Expiration date: 04/2025

Active substance: Indapamide

Arifon:

Structure and Composition:

1 film-coated tablet contains indapamide hemihydrate 2.5 mg in blister 30 pcs., In a carton one blister.

Dosage and administration:

Inside, preferably in the morning, 1 tab. / Day.

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

Arifon retard:

Structure and Composition:

Controlled release tablets, coated tablets. 1 tablet contain indapamide 1.5 mg

Excipients: lactose monohydrate, povidone, hydroxypropyl colloidal silicon dioxide magnesium stearate, macrogol 6000 glycerol titanium dioxide

in blister 30 pcs. in one blister box.

Description pharmaceutical form:

Round, biconvex tablets, film-coated, white.

Pharmacokinetics:

In tablets, retard Arifon active substance is in a special matrix carrier that provides a gradual controlled release of indapamide in the gastrointestinal tract.

Suction

Liberate indapamide is rapidly and completely absorbed in the digestive tract.

Eating slightly increases the absorption of the drug while not affecting the completeness of removals.

Cmax plasma levels achieved within 12 hours after ingestion of a single dose. Repeated receptions fluctuations in plasma concentrations of drug in the smoothed interval between doses of the drug.

There is individual variability of absorption of the drug.

Distribution

About 79% of the drug binds to plasma proteins. T1 / 2 - 14-24 hours (mean 18 hours).

Css achieved within 7 days of dosing.

When re-taking the drug is not observed its accumulation.

Metabolism

Indapamide is displayed as inactive metabolites in the kidney (70% of the administered dose) through the intestines and (22%).

Patients belonging to high-risk patients

In patients with renal insufficiency The pharmacokinetics of the drug Arifon retard does not change.

Description of the pharmacological actions:

Indapamide relates to sulfonamide derivatives with the indole ring and pharmacologically similar to thiazide diuretics which inhibit the reabsorption of sodium in the cortical segment of the loop of the nephron. This increases the excretion of sodium by the kidneys, and chlorine to a lesser extent of potassium and magnesium ions, which is accompanied by an increase in diuresis and hypotensive effect.

In clinical studies, phase II and III using indapamide monotherapy at doses that do not have a pronounced diuretic effect has been demonstrated 24-hour antihypertensive effect.

The antihypertensive activity of indapamide is related to the improvement of the elastic properties of the large arteries, a decrease in arteriolar and total peripheral vascular resistance.

Indapamide reduces left ventricular hypertrophy.

Thiazide and thiazide diuretics at a defined dose therapeutic effect reaches a plateau, whereas the incidence of adverse events continues to increase with further increase in dose. Therefore it is not necessary to increase the dose, if receiving the recommended dosage is not reached therapeutic effect.

In short, middle and long duration trials involving patients with hypertension it has been shown that indapamide:

- No influence on lipid metabolism, including at the level of triglycerides, cholesterol, LDL and HDL

- Does not affect the parameters of carbohydrate metabolism, including in patients with diabetes.

Testimony: Arterial hypertension.

Contraindications:

• Hypersensitivity to indapamide, other sulfonamide derivatives or any of the excipients
  
• severe renal impairment (Cl creatinine <30 ml / min)
  
• hepatic encephalopathy or severe hepatic dysfunction
  
• hypokalemia.
  

Due to the fact that the product contains lactose, it retards Arifon not recommended for patients with lactose intolerance, galactosemia, glucose-galactose malabsorption.

The caution (see details in "Special Instructions".): Violation of liver and kidney function, fluid and electrolyte balance, weakened patients or patients receiving combination therapy with antiarrhythmic drugs (see "Interaction".), Diabetes mellitus, increased level of uric acid patients with prolonged QT-interval hyperparathyroidism.

Due to the lack of sufficient clinical data product is not recommended for use in children under 18 years.

Application of pregnancy and breastfeeding:

Pregnancy

As a general rule, during pregnancy should not prescribe diuretic drugs. You can not use these drugs to treat physiological edema of pregnancy. Diuretic drugs can cause fetoplacental ischemia and lead to impaired development of the fetus.

The period of breast-feeding

Do not appoint Arifon retard nursing mothers (indapamide is excreted in breast milk).

Side effect:

The majority of adverse reactions (clinical and laboratory parameters) are dose-dependent.

The frequency of adverse reactions that can be caused by thiazide diuretics, including indapamide, is shown in the following grading: very common (> 1/10), common (> 1/100, <1/10), uncommon (> 1/1000, <1 / 100), rare (> 1/10000, <1/1000), very rare (<1/10000) unspecified frequency (frequency can not be calculated from the available data).

From the blood and lymphatic system: very rarely - thrombocytopenia, leukopenia, agranulocytosis, aplastic anemia, hemolytic anemia.

CNS: rarely - dizziness, fatigue, headache, paresthesia.

From the CCC: rarely - arrhythmias, lowering blood pressure.

From the digestive system: rarely - vomiting rarely - nausea, constipation, dry mouth, rarely - pancreatitis.

From the urinary system: rarely - renal failure.

On the part of the liver and biliary tract: rarely - a violation of unspecified liver function of frequency - the possibility of development of hepatic encephalopathy in case of hepatic insufficiency (see "Contraindications", "Special Instructions".).

With the Skin: hypersensitivity reactions, mainly dermatological, in patients with a predisposition to allergic and asthmatic reactions: often - maculopapular rash rarely - hemorrhagic vasculitis is very rare - angioneurotic edema and / or urticaria, toxic epidermal necrolysis, Stevens-Johnson syndrome, unspecified frequency - possibly the deterioration in the presence of an acute form of disseminated lupus erythematosus. Cases of photosensitivity reactions.

Laboratory parameters: clinical studies hypokalemia (potassium content in blood & le3,4 mmol / l of plasma) was observed in 10% of patients and 3.2 mmol / l - 4% of patients after 4-6 weeks of treatment. After 12 weeks of treatment in plasma potassium levels decreased by an average of 0.23 mmol / L.

Very seldom - hypercalcemia unspecified frequency - reduced potassium level and the development of hypokalemia, especially significant for patients at risk (see "Special Instructions".) Hyponatremia, accompanied by hypovolemia, dehydration and orthostatic hypotension. Simultaneous loss of chloride ion can lead to compensatory metabolic alkalosis, however, the rate of development and severity alkalosis negligible increase in uric acid and plasma glucose.

Thiazide and thiazide diuretics should be used with caution in patients with gout and diabetes.

Drug Interactions:

Unwanted combination of drugs

lithium preparations. With simultaneous use of indapamide and drugs lithium may increase the concentration of lithium observed in plasma due to the reduction of its excretion is accompanied by the appearance of signs of overdose. If necessary, diuretic drugs can be used in combination with drugs lithium, and should be carefully selected dose drugs, constantly monitoring plasma lithium content.

The combination of drugs that require special attention

Drugs that can cause arrhythmia type "pirouette":

• Antiarrhythmics class IA (quinidine, gidrohinidin, disopyramide)
  
• Class III antiarrhythmic drugs (amiodarone, sotalol, dofetilide, Ibutilide)
  
• Some antipsychotics: phenothiazines (chlorpromazine, tsiamemazin, Levomepromazine, thioridazine, trifluoperazine), benzamides (amisulpride, sulpiride, sultopride, tiaprid), butyrophenones (droperidol, haloperidol)
  
• Others: bepridil, cisapride, difemanil, erythromycin (w / w), halofantrine, mizolastine, pentamidine, sparfloxacin, moxifloxacin, astemizole, vincamine (w / w).
  

Increased risk of ventricular arrhythmias, especially arrhythmias "pirouette" type (risk factor - hypokalemia).

It should determine the level of potassium in the blood plasma and, if necessary, to correct it before the combination therapy indapamide and the above drugs. Necessary to control the patient's clinical status, control the level of blood plasma electrolytes and ECG parameters.

In patients with hypokalemia is necessary to use drugs, do not cause arrhythmia type "pirouette".

NSAIDs (for systemic administration), including selective COX-2 inhibitors, high dose salicylates (& ge3 g / day). Perhaps the reduction in the antihypertensive effect of indapamide. When a significant loss of fluid may develop acute renal failure (due to decreased glomerular filtration). Patients need to compensate for fluid loss and the beginning of treatment carefully monitor renal function.

ACE inhibitors. Appointment of ACE inhibitors in patients with a reduced concentration of sodium ions in the blood (especially in patients with renal artery stenosis) is accompanied by a risk of sudden hypotension and / or acute renal failure.

Patients with hypertension and possibly reduced due to diuretics content of sodium ions in the blood plasma, it is necessary:

• 3 days prior to initiation of treatment with an ACE inhibitor stop taking diuretics. Subsequently,, diuretics can be resumed if necessary
  
• Starting or ACE inhibitor therapy with low doses, followed by a gradual increase in the dose if necessary.
  

In chronic heart failure treatment with ACE inhibitors should be started at low doses with a possible decrease in pre-dose diuretics.

In all cases the first week of ACE inhibitor in patients need to monitor renal function (creatinine content in blood plasma).

Other medications that can cause hypokalaemia: amphotericin B (w / w), corticosteroids and mineralokortikosteroidy (at system assignment) tetrakozaktid, laxative, stimulating bowel motility. Increased risk of hypokalaemia (additive effect).

Continuous monitoring of potassium level in the blood plasma, if necessary - its correction. Particular attention should be given to patients while receiving cardiac glycosides. It is recommended to use laxatives, do not stimulate bowel motility.

Baclofen. It is noted increased hypotensive effect.

Patients need to compensate for fluid loss and the beginning of treatment carefully monitor renal function.

Cardiac glycosides. Hypokalemia increases the toxic effects of cardiac glycosides.

With simultaneous use of cardiac glycosides and indapamide should control the potassium level in the blood plasma, ECG, and, if necessary, adjust therapy.

The combination of drugs that require attention

Potassium-sparing diuretics (amiloride, spironolactone, triamterene). Combination therapy with indapamide and potassium-sparing diuretics suitable for some patients, but it does not exclude the possibility of hypokalemia (especially in diabetic patients and in patients with renal failure) or hyperkalemia.

It is necessary to control the potassium level in the blood plasma, ECG, and if necessary, adjust therapy.

Metformin. Functional renal failure, which can occur in the background of diuretics, especially the loop, while the appointment of metformin increases the risk of lactic acidosis.

Metformin should not be used if the creatinine level exceeds 15 mg / l (135 mol / l) in men and 12 mg / l (110 mol / L) in women.

Iodine-containing contrast agents. Dehydration in patients receiving diuretics increases the risk of acute renal failure, especially with high doses of iodinated contrast media.

Before use of iodine-containing contrast agents to patients is necessary to compensate for fluid loss.

Tricyclic antidepressants, antipsychotic drugs (neuroleptics). Drugs of these classes enhance indapamide antihypertensive effect and increase the risk of orthostatic hypotension (additive effect).

Calcium salts. When concomitant administration may develop hypercalcemia due to decreased excretion of calcium by the kidneys.

Cyclosporin, tacrolimus. Possible to increase the content of creatinine in the blood plasma concentration of unchanged circulating cyclosporine, even with normal fluid and sodium ions.

Corticosteroids, tetrakozaktid (with appointment system). Reduced hypotensive action (fluid retention and sodium ions by the action of corticosteroids).

Dosage and administration:

Inside, swallowing whole, without chewing, drinking water, 1 table. per day, preferably in the morning.

In the treatment of hypertensive patients increasing the dose does not increase the antihypertensive effect, but strengthens the diuretic effect.

Elderly patients

Older patients should monitor plasma levels of creatinine according to the age, weight and sex.

Arifon retard in a dose of 1.5 mg / day (Table 1.) May be administered to elderly patients with normal or mildly impaired renal function (see. "Contraindications").

Overdose:

Indapamide even at very high doses (up to 40 mg, i.e. 27 times more than the therapeutic dose) does not have a toxic effect.

Symptoms of acute poisoning with medication in the first place related to the violation of water-electrolyte balance (hyponatremia, hypokalemia). From the clinical symptoms of an overdose may experience nausea, vomiting, decreased blood pressure, cramps, dizziness, drowsiness, confusion, polyuria or oliguria, leading to anuria (due to hypovolaemia).

emergency measures to reduce the excretion of the drug from the body: gastric lavage and / or administration of activated charcoal, followed by restoration of water and electrolyte balance.

Special instructions:

Disturbances of liver function

In the appointment of thiazide and thiazide diuretics in patients with impaired hepatic function may develop hepatic encephalopathy, particularly in case of electrolyte imbalance. In this case, the diuretic should be stopped immediately.

Photosensitivity

In patients receiving thiazide and thiazide diuretics reported cases of photosensitivity reactions (see. "Side effects"). In the case of photosensitivity reactions in patients receiving the drug should be discontinued treatment. If necessary, continue diuretic therapy is recommended to protect the skin from exposure to sunlight or artificial UV rays.

Water and electrolyte balance:

• The content of sodium ions in plasma. Before treatment is necessary to determine the content of sodium ions in plasma. While taking the drug, the figure should be regularly monitored. All diuretic drugs can cause hyponatraemia, sometimes leading to dire consequences. Constant control of the content of sodium ions, as initially lowering the sodium concentration in the plasma may not be accompanied by the appearance of pathologic symptoms. The most careful control of the content of sodium ions is indicated for patients with cirrhosis and in the elderly (see. "Side effects" and "Overdose").
  
• The content of potassium ions in the blood plasma. In therapy thiazide and thiazide diuretics main risk is a sharp decrease in the level of potassium in the blood plasma and the development of hypokalemia. It is necessary to avoid the risk of hypokalemia (<3.4 mmol / l) in patients with the following categories: the elderly, debilitated or receiving concomitant medication with antiarrhythmic drugs and drugs that may increase the QT interval, patients with cirrhosis, peripheral edema or ascites , coronary artery disease, heart failure. Hypokalemia in these patients increases the toxic effects of cardiac glycosides and increased risk of arrhythmia.
  

In addition, the high-risk group includes patients with an increased QT interval in this case is not important, it is caused by an increase in congenital causes or the action of drugs.

Hypokalemia, as well as bradycardia, is a condition conducive to the development of severe arrhythmias, especially arrhythmias such as "pirouette", which can lead to death. In all the above cases it is necessary to regularly monitor the content of potassium in the blood plasma. The first measurement of potassium ion concentration in the blood must be held during the first weeks of treatment.

When hypokalaemia should be assigned the appropriate treatment.

• The calcium content in the blood plasma. It should be borne in mind that thiazide and thiazide diuretics may reduce renal excretion of calcium ions, resulting in a slight and transient increase in calcium concentration in the blood plasma. Marked hypercalcemia may be due to previously undiagnosed hyperparathyroidism.
  
• It should stop taking diuretics before the study the function of the parathyroid glands.
  
• The content of glucose in plasma. It is necessary to monitor blood glucose levels in patients with diabetes, especially in the presence of hypokalemia.
  
• Uric acid. Patients with gout may increase the incidence of stroke or worsen gout.
  

Diuretic drugs and kidney function. Thiazide and thiazide diuretics fully effective only in patients with normal or mildly impaired renal function (creatinine in the blood plasma content in adults below 25 mg / l or 220 mmol / l). Elderly patients normal levels of creatinine in blood plasma is calculated according to the age, weight and sex.

Note that at the beginning of treatment, patients may experience a decrease in glomerular filtration rate due to hypovolemia, which in turn is caused by loss of fluids and sodium ions in patients receiving diuretics. As a result, the plasma can be increased concentration of urea and creatinine. If renal function is not impaired, such temporary functional renal failure usually takes place without consequences, but the patient's condition may deteriorate when existing renal insufficiency.

Athletes

The active substance, which is part of the preparation Arifon retard, can give a positive result in doping control in athletes.

Effects on ability to drive and perform activities that require high speed physical and mental reactions

The active ingredients of the drug Arifon retard, does not lead to a breach of psychomotor reactions. However, some people in response to a decrease in blood pressure may develop various individual reactions, especially early in therapy, or, when added to the therapy of other antihypertensives. In this case, the ability to drive a motor vehicle or other machinery can be reduced.