Indapamide retard, 1.5 mg 30 pcs

Pharmacotherapeutic group:

Diuretic.

ATC code: C03BA11

Pharmacological properties:

Pharmacodynamics

Indapamide is a sulfonamide derivative with pharmacological properties similar to thiazide diuretics (disruption of sodium ion reabsorption in the cortical segment of the Genle loop). It increases renal excretion of sodium and chlorine ions and, to a lesser extent, potassium and magnesium ions, which is accompanied by increased diuresis and hypotensive effect. Hypotensive effect is maintained for 24 hours after single use with moderate increase in diuresis.

The antihypertensive activity is associated with improvement of elastic properties of large arteries, reduction of arterial and total peripheral vascular resistance. Indapamide reduces left ventricular hypertrophy. Thiazide and thiazide-like diuretics reach a plateau of therapeutic effect at a certain dose, while the frequency of side effects continues to increase with further increases in the drug dose. Therefore, do not increase the dose of the drug if the therapeutic effect is not achieved at the recommended dose.

Indapamide does not influence plasma lipid levels (triglycerides, low-density lipoproteins, high-density lipoproteins); it does not influence parameters of carbohydrate metabolism, including in diabetic patients.

Pharmacokinetics

Intake
After oral administration is quickly and completely absorbed from the gastrointestinal tract; bioavailability is high (93%). Food intake slightly slows down the absorption rate, but does not affect the amount absorbed. Maximum plasma concentration is reached 12 hours after a single oral dose. When repeated doses are taken, the fluctuations in plasma concentrations between two doses are reduced.

Distribution
Blood protein binding is 79 %. The elimination half-life is 14 – 24 hours (on average, 18 hours). It passes through the histohematic barriers (including the placental barrier) and is excreted in breast milk. The equilibrium concentration is reached after 7 days of taking the drug. No cumulation is observed when reuptake.

Metabolism
Indapamide is excreted as inactive metabolites, mainly by the kidneys (70%) and through the intestine (22%).

Patients at high risk
In patients with renal impairment the pharmacokinetics of the drug is not changed.

Indications

-Arterial hypertension.
-High sensitivity to indapamide, other sulfonamide derivatives or to any of the excipients;
-Severe renal insufficiency (creatinine clearance less than 30 ml/min);
-Hepatic encephalopathy or severe liver function disorders;
-Hypokalemia;
-Pregnancy, lactation;
-Before 18 years of age (effectiveness and safety is not established);

-Current use of drugs that prolong the QT interval;
-Lactase deficiency, lactose intolerance, glucose-galactose malabsorption.

Active ingredient

Composition

Tablets.

1 tablet contains:

Active substance:

Indapamide 1.5 mg;

Associates:

Hypromellose, 77.36 mg;

Lactose monohydrate (milk sugar), 119.14 mg;

colloidal silicon dioxide (aerosil) – 1 mg;

p> magnesium stearate – 1 mg;

Opadray II (hypromellose – 2.24 mg, lactose monohydrate – 2.88 mg, polyethylene glycol – 0.8 mg, titanium dioxide – 2.08 mg) – 8 mg

How to take, the dosage

Overly, 1 tablet daily, preferably in the morning. The tablet should be swallowed whole, without chewing, with water.
Increasing the dose does not increase antihypertensive effect, but increases diuretic effect.
Elderly patients.

In elderly patients, plasma creatinine concentration should be monitored taking into account age, body weight and sex.
Indapamide retard may be used in elderly patients with normal or mildly impaired renal function.

Interaction

-Lithium preparations
Simultaneous use of indapamide and lithium preparations may result in increased plasma lithium concentrations due to decreased excretion, accompanied by signs of overdose. If necessary, diuretics may be prescribed in combination with lithium preparations, and the dose of preparations should be carefully selected, constantly monitoring the plasma concentration of lithium.

Combinations requiring special caution
-Drugs that can cause pirouette arrhythmias
-Class III antiarrhythmic drugs (amiodarone, dofetilide, ibutilide), sotalol;
-some neuroleptics: phenothiazines (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluorperazine), benzamides (amisulpride, sulpiride, sultopride, thiapride), butyrophenones (droperidol, haloperidol);
-others: bepridil, cisapride, difemanil, erythromycin (w/v), halofantrine, misolastin, pentamidine, sparfloxacin, moxifloxacin, astemizole, vincamine (w/v).

The risk of ventricular arrhythmias, especially pirouette arrhythmias, increases (hypokalemia is a risk factor).
Plasma potassium levels should be determined and, if necessary, corrected before the start of combined therapy with indapamide and the above drugs. The patient’s clinical condition should be monitored, plasma electrolytes and ECG parameters should be controlled.

Patients with hypokalemia should be prescribed drugs that do not cause pirouette-type arrhythmias.
-Non-steroidal anti-inflammatory drugs (when used systemically), including selective cyclooxygenase-2 (COX-2) inhibitors, high doses of salicylates (≥ 3 g/day)

The antihypertensive effect of indapamide may decrease. If significant fluid loss occurs, acute renal failure may develop (due to decreased glomerular filtration). Patients should compensate for fluid loss and carefully monitor renal function at the beginning of treatment.

-Angiotensin-converting enzyme inhibitors (ACE)
The use of ACE inhibitors in patients with decreased sodium ions in blood (especially in patients with renal artery stenosis) is accompanied by the risk of sudden arterial hypotension and/or acute renal failure.

Patients with arterial hypertension and possibly decreased, due to taking diuretics, plasma sodium ion content is necessary:

-3 days before starting treatment with an ACE inhibitor, discontinue diuretics. Further, if necessary, diuretics administration may be resumed;
-or therapy with ACE inhibitor should be started from low doses with subsequent gradual increase of doses, if necessary.
In chronic heart failure treatment with ACE inhibitors should be started from low doses with possible prior decrease of diuretics doses.

In all cases in the first week of ACE inhibitor therapy, patients should have their renal function (plasma creatinine concentration) monitored.
– Other drugs that may cause hypokalemia: amphotericin B (IV), gluco- and mineralocorticosteroids (when used systemically), tetracosactide, intestinal motility stimulating laxatives
Increased risk of hypokalemia (additive effect).
Regular monitoring of plasma potassium content, and correction if necessary. Particular attention should be paid to patients concomitantly receiving cardiac glycosides.
It is recommended to use laxatives that do not stimulate intestinal motility. Patients should compensate for fluid loss and, at the beginning of treatment, carefully monitor renal function.
-Cardiac glycosides

Hypokalemia increases toxic effects of cardiac glycosides. When concomitant use of indapamide and cardiac glycosides, plasma potassium content and ECG parameters should be monitored and, if necessary, the therapy should be adjusted.

Preparation combinations requiring attention
-Kalium-saving diuretics (amiloride, spironolactone, triamterene)
Combination therapy with indapamide and potassium-saving diuretics is reasonable in some patients, but it does not exclude the possibility of hypokalemia (especially in patients with diabetes and renal failure) or hyperkalemia.
It is necessary to monitor the plasma potassium content and ECG indexes and, if necessary, adjust the therapy.
-Metformin
Functional renal insufficiency, which may occur with diuretics, especially “loop” diuretics, with concomitant use of metformin increases the risk of lactic acidosis.
Metformin should not be prescribed if creatinine concentrations exceed 15 mg/L (135 μmol/L) in men and 12 mg/L (110 μmol/L) in women.
-Iodine-containing contrast agents

Dehydration from diuretics increases the risk of acute renal failure, especially when using high doses of iodine-containing contrast agents.
Patients should compensate for fluid loss before using iodine-containing contrast agents.
-Tricyclic antidepressants, antipsychotics (neuroleptics)
Drugs of these classes increase the antihypertensive effect of indapamide and increase the risk of orthostatic hypotension (additive effect).
-Calcium salts
Simultaneous use may result in hypercalcemia due to reduced renal excretion of calcium ions.
-Cyclosporine, tacrolimus
It is possible to increase the concentration of creatinine in plasma without changing the concentration of circulating cyclosporine, even with normal fluid and sodium ion content.
-Corticosteroid drugs, tetracosactide (when used systemically)
Reduced hypotensive effect (fluid and sodium ion retention as a result of corticosteroid action).

Special Instructions

Hepatic disorders

When using thiazide and thiazide-like diuretics in patients with hepatic impairment, hepatic encephalopathy may develop, especially in case of electrolyte-water imbalance. In this case the use of diuretics should be stopped immediately.

Photosensitivity reactions
Cases of photosensitivity reactions have been reported with thiazide and thiazide-like diuretics (see “Side effects”). In case of photosensitivity reactions during the drug administration, the treatment should be discontinued. If continuation of therapy with diuretics is necessary, it is recommended to protect the skin from exposure to sunlight or artificial ultraviolet rays.

Water-electrolyte balance
-The content of sodium ions in plasma

Before starting treatment, the content of sodium ions in plasma should be determined. Against the background of the drug administration this index should be controlled regularly. All diuretics may cause hyponatremia, which sometimes leads to extremely severe consequences. Regular control of sodium ions content is necessary, since initially decrease of sodium content in blood plasma may not be accompanied by the appearance of pathological symptoms. The most careful control of sodium ions content is recommended to patients with liver cirrhosis and elderly patients (see sections “Side effects” and “Overdose”).
-Content of potassium ions in plasma

In therapy with thiazide and thiazide-like diuretics the main risk is sharp decrease of potassium content in plasma and development of hypokalemia. It is necessary to avoid the risk of hypokalemia (< 3.4 mmol/l) in patients of the following categories: elderly, weakened or receiving combined drug therapy with other antiarrhythmic drugs and drugs that may increase QT interval, patients with liver cirrhosis, peripheral edema or ascites, coronary heart disease, heart failure. Hypokalemia in these patients increases the toxic effects of cardiac glycosides and increases the risk of arrhythmias. Moreover, the group of increased risk includes patients with prolonged QT interval, and it does not matter if the prolongation is caused by congenital causes or by medications.
Hypokalemia, as well as bradycardia, is a condition contributing to severe arrhythmias and, especially, pirouette arrhythmias, which may be fatal. In all cases described above, plasma potassium content should be monitored regularly. The first measurement of blood potassium ions should be made during the first week of treatment. In case of hypokalemia appropriate treatment should be prescribed.

– Plasma calcium
Note that thiazide and thiazide-like diuretics may decrease renal excretion of calcium ions, resulting in a slight and temporary increase in plasma calcium. Severe hypercalcemia may result from previously undiagnosed hyperparathyroidism.

The use of diuretics should be discontinued prior to parathyroid function testing.

Plasma glucose
Blood glucose concentrations should be monitored in patients with diabetes mellitus, especially if hypokalemia is present.

Uracilic acid
Patients with gout may have an increased incidence of attacks or worsen the course of gout.

Diuretics and renal function
Thiazide and thiazide-like diuretics are only fully effective in patients with normal or mildly impaired renal function (plasma creatinine concentration in adults below 25 mg/l or 220 μmol/L). In elderly patients the normal plasma creatinine concentration is calculated taking into account age, body weight and sex.

It should be taken into account that at the beginning of treatment patients may have decreased glomerular filtration rate due to hypovolemia, which in turn is caused by loss of fluid and sodium ions due to diuretic therapy. As a consequence, plasma concentrations of urea and creatinine may increase. If renal function is not impaired, such temporary functional renal failure usually goes without consequences, but if renal failure is already present, the patient’s condition may worsen.

Athletes
The active ingredient in Indapamide Retard may work well in doping controls in athletes.

Influence on ability to drive and operate vehicles:

The effects of the substances in Indapamide retard do not result in impairment of psychomotor reactions. However, some patients may have various individual reactions in response to blood pressure decrease, especially at the beginning of therapy or when other hypotensive drugs are added to the current therapy. In this case, the ability to drive motor transport or other mechanisms may be reduced.

Contraindications

With caution:
Use with caution in patients with liver and/or kidney function disorders, impaired water-electrolyte balance, hyperparathyroidism, patients with prolonged QT interval on ECG or receiving concomitant therapy, decompensated diabetes, hyperuricemia (especially accompanied by gout and urate nephrolithiasis).

Side effects

Most adverse reactions are dose-dependent.

In the digestive system: nausea, anorexia, dry mouth, gastralgia, vomiting, diarrhea, constipation, abdominal pain, liver dysfunction, hepatic encephalopathy, hepatitis, increased “liver” transaminases activity, pancreatitis.

Hematopoietic system disorders: Hyperuricemia, hyperglycemia, hypokalemia, hypochloremia, hyponatremia, hyponatremia, hypomagnesemia, hypercalcemia, increase in plasma urea nitrogen, hypercreatininemia, glucosuria, thrombocytopenia, leukopenia, agranulocytosis, aplastic anemia, hemolytic anemia.

Allergic reactions: skin rash, angioneurotic edema, urticaria, pruritus, toxic epidermal necrolysis, Stevens-Johnson syndrome, hemorrhagic vasculitis.

Central nervous system disorders: asthenia, nervousness, headache, dizziness, somnolence, vertigo, insomnia, depression, increased fatigue, general weakness, malaise, muscle spasm, paresthesias, tension, irritability, anxiety.

Respiratory system: cough, pharyngitis, sinusitis, rhinitis.

Cardiovascular system disorders: fainting, significant decrease in blood pressure, electrocardiogram (ECG) changes (characteristic of hypokalemia), prolongation of QT interval in ECG, arrhythmia, pirouette arrhythmia, palpitations.

Urinary system disorders: frequent infections, nycturia, polyuria, renal failure.

Others: exacerbation of systemic lupus erythematosus, photosensitization reaction.

Overdose

Indapamide even in doses up to 40 mg, i.e. 27 times the therapeutic dose, has no toxic effect.
The signs of acute poisoning by the drug are primarily associated with disruptions of the water-electrolyte balance (hyponatremia, hypokalemia).

The clinical symptoms of overdose may include nausea, vomiting, decreased blood pressure, seizures, dizziness, drowsiness, confusion, polyuria or oliguria leading to anuria (due to hypovolemia).

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

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