Ipamid

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT IPAMID (IPAMID)

Composition:

Active substance: 1 tablet contains indapamide 2.5 mg;

Excipients: lactose monohydrate, microcrystalline cellulose, hypromellose (hydroxypropylmethylcellulose), copovidone, silicon dioxide colloidal anhydrous, magnesium stearate;

Coating: film coating mixture Opadry II Yellow: hypromellose (hydroxypropyl-methylcellulose); lactose monohydrate; polyethylene glycol (macrogol); triacetin; quinoline yellow (E 104); titanium dioxide (E 171); indigo carmine (E 132); yellow FCF (E 110).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, biconvex tablets with a yellow film coating.

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 chloride, 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 action persists even in patients with arterial hypertension undergoing hemodialysis.

Indapamide acts at the vascular level by:

• reducing the contractility 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).

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 is insufficiently effective, the dose should not be increased.

Pharmacokinetics.

Absorption. Indapamide has high bioavailability – 93%.

Maximum plasma concentration (Tmax) after a 2.5 mg dose is reached approximately within 1–2 hours.

Distribution. Plasma protein binding exceeds 75%.

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

With regular administration, a steady-state plasma concentration (plateau) is achieved, higher than the concentration observed after a single dose. This plasma concentration level remains stable over a prolonged period without accumulation.

Elimination. Renal clearance accounts for 60–80% of total clearance.

Indapamide is primarily excreted as metabolites; the fraction excreted unchanged by the kidneys is 5%.

Patients with renal impairment. Pharmacokinetic parameters are not altered in patients with renal impairment.

Clinical Characteristics.

Indications.

Essential hypertension.

Contraindications.

• Hypersensitivity to indapamide, other sulfonamides, or to any 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 appearance of symptoms of lithium overdose, as with a low-salt diet (reduced urinary excretion of lithium). If a diuretic must be administered, careful monitoring of plasma lithium levels and adjustment of lithium dosage are required.

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 antipsychotic agents:
  • 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.

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

Before prescribing such combinations, 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 should be preferred.

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

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

ACE inhibitors. Sudden onset of arterial hypotension and/or acute renal failure may occur in patients with hyponatremia (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, and then either diuretic therapy should be resumed or ACE inhibitor therapy initiated at a low dose with gradual dose escalation.

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

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

Medicinal products that may cause 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, with particular attention to concomitant therapy with cardiac glycosides. Non-stimulant laxatives are recommended.

Cardiac glycosides. Hypokalemia predisposes to cardiotoxicity of cardiac glycosides. Monitoring of plasma potassium and ECG, and dose adjustment if necessary, are required.

Digitalis preparations. Digitalis toxicity may lead to hypokalemia and/or hypomagnesemia. Monitoring of plasma potassium and magnesium levels and ECG monitoring are recommended, with therapy adjustment if necessary.

Baclofen enhances the antihypertensive effect of the medicinal product. 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 increases the risk of hypersensitivity reactions to allopurinol.

Combinations requiring attention

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

Metformin. The 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. In cases of dehydration caused by diuretic use, the risk of acute renal failure increases, especially with high doses of iodinated contrast agents. Fluid balance should be restored before 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 elimination of calcium.

Cyclosporine, tacrolimus. Risk of increased plasma creatinine without affecting circulating cyclosporine levels, even in the absence of fluid and sodium depletion.

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

Special precautions for use.

Patients with hepatic impairment

Administration of thiazide-like diuretics in patients with impaired liver function may lead to hepatic encephalopathy, particularly in the presence of electrolyte imbalance. 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 light sources.

Excipients

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

The medicinal product contains the dye "Sunset Yellow FCF" (E110), which may cause allergic reactions.

Fluid and electrolyte balance

Sodium

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

Potassium

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

Patients with congenital or drug-induced prolonged QT interval also belong to the risk group. Hypokalemia, as well as bradycardia, may predispose to severe cardiac rhythm disturbances, including torsade de pointes ventricular tachycardia, 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 concentration may be poorly responsive to treatment unless serum magnesium levels are also corrected.

Magnesium

Thiazide and thiazide-like 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 "Adverse reactions").

Calcium

Thiazide and thiazide-like diuretics may reduce urinary calcium excretion and cause 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 evaluated.

Blood glucose

In patients with diabetes mellitus, blood glucose levels should be closely monitored, especially 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 appropriate for age, body weight, and sex. Hypovolemia due to fluid and sodium loss following diuretic use at the beginning of treatment may reduce glomerular filtration rate. This may lead to 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.

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

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 medication.

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 intervention may be required. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

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 delayed fetal development. Animal studies have not revealed any direct or indirect toxic effects on reproduction. 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 develop. Risk to newborns/infants cannot be excluded. Indapamide belongs to 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 effect on fertility in male and female rats. No effect on human fertility is expected.

Ability to influence reaction speed when driving or operating machinery.

Indapamide does not affect alertness. However, if adverse reactions occur (see section "Adverse reactions"), including symptoms related to decreased blood pressure—especially at the beginning of treatment or when used in combination with another antihypertensive agent—the ability to drive a car or operate machinery may be impaired.

Dosage and Administration.

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

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

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

The use of the medicinal product 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 adjusted according to age, body weight, and gender. Ipamid 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 medicinal product is contraindicated in cases of severe hepatic impairment.

Children

Ipamid is not recommended for use in children due to insufficient data on safety and efficacy of the medicinal product in this patient group.

Overdose.

Symptoms. 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.

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

Side effects.

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

Most adverse effects, both clinical symptoms and laboratory test abnormalities, are dose-dependent.

Metabolism and nutritional disorders:
Hypokalemia (see section "Special precautions"); hyponatremia (see section "Special precautions"); hypochloremia, hypomagnesemia; hypercalcemia.

Nervous system disorders:
Dizziness (vertigo), fatigue, headache, paresthesia; loss of consciousness.

Eye disorders:
Choroidal effusion, myopia, blurred vision, visual disturbances.

Cardiovascular disorders:
Arrhythmia, hypotension; paroxysmal ventricular tachycardia of the torsades de pointes type, which may be fatal (see sections "Special precautions", "Interaction with other medicinal products and other forms of interaction").

Gastrointestinal disorders:
Vomiting; nausea, constipation, dry mouth; pancreatitis.

Renal and urinary disorders:
Renal failure.

Hepatobiliary disorders:
Liver function abnormalities; hepatic encephalopathy may occur in patients with liver insufficiency (see sections "Special precautions", "Contraindications"), hepatitis.

Reproductive system and breast disorders:
Erectile dysfunction (uncommon).

Skin and subcutaneous tissue disorders:
Hypersensitivity reactions, maculopapular rashes; purpura; angioneurotic edema and/or urticaria, toxic epidermal necrolysis, Stevens-Johnson syndrome; exacerbation of pre-existing systemic lupus erythematosus; cases of photosensitivity reactions have been reported (see section "Special precautions").

Investigations:
Prolongation of the QT interval 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; therefore, the use of diuretics should be carefully considered in patients with gout or diabetes mellitus; increased levels of liver enzymes.

Description of selected adverse reactions.

During Phase II and III studies 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. 4 years.

Storage conditions.
Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach of children.

Packaging. 10 tablets in a blister; 3 blisters per carton.

Prescription status. Prescription only.

Manufacturer: JSC "KYIV VITAMIN PLANT".

Manufacturer's address and place of business:
38 Kopilivska Street, Kyiv, 04073, Ukraine.

Web-site: www.vitamin.com.ua