2010/09/21

Arifon Retard

Composition, structure and packing

Controlled release tablets, coated white, round, biconvex.

1 tab. indapamide 1.5 mg.

Excipients: lactose, hydroxypropylmethylcellulose, povidone, colloidal silicon dioxide, magnesium stearate, macrogol 6000, glycerol, titanium dioxide.

Clinico-pharmacological group: diuretics. Antihypertensives.

Pharmacological action

Antihypertensive (diuretic) drug, a derivative of sulfonamide containing the indole ring. On the pharmacological properties of indapamide is close to the thiazide diuretics. Indapamide increases the urinary excretion of sodium, chlorine, and, to a lesser extent, potassium ions and magnesium, which is accompanied by increased diuresis. Indapamide has antihypertensive effect in doses that do not have a pronounced diuretic effect.

The mechanism of action of indapamide is due to change in transmembrane ion current (in the first place - calcium), which leads to relaxation of vascular smooth muscle cells, as well as increased synthesis of prostaglandins PGE2 and prostacyclin PGI2 (vasodilator and platelet aggregation inhibitor).

The drug reduces the hypertrophy of the left ventricle of the heart. Regardless of the duration of Arifon retard does not alter the lipid profile (blood levels of triglycerides, cholesterol, LDL, HDL) does not alter carbohydrate metabolism (including patients with hypertension and diabetes). Indapamide is effective in patients with one kidney. Indapamide has antihypertensive effect in doses that do not have a pronounced diuretic effect.

Pharmacokinetics

Absorption

In tablets ArifOn retard the active ingredient is in a special matrix carrier that provides a gradual release of indapamide in the gastrointestinal tract. Released Indapamide is rapidly and completely absorbed from the gastrointestinal tract. After oral single dose Cmax is achieved within 12 hours

Repeated receptions fluctuations in the concentration of indapamide in the blood plasma in the interval between doses of two doses are reduced. Eating a slow rate of absorption of the drug, but it does not affect the number has grown deep substance. There is individual variability of drug absorption rates.

Distribution

Binding to plasma proteins is about 79%. Css achieved within 7 days of regular use. If readmission ArifOn retard there is no accumulation of indapamide in the body.

Metabolism and excretion

Indapamide Biotransformation and displayed in the form of inactive metabolites mainly in urine - 70% and feces - 22%. T1 / 2 of 14-24 h (average 18 h).

Pharmacokinetics in special clinical situations

In patients with renal insufficiency pharmacokinetic parameters ArifOn retard did not change.

Statement
hypertension.

Dosage regimen

Arifon retard appointed interior to 1 tab. / day, preferably in the morning. Increasing the dose does not result in a stronger antihypertensive action, but also enhances the diuretic effect.

Side effect

From the water-electrolyte balance: reducing the level of potassium and the development of hypokalemia (especially pronounced in patients at risk). According to clinical studies hypokalemia (potassium ion concentration in the blood plasma of ≤ 3.4 mmol / l) was observed in 10% of patients receiving Arifon retard.

Reducing the amount of potassium below 3.2 mmol / l after 4-6 weeks of indapamide was observed in 4% of patients. After 12 weeks of drug administration the average decrease in the concentration of potassium ions in blood plasma was 0.23 mmol / liter. It is 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 small. In a few cases - raising the level of calcium in the body.

On the part of metabolism: possible increase in urea and glucose in the blood plasma.

On the part of the hemopoietic system: rarely - thrombocytopenia, leukopenia, agranulocytosis, aplastic anemia, hemolytic anemia, bone marrow aplasia.

On the part of the digestive system: rarely - nausea, constipation, feeling of dryness in the mouth and in rare cases - pancreatitis. Allergic reactions: in patients prone to allergic reactions, skin manifestations may be increased sensitivity to the drug; hemorrhagic vasculitis, exacerbation of SLE.

From the side of the central nervous system 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 nature, their frequency decreases with the appointment of the drug in the lowest effective dose.

Contraindications
renal failure, severe;
hepatic encephalopathy;
hypokalemia;
simultaneous reception with drugs prolong the interval QT;
Hypersensitivity to indapamide or other sulfonamide derivatives.

Pregnancy and lactation

Typically, Arifon retard is not recommended during pregnancy, including for removal of physiological edema. It should be borne in mind that diuretics can cause placental ischemia and lead to a breach of fetal development.

Due to the fact that indapamide is excreted in breast milk is not recommended the appointment of the drug during breastfeeding.

Application for violations of liver function

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

Application for violations of renal function

The drug is contraindicated in severe renal insufficiency. Thiazide diuretics are often effective in full only in the absence of irregularities or with moderately pronounced renal dysfunction (creatinine in the blood content of less than 2.5 mg / dL or 220 mmol / l).

Note that in the beginning of treatment, patients may see the decline of glomerular filtration due to hypovolemia, which is caused by loss of water and sodium ions on the diuretic. As a result, plasma levels may increase the concentration of urea and creatinine. If renal function is not broken, so a temporary kidney failure, usually passes without consequences. However, the already-existing renal failure patient's condition may deteriorate.

Cautions

Precautions should use the drug in patients with impaired liver function and kidney disorders of water and electrolyte balance, with an increase in QT interval on an electrocardiogram, or immunocompromised patients receiving concomitant therapy with hyperparathyroidism, diabetes, gout, high blood uric acid. As with the drug include lactose, his appointment is contraindicated in patients with lactose intolerance, galactosemia, malabsorption syndrome glucose / galactose.

In appointing ArifOn retard in patients with diabetes is extremely important to monitor glucose levels, especially in the presence of hypokalemia. During the period of treatment should be closely monitored the content of urea and glucose in the blood plasma. Patients with elevated levels of uric acid may increase the frequency of attacks of gout.

In the appointment of thiazide diuretics in patients with hepatic insufficiency may develop hepatic encephalopathy. In such cases, taking the drug should be stopped immediately. Thiazide diuretics are often effective in full only in the absence of irregularities or with moderately pronounced renal dysfunction (creatinine content in the blood of less than 25 mg / l or 220 mmol / l). Patients older spacecraft is calculated taking into account age, weight and sex of the patient by Cockcroft.

For men aged: CC (ml / min) = (140 - age / x body weight / kg) / (72 x serum creatinine / mg / dl). For women: the result of the calculation should be multiplied by 0.85.

Note that in the beginning of treatment, patients may see the decline of glomerular filtration due to hypovolemia, which is caused by loss of water and sodium ions on the diuretic. As a result, plasma levels may increase the concentration of urea and creatinine. If renal function is not broken, so a temporary kidney failure, usually passes without consequences. However, the already-existing renal failure patient's condition may deteriorate. Prior to treatment should determine the content of sodium ions in blood plasma. In the course of treatment requires regular monitoring of this indicator, as initially reduce the concentration of sodium in the blood plasma may not be accompanied by the appearance of pathological symptoms.

Very often such an analysis should be conducted in patients with cirrhosis and in elderly patients. In therapy thiazide diuretics main risk is the sharp decrease in the content of potassium ions and the development of hypokalemia. At a certain category of patients, especially elderly patients, debilitated or receiving concomitant therapy in liver cirrhosis with developing edema, or ascites, coronary heart disease, chronic heart failure to avoid the development of hypokalemia (<3.4 mmol / l). Hypokalemia in these patients leads to increased toxic effects of cardiac glycosides and increases the risk of arrhythmias. In addition, the increased risk include patients with bradycardia or with an increased QT interval on the ECG, it does not matter, cause such an increase in congenital causes or the presence of a pathological process.

Hypokalemia, as well as bradycardia, is a condition that promotes the development of severe cardiac arrhythmias, especially type "pirouette", often fatal. In all the cases described above should be more often determine the content of potassium ions in blood plasma. The first measurement of the concentration of potassium ions in the blood should be carried out during the first week of starting treatment.

When hypokalaemia should appoint appropriate treatment, while avoiding use of drugs that cause arrhythmias such as "pirouette". It should be borne in mind that thiazide diuretics may decrease the excretion of calcium in the urine, which leads to slight and temporary hypercalcaemia. Severe hypercalcemia may be due to previously undiagnosed hyperparathyroidism. It should stop taking the diuretic before starting the study the function of parathyroid glands.

When applied simultaneously with other antihypertensive drugs, the dose should be reduced ArifOn retard, at least in the beginning of treatment. During the course of indapamide, possible positive result during the doping control in athletes. Use in pediatrics because of the lack of sufficient clinical data product is not recommended for use in children and adolescents under 18 years.

Effects on ability to drive vehicles and management mechanisms

Effects of substances comprising ArifOn retard, does not lead to a breach of psychomotor reactions. However, please note that in some cases, lowering blood pressure can occur individual reactions (especially in the beginning of therapy or the combination of several antihypertensive drugs). In this case, the ability to engage in activities that require attention and quickness of psychomotor reactions, can be reduced. Indapamide Overdose even in very high concentrations (up to 40 mg, ie 27 times more than the therapeutic dose) does not have a toxic effect.

Symptoms: possible violations of water-electrolyte balance (hyponatremia, hypokalemia), nausea, vomiting, hypotension, convulsions, dizziness, drowsiness, confusion, polyuria or oliguria, anuria terminated (due to hypovolemia).

Treatment: immediate measures to remove the drug from the body: gastric lavage and / or the appointment of activated carbon with subsequent restoration of normal water and electrolyte balance.

Drug Interactions

Deprecated combination of drugs

With simultaneous use of thiazide diuretics and drugs lithium may increase the concentration of lithium in blood plasma, accompanied by signs of overdose (due to the excretion of lithium in the urine). If necessary, the appointment of this combination should carefully choose the dose of drugs, constantly monitoring the concentration of lithium in blood plasma.

With simultaneous use of diuretics with astemizolom, bepridilom, erythromycin (IV), galofantrinom, pentamidine, sultopridom, terfenadinom, vinkaminom increases the likelihood of arrhythmias such as "pirouette". This state may contribute to hypokalemia, bradycardia, or an extended interval QT.

Combinations which require special control

With the simultaneous use of NSAIDs (for systemic use), high doses of salicylates may decrease the hypotensive action of indapamide.

With a significant loss of fluid may develop acute renal failure (due to the sharp decline of glomerular filtration). If necessary, the appointment of NSAIDs during therapy Arifon retard should be compensated for the loss of water and carefully monitor renal function.

With simultaneous use of indapamide with other drugs that can cause hypokalemia, including with amphotericin B (IV), gluco-and mineralocorticoid (upon system application), tetrakozaktidom, laxatives, stimulating peristalsis, increases the risk of hypokalemia due to 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 in the hypotensive effect due to delay of water and sodium ions under the influence of SCS.

When applied simultaneously with cardiac glycosides may be increased toxic effect of the latter due to hypokalemia (need to control the level of potassium in the blood plasma and performance of ECG).

With the simultaneous use of indapamide with baklofenom highlights increasing hypotensive effect (to be offset by the loss of water and the beginning of treatment carefully monitor renal function).

With simultaneous use of indapamide and potassium-sparing diuretics (including amiloride, spironolactone, triamterene) can not completely exclude the possibility of hypokalemia or hyperkalemia, especially in patients with diabetes and renal insufficiency. In such cases, should monitor the level of potassium in the blood plasma, the parameters of ECG and, if necessary, to adjust therapy.

With the simultaneous 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 hypertension and reduced as a result of taking diuretics for the content of sodium ions in the blood plasma must be 3 days before the start of treatment with ACE inhibitors stop taking diuretics.

In the future, if necessary, diuretics resume. In addition, set a low, gradually increasing doses of ACE inhibitors. In chronic heart failure treatment should be started with low doses of ACE inhibitors, after lowering the dose of diuretics. In all cases in the first week of taking ACE inhibitors need to monitor renal function (creatinine content in blood plasma).

In case of simultaneous appointment of indapamide and antiarrhythmic drugs that may cause arrhythmia type "pirouette" (including quinidine, gidrohinidina, dizopiramid, amiodarone, bretiliuma, sotalol), the risk of developing this condition increases (especially against the background of hypokalemia, bradycardia, initially extended interval QT). If necessary, the appointment of this combination should monitor the level of potassium in the blood plasma and the interval QT, adjusting the dosing regimen.

With the simultaneous use of diuretics and metformin may cause lactic acidosis, which is connected, apparently, with the development of functional renal insufficiency caused by the action of diuretics (to a greater degree of "loop"). Not recommended for use in combination with metformin Arifon retard in creatinine level of more than 15 mg / L (135 mmol / l) in men and 12 mg / l (110 mmol / l) in women.

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 using iodine radiopaque substances sick to restore lost fluids.

With simultaneous use of indapamide and tricyclic antidepressants, antipsychotic means there 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 the reduction of calcium excretion in the urine.

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

Terms and Conditions of storage

The product should be stored at temperatures not above 30 ° C, the reach of children. Shelf life - 2 years.