SR-Indamed (Tablets) Instructions for Use

Marketing Authorization Holder

Edge Pharma Private Limited (India)

Contact Information

Edge Pharma Private Limited COO (India)

ATC Code

C03BA11 (Indapamide)

Active Substance

Indapamide (Rec.INN registered by WHO)

Dosage Form

SR-Indamed

Extended-release tablets, film-coated, 1.5 mg: 10, 14, 20, 28, 30 or 42 pcs.

Dosage Form, Packaging, and Composition

Extended-release tablets, film-coated white or almost white, round, biconvex.

Excipients: mannitol – 54.925 mg, hypromellose – 25 mg, colloidal silicon dioxide – 3 mg, magnesium stearate – 1.5 mg.

Film coating composition dye Vinkout WT-1001 – 5 mg (titanium dioxide – 1.85 mg, hypromellose – 2.78 mg, macrogol – 0.4 mg).

10 pcs. – blisters (1) – cardboard packs.
10 pcs. – blisters (2) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
14 pcs. – blisters (1) – cardboard packs.
14 pcs. – blisters (2) – cardboard packs.
14 pcs. – blisters (3) – cardboard packs.

Clinical-Pharmacological Group

Diuretic. Antihypertensive drug

Pharmacotherapeutic Group

Diuretic agent

Pharmacological Action

Indapamide – belongs to sulfonamide derivatives and is close in pharmacological properties to thiazide diuretics. It has a moderate saluretic and diuretic effect, which is due to the inhibition of the reabsorption of sodium, chloride ions and, to a lesser extent, potassium and magnesium ions in the proximal tubules of the kidneys, as well as in the cortical segment of the distal tubule of the nephron.

Indapamide reduces the tone of arterial smooth muscles and has a vasodilating effect, reduces total peripheral vascular resistance. These effects are mediated by a decrease in the reactivity of the vascular wall to norepinephrine and angiotensin II; an increase in the synthesis of prostaglandin E2, which has vasodilating activity; inhibition of calcium influx into vascular smooth muscle cells.

Indapamide helps to reduce left ventricular hypertrophy of the heart. It has an antihypertensive effect at doses that do not have a pronounced diuretic effect. In therapeutic doses, it does not affect lipid and carbohydrate metabolism (including in patients with concomitant diabetes mellitus).

After a single dose, the maximum effect is noted after 24 hours.

Pharmacokinetics

The drug SR-Indamed is available in the form of a tablet with extended release of the active substance. Indapamide is rapidly and almost completely absorbed from the gastrointestinal tract. Food intake somewhat slows down absorption but does not significantly affect the amount of the absorbed drug. C_max in blood plasma is reached 12 hours after a single oral dose. With repeated doses, fluctuations in the drug concentration in the blood plasma between doses are smoothed out. However, there is individual variability in drug absorption parameters. Plasma protein binding is 71-79%. T_1/2 ranges from 14 to 24 hours (average 18 hours). C_ss is established after 7 days of regular drug use. Does not accumulate.

Has a high V_d, penetrates histohematic barriers (including the placental barrier). Excreted in breast milk.

Metabolized mainly in the liver. 70% of indapamide is excreted by the kidneys in the form of inactive metabolites (about 5% is excreted unchanged) and 22% is excreted through the intestines.

In patients with impaired renal function, the pharmacokinetic parameters of the drug do not change significantly.

Indications

• Arterial hypertension.

ICD codes

Dosage Regimen

Take orally, one tablet (1.5 mg) once daily.

Administer preferably in the morning.

Take with a sufficient amount of liquid.

Do not chew the tablet.

Administration is independent of food intake.

Do not exceed the recommended dose; increasing the dose does not enhance the antihypertensive effect.

For patients with mild to moderate renal impairment (creatinine clearance ≥30 mL/min), no dosage adjustment is required.

In patients with mild to moderate hepatic impairment, use with caution and monitor for signs of encephalopathy.

Regularly monitor plasma potassium levels, especially within the first week of therapy and in at-risk patients.

Regularly monitor plasma sodium levels, particularly in elderly patients and those with cirrhosis.

In patients with diabetes, monitor blood glucose concentrations, especially if hypokalemia is present.

In patients with hyperuricemia, monitor for gout exacerbation.

Adverse Reactions

Classification of the frequency of side effects (WHO): very common 10% or more; common – 1% or more, but less than 10%; uncommon – 0.1% or more, but less than 1%; rare – 0.01% or more, but less than 0.1%, including isolated reports.

From the cardiovascular system very rarely – marked decrease in blood pressure, arrhythmia, orthostatic hypotension, palpitations, ECG changes characteristic of hypokalemia, hemorrhagic vasculitis.

From the hematopoietic organs very rarely – thrombocytopenia, leukopenia, agranulocytosis, aplastic anemia, hemolytic anemia, bone marrow aplasia.

From the central and peripheral nervous system: rarely – dizziness, headache, paresthesia, increased excitability, asthenia, drowsiness, vertigo, insomnia, depression, increased fatigue, limb muscle cramps, tension, irritability, anxiety.

From the digestive system uncommon – vomiting; rarely – nausea, constipation, dry oral mucosa; very rarely – pancreatitis, anorexia, abdominal pain, diarrhea. In patients with hepatic insufficiency, the development of hepatic encephalopathy is possible.

From the genitourinary system very rarely – renal failure, nocturia, infections, polyuria.

From the respiratory system cough, pharyngitis, sinusitis, rhinitis.

Allergic reactions common – maculopapular rash; uncommon – purpura, very rarely – angioedema and/or urticaria, toxic epidermal necrolysis, Stevens-Johnson syndrome, skin itching.

Other isolated reports – exacerbation of systemic lupus erythematosus (SLE), photosensitivity reactions.

Laboratory data in clinical studies, hypokalemia (plasma potassium level less than 3.4 mmol/L) was observed in 10% of patients and 3.2 mmol/L – > 4% of patients after 4-6 weeks of treatment. After 12 weeks of therapy, the plasma potassium level decreased, on average, by 0.23 mmol/L. Very rarely – hypercalcemia; frequency not specified: decrease in potassium content and development of hypokalemia, especially significant for patients at risk (see section “Special Precautions”); hyponatremia, accompanied by hypovolemia and orthostatic hypotension. Simultaneous loss of chloride ions can lead to compensatory metabolic alkalosis, but the frequency of development of metabolic alkalosis and its severity are insignificant; hyperuricemia and hyperglycemia (frequency not specified), increased blood urea nitrogen concentration, hypercreatininemia.

Contraindications

• Hypersensitivity to indapamide, other sulfonamide derivatives or any component of the drug;
• Severe renal failure (creatinine clearance less than 30 ml/min);
• Severe hepatic insufficiency, incl. hepatic encephalopathy;
• Hypokalemia;
• Pregnancy and lactation period;
• Age under 18 years (efficacy and safety have not been established).

With caution: impaired renal and/or hepatic function, decompensated diabetes mellitus, water-electrolyte imbalance, hyperuricemia (especially accompanied by gout and urate nephrolithiasis), hyperparathyroidism; patients with prolonged QT interval on ECG or receiving therapy that may prolong the QT interval (astemizole, erythromycin (IV), pentamidine, sultopride, terfenadine, vincamine (IV), class IA antiarrhythmic drugs (quinidine, disopyramide) and class III (amiodarone, bretylium tosilate).

Use in Pregnancy and Lactation

Use of the drug SR-Indamed is not recommended for pregnant women. Use of the drug may cause fetoplacental ischemia with a risk of fetal developmental delay. It is not recommended to use the drug during breastfeeding, because Indapamide is excreted in breast milk.

If treatment with SR-Indamed is necessary during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

Contraindicated in severe hepatic insufficiency, incl. hepatic encephalopathy.

With caution: impaired liver function.

Use in Renal Impairment

Contraindicated in severe renal failure (creatinine clearance less than 30 ml/min).

With caution: impaired renal function.

Pediatric Use

Contraindicated under the age of 18 years (efficacy and safety have not been established).

Special Precautions

Impaired liver function

In patients with hepatic insufficiency, when prescribing thiazide-like diuretics, the development of hepatic encephalopathy is possible, especially in case of impaired water-electrolyte balance. If it develops, diuretic use should be discontinued.

Photosensitivity

Cases of photosensitivity reactions have been observed with the use of thiazide-like diuretics. If they develop, the drug should be discontinued. During therapy with SR-Indamed, it is necessary to protect exposed areas of the body from exposure to sunlight and artificial ultraviolet radiation.

Water-electrolyte balance

• Plasma sodium ion content: all diuretic drugs can cause hyponatremia. Plasma sodium ion levels should be measured before starting treatment with SR-Indamed and then regularly during treatment. It is important to regularly monitor plasma sodium ion levels, because initially hyponatremia may be asymptomatic. The most careful monitoring of sodium ion levels is indicated for elderly patients and patients with liver cirrhosis.
• Plasma potassium ion content: the greatest risk when treating with thiazide-like diuretics is hypokalemia.

Special attention to prevent hypokalemia (less than 3.4 mmol/L) should be paid in the following cases: debilitated patients and/or those receiving other therapy (antiarrhythmic drugs and agents that may prolong the QT interval on ECG), in old age, patients with liver cirrhosis, peripheral edema and ascites; with coronary heart disease and chronic heart failure. Hypokalemia in such patients enhances the toxic effect of cardiac glycosides and increases the risk of arrhythmia.

Patients with a prolonged QT interval on ECG are also at increased risk. Hypokalemia is a predisposing factor for the occurrence of severe arrhythmia, and especially torsades de pointes arrhythmia, which can be fatal.

In all the cases described, it is necessary to regularly monitor the plasma potassium level. The first determination of plasma potassium level should be carried out within the first week of therapy with SR-Indamed. If hypokalemia is detected, appropriate therapy should be carried out.

• Plasma calcium ion content: thiazide-like and thiazide diuretics can reduce the excretion of calcium ions by the kidneys, leading to slight and/or temporary hypercalcemia. Severe hypercalcemia while taking SR-Indamed may be a consequence of previously undiagnosed hyperparathyroidism. Diuretics should be discontinued before testing parathyroid function.
• Plasma glucose concentration: in patients with diabetes mellitus, especially in the presence of hypokalemia, monitoring of plasma glucose concentration is necessary.
• Uric acid: in patients with hyperuricemia, it may increase the frequency of attacks or exacerbation of gout.

Renal function and diuretic drugs

Thiazide and thiazide-like diuretics are fully effective only in patients with normal or slightly reduced (plasma creatinine in adults less than 25 mg/L or 220 µmol/L) renal function.

Severe hypovolemia can lead to the development of acute renal failure (decreased glomerular filtration rate), which may be accompanied by an increase in plasma urea and creatinine concentrations. With normal renal function, transient functional renal failure usually resolves without consequences. In existing renal failure, the patient’s condition may worsen.

Elderly patients

Regular monitoring of plasma creatinine and potassium levels is recommended, taking into account the patient’s age, body weight and gender. SR-Indamed can be prescribed to elderly patients with preserved or slightly impaired renal function (creatinine clearance above 30 ml/min).

Athletes

Indapamide may give a positive result during doping control.

Effect on the ability to drive vehicles and mechanisms

The use of indapamide does not lead to impaired psychomotor reactions. However, in some patients, various individual reactions may develop in response to a decrease in blood pressure, especially at the beginning of therapy or when other antihypertensive agents are added to the ongoing therapy. In this regard, at the beginning of treatment with SR-Indamed, it is not recommended to drive a car or other complex mechanisms requiring increased attention.

Overdose

Symptoms marked decrease in blood pressure, water-electrolyte disturbances (hyponatremia, hypokalemia), nausea, vomiting, convulsions, dizziness, drowsiness, lethargy, confusion, respiratory depression, polyuria or oliguria up to anuria (due to hypovolemia). In patients with liver cirrhosis, the development of hepatic coma is possible.

Treatment: symptomatic (gastric lavage and/or administration of activated charcoal, restoration of water-electrolyte balance). There is no specific antidote.

Drug Interactions

Not recommended combinations

With simultaneous use with lithium preparations, an increase in the concentration of lithium ions in the blood plasma is possible due to a decrease in its excretion from the body by the kidneys, accompanied by signs of overdose (nephrotoxic effect), as well as when following a salt-free diet (decreased excretion of lithium ions by the kidneys).

Combinations requiring special attention

1. Drugs that can cause torsades de pointes arrhythmia: class IA antiarrhythmic agents (quinidine, hydroquinidine, disopyramide), class III antiarrhythmic agents (amiodarone, dofetilide, ibutilide, bretylium tosilate), sotalol, some antipsychotics: phenothiazines (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine), benzamides (amisulpride, sulpiride, sultopride, tiapride), butyrophenones (droperidol, haloperidol), others (bepridil, cisapride, difemanil, erythromycin (intravenous administration (IV)), halofantrine, mizolastine, pentamidine, sparfloxacin, moxifloxacin, vincamine (IV), astemizole. Simultaneous use with any of these drugs, especially against the background of hypokalemia, increases the risk of ventricular arrhythmias of the torsades de pointes type. Before starting combination therapy with SR-Indamed and the above drugs, plasma potassium levels should be monitored and, if necessary, corrected. It is recommended: monitoring of the patient’s clinical condition, as well as plasma electrolyte levels and ECG. In patients with hypokalemia, drugs that do not provoke the development of torsades de pointes arrhythmia should be used.

2. With simultaneous prescription of NSAIDs (for systemic use), including selective cyclooxygenase-2 (COX-2) inhibitors, high doses of salicylic acid (3 g/day and more) possible: reduction of the antihypertensive effect of indapamide, development of acute renal failure in dehydrated patients (due to decreased glomerular filtration rate). At the beginning of therapy with indapamide, it is necessary to restore water-electrolyte balance and monitor renal function.

3. ACE inhibitors in patients with hyponatremia (especially in patients with renal artery stenosis) increase the risk of arterial hypotension and/or acute renal failure. Patients with arterial hypertension and possibly with hyponatremia due to diuretic use must

• Discontinue the drug 3 days before starting therapy with ACE inhibitors and switch to therapy with potassium-sparing diuretics;
• Or start therapy with ACE inhibitors with low doses, followed by a gradual increase in the dose if necessary. During the first week of therapy with ACE inhibitors, monitoring of plasma creatinine concentration is recommended.

4. Other drugs that can cause hypokalemia

• Amphotericin B (IV);
• Gluco- and mineralocorticosteroids (for systemic use) (see also information in the section “Drug combinations requiring attention”);
• Tetracosactide (see also information in the section “Drug combinations requiring attention”);
• Laxatives that stimulate intestinal motility.

When taken simultaneously with indapamide, the above drugs increase the risk of hypokalemia (additive effect).

If necessary, plasma potassium ion levels should be monitored and corrected.

5. Simultaneous therapy with baclofen enhances the antihypertensive effect of indapamide.

6. Cardiac glycosides: hypokalemia increases the toxic effect of cardiac glycosides (digitalis intoxication). With simultaneous use of indapamide and cardiac glycosides, plasma potassium ion levels, ECG parameters should be monitored, and, if necessary, therapy should be adjusted.

Drug combinations requiring attention

1. Simultaneous use with potassium-sparing diuretics (amiloride, spironolactone, triamterene) is advisable in some patients, but the possibility of developing hypokalemia is not excluded. In diabetes mellitus or renal failure, hyperkalemia may develop. It is necessary to monitor plasma potassium ion levels, ECG parameters, and, if necessary, adjust therapy.

2. Metformin increases the risk of lactic acidosis, because the development of renal failure is possible while taking diuretics, especially “loop” diuretics. Metformin should not be taken when plasma creatinine concentration is more than 15 mg/L (135 µmol/L) in men and 12 mg/L (110 µmol/L) in women.

3. Simultaneous use of large doses of iodine-containing contrast agents against the background of hypovolemia and diuretic use increases the risk of acute renal failure. It is recommended to restore blood water-electrolyte balance before using the drugs.

4. Tricyclic antidepressants (imipramine-like) and antipsychotics enhance the antihypertensive effect and the risk of orthostatic hypotension (additive effect).

5. Drugs containing calcium salts increase the risk of hypercalcemia due to reduced excretion of calcium ions by the kidneys.

6. Cyclosporine, tacrolimus – risk of increased plasma creatinine concentration without changing the concentration of circulating cyclosporine.

7. Glucocorticosteroid drugs, tetracosactide (for systemic use) reduce the antihypertensive effect (retention of sodium ions and fluid).

Storage Conditions

Store in a place inaccessible to children, in a dry place, protected from light, at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 2 years.

Do not use after the expiration date printed on the package.

Dispensing Status

Dispensed by prescription

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.