Арифон® ретард

General characteristics. Structure:

Active ingredient: 1,5 mg of an indapamid.

Excipients: lactoses monohydrate, gipromelloz, magnesium stearate, povidone, silicon dioxide colloid anhydrous, macrogoal 6000, глицерол, titanium dioxide.

Pharmacological properties:

Pharmacodynamics. Indapamid treats sulfonamide derivatives with an indole ring and on pharmacological properties is close to thiazide diuretics which inhibit a reabsorption of ions of sodium in a cortical segment of a nephronic loop. At the same time allocation by kidneys of ions of sodium, chlorine and to a lesser extent potassium ions and magnesium increases that is followed by increase in a diuresis and hypotensive effect.

In clinical trials II and III phases when using an indapamid in the monotherapy mode in the doses which are not rendering the expressed diuretic effect the 24-hour hypotensive effect was shown.

Anti-hypertensive activity of an indapamid is connected with improvement of elastic properties of large arteries, reduction of arteriolar and general peripheric vascular resistance.
Indapamid reduces a hypertrophy of a left ventricle.

Thiazide and tiazidopodobny diuretics at a certain dose reach the plateau of therapeutic effect while the frequency of side effects continues to increase at further increase in a dose of drug. Therefore it is not necessary to increase a drug dose if at reception of the recommended dose do not reach therapeutic effect.

In short, the average duration and long-term researches with participation of patients with arterial hypertension it was shown that индапамид:
- does not influence indicators of lipidic exchange, including for the level of triglycerides, cholesterol, lipoproteins of low density and lipoproteins of high density;
- does not influence indicators of exchange of carbohydrates, including at patients with a diabetes mellitus.

Pharmacokinetics. In tablets Arifon ретард active agent is in the special matrix carrier providing gradual controlled release of an indapamid in digestive tract.

Absorption. Released индапамид it is quickly and completely soaked up in digestive tract.

Meal slightly increases drug absorption time, without influencing at the same time completeness of absorption.

The maximum concentration in a blood plasma is reached in 12 hours after intake of a single dose. At repeated methods of fluctuation of concentration of drug in a blood plasma in an interval between administrations of drug smooth out. There is an individual variability of indicators of absorption of drug.

Distribution. About 79% of drug contact proteins of a blood plasma. The elimination half-life makes 14-24 hours (on average, 18 hours).

Equilibrium concentration is reached in 7 days of administration of drug. At repeated administration of drug its cumulation is not observed.

Metabolism. Indapamid is brought in the form of inactive metabolites, generally by kidneys (70% of the entered dose) and through intestines (22%).

The patients belonging to group of high risk. At patients with a renal failure the drug Arifon® pharmacokinetics ретард does not change.

Indications to use:

Arterial hypertension.

Route of administration and doses:

About 1 tablet in days is applied inside, it is desirable in the morning; the tablet should be swallowed entirely, without chewing, washing down with water.

At treatment of patients with arterial hypertension increase in a dose of drug does not lead to increase in anti-hypertensive action, but strengthens diuretic effect.

Elderly patients. At elderly patients it is necessary to control the plasma level of creatinine taking into account age, body weight and a floor.

Арифон® ретард in a dose of 1,5 mg/days (1 tablet) elderly patients can appoint with normal or insignificantly an impaired renal function (see. "Contraindication").

Features of use:

Abnormal liver functions. At purpose of thiazide and tiazidopodobny diuretics at patients with abnormal liver functions development of hepatic encephalopathy, especially in case of disturbance of electrolytic balance is possible. In this case reception of diuretics should be stopped immediately.

Photosensitivity. Against the background of reception of thiazide and tiazidopodobny diuretics it was reported about cases of development of reactions of photosensitivity (see. "Side effect"). In case of development of reactions of photosensitivity against the background of administration of drug it is necessary to stop treatment. In need of therapy continuation by diuretics, it is recommended to protect integuments from influence of sunshine or artificial ultraviolet rays.

Water and electrolytic balance:
- The maintenance of ions of sodium in a blood plasma: prior to treatment it is necessary to define the maintenance of ions of sodium in a blood plasma. Against the background of administration of drug it is necessary to control this indicator regularly. All diuretic drugs can cause the hyponatremia leading sometimes to extremely serious consequences. Constant control of maintenance of ions of sodium as originally decrease in concentration of sodium in a blood plasma can not be followed by emergence of pathological symptoms is necessary. The most careful control of maintenance of ions of sodium is shown to patients with cirrhosis and to elderly people (see the sections "Side Effect" and "Overdose").
- The maintenance of potassium ions in a blood plasma. At therapy by thiazide and tiazidopodobny diuretics the main risk consists in sharp decrease in level of potassium in a blood plasma and development of a hypopotassemia. It is necessary to avoid risk of development of a hypopotassemia (<3,4 mmol/l), at sick following categories: advanced age, weakened or receiving the combined medicamentous therapy with dragy antiarrhytmic drugs and drugs which can increase an interval of QT sick with cirrhosis, peripheral hypostases or ascites, coronary heart disease, heart failure. The hypopotassemia at these patients strengthens toxic effect of cardiac glycosides and increases risk of development of arrhythmias.

Besides, patients with the increased QT interval treat group of the increased risk, at the same time does not matter, this increase is caused by the inborn reasons or effect of medicines.

Hypopotassemia as well as bradycardia, is the state promoting development of heavy arrhythmias and, especially, arrhythmias like "pirouette" which can lead to a lethal outcome. In all the cases described above it is regularly necessary to control the content of potassium in a blood plasma. The first measurement of concentration of potassium ions in blood needs to be taken within the first week from an initiation of treatment.

At emergence of a hypopotassemia the corresponding treatment has to be appointed.
- Content of calcium in a blood plasma. It must be kept in mind that thiazide and tiazidopodobny diuretics can reduce removal of calcium ions kidneys, leading to slight and temporary increase of concentration of calcium in a blood plasma. The expressed hypercalcemia can be a consequence of earlier not diagnosed hyperparathyreosis. It is necessary to cancel reception of diuretic drugs before a research of function of epithelial bodies.

Content of glucose in a blood plasma: it is necessary to control glucose level in blood at patients with a diabetes mellitus, especially in the presence of a hypopotassemia.

Uric acid: at patients with gout the frequency of emergence of attacks can increase or become aggravated the course of gout.

Diuretic drugs and function of kidneys: thiazide and tiazidopodobny diuretics are effective fully only at patients from normal or insignificantly an impaired renal function (content of creatinine in a blood plasma at adult persons lower than 25 mg/l or 220 µmol/l). At patients of advanced age the normal level of creatinine in a blood plasma is calculated taking into account age, body weight and a floor.

It is necessary to consider that in an initiation of treatment at patients the reduction in the rate of glomerular filtering caused by a hypovolemia which, in turn, is caused by loss of liquid and ions of sodium against the background of reception of diuretic drugs can be observed. As a result, in a blood plasma concentration of urea and creatinine can increase. If function of kidneys is not broken, such temporary functional renal failure, as a rule, passes without effects, however at already available renal failure the condition of the patient can worsen.

Athletes. The active agent which is a part of the drug Arifon® ретард can yield a positive take when carrying out a drug test at athletes.

Influence on ability to drive the car and performance of work, demanding the increased speed of physical and mental reactions. Effect of the substances which are a part of the drug Arifon® ретард does not lead to disturbance of psychomotor reactions. However at some people in response to a lowering of arterial pressure various individual reactions, especially at the beginning of therapy can develop or at addition to the carried-out therapy of other antihypertensives. In this case ability to drive the car or other mechanisms can be reduced.

Side effects:

The majority of side reactions (laboratory and clinical indicators) have dozozavisimy character. Frequency of side reactions which can be caused by tiazidopodobny diuretics including индапамид, is specified in a type of the following gradation: very often (> 1/10); often (> 1/100, <1/10); infrequently (> 1/1000, <1/100); seldom (> 1/10000, <1/1000); very seldom (<1/10000); not specified frequency (frequency cannot be counted according to available data).

From circulatory and lymphatic system. Very seldom: thrombocytopenia, leukopenia, agranulocytosis, aplastic anemia, hemolitic anemia.

From the central nervous system. Seldom: dizziness, fatigue, headache, paresthesias.

From cardiovascular system. Very seldom: arrhythmia, lowering of arterial pressure.

From the alimentary system. Infrequently: vomiting. Seldom: nausea, a lock, dryness in a mouth. Very seldom: pancreatitis.

From an urinary system. Very seldom: renal failure.

From a liver and biliary tract. Very seldom: abnormal liver function. Not specified frequency: a possibility of development of hepatic encephalopathy in case of a liver failure (see. "Contraindications", "Special instructions").

From integuments. Hypersensitivity reactions, generally dermatological, at patients with predisposition to allergic and asthmatic reactions. Often: makulopapulezny rash. Infrequently: hemorrhagic vasculitis. Very seldom: Quincke's disease and/or small tortoiseshell, toxic epidermal necrolysis, Stephens-Johnson's syndrome. Not specified frequency: deterioration in the presence of an acute form of the disseminated lupus erythematosus is possible.

Cases of reactions of photosensitivity are described.

Laboratory indicators. In clinical trials the hypopotassemia (content of potassium in a blood plasma ≤ 3,4 mmol/l) was observed at 10% of patients and 3,2 mmol/l - at 4% of patients after 4 - 6 weeks of treatment. After 12 weeks of therapy potassium level in a blood plasma decreased, on average, by 0,23 mmol/l. Very seldom: hypercalcemia.

Not specified frequency:
- decrease in level of potassium and development of a hypopotassemia, especially significant for the patients belonging to risk group (see. "Special instructions");
- the hyponatremia which is followed by a hypovolemia, dehydration and orthostatic hypotension. Simultaneous loss of ions of chlorine can lead to a compensatory metabolic alkalosis, however the frequency of development of an alkalosis and its expressiveness is insignificant;
- increase in level of uric acid and glucose in a blood plasma.

Thiazide and tiazidopodobny diuretics should be applied with care at patients with gout and a diabetes mellitus.

Interaction with other medicines:

- Lithium drugs. At simultaneous use of an indapamid and drugs of lithium the increase in concentration of lithium in a blood plasma owing to decrease in its excretion which is followed by emergence of signs of overdose can be observed. If necessary diuretic drugs can be used in combination with lithium drugs, at the same time it is necessary to select carefully a dose of drugs, constantly controlling the content of lithium in a blood plasma.

Combination of drugs, trebuyeshchy special attention. The drugs capable to cause arrhythmia like "pirouette":
• antiarrhytmic drugs IA of a class (quinidine, hydroquinidine, Disopyramidum);
• antiarrhytmic drugs III of a class (Amiodaronum, соталол, дофетилид, ибутилид);
• some neuroleptics: fenotiazina (Chlorpromazinum, циамемазин, levomepromazinum, thioridazine, трифторперазин), benzamides (амисульприд, Sulpiridum, сультоприд, тиаприд), phenyl propyl ketones (Droperidolum, haloperidol);
• others: bepridit, цизаприд, difemanit, erythromycin (in/in), галофантрин, мизоластин, pentamidine, спарфлоксацин, moxifloxacin, астемизол, Vincaminum (in/in).

Increase in risk of ventricular arrhythmias, especially arrhythmias like "pirouette" (risk factor - a hypopotassemia). It is necessary to determine potassium level in a blood plasma and, if necessary, to adjust it prior to the beginning of a combination therapy indapamidy and the drugs stated above. Control of a clinical condition of the patient, control of level of electrolytes of a blood plasma, ECG indicators is necessary. At patients with a hypopotassemia it is necessary to use the drugs which are not causing arrhythmia like "pirouette".

- Non-steroidal anti-inflammatory drugs (at system appointment), including the selection TsOG-2 inhibitors, high doses of salicylates (≥ 3 g/days). Decrease in anti-hypertensive effect of an indapamid is possible. At considerable loss of liquid the acute renal failure can develop (owing to decrease in glomerular filtering). Patients need to offset loss of liquid and in an initiation of treatment carefully to control function of kidneys.

- Inhibitors of the angiotensin-converting enzyme (ACE). Purpose of APF inhibitors to patients with reduced concentration of ions of sodium in blood (especially to patients with a renal artery stenosis) is followed by risk of sudden arterial hypotension and/or acute renal failure. And perhaps reduced, owing to reception of diuretics, the maintenance of ions of sodium in a blood plasma it is necessary for patients with arterial hypertension:
- in 3 days prior to treatment by APF inhibitor to stop reception of diuretics. Further, if necessary, reception of diuretics can be resumed;
- or to begin therapy with APF inhibitor with low doses, with the subsequent gradual increase in a dose in case of need.

At chronic heart failure treatment by APF inhibitors should be begun with low doses with possible preliminary decrease in doses of diuretics. In all cases in the first week of reception of APF inhibitors at patients it is necessary to control function of kidneys (content of creatinine in a blood plasma).
- Other drugs capable to cause a hypopotassemia: Amphotericinum In (in/in), glyuko-and mineralokortikosteroida (at system appointment), тетракозактид, the purgatives stimulating motility of intestines. Increase in risk of development of a hypopotassemia (additive effect). Constant control of level of potassium in a blood plasma, if necessary - its correction is necessary. Special attention should be paid to the patients who is at the same time receiving cardiac glycosides. It is recommended to use the purgatives which are not stimulating motility of intestines.

- Baclofenum. Strengthening of hypotensive effect is noted. Patients need to offset loss of liquid and in an initiation of treatment carefully to control function of kidneys.

- Cardiac glycosides. The hypopotassemia strengthens toxic effect of cardiac glycosides.
At simultaneous use of an indapamid and cardiac glycosides it is necessary to control potassium level in a blood plasma, ECG indicators, and, if necessary, to adjust therapy.

Combination of drugs, trebushchy attention.
- Kaliysberegayushchy diuretics (amiloride, Spironolactonum, Triamterenum). The combination therapy indapamidy and kaliysberegayushchy diuretics is reasonable at some patients, however at the same time the possibility of development of a hypopotassemia (especially at patients with a diabetes mellitus and patients with a renal failure) or hyperpotassemias is not excluded. It is necessary to control potassium level in a blood plasma, indicators of an ECG and, if necessary, to adjust therapy.

- Metforminum. The functional renal failure which can arise against the background of diuretics especially loopback, at co-administration of Metforminum increases risk of development of lactic acidosis it is not necessary to use Metforminum if the level of creatinine exceeds 15 mg/l (135 µmol/l) at men and women have 12 mg/l (110 µmol/l).

- Iodinated contrast agents. Organism dehydration against the background of reception of diuretic drugs increases risk of development of an acute renal failure, especially when using high doses of iodinated contrast agents. Before use of iodinated contrast agents by the patient it is necessary to offset liquid loss.

- Tricyclic antidepressants, antipsychotic means (neuroleptics). Drugs of these classes strengthen anti-hypertensive action of an indapamid and increase risk of orthostatic hypotension (the additive effect).

- Calcium salts. At co-administration development of a hypercalcemia owing to decrease in removal of calcium ions by kidneys is possible.

- Cyclosporine, такролимус. Increase in content of creatinine in a blood plasma without change of concentration of the circulating cyclosporine, even is possible at the normal content of liquid and ions of sodium.

- Corticosteroid drugs, тетракозактид (at system appointment). Decrease in hypotensive action (a delay of liquid and ions of sodium as a result of action of corticosteroids).

Contraindications:

- Hypersensitivity to an indapamid, other derivatives of sulfonamide or to any of excipients.
- Severe form of a renal failure (clearance of creatinine less than 30 ml/min.).
- Hepatic encephalopathy or heavy abnormal liver functions.
- Hypopotassemia.

Because lactose is a part of drug, Arifon® ретард is not recommended to patients with a lactose intolerance, a galactosemia, glyukozo-galaktozny malabsorption.

With care. An abnormal liver function and kidneys, the disturbances of water and electrolytic balance weakened the patients or patients receiving the combined therapy with other antiarrhytmic drugs (see. "Interaction with other medicines"), a diabetes mellitus, the increased level of uric acid, patients with the interval extended with QT-, a hyperparathyreosis.

Due to the lack of enough clinical data drug is not recommended to be used at children up to 18 years.

Pregnancy and period of feeding by a breast. Pregnancy. As a rule, during pregnancy it is not necessary to appoint diuretic drugs. It is impossible to use these drugs for treatment of physiological hypostases at pregnancy. Diuretic drugs can cause fetoplacental ischemia and lead to disturbance of fetation. Feeding period breast. It is not recommended to appoint Arifon® ретард to nursing mothers (индапамид it is allocated with breast milk).

Overdose:

Indapamid even in very high doses (to 40 mg, i.e. in 27 times more of a therapeutic dose) has no toxic effect.

Symptoms of acute poisoning with drug first of all are connected with disturbance of water and electrolytic balance (a hyponatremia, a hypopotassemia). From clinical symptoms of overdose nausea, vomiting, a lowering of arterial pressure, spasms, dizziness, the drowsiness, confusion of consciousness, a polyuria or an oliguria leading to an anury can be noted (owing to a hypovolemia).

Measures of acute management come down to removal of drug from an organism: a gastric lavage and/or purpose of absorbent carbon with the subsequent recovery of water and electrolytic balance.

Storage conditions:

To store at a temperature not above 30 °C. To store in places, unavailable to children. Period of validity 2 years. Drug cannot be used on expiry date, specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets with controlled release, film coated, 1,5 mg.
On 15 tablets in the blister (PVC / Is scarlet). On 2 blisters together with the application instruction in a cardboard pack.
On 30 tablets in the blister (PVC / Is scarlet). On 1 blister together with the application instruction in a cardboard pack.
When packaging (packaging) / production on LLC Serdiks:
Tablets with controlled release, film coated, 1,5 mg.
On 30 tablets in the blister (PVC / Is scarlet). On 1 blister together with the application instruction in a cardboard pack.
Packaging for hospitals:
On 30 tablets in the blister (PVC / Is scarlet). On 3 blisters with the instruction on a medical use in a pack cardboard.
On 30 tablets in the blister (PVC / Is scarlet). On 10 blisters in a pack cardboard (the pack is not marked). On 3 packs cardboard with instructions on a medical use in a box cardboard.