Arifon, 2,5mg 30 pcs.

Pharmaceutical group: diuretic agent.

Pharmaceutical action:

Hypotensive agent (diuretic, vasodilator). By pharmacological properties it is close to thiazide diuretics (disruption of Na+ reabsorption in the cortical segment of the Genle loop). Increases urinary excretion of Na+, Cl- and, to a lesser extent, K+ and Mg2+. Having the ability to selectively block “slow” calcium channels, increases the elasticity of arterial walls and reduces RPS. It helps to reduce LV hypertrophy of the heart.

Does not affect plasma lipid levels (TG, LDL, HDL); does not affect carbohydrate metabolism (including in patients with concomitant diabetes). It reduces sensitivity of the vascular wall to noradrenaline and angiotensin II, stimulates the synthesis of PgE2 and prostacyclin PgI2, reduces the production of free and stable oxygen radicals. When administered in high doses, it does not affect the degree of BP reduction, despite the increase in diuresis.

Therapeutic effect is seen in 1-2 weeks after multiple dosing, reaches maximum by 8-12 weeks and lasts up to 8 weeks; after a single dose maximum effect is seen in 24 hours.

Pharmacokinetics:

Fast and complete absorption from the gastrointestinal tract; bioavailability is high. Food intake slightly slows down the absorption rate, but does not affect the final amount of absorbed drug. TCmax is 1-2 hours after taking the usual dosage form and 12 hours after taking the retard tablets. Cmax after an oral dose of 5 mg is 260 ng/ml. When repeated doses are taken, the fluctuations in plasma concentrations between 2 doses are reduced. Css is established after 7 days of regular use.

Binding with plasma proteins is 71-79%. It also binds with elastin of smooth muscles of the vascular wall. It has a high volume of distribution and passes through histohematic barriers (including the placental one).

It is metabolized in the liver. T1/2 is 14 hours, final T1/2 is 26 hours. The drug is excreted by the kidneys 60-70% as metabolites (about 5-7% is excreted unchanged), 20-23% – through the intestines. Pharmacokinetics does not change in patients with renal insufficiency. It does not cumulate.

Indications

Active ingredient

Composition

1 tablet contains:

Active ingredient:

indapamide2.5 mg;

Associates:

Lactose monohydrate – 59.25 mg;

Corn starch – 20.00 mg;

Magnesium stearate, 0.75 mg;

Povidone, 4.00 mg;

Taalc, 3.5 mg;

Film coating:

Glycerol, 0.087 mg; macrogol 6000, 0.035 mg; magnesium stearate, 0.087 mg; hypromellose, 1.449 mg; sodium lauryl sulfate, 0.017 mg; titanium dioxide, 0.278 mg; white beeswax, 0.047 mg.

How to take, the dosage

Ingestion, preferably in the morning, 1 tablet daily.

When treating patients with arterial hypertension, the drug dose should not exceed 2.5 mg/day (increased risk of side effects without increasing the antihypertensive effect).

Interaction

In concomitant use of indapamide and tricyclic antidepressants such as imipramine, an increase in hypotensive effect and increased risk of orthostatic hypotension are observed.

Concomitant use of thiazide diuretics and calcium salts may lead to hypercalcemia due to decrease of calcium ions excretion with urine. Concomitant use of indapamide and cyclosporine may increase plasma creatinine, which is observed even with normal water and sodium ions. Concomitant use of thiazide diuretics and lithium preparations may lead to increased concentration of lithium in blood plasma, accompanied by the appearance of signs of overdose (due to decrease of lithium excretion with urine).

When it is necessary to prescribe this combination, plasma lithium concentration should be monitored. In concomitant use of diuretics with astemizole, bepridil, erythromycin (IV), halofantrine, pentamidine, sultopride, terfenadine, vincamine the possibility of “pirouette” type arrhythmia increases. Hypokalemia, bradycardia, or prolonged QT interval may contribute to this condition.

In concomitant use with cardiac glycosides toxic effect of the latter is increased (it is necessary to control the level of potassium in plasma and ECG indexes). Concomitant use with NSAIDs (for systemic use), high doses of salicylates may reduce the hypotensive effect of indapamide.

In case of significant fluid loss, acute renal failure may develop (due to a sharp decrease in glomerular filtration). If it is necessary to prescribe NSAIDs during therapy with Arifon, it is necessary to compensate the loss of water and carefully monitor renal function. Co-administration of indapamide with other drugs which may cause hypokalemia, including amphotericin B (IV), gluco- and mineralocorticoids (when used systemically), tetracosactide, laxatives stimulating peristalsis, increases the risk of hypokalemia (continuous monitoring of plasma potassium levels and, if necessary, appropriate treatment is required).

In concomitant use of thiazide diuretics with GCS, tetracosactide for systemic use the reduction of hypotensive effect due to water and sodium ion retention under the influence of GCS is observed. When concomitant use of indapamide with baclofen, an increase in hypotensive effect is observed (it is necessary to compensate the loss of water and carefully monitor renal function at the beginning of treatment). In concomitant use of indapamide and potassium-saving diuretics (including amiloride, spironolactone, triamterene) the possibility of hypokalemia or hyperkalemia cannot be excluded, especially in patients with diabetes and renal failure.

In such cases the plasma potassium level and ECG parameters should be monitored and the therapy should be corrected if necessary. When concomitant use of indapamide with ACE inhibitors, hyponatremia in patients receiving ACE inhibitors increases the risk of sudden arterial hypotension and/or acute renal failure (especially with renal artery stenosis). Patients with essential arterial hypertension and decreased content of sodium ions in blood plasma due to taking diuretics should stop taking diuretics 3 days before starting treatment with ACE inhibitors.

Thereafter, if necessary, the use of diuretics should be resumed. In addition, low, gradually increasing doses of ACE inhibitors are prescribed. In chronic heart failure, treatment should be started with low doses of ACE inhibitors, having previously reduced the dose of diuretics. In all cases during the first week of ACE inhibitors use it is necessary to monitor renal function (creatinine content in blood plasma).

In concomitant administration of indapamide and antiarrhythmic drugs which may cause “pirouette” arrhythmia (including quinidine, hydroquinidine, disopyramide, amiodarone, bretilium, sotalol) the risk of this condition increases (especially with hypokalemia, bradycardia, initially prolonged QT interval). If it is necessary to administer this combination, plasma potassium level and QT interval should be monitored by adjusting the dosing regimen.

The simultaneous use of diuretics and metformin may result in lactic acidosis, which appears to be associated with the development of functional renal failure due to the action of diuretics (mostly “loop” diuretics). It is not recommended to use metformin in combination with Arifon in creatinine level more than 15 mg/l (135 µmol/l) in men and 12 mg/l (110 µmol/l) in women.

When using iodine-containing radiopaque agents, it should be borne in mind that the diuretic effect of indapamide, increases the risk of renal failure. This risk is especially high when using iodine-containing radiopaque agents in high doses. Patients should restore fluid loss before using iodine-containing radiopaque agents.

Special Instructions

When prescribing Arifon to patients with diabetes mellitus it is extremely important to monitor glucose levels, especially in the presence of hypokalemia.
In patients with elevated uric acid there is a tendency to increase the number of gout attacks.

When thiazide diuretics are prescribed to patients with hepatic insufficiency, hepatic encephalopathy may develop. In these cases the drug should be stopped immediately.

The thiazide diuretics show their full effectiveness only in absence or moderately marked impairment of renal function (blood creatinine less than 25 mg/l or 220 µmol/l).

In elderly patients the normal plasma creatinine level is calculated with consideration of age, body weight and sex of the patient according to the Cockroft formula:

ClCR=(140-age/years/) x body weight(kg)/0.814 x plasma creatinine(μmol/L).

This formula is used to calculate creatinine levels in men, for women the final result should be multiplied by 0.85.

Please note that at the start of treatment, patients may have decreased glomerular filtration due to hypovolemia caused by the loss of water and sodium ions due to diuretics. As a consequence, plasma concentrations of urea and creatinine may increase. If kidney function is not impaired, such temporary renal failure usually passes without consequences. However, if renal failure is already present, the patient’s condition may worsen.

An exacerbation of disseminated lupus erythematosus is possible with Arifon therapy.

Before treatment, plasma sodium ions should be determined. Regular monitoring of this index is necessary during treatment, since initially the decrease of sodium concentration in blood plasma may not be accompanied by the appearance of pathological symptoms. Particularly often this test should be done in patients with cirrhosis and in elderly people.

In thiazide diuretic therapy, the main risk is a sharp decrease in potassium ions and the development of hypokalemia. Hypokalemia should be avoided in certain patients, particularly in elderly patients, those who are weak or on concomitant therapy, cirrhosis with edema or ascites, CHD, chronic heart failure (hypokalemia – similarly to bradycardia – is a contributing factor for severe cardiac arrhythmias, especially pirouette, which are often fatal). In all cases described above, it is necessary to determine the content of potassium ions in blood plasma more frequently. The first measurement of blood concentration of potassium ions should be performed within the first week from the beginning of treatment.

In case of hypokalemia, appropriate treatment should be prescribed, while avoiding the use of drugs that cause “pirouette-type” arrhythmias. If this arrhythmia occurs, antiarrhythmic drugs should not be used, and an artificial pacemaker should be installed.

Please note that thiazide diuretics may decrease urinary excretion of calcium ions, resulting in mild and temporary hypercalcemia. Severe hypercalcemia may result from previously undiagnosed hyperparathyroidism.
Diuretics should be discontinued before starting a parathyroid function study.

If it is necessary to prescribe laxatives against the background of Arifon therapy, drugs that do not affect intestinal peristalsis should be prescribed.

Addapamide may cause a positive result in doping control in athletes.
Increase in the dose of thiazide diuretics above the optimal one is not accompanied by increase in antihypertensive effect, but it may be accompanied by the occurrence of serious adverse reactions. If therapy with thiazide diuretics does not lead to the desired therapeutic effect, the drug dose should not be increased.

In concomitant use with other antihypertensive drugs, the dose of Arifon should be reduced, at least at the beginning of treatment.

Pediatric use

In the absence of sufficient clinical data, the drug is not recommended for use in children and adolescents under 18 years of age.

Impact on the ability to drive and operate machinery

The action of the substances included in Arifon does not lead to impairment of psychomotor reactions. However, it should be considered that in some cases individual reactions may occur while lowering the BP (especially at the beginning of therapy or in combination with several antihypertensive drugs). In this case, the ability to perform work requiring increased attention and rapid psychomotor reactions may be reduced.

Contraindications

Combined administration of Arifon and agents that prolong the QT interval should be avoided.

Overdose

Symptoms: water-electrolyte balance disorders (hyponatremia, hypokalemia), nausea, vomiting, arterial hypotension, seizures, dizziness, drowsiness, confusion, polyuria or oliguria ending in anuria (due to hypovolemia) are possible.

Treatment: immediate measures aimed at elimination of the drug from the body: gastrointestinal flushing and/or administration of activated charcoal with subsequent restoration of normal water-electrolyte balance.

Pregnancy use

As a rule, Arifon is not recommended for use in pregnancy, including to relieve physiological edema. It should be borne in mind that diuretics may cause fetoplacental ischemia and impair fetal development.

Because of the fact that indapamide is excreted with breast milk, it is also not recommended to prescribe the drug during breastfeeding. Breast-feeding should be stopped if therapy is necessary.

Similarities