ARIFON RETARD

Active material: Indapamid
When ATH: C03BA11
CCF: Diuretic. Antihypertensive drugs
ICD-10 codes (testimony): I10
Registration Date: 08.07.08
Manufacturer: Servier Laboratories (France)

PHARMACEUTICAL FORM, COMPOSITION AND PACKAGING

Controlled release tablets, Film-coated white, round, lenticular.

Excipients: gipromelloza, Colloidal anhydrous silica, lactose monohydrate, magnesium stearate, povidone.

The composition of the coating film: gipromelloza, glycerol, magnesium stearate, macrogol, Titanium dioxide.

15 PC. – blisters (2) – packs cardboard.
30 PC. – blisters (1) – packs cardboard.

Pharmacological action

Antihypertensive (diuretic) preparation, sulfonamide derivative, containing an indole ring. On pharmacologically similar to indapamide thiazide diuretics.

Indapamide increases the urinary excretion of sodium ions, chlorine, less, potassium and magnesium ions, that is accompanied by increased urine output. Indapamide has antihypertensive effect in doses, does not have a pronounced diuretic effect.

The mechanism of action of indapamide is due to a change in the transmembrane ion current (Firstly – Calcium), that causes relaxation of vascular smooth muscle cells, as well as increased synthesis of prostaglandins PGE₂ and prostacyclin PGI₂ (vasodilator and inhibitor of platelet aggregation).

The drug reduces left ventricular hypertrophy.

Regardless of the duration of application Arifon^® retard does not alter lipid metabolism (blood levels of triglycerides, cholesterol, LDL, HDL); It does not alter the carbohydrate metabolism (incl. patients with hypertension and diabetes).

Indapamide is effective in patients, with one kidney.

Indapamide has antihypertensive effect in doses, does not have a pronounced diuretic effect.

Pharmacokinetics

Absorption

In tablets ArifOn^® retard the active substance is in a special carrier matrix, which provides a gradual release of indapamide in the digestive tract. Liberate indapamide is rapidly and completely absorbed from the gastrointestinal tract.

After oral administration of a single dose C_max achieved through 12 no. Repeated receptions fluctuations indapamide concentration in blood plasma in the interval between receptions of two doses decreased.

Eating slows down the absorption rate of the drug, but it does not affect the amount of the absorbed compound.

There is individual variability in absorption rates of the drug.

Distribution

Plasma protein binding is about 79%. C_ss achieved through 7 regular admission days.

If readmission ArifOn^® Retard not accumulated in the body indapamide.

Metabolism and excretion

Indapamide biotransformation and is excreted as inactive metabolites, mainly in the urine – 70% and feces – 22%.

T_1/2 is 14-24 no (average 18 no).

Pharmacokinetics in special clinical situations

In patients with renal insufficiency pharmacokinetic parameters ArifOn^® retard unchanged.

Testimony

- Arterial hypertension.

Dosage regimen

Arifon^® retard appointed interior 1 tab. / day, preferably in the morning.

Increasing the dose of the drug did not lead to increased antihypertensive effect, but enhances the diuretic effect.

Side effect

From the water-electrolyte balance: decrease in potassium and hypokalemia (especially pronounced in patients, at risk). According to clinical studies hypokalemia (potassium ion concentration in plasma ≤ 3.4 mmol / l) I observed in 10% patients, receiving Arifon^® retard. Reduction of potassium below 3.2 mmol / l after 4-6 weeks of indapamide was observed in 4% patients. Through 12 weeks of treatment the average decrease in potassium ion concentration in blood plasma was 0.23 mmol / l.

Possible hyponatremia, accompanied by hypovolemia, dehydration and orthostatic hypotension. The simultaneous loss of chloride ions may lead to compensatory metabolic alkalosis, the frequency and severity of which is not high.

In rare cases, – increasing the level of calcium in the body.

Metabolism: possible to increase the content of urea and glucose in plasma.

From the hematopoietic system: rarely – thrombocytopenia, leukopenia, agranulocytosis, aplasticheskaya anemia, gemoliticheskaya anemia, bone marrow aplasia.

From the digestive system: rarely – nausea, constipation, feeling of dry mouth; in a few cases – pancreatitis.

Allergic reactions: patients, predisposed to allergic reactions, possible skin manifestations of hypersensitivity to the drug; gemorragicheskiy vasculitis, exacerbation of SLE.

From the central and peripheral nervous system: rarely – dizziness, asthenia, paresthesia, headache (These effects are usually held at lower dose); in patients with hepatic insufficiency may develop hepatic encephalopathy.

Most side effects are dose-dependent, their frequency decreases as the appointment of the drug in the lowest effective dose.

Contraindications

- Severe renal insufficiency;

- Hepatic encephalopathy;

- Hypokalemia;

- Concomitant use of drugs with, prolonging the QT interval;

- Hypersensitivity to indapamide or other sulfonamide derivatives.

Pregnancy and lactation

Usually, Arifon^® retard should not be used during pregnancy, incl. for removal of physiological edema. It will be appreciated, diuretics can cause fetoplacental ischemia and lead to impaired fetal growth.

Because, that indapamide is excreted in breast milk, also recommended the appointment of the drug during breastfeeding.

Cautions

Precautions should use the drug in patients with impaired liver and kidney function, for violations of water-electrolyte balance, with an increase in the QT interval on an electrocardiogram, or debilitated patients receiving combination therapy, when hyperparathyroidism, diabetes, podagre, elevated levels of uric acid.

As with the drug includes lactose, its purpose is contraindicated in patients with lactose intolerance, galaktozemiey, malabsorption syndrome glucose / galactose.

In appointing ArifOn^® retard patients with diabetes extremely important to control the level of glucose, especially in the presence of hypokalemia.

The treatment should be carefully monitored and the urea content in plasma glucose.

In patients with elevated levels of uric acid may increase the incidence of gout.

In the appointment of thiazide diuretics in patients with hepatic insufficiency may develop hepatic encephalopathy. In such cases, the drug should be stopped immediately.

Thiazide diuretics show its effectiveness in full only in the absence of irregularities or with moderately severe renal impairment (creatinine in the blood less 2.5 mg / dL or 220 mmol / l).

Elderly patients QC is calculated based on age, body weight and sex of the patient by Cockcroft. For older men: CC (ml / min) = (/140 - Age / x body weight / kg /)/(72 x serum creatinine / mg / dL /).

For women: the calculation result should be multiplied by 0.85.

It should be taken into account, that at the beginning of treatment, patients may experience a decrease in glomerular filtration rate, due to hypovolemia, which is caused by the loss of water and sodium ions in patients receiving diuretics. Consequently, in plasma can be increased concentration of urea and creatinine. If renal function is not impaired, such temporary renal insufficiency, usually, passes without consequences. However, with existing renal failure patient's condition may worsen.

Prior to treatment, should determine the content of sodium ions in plasma. During treatment requires regular monitoring of this indicator, since initially decrease the concentration of sodium in the blood plasma can not be accompanied by the appearance of pathologic symptoms. Most often, such an analysis should be performed in patients with liver cirrhosis and in the elderly.

In therapy thiazide diuretics main risk is a sharp decrease in the content of potassium ions and the development of hypokalemia. In certain patients, especially in the elderly, debilitated or receiving combination therapy, liver cirrhosis with ascites or edema developed,, CHD, chronic heart failure to avoid the development of hypokalemia (<3.4 mmol / l). Hypokalemia in these patients leads to increased toxic effect of cardiac glycosides and increased risk of arrhythmias. Besides, high risk include patients with bradycardia or with an increased QT interval on an electrocardiogram, it does not matter, caused by this increase in congenital causes or the presence of a pathological process.

Kaliopenia, as well as bradycardia, It is a condition, contributing to the development of severe cardiac arrhythmias, especially type “pirouette”, often-fatal. In all the above cases it is necessary more frequently to determine the content of potassium ions in blood plasma. The first measurement of potassium ion concentration in the blood should be carried out during the first week of treatment.

When hypokalemia should be appropriate treatment, while avoiding the use of drugs, causing arrhythmia type “pirouette”.

It will be appreciated, that thiazide diuretics may reduce the excretion of calcium in the urine, that leads to slight and temporary hypercalcaemia. Marked hypercalcemia may be due to previously undiagnosed hyperparathyroidism.

Should stop taking diuretics before the study function of the parathyroid glands.

When applied simultaneously with other antihypertensive drugs dose ArifOn^® retard should be reduced, at least, at the beginning of treatment.

While taking indapamide possible positive during a doping control in athletes.

Use in Pediatrics

Due to the lack of sufficient clinical data product is not recommended in children and adolescents up to 18 years.

Effects on ability to drive vehicles and management mechanisms

Action substances, members of the ArifOn^® retard, It does not lead to a breach of psychomotor reactions. However, it should be taken into account, in some cases, lowering of blood pressure may occur individual reactions (especially at the beginning of therapy, or a combination of several antihypertensive drugs). In this case, the ability to engage in activities, require increased attention and psychomotor speed reactions, It may be reduced.

Overdose

Indapamide even in very high concentrations (to 40 mg, ie. in 27 times the therapeutic dose) no toxic effect.

Symptoms: possible violations of water-electrolyte balance (giponatriemiya, kaliopenia), nausea, vomiting, hypotension, convulsions, dizziness, drowsiness, confusion, polyuria or oliguria, ending anuriei (due to hypovolemia).

Treatment: urgent measures, aimed at removing the drug from the organism: gastric lavage and / or administration of activated charcoal, followed by restoration of normal water and electrolyte balance.

Drug Interactions

Unacceptable drug combination

With simultaneous use of thiazide diuretics and drugs lithium may increase the concentration of lithium in the blood plasma, accompanied by the appearance of symptoms of overdose, (due to reduced excretion of lithium in urine). The appointment of this combination should be monitored closely to select a dose of drugs, constantly monitoring the concentration of lithium in the blood plasma.

With simultaneous use of diuretics with astemizole, bepridil, Erythromycin (I /), galofantrinom, pentamidine, sultoprydom, terfenadine, vincamine increases the likelihood of arrhythmia type “pirouette”. This state may contribute to hypokalemia, bradycardia or QT interval udlinennыy.

Shortcuts, requiring special monitoring

In an application with NSAIDs (for systemic use), high doses of salicylates may reduce antihypertensive action of indapamide. With a significant loss of fluid may develop acute renal failure (because of the sharp decline in glomerular filtration rate). The appointment of NSAIDs during therapy Arifon^® retard should compensate for the loss of water and carefully monitor renal function.

With simultaneous use of indapamide with other drugs, which can cause hypokalemia, incl. with amphotericin B (I /), glitches- and mineralocorticoid (when administered systemically), tetrakozaktidom, laxatives, stimulating peristalsis, It increases the risk of hypokalemia due to the additive effect (continuous monitoring of the level of potassium in the blood plasma and, if necessary, appropriate treatment).

With simultaneous use of thiazide diuretics with GCS, tetrakozaktidom for systemic use a decrease of antihypertensive effect due to water retention and sodium ions under the influence of SCS.

In an application with cardiac glycosides may increase the toxic effect of the latter due to hypokalemia (necessary to control the potassium level in blood plasma and ECG).

With simultaneous use of indapamide with baclofen noted increased hypotensive effect (necessary to compensate for water loss and early treatment carefully monitor renal function).

With simultaneous use of indapamide and potassium-sparing diuretics (incl. amilorida, spironolactone, triamteren) you can not completely exclude the possibility of hypokalemia or hyperkalemia, especially in patients with diabetes and renal failure. In such cases it is necessary to control the potassium level in blood plasma, ECG parameters and, if necessary, adjust therapy.

With simultaneous use of indapamide with ACE inhibitors hyponatremia patients, receiving ACE inhibitors, It increases the risk of sudden hypotension and / or acute renal failure (especially with renal artery stenosis). Patients with essential hypertension and reduced as a result of diuretics content of sodium ions in the blood plasma is necessary for 3 days before the start of treatment with ACE inhibitors stop taking diuretics. Further, if necessary, diuretics resume. Besides, to low, gradually increasing doses of ACE inhibitors. In chronic heart failure treatment should be started with low doses of ACE inhibitors, reducing pre-dose diuretics. In all cases in the first week of ACE inhibitors need to monitor renal function (creatinine in blood plasma).

When concomitant administration of indapamide and antiarrhythmic drugs, can cause arrhythmia type “pirouette” (incl. xinidina, gidroxinidina, dizopiramida, amiodarona, bretylium, sotalol), the risk of developing this condition increases (especially against the background of hypokalemia, ʙradikardii, baseline long QT). The appointment of the combination should control the potassium level in blood plasma and QT interval, adjusting the dosing regimen.

With simultaneous use of diuretics and metformin may cause lactic acidosis, which is connected, apparently, with the development of functional renal failure, due to the action of diuretics (more “loop”). Not recommended for use in combination with metformin Arifon^® retard in the level of creatinine 15 mg / l (135 mmol / l) in men and 12 mg / l (110 mmol / l) female.

When using iodine radiopaque drugs should be borne in mind, that the diuretic effect of indapamide increases the risk of renal failure. This risk is particularly high when using iodine radiopaque substances in high doses. Before use of iodine-containing contrast media to patients need to restore lost fluids.

With simultaneous use of indapamide and tricyclic antidepressants, antipsychotic drugs has been increasing additive enhancement of the hypotensive action and increased risk of orthostatic hypotension.

With simultaneous use of thiazide diuretics and calcium salts may develop hypercalcemia due to decreased excretion of calcium in the urine.

With simultaneous use of indapamide and cyclosporine can increase creatinine in the blood plasma, observed that even with normal water and sodium ions.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

The drug should be stored out of reach of children. Special storage conditions are required. Shelf life – 2 year.