Arifon Retard prolonged-release film-coated tablets 1.5 mg No. 30

Instructions Arifon Retard prolonged-release film-coated tablets 1.5 mg No. 30

Composition

active ingredient: indapamide;

1 tablet contains 1.5 mg of indapamide;

Excipients: lactose monohydrate, hypromellose (E 464), povidone, colloidal anhydrous silica (E 551), magnesium stearate (E 470 B), titanium dioxide (E 171), glycerol (E 422), macrogol 6000.

Dosage form

Film-coated tablets, prolonged-release.

Main physicochemical properties: white, round tablets, film-coated.

Pharmacotherapeutic group

Diuretics with moderately pronounced diuretic activity, excluding thiazides. Sulfonamides, simple. Indapamide. ATC code C03B A11.

Pharmacological properties

Pharmacodynamics

Mechanism of action

Indapamide is a sulfonamide diuretic with an indole ring, pharmacologically related to thiazide diuretics and prescribed for the treatment of arterial hypertension.

Indapamide acts at the level of the kidneys and blood vessels.

Indapamide inhibits sodium reabsorption in the cortical segment of the kidneys. This increases the excretion of sodium and chlorides into the urine and, to a lesser extent, potassium and magnesium, thereby increasing diuresis.

Pharmacodynamic effects

Phase II–III clinical trials with indapamide as monotherapy demonstrated that the antihypertensive effect of indapamide persists for 24 hours. The diuretic effect was moderate. The antihypertensive effect of indapamide is associated with an improvement in arterial elasticity and a decrease in arteriolar resistance and total peripheral vascular resistance.

Indapamide reduces left ventricular hypertrophy.

When the recommended dose is exceeded, the therapeutic effect of thiazides and thiazide-like diuretics does not increase, while the number of undesirable effects increases. If the treatment is not effective enough, increasing the dose is not recommended.

As shown in studies of various durations (short, medium and long) in patients with arterial hypertension, indapamide:

does not affect lipid metabolism (triglycerides, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol),

does not affect carbohydrate metabolism, even in patients with diabetes and hypertension.

Indapamide acts at the vascular level by:

decreased contractility of vascular smooth muscles, which is associated with changes in transmembrane ion exchange (mainly calcium);

stimulation of the synthesis of prostaglandin PGE2 and prostacyclin PGI2 (vasodilator and platelet aggregation inhibitor).

Pharmacokinetics

1.5 mg of indapamide is contained in a prolonged-release tablet based on a matrix. The distribution of indapamide in the matrix system ensures its uniform release from the tablet.

Absorption

The released fraction of indapamide is rapidly and completely absorbed from the gastrointestinal tract. Food intake slightly increases the rate of absorption but does not affect the amount of the drug absorbed.

The maximum concentration in the blood plasma after taking a single dose is reached after approximately 12 hours, subsequent use of the drug reduces fluctuations in the level of indapamide in the blood plasma in the inter-dose interval. There are intra-individual fluctuations.

Distribution

Binding to blood plasma proteins is 79%.

The half-life is 14 to 24 hours (average 18 hours).

Steady-state concentrations are reached after 7 days. Regular use does not cause accumulation.

Breeding

Indapamide is excreted in the urine (70% of the dose) and feces (22%) in the form of inactive metabolites.

High-risk patients

In patients with renal insufficiency, pharmacokinetic parameters do not change.

Indication

ARIFON® RETARD is indicated for essential hypertension in adults.

Contraindication

- Hypersensitivity to the active substance, other sulfonamides or to any of the excipients;

- severe renal failure;

- hepatic encephalopathy or severe liver dysfunction;

- hypokalemia.

Interaction with other medicinal products and other types of interactions

Not recommended combinations

Lithium: Increased plasma lithium levels and symptoms of overdose may occur, as with a salt-free diet (reduced urinary lithium excretion). If diuretic therapy is necessary, careful monitoring of plasma lithium levels and adjustment of the lithium dose are necessary.

Combinations requiring caution

Drugs that may cause paroxysmal torsades de pointes, such as (the list is not exhaustive):

Class Ia antiarrhythmic drugs (e.g. quinidine, hydroquinidine, disopyramide);

class III antiarrhythmic drugs (e.g. amiodarone, sotalol, dofetilide, ibutilide, bretylium);

some antipsychotic drugs:

phenothiazines (e.g. chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine);

benzamides (e.g. amisulpride, sulpiride, sultopride, tiapride);

butyrophenones (e.g. droperidol, haloperidol);

other medicines: (e.g. bepridil, cisapride, diphemanil, intravenous erythromycin, halofantrine, mizolastine, pentamidine, sparfloxacin, moxifloxacin, intravenous vincamine, methadone, astemizole, terfenadine).

When using indapamide with the above-mentioned drugs, the risk of ventricular arrhythmias increases, in particular torsades de pointes - paroxysmal ventricular tachycardia of the "pirouette" type (hypokalemia is a risk factor).

Before prescribing such a combination, potassium levels should be checked and corrected if necessary. Patients should be monitored for clinical status, plasma electrolytes, and ECG. In the presence of hypokalemia, it is recommended to prescribe drugs that do not cause torsades de pointes.

Nonsteroidal anti-inflammatory drugs (for systemic use), including selective cyclooxygenase 2 inhibitors, high doses of acetylsalicylic acid (≥ 3 g/day):

may reduce the antihypertensive effect of indapamide;

Dehydrated patients are at increased risk of acute renal failure (due to decreased glomerular filtration). Before starting treatment, it is necessary to restore water balance and check kidney function.

ACE inhibitors: Sudden hypotension and/or acute renal failure may occur in patients with low sodium levels (especially in patients with renal artery stenosis).

Arterial hypertension. If previous use of a diuretic has caused a decrease in sodium levels, it is necessary to stop taking the diuretic 3 days before starting treatment with an angiotensin-converting enzyme (ACE) inhibitor and then, if necessary, resume diuretic therapy or start taking the ACE inhibitor at a low initial dose with subsequent gradual increase.

In congestive heart failure, the use of an ACE inhibitor should be initiated at the lowest dose, and possibly after reducing the dose of the previously prescribed potassium-sparing diuretic.

In any case, renal function (plasma creatinine) should be monitored during the first weeks of treatment with an ACE inhibitor.

Drugs that can cause hypokalemia: gluco- and mineralocorticoids (for systemic use), amphotericin B (intravenous), tetracosactide, laxatives that stimulate peristalsis increase the risk of hypokalemia (additive effect). The level of potassium in the blood plasma should be monitored and, if necessary, corrected, special attention should be paid to simultaneous therapy with cardiac glycosides. It is recommended to prescribe laxatives that do not stimulate peristalsis.

Digitalis preparations.

Hypokalemia and/or hypomagnesemia contribute to the toxicity of digitalis. Monitoring of plasma potassium, magnesium and ECG is recommended, and treatment should be adjusted if necessary.

Baclofen enhances the antihypertensive effect of the drug. At the beginning of therapy, it is necessary to restore the water and electrolyte balance and monitor the patient's kidney function.

Combinations that require special attention

Allopurinol: Concomitant use with indapamide may lead to an increased incidence of hypersensitivity reactions to allopurinol.

Combinations that require attention

Potassium-sparing diuretics (amiloride, spironolactone, triamterene). If such a combination is appropriate for some patients, the possibility of hypokalemia or hyperkalemia cannot be ruled out (especially in patients with diabetes mellitus or renal failure). Plasma potassium should be monitored, ECG monitoring should be performed, and therapy should be adjusted if necessary.

Metformin: The risk of lactic acidosis increases in patients with functional renal failure due to diuretics, especially loop diuretics. Metformin should not be prescribed if the plasma creatinine level exceeds 15 mg/L (135 μmol/L) in men and 12 mg/L (110 μmol/L) in women.

Iodine contrast media. In case of dehydration caused by diuretics, the risk of developing acute renal failure increases, especially when using large doses of iodinated contrast media. It is necessary to restore the water balance before administering iodinated contrast media.

Imipramine-like antidepressants, neuroleptics. Increased antihypertensive effect and risk of orthostatic hypotension due to additive effect.

Calcium salts: Hypercalcemia may occur due to decreased renal calcium elimination.

Cyclosporine, tacrolimus: Risk of increased plasma creatinine without effect on circulating cyclosporine levels, even in the absence of water/sodium depletion.

Corticosteroids, tetracosactide (systemic action). Decreased antihypertensive effect of indapamide due to water and sodium retention under the influence of corticosteroids.

Application features

Patients with hepatic impairment

In patients with impaired liver function, the use of thiazide-like diuretics, especially in the presence of electrolyte imbalance, may cause hepatic encephalopathy, which may progress to hepatic coma. In such cases, the diuretic should be discontinued immediately.

Photosensitivity reactions have been reported in patients receiving thiazide and thiazide-like diuretics (see section 4.8). If such reactions occur, it is recommended that diuretic therapy be discontinued. If diuretics are re-administered, exposed areas should be protected from the sun or artificial ultraviolet light.

Excipients

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Water and electrolyte balance

Sodium in blood plasma

Plasma sodium levels should be monitored before starting treatment and regularly during treatment. Decreased plasma sodium levels may be asymptomatic at first, so regular monitoring is necessary. Monitoring of sodium levels should be performed more frequently in elderly patients and in patients with cirrhosis of the liver. Any diuretic can cause hyponatremia, which sometimes has serious consequences. Hyponatremia with hypovolemia can lead to dehydration and orthostatic hypotension; concomitant loss of chloride ions can cause secondary compensatory metabolic alkalosis (the frequency and severity of this phenomenon are low).

Potassium in blood plasma

A decrease in plasma potassium with hypokalemia is the main risk with thiazide and thiazide-like diuretics. Hypokalemia can cause muscle disorders. Rhabdomyolysis has been reported, mostly in association with severe hypokalemia. The possibility of hypokalemia (< 3.4 mmol/L) should be considered in certain high-risk patient groups, such as the elderly, malnourished and/or heavily medicated patients, patients with cirrhosis of the liver accompanied by edema and ascites, patients with ischemic heart disease, and patients with heart failure. In such cases, hypokalemia increases the cardiotoxicity of cardiac glycosides and the risk of arrhythmias.

Patients with congenital or iatrogenic QT prolongation are also at risk. Hypokalemia, like bradycardia, can predispose to serious arrhythmias, including torsades de pointes, which can be fatal.

In all of the above cases, more frequent monitoring of potassium levels in the blood is necessary. The first analysis should be performed within the 1st week of treatment.

Hypokalemia should be corrected if detected. Hypokalemia resulting from low serum magnesium levels may be refractory to treatment unless serum magnesium levels are corrected.

Magnesium in blood plasma

Thiazides and related diuretics, including indapamide, have been shown to increase urinary magnesium excretion, which may lead to hypomagnesemia (see sections 4.5 and 4.8).

Calcium in blood plasma

Thiazide and thiazide-like diuretics may reduce urinary calcium excretion and lead to a slight and transient increase in plasma calcium levels. Marked hypercalcemia may be a consequence of previously undiagnosed hyperparathyroidism. In such cases, treatment should be discontinued and parathyroid function should be monitored.

Blood glucose

In patients with diabetes, it is important to control blood glucose, especially in the presence of hypokalemia.

Uric acid

Patients with elevated uric acid levels may have a tendency to have an increased number of gout attacks.

Kidney function and diuretics

Thiazide and thiazide-like diuretics are most effective when renal function is not impaired or only mildly impaired (plasma creatinine < 25 mg/l, i.e. 220 mmol/l in adults). In elderly patients, plasma creatinine should be at a level appropriate for age, weight and sex. Hypovolemia, associated with water and sodium loss due to diuretics, causes a decrease in glomerular filtration rate at the beginning of treatment. This may lead to an increase in blood urea and creatinine. Such transient functional renal failure is of no consequence in individuals with normal renal function, but may worsen existing renal failure.

In athletes, indapamide may cause a positive reaction during doping control.

Choroidal effusion, acute myopia (short-sightedness) and secondary angle-closure glaucoma. Sulfonamide- or sulfonamide-derived drugs may cause an idiosyncratic reaction resulting in choroidal effusion with visual field defect, transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or eye pain and usually occur within hours to weeks of starting the drug. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue the drug as soon as possible. If intraocular pressure remains uncontrolled, prompt medical or surgical treatment may be necessary. Risk factors for acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

Use during pregnancy or breastfeeding

Pregnancy

There are no or limited (less than 300) data from the use of indapamide in pregnant women. Prolonged use of a thiazide diuretic during the third trimester of pregnancy may result in a decrease in maternal blood volume and uteroplacental blood flow, which may lead to fetoplacental ischemia and fetal growth retardation. Animal studies do not indicate direct or indirect toxic effects with respect to reproductive toxicity. As a precautionary measure, it is preferable to avoid the use of indapamide during pregnancy.

Breast-feeding

There is insufficient data on the excretion of indapamide/metabolites in breast milk. Hypersensitivity to sulfonamide derivatives and hypokalemia may develop. A risk to the newborn/infants cannot be excluded. Indapamide belongs to the thiazide-like diuretics, the use of which during breastfeeding has been associated with a decrease or even suppression of lactation. Indapamide is not recommended during breastfeeding.

Fertility

Reproductive toxicity studies showed no effect on fertility in male and female rats. No effect on human fertility is expected.

Ability to influence reaction speed when driving vehicles or other mechanisms

ARIFON® RETARD does not affect alertness. However, in the event of adverse reactions (see section "Adverse reactions"), including symptoms associated with a decrease in blood pressure, especially at the beginning of treatment or when used in combination with another antihypertensive agent, the ability to drive a car or operate other mechanisms may be impaired.

Method of administration and doses

Method of application

For oral use.

Dosage

1 tablet per day, preferably in the morning. The tablet should be swallowed whole, without chewing, with water.

The use of higher doses of the drug does not lead to an increase in the antihypertensive effect, but the diuretic effect increases.

Special patient groups

Renal failure (see sections "Special instructions" and "Contraindications")

The drug is contraindicated in patients with severe renal insufficiency (creatinine clearance < 30 ml/min). Thiazide and thiazide-like diuretics are most effective if renal function is not impaired or if the impairment is minor.

Elderly (see section "Special instructions")

In elderly patients, plasma creatinine should be at a level appropriate for age, body weight and gender. Elderly patients can be prescribed ARIFON® RETARD if renal function is not impaired or if the impairment is minor.

Hepatic failure (see sections "Special instructions" and "Contraindications")

In case of severe liver dysfunction, treatment with the drug is contraindicated.

Children

The safety and efficacy of ARIFON® RETARD in children have not been established. Data are not available.

Overdose

Symptoms

Symptoms of overdose are primarily manifestations of water and electrolyte disturbances (hyponatremia, hypokalemia). Clinically, nausea, vomiting, hypotension, convulsions, drowsiness, dizziness (vertigo), confusion, polyuria or oliguria up to anuria (caused by hypovolemia) are possible.

Treatment

First aid measures include rapid removal of the drug by gastric lavage and/or administration of activated charcoal, followed by restoration of water and electrolyte balance in a hospital setting.

Adverse reactions

The most frequently reported adverse reactions were: hypokalemia, hypersensitivity reactions, mainly dermatological, in individuals with a predisposition to allergic and asthmatic reactions, and maculopapular rashes.

The following adverse reactions have been observed during treatment with indapamide with the following frequencies: very common (≥ 1/10), common (≥ 1/100, <1/10), uncommon (≥ 1/1000, <1/100), rare (≥ 1/10000, <1/1000), very rare (≥ 1/100000, <1/10000), frequency unknown (cannot be estimated from the available information).

Description of selected adverse reactions

In phase II and III studies comparing 1.5 and 2.5 mg indapamide, analysis of plasma potassium levels showed a dose-dependent effect of indapamide:

Indapamide 1.5 mg: plasma potassium < 3.4 mmol/l was observed in 10% of patients and < 3.2 mmol/l in 4% of patients after 4-6 weeks of treatment. After 12 weeks of treatment, the mean decrease in plasma potassium was 0.23 mmol/l.

Indapamide 2.5 mg: plasma potassium < 3.4 mmol/L was observed in 25% of patients and < 3.2 mmol/L in 10% of patients after 4-6 weeks of treatment. After 12 weeks of treatment, the mean decrease in plasma potassium was 0.41 mmol/L.

Expiration date

2 years.

Storage conditions

Store at temperatures up to 30 °C.

Keep out of reach of children.

Packaging

30 tablets in a blister; 1 blister in a cardboard box (for the manufacturer ANFARM Pharmaceutical Enterprise JSC, Poland).

15 tablets in a blister; 2 blisters in a cardboard box (for manufacturers Servier Industries Laboratories, France and Servier (Ireland) Industries Ltd, Ireland).

Vacation category

According to the recipe.

Producer

Servier Industry Laboratories/Les Laboratoires Servier Іndustrie.

Location of the manufacturer and address of its place of business

905 route de Saran, 45520 Gidy, France/905 route de Saran, 45520 Gidy, France.

Producer

Servier (Ireland) Industries Ltd.

Location of the manufacturer and address of its place of business

Moneylands, Gorey Road, Arklow, Co. Wicklow, Ireland/Moneylands, Gorey Road, Arklow, Co. Wicklow, Ireland.

Producer

ANPHARM Pharmaceutical Enterprise SA/ANPHARM Przedsiębiorstwo Farmaceutyczne SA

Location of the manufacturer and address of its place of business

Annopol 6B, Warszawa, 03-236, Poland.

Applicant

LE LABORATORY SERVIER/LES LABORATOIRES SERVIER.

Applicant's location

50 rue Carnot, 92284 Suresnes cedex, France/50 rue Carnot, 92284 Suresnes cedex, France.

If you have any questions about the medicinal product, please contact the applicant's representative in Ukraine, Servier Ukraine LLC, by phone: (044) 490 3441, fax: (044) 490 3440.