Instructions Indapamide SR prolonged-release tablets 1.5 mg blister No. 30
Composition
active ingredient: indapamide;
1 tablet contains indapamide 1.5 mg;
Excipients: lactose monohydrate, hypromellose, colloidal anhydrous silica, magnesium stearate, glycerin, titanium dioxide (E 171).
Dosage form
Film-coated tablets, prolonged-release.
Main physicochemical properties: round, biconvex tablets of white or almost white color, film-coated.
Pharmacotherapeutic group
Drugs affecting the cardiovascular system. Non-thiazide diuretics with moderate activity. Indapamide. ATC code S0ZV A11.
Pharmacological properties
Pharmacodynamics.
Mechanism of action
Indapamide is a sulfonamide diuretic with an indole ring, pharmacologically related to thiazide diuretics, and is indicated for the treatment of arterial hypertension. Indapamide acts at the renal and vascular levels.
Indapamide inhibits sodium reabsorption in the cortical segment of the kidneys. This increases the excretion of sodium and chlorides into the urine and, to a lesser extent, potassium and magnesium, thereby increasing diuresis.
Pharmacodynamic effects
Phase II-III clinical trials with indapamide as monotherapy demonstrated that the antihypertensive effect of indapamide persists for 24 hours. The diuretic effect was moderate. The antihypertensive effect of indapamide is associated with an improvement in arterial elasticity and a decrease in 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 number of undesirable effects increases. If the treatment is not effective enough, increasing the dose is not recommended.
As shown in studies of various durations (short, medium and long) in 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 and hypertension.
Indapamide acts at the vascular level by:
a decrease in the contractile ability of vascular smooth muscles, which is associated with changes in transmembrane ion exchange (mainly calcium);
stimulation of the synthesis of prostaglandin PGE2 and prostacyclin PGI2 (vasodilator and platelet aggregation inhibitor).
Pharmacokinetics.
The active substance – 1.5 mg of indapamide is contained in a prolonged-release tablet created on the basis of a matrix. The distribution of indapamide in the matrix system ensures its uniform release from the tablet.
Absorption
The released fraction of indapamide is rapidly and completely absorbed from the gastrointestinal tract. Food intake slightly increases the rate of absorption but does not affect the amount of the drug absorbed.
The maximum concentration in the blood plasma after taking a single dose is reached after approximately 12 hours, subsequent use of the drug reduces fluctuations in the level of indapamide in the blood plasma in the inter-dose interval. There are intra-individual fluctuations.
Distribution
Binding to blood plasma proteins is 79%.
The half-life is 14 to 24 hours (average 18 hours).
Steady-state concentrations are reached after 7 days. Regular use does not cause accumulation.
Breeding
Indapamide is excreted in the urine (70% of the dose) and feces (22%) in the form of inactive metabolites.
High-risk patients
In patients with renal insufficiency, pharmacokinetic parameters do not change.
Indication
Essential hypertension in adults.
Contraindication
Hypersensitivity to indapamide, other sulfonamides or to any of the excipients;
severe renal failure;
hepatic encephalopathy or severe liver dysfunction;
hypokalemia.
Interaction with other medicinal products and other types of interactions
Not recommended combinations
Lithium: Increased plasma lithium levels and symptoms of overdose may occur, as with a salt-free diet (reduced urinary lithium excretion). If diuretic therapy is necessary, careful monitoring of plasma lithium levels and adjustment of the lithium dose are necessary.
Diuretics: The concomitant use of indapamide with diuretics that may cause hypokalemia (bumetanide, furosemide, piretanide, thiazides and xipamide) is not recommended.
Combinations requiring caution
Drugs that can cause paroxysmal torsades de pointes:
class Ia antiarrhythmic drugs (quinidine, hydroquinidine, disopyramide);
class III antiarrhythmic drugs (amiodarone, sotalol, dofetilide, ibutilide);
some antipsychotic drugs:
phenothiazines (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine);
benzamides (amisulpride, sulpiride, sultopride, tiapride);
butyrophenones (droperidol, haloperidol);
When using indapamide with the above-mentioned drugs, the risk of ventricular arrhythmias increases, in particular torsades de pointes - paroxysmal ventricular tachycardia of the "pirouette" type (hypokalemia is a risk factor).
Before prescribing this combination, potassium levels should be checked and, if necessary, corrected. Patients should be monitored for clinical status, plasma electrolytes, and ECG. In the presence of hypokalemia, it is recommended to prescribe drugs that do not cause torsades de pointes.
Nonsteroidal anti-inflammatory drugs (for systemic use), including selective cyclooxygenase 2 inhibitors, high doses of salicylates (≥3 g/day):
may reduce the antihypertensive effect of indapamide;
Dehydrated patients are at increased risk of acute renal failure (due to decreased glomerular filtration). Before starting treatment, it is necessary to restore water balance and check kidney function.
ACE inhibitors: Sudden hypotension and/or acute renal failure may occur in patients with low sodium levels (especially in patients with renal artery stenosis).
Arterial hypertension. If previous use of a diuretic caused a decrease in sodium levels, it is necessary to stop taking the diuretic 3 days before starting treatment with an angiotensin-converting enzyme (ACE) inhibitor and then, if necessary, resume therapy with a hypokalemic diuretic or start taking the ACE inhibitor at a low initial dose with subsequent gradual increase.
In congestive heart failure, the use of an ACE inhibitor should be initiated at the lowest dose, and possibly after reducing the dose of the previously prescribed potassium-sparing diuretic.
In any case, renal function (plasma creatinine) should be monitored during the first weeks of treatment with an ACE inhibitor.
Drugs that can cause hypokalemia: gluco- and mineralocorticoids (for systemic use), amphotericin B (intravenous), tetracosactide, laxatives that stimulate peristalsis increase the risk of hypokalemia (additive effect). Plasma potassium should be monitored and corrected if necessary, special attention should be paid to simultaneous therapy with cardiac glycosides. It is recommended to prescribe laxatives that do not stimulate peristalsis.
Cardiac glycosides. The presence of hypokalemia and/or hypomagnesemia contributes to the cardiotoxicity of cardiac glycosides. It is recommended to monitor potassium, magnesium in blood plasma, ECG control and, if necessary, adjust treatment.
Baclofen. Enhances the antihypertensive effect of the drug. At the beginning of therapy, it is necessary to restore the patient's water and electrolyte balance and monitor kidney function.
Combinations that require attention
Potassium-sparing diuretics (amiloride, spironolactone, triamterene). If such a combination is appropriate for some patients, the possibility of hypokalemia or hyperkalemia cannot be ruled out (especially in patients with diabetes mellitus or renal failure). Plasma potassium should be monitored, ECG should be monitored and therapy adjusted if necessary.
Metformin: The risk of lactic acidosis increases in patients with functional renal failure due to diuretics, especially loop diuretics. Metformin should not be prescribed if the plasma creatinine level exceeds 15 mg/L (135 μmol/L) in men and 12 mg/L (110 μmol/L) in women.
Iodine contrast media. In case of dehydration caused by diuretics, the risk of developing acute renal failure increases, especially when using large doses of iodinated contrast media. It is necessary to restore the water balance before administering iodinated contrast media.
Imipramine-like antidepressants, neuroleptics. Increased antihypertensive effect and risk of orthostatic hypotension due to additive effect.
Calcium salts: Hypercalcemia may occur due to decreased renal calcium elimination.
Cyclosporine, tacrolimus: Risk of increased plasma creatinine without effect on circulating cyclosporine levels, even in the absence of water/sodium depletion.
Corticosteroids, tetracosactide (systemic action). Decreased antihypertensive effect of indapamide due to water and sodium retention under the influence of corticosteroids.
Application features
Patients with hepatic impairment
In patients with impaired liver function, the use of thiazide-like diuretics may cause hepatic encephalopathy, especially if electrolyte imbalance is present. In such cases, the diuretic should be discontinued immediately.
Photosensitivity
Photosensitivity reactions have been reported in patients receiving thiazide and thiazide-like diuretics (see section 4.8). If such reactions occur, diuretic treatment should be discontinued. If diuretics are re-administered, the affected areas should be protected from sunlight or artificial ultraviolet light sources.
Excipients
The drug contains lactose, so it should not be prescribed to patients with congenital galactose intolerance, glucose-galactose malabsorption syndrome, Lapp lactase deficiency.
Plasma sodium
Plasma sodium levels should be monitored before starting treatment and regularly during treatment. Decreased plasma sodium levels may be asymptomatic at first, so regular monitoring is necessary. Monitoring of sodium levels should be more frequent in elderly patients and in patients with cirrhosis of the liver. Any diuretic can cause hyponatremia, which can sometimes have serious consequences.
Hyponatremia with hypovolemia can lead to dehydration and orthostatic hypotension; the concomitant loss of chloride ions can cause secondary compensatory metabolic alkalosis (the frequency and severity of this phenomenon are low).
Plasma potassium
A decrease in plasma potassium with hypokalemia is a major risk with thiazide and thiazide-like diuretics. The possibility of hypokalemia (<3.4 mmol/L) should be considered in certain high-risk patient groups, such as the elderly, malnourished and/or heavily medicated patients, patients with cirrhosis of the liver with edema and ascites, patients with ischemic heart disease, and patients with heart failure. In such cases, hypokalemia increases the cardiotoxicity of cardiac glycosides and the risk of arrhythmias.
Patients with a prolonged QT interval, congenital or iatrogenic, are also at risk. Hypokalemia, like bradycardia, can contribute to the development of serious cardiac arrhythmias, including paroxysmal ventricular tachycardia of the "pirouette" type, which can be fatal.
In all of the above cases, more frequent monitoring of potassium levels in the blood is necessary. The first analysis should be performed within the 1st 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 corrected.
Plasma magnesium
Thiazide and thiazide-like diuretics, including indapamide, may increase urinary magnesium excretion 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 calcium excretion and lead to a slight and transient increase in plasma calcium levels. Marked hypercalcemia may be a consequence of previously undiagnosed hyperparathyroidism. In such cases, treatment should be discontinued and parathyroid function should be monitored.
Blood glucose
In patients with diabetes, it is important to control blood glucose, especially in the presence of hypokalemia.
Uric acid
Patients with elevated uric acid levels may have a tendency to have an increased number of gout attacks.
Kidney function and diuretics
Thiazide and thiazide-like diuretics are most effective when renal function is not impaired or only mildly impaired (plasma creatinine <25 mg/l, i.e. 220 μmol/l in adults). In elderly patients, plasma creatinine should be at a level appropriate for age, weight and sex. Hypovolemia, associated with water and sodium loss due to diuretics, causes a decrease in glomerular filtration rate at the beginning of treatment. This may lead to an increase in blood urea and creatinine. Such transient functional renal failure is of no consequence in individuals with normal renal function, but may worsen existing renal failure.
Choroidal effusion, acute myopia, and secondary angle-closure glaucoma
Sulfonamide drugs or sulfonamide derivatives may cause an idiosyncratic reaction resulting in choroidal effusion with visual field defect, 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 of starting the drug. Untreated acute angle-closure glaucoma may lead to irreversible vision loss. Initial treatment includes discontinuation of the drug as soon as possible. If intraocular pressure remains uncontrolled, a decision may be made to consider prompt medical or surgical treatment. Risk factors for acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.
In athletes, indapamide may cause a positive reaction during doping control.
Use during pregnancy or breastfeeding
Pregnancy
There are no or limited (less than 300) data from the use of indapamide in pregnant women. Prolonged use of a thiazide diuretic during the third trimester of pregnancy may result in a decrease in maternal blood volume and uteroplacental blood flow, which may lead to fetoplacental ischemia and fetal growth retardation. Animal studies do not indicate direct or indirect toxic effects with respect to reproductive toxicity. As a precautionary measure, it is preferable to avoid the use of indapamide during pregnancy.
There is insufficient data on the excretion of indapamide/metabolites in breast milk. Hypersensitivity to sulfonamide derivatives and hypokalemia may develop. A risk to the newborn/infants cannot be excluded. Indapamide belongs to the thiazide-like diuretics, the use of which during breastfeeding has been associated with a decrease or even suppression of 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 vehicles or other mechanisms
Indapamide has minor or moderate influence on the ability to drive and use machines. Indapamide does not affect alertness. However, in the event of adverse reactions (see section "Adverse reactions"), including symptoms associated with a decrease in blood pressure, especially at the beginning of treatment or in combination with another antihypertensive agent, the ability to drive or use other mechanisms may be impaired.
Method of administration and doses
Method of application
For oral use.
Dosage
1 tablet per day, preferably in the morning. The tablet should be swallowed whole, without chewing, with water.
The use 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 failure (see sections "Special instructions" and "Contraindications")
In patients with severe renal insufficiency (creatinine clearance < 30 ml/min), the use of the drug is contraindicated. Thiazide and thiazide-like diuretics are most effective if renal function is not impaired or if the impairment is minor.
Elderly (see section "Special instructions")
In elderly patients, plasma creatinine should be at a level appropriate for age, body weight and sex. Indapamide SR can be administered to elderly patients if renal function is not impaired or if the impairment is minor.
Patients with impaired liver function (see sections "Special instructions" and "Contraindications")
In case of severe liver dysfunction, treatment with the drug is contraindicated.
Children.
The safety and efficacy of Indapamide-Teva SR in children have not been established. Data are lacking.
Overdose
Indapamide does not show toxicity when used in doses up to 40 mg, i.e. in a dose 27 times higher than the therapeutic dose.
Symptoms of overdose are primarily manifestations of water and electrolyte disturbances (hyponatremia, hypokalemia). Clinically, nausea, vomiting, hypotension, convulsions, drowsiness, dizziness (vertigo), confusion, polyuria or oliguria up to anuria (caused by hypovolemia) are possible.
First aid measures include rapid drug elimination by gastric lavage and/or administration of activated charcoal, followed by restoration of fluid and electrolyte balance in a hospital setting.
Side effects
The most frequently 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 and laboratory, are dose-dependent.
The following adverse reactions have been observed during treatment with indapamide, listed below, with the following frequencies: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), frequency unknown (cannot be estimated from the available information).
Blood and lymphatic system disorders
Very rare: thrombocytopenia, leukopenia, agranulocytosis, aplastic anemia, hemolytic anemia.
Metabolism and metabolism
Often - hypokalemia (see section "Special instructions for use");
infrequently - hyponatremia (see section "Special instructions for use");
rarely – hypochloremia, hypomagnesemia;
very rarely - hypercalcemia.
From the nervous system
Rarely – dizziness (vertigo), fatigue, headache, paresthesia;
frequency unknown – fainting.
From the organs of vision
Frequency unknown - myopia, blurred vision, visual impairment, choroidal effusion.
From the heart
Very rare – arrhythmia;
frequency unknown - paroxysmal ventricular tachycardia of the "pirouette" type (torsades de pointes), which can be fatal (see sections "Special instructions", "Interaction with other medicinal products and other types of interactions").
From the vascular system
Very rare: hypotension.
From the digestive system
Uncommon: vomiting;
rarely - nausea, constipation, dry mouth;
very rarely - pancreatitis.
Renal and urinary disorders
Very rare - renal failure.
Reproductive system and breast disorders
Uncommon: erectile dysfunction.
Hepatobiliary system
Very rare - liver dysfunction;
frequency unknown – in case of liver failure, hepatic encephalopathy may occur (see sections “Special instructions for use”, “Contraindications”), hepatitis.
Hypersensitivity reactions, mainly of the skin, in patients with a predisposition to allergic and asthmatic reactions:
often – maculopapular rashes;
infrequently – purpura;
very rarely - angioedema and/or urticaria, toxic epidermal necrolysis, Stevens-Johnson syndrome;
frequency unknown - possible exacerbation of existing acute systemic lupus erythematosus. Cases of photosensitivity reactions have been reported (see section "Special warnings and precautions for use").
Research
Frequency unknown - prolongation of the QT interval on the electrocardiogram (see sections "Special instructions for use", "Interaction with other medicinal products and other types of interactions"); increased levels of uric acid and glucose in the blood plasma during treatment with diuretics, the rationality of their administration should be carefully weighed before prescribing to patients with gout or diabetes mellitus; increased levels of liver enzymes.
Description of selected adverse reactions
Phase II and III studies comparing indapamide 1.5 mg and 2.5 mg showed a dose-dependent effect of indapamide on plasma potassium levels:
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 treatment, the mean decrease in serum potassium 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 treatment, the mean decrease in serum potassium was 0.41 mmol/L.
Expiration date
3 years.
Storage conditions
Store at a temperature not exceeding 30 °C out of the reach of children.
Packaging
10 tablets in a blister; 3 blisters in a box.
Vacation category
According to the recipe.
Producer
Merkle GmbH.
Location of the manufacturer and address of its place of business.
Ludwig-Merkle-Strasse 3, 89143 Blaubeuren, Germany.
