG control are required, with treatment adjustment as needed.

Metformin

Metformin may cause lactic acidosis. Acidosis may also develop in functional renal impairment due to diuretic use, especially loop diuretics. Metformin should not be administered if serum creatinine concentration exceeds 15 mg/L (135 µmol/L) in men and 12 mg/L (110 µmol/L) in women.

Iodinated contrast media

Due to diuretic-induced dehydration, the risk of acute renal failure increases, particularly after administration of high doses of iodinated contrast agents. Adequate hydration should be ensured prior to administration of such agents.

Tricyclic antidepressants, neuroleptics

Enhanced antihypertensive effect and increased risk of orthostatic hypotension (additive effect).

Calcium salts

Risk of hypercalcemia due to impaired renal excretion of calcium.

Cyclosporine, tacrolimus

Risk of increased serum creatinine concentration without changes in cyclosporine levels, even in the absence of water or sodium depletion.

Corticosteroids, tetracosactide (oral administration)

Reduced antihypertensive effect (sodium and water retention due to corticosteroid action).

Special precautions for use.

In patients with hepatic insufficiency, thiazide-like diuretic medicinal products may accelerate the development of hepatic encephalopathy. If symptoms of hepatic encephalopathy occur, indapamide should be discontinued immediately.

Photosensitization

Allergic reactions to light caused by thiazide diuretics and thiazide-like medicinal products are possible. If a photosensitization reaction occurs during treatment, the drug should be discontinued. If re-administration of the diuretic is necessary, it is recommended to protect exposed areas of skin from sunlight or artificial UV radiation.

Water and electrolyte balance

Serum sodium concentration

Serum sodium concentration should be monitored before starting treatment and periodically thereafter. Any diuretic therapy may lead to hyponatremia, sometimes with serious consequences. A decrease in sodium concentration in the initial period may be asymptomatic; therefore, regular monitoring of its concentration is also required. In elderly patients or patients with liver cirrhosis, such monitoring should be performed more frequently.

Serum potassium concentration

A decrease in plasma potassium levels leading to hypokalemia is the main risk associated with the use of thiazide and thiazide-like diuretics. The risk of hypokalemia (<3.4 mmol/L) should be anticipated in certain high-risk patient groups.

Particular caution is required when prescribing these drugs to patients at highest risk of developing hypokalemia, e.g., elderly patients; debilitated patients; those taking multiple medications; patients with malnutrition; patients with liver cirrhosis, edema, and ascites; and those with ischemic heart disease and heart failure. Hypokalemia increases the cardiotoxicity of cardiac glycosides and the risk of cardiac arrhythmias. Patients with prolonged QT interval, whether congenital or drug-induced, belong to the risk group. Hypokalemia, similar to bradycardia, promotes the development of serious cardiac arrhythmias, particularly ventricular fibrillation (torsades de pointes).

Serum potassium concentration should be monitored regularly during treatment. The first measurement should be performed within the first week of treatment. If hypokalemia develops, potassium supplementation should be administered. Hypokalemia associated with low serum magnesium concentration may respond poorly to treatment unless serum magnesium levels are corrected.

Plasma 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 "Undesirable effects").

Serum calcium concentration

Thiazide and thiazide-like diuretic medicinal products may reduce calcium excretion in urine, causing mild transient hypercalcemia. Marked hypercalcemia may be a consequence of unrecognized hyperparathyroidism. In such cases, treatment should be discontinued and the patient should be evaluated for parathyroid gland function.

Blood glucose concentration

In patients with diabetes mellitus, particularly those with concomitant hypokalemia, serum glucose concentration should be monitored.

Patients with gout

In patients with hyperuricemia, there may be a tendency toward increased frequency of gout attacks.

Renal function and diuretics

Thiazides and thiazide-like diuretic agents are effective only under conditions of normal renal function or mild renal impairment (serum creatinine concentration < 25 mg/L, i.e., 220 µmol/L in adults). When assessing renal function based on serum creatinine concentration, age, sex, and body weight of the patient should be taken into account.

Hypovolemia caused by loss of fluid and sodium, which may occur at the beginning of diuretic therapy, leads to a decrease in glomerular filtration rate, which in turn causes an increase in blood urea and creatinine concentrations. This transient functional renal insufficiency resolves without consequences in patients with normal renal function, but may worsen pre-existing renal insufficiency.

Athletes

The medicinal product may cause false-positive results in anti-doping tests in athletes.

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 the drug.

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.

Excipients

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

Use during pregnancy or breastfeeding.

Pregnancy

Diuretics should be avoided in pregnant women and never used to treat physiological edema of pregnancy. Diuretics may lead to fetoplacental ischemia with a risk of fetal growth retardation.

Breastfeeding

Indapamide is not recommended during breastfeeding due to evidence of its passage into breast milk.

Ability to affect reaction speed when driving vehicles or operating machinery.

Indapen SR does not affect alertness. However, if adverse reactions occur (see section "Undesirable effects"), including symptoms related to decreased arterial pressure, especially at the beginning of treatment or in combination with other antihypertensive agents, the ability to drive a vehicle or operate machinery may be impaired.

Administration and Dosage

For oral use. Indapamide SR should be administered at a dose of 1 tablet daily, preferably in the morning.

Tablets should be swallowed whole with water.

When higher doses are used, indapamide does not exert greater antihypertensive effect, but the diuretic effect is enhanced.

Renal impairment (see sections "Special 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 (see section "Special precautions for use")

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

Patients with hepatic impairment (see sections "Special precautions for use" and "Contraindications")

The treatment with the drug is contraindicated in case of severe hepatic impairment.

Children

Due to lack of safety and efficacy data, the use of the medicinal product in pediatric practice is not recommended.

Overdose

Symptoms of overdose are primarily associated with water and 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 removal 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 include hypokalemia, hypersensitivity reactions (mainly dermatological) in individuals predisposed to allergic and asthmatic reactions, and maculopapular rashes.

Most of the adverse effects observed both clinically and through laboratory findings are dose-dependent.

Thiazide-like diuretics, including indapamide, may cause the following adverse events categorized 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), and frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders

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

Nervous system disorders

Rare – dizziness (vertigo), increased fatigue, headache, paresthesia;
Frequency not known – loss of consciousness.

Cardiac disorders

Very rare – arrhythmia, arterial hypotension;
Frequency not known – paroxysmal ventricular tachycardia of the torsades de pointes type, which may lead to fatal outcomes (see sections "Special Warnings and Precautions for Use", "Interaction with Other Medicinal Products and Other Forms of Interaction").

Gastrointestinal disorders

Uncommon – vomiting;
Rare – nausea, constipation, dry mouth;
Very rare – pancreatitis.

Renal and urinary disorders

Very rare – renal failure.

Hepatobiliary disorders

Very rare – hepatic function abnormalities;
Frequency not known – in patients with liver insufficiency, hepatic encephalopathy may occur (see sections "Special Warnings and Precautions for Use", "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 Warnings and Precautions for Use").

Eye disorders

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

Investigations

Frequency not known – QT interval prolongation on electrocardiogram (see sections "Special Warnings and Precautions for Use", "Interaction with Other Medicinal Products and Other Forms of Interaction"); increased plasma levels of uric acid and glucose during diuretic therapy; the benefit-risk ratio should be carefully evaluated before prescribing to patients with gout or diabetes mellitus; elevated liver enzymes.

Metabolism and nutrition disorders

Common – hypokalemia (see section "Special Warnings and Precautions for Use").
Uncommon – hyponatremia (see section "Special Warnings and Precautions for Use").
Rare – hypochloremia, hypomagnesemia.
Very rare – hypercalcemia.

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 occurred 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 occurred 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. 2 years. Do not use after the expiry date.

Storage conditions. Store in a dry, light-protected place at a temperature below 25 °C. Keep out of reach and sight of children.

Packaging.

14 tablets in a blister pack, 2 blisters or 4 blisters per cardboard box.

15 tablets in a blister pack, 2 blisters or 4 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Pharmaceutical Works «POLPHARMA» S.A.

Manufacturer's address and place of business.

19, Pelplinska Str., 83-200 Starogard Gdanski, Poland.