Arifon® retard

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ARIFFON® RETARD (ARIFON® RETARD)

Composition:

Active ingredient: indapamide;

1 tablet contains 1.5 mg of indapamide;

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

Pharmaceutical form. Prolonged-release film-coated tablets.

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

Pharmacotherapeutic group. Diuretics with moderately pronounced diuretic activity, excluding thiazides. Simple sulfonamides. Indapamide. ATC code C03BA11.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Indapamide is a sulfonamide diuretic with an indole ring, pharmacologically related to thiazide diuretics, and is indicated 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 urinary excretion of sodium and chloride, and to a lesser extent, potassium and magnesium, thereby enhancing diuresis.

Pharmacodynamic effects

Phase II–III clinical trials using indapamide as monotherapy have demonstrated that the antihypertensive effect of indapamide lasts for 24 hours. The diuretic effect was moderate. The antihypertensive action of indapamide is associated with improved arterial elasticity and reduced 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 incidence of adverse effects rises. If treatment is insufficiently effective, dose escalation is not recommended.

As demonstrated in studies of varying duration (short-, medium-, and long-term) involving 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 mellitus and arterial hypertension.

Indapamide acts at the vascular level by:

• reducing the contractility of vascular smooth muscle, related to alterations in transmembrane ion exchange (primarily calcium);
• stimulating the synthesis of prostaglandin PGE2 and prostacyclin PGI2 (a vasodilator and inhibitor of platelet aggregation).

Pharmacokinetics.

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

Absorption

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

Maximum plasma concentration after a single dose is reached approximately 12 hours post-administration. Continued use reduces fluctuations in plasma indapamide levels during the interdose interval. There is interindividual variability.

Distribution

Plasma protein binding is 79%.

The elimination half-life ranges from 14 to 24 hours (on average, 18 hours).

Steady-state concentration is achieved within 7 days. Regular administration does not lead to accumulation.

Elimination

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

High-risk patients

Pharmacokinetic parameters are not altered in patients with renal impairment.

Clinical characteristics.

Indications.

ARIFON® RETARD is indicated for the treatment of essential hypertension in adults.

Contraindications.

• Hypersensitivity to the active substance, to other sulfonamides, or to any of the excipients;
• severe renal impairment;
• hepatic encephalopathy or severe hepatic dysfunction;
• hypokalemia.

Interaction with other medicinal products and other forms of interaction.

Not recommended combinations

Lithium. Possible increase in plasma lithium levels and symptoms of lithium toxicity, as may occur with a low-sodium diet (due to reduced lithium urinary excretion). If concomitant diuretic therapy is necessary, careful monitoring of plasma lithium levels and dose adjustment of lithium are required.

Combinations requiring caution

Medicinal products that may induce torsade de pointes-type ventricular tachycardia, such as (the list is not exhaustive):

• class Ia antiarrhythmics (e.g., quinidine, hydroquinidine, disopyramide);
• class III antiarrhythmics (e.g., amiodarone, sotalol, dofetilide, ibutilide, bretylium);
• certain antipsychotics:
  • phenothiazines (e.g., chlorpromazine, thiamylal, levomepromazine, thioridazine, trifluoperazine);
  • benzamides (e.g., amisulpride, sulpiride, sultopride, tiapride);
  • butyrophenones (e.g., droperidol, haloperidol);
• other antipsychotics (e.g., pimozide);
• other medicinal products: (e.g., bepridil, cisapride, difemanil, intravenous erythromycin, halofantrine, mizolastine, pentamidine, sparfloxacin, moxifloxacin, intravenous vincamine, methadone, astemizole, terfenadine).

The use of indapamide with the above-mentioned medicinal products increases the risk of ventricular arrhythmias, including torsades de pointes – a form of polymorphic ventricular tachycardia (hypokalemia being a risk factor).

Before initiating such a combination, serum potassium levels should be checked and corrected if necessary. Clinical status, plasma electrolytes, and ECG should be monitored. In the presence of hypokalemia, it is recommended to use agents that do not predispose to torsades de pointes.

Non-steroidal anti-inflammatory drugs (for systemic use), including selective cyclooxygenase-2 inhibitors, and high-dose acetylsalicylic acid (≥ 3 g/day):

• may reduce the antihypertensive effect of indapamide;
• in dehydrated patients, the risk of acute renal failure increases (due to reduced glomerular filtration). Fluid balance should be restored and renal function assessed prior to initiating treatment.

ACE inhibitors. Sudden onset of arterial hypotension and/or acute renal failure may occur in patients with low sodium levels (particularly in patients with renal artery stenosis).

Hypertension. If prior diuretic therapy has led to reduced sodium levels, diuretic treatment should be discontinued 3 days before starting angiotensin-converting enzyme (ACE) inhibitor therapy, and then either resumed or initiated again, or ACE inhibitor therapy should be started at a low initial dose with gradual dose escalation.

In congestive heart failure, ACE inhibitor therapy should be initiated at the lowest dose, possibly after reducing the dose of a previously prescribed potassium-wasting diuretic.

In all cases, renal function (plasma creatinine) should be monitored during the first weeks of ACE inhibitor therapy.

Medicinal products that may induce hypokalemia: glucocorticoids and mineralocorticoids (for systemic use), intravenous amphotericin B, tetracosactide, stimulant laxatives – increase the risk of hypokalemia (additive effect). Plasma potassium levels should be monitored and corrected if necessary, especially when concomitant therapy with cardiac glycosides is used. Non-stimulant laxatives are recommended.

Cardiac glycosides.

Hypokalemia and/or hypomagnesemia may potentiate the toxic effects of cardiac glycosides. Monitoring of plasma potassium and magnesium levels and ECG is recommended, with treatment adjustment if necessary.

Baclofen enhances the antihypertensive effect of the drug. At the beginning of therapy, fluid and electrolyte balance should be restored and renal function monitored.

Combinations requiring special attention

Allopurinol. Concomitant use with indapamide may increase the frequency of hypersensitivity reactions to allopurinol.

Combinations requiring attention

Potassium-sparing diuretics (amiloride, spironolactone, triamterene). If combination therapy is considered appropriate for certain patients, the possibility of hypokalemia or hyperkalemia cannot be excluded (especially in patients with diabetes or renal impairment). Monitoring of plasma potassium levels and ECG is required, with treatment adjustment if necessary.

Metformin. The risk of lactic acidosis increases if functional renal impairment develops due to diuretic therapy, particularly loop diuretics. Metformin should not be prescribed if plasma creatinine exceeds 15 mg/L (135 µmol/L) in men or 12 mg/L (110 µmol/L) in women.

Iodinated contrast agents. In cases of dehydration caused by diuretic use, the risk of acute renal failure increases, especially with high doses of iodinated contrast agents. Fluid balance should be restored prior to administration of iodinated contrast agents.

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

Calcium salts. Hypercalcemia may occur due to reduced renal elimination of calcium.

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

Corticosteroids, tetracosactide (systemic action). Reduced antihypertensive effect of indapamide due to water and sodium retention induced by corticosteroids.

Special precautions for use.

Patients with impaired liver function

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

Photosensitivity

Cases of photosensitivity reactions have been reported in patients taking thiazide and thiazide-like diuretics (see section "Undesirable effects"). If such reactions occur, diuretic treatment should be discontinued. If re-administration of diuretics is necessary, vulnerable areas of the skin should be protected from sunlight or artificial ultraviolet sources.

Excipients

Patients with rare hereditary conditions such as galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medication.

Water and electrolyte balance

Serum sodium

Serum sodium levels should be monitored before initiating treatment and regularly during therapy. Hyponatremia may initially be asymptomatic; therefore, regular monitoring is essential. Monitoring should be performed more frequently in elderly patients and in patients with liver cirrhosis. Any diuretic may cause hyponatremia, which can sometimes have serious consequences. Hyponatremia with hypovolemia may lead to dehydration and orthostatic hypotension; concomitant chloride ion loss may result in secondary compensatory metabolic alkalosis (this phenomenon is infrequent and mild).

Serum potassium

Reduction in serum potassium levels leading to hypokalemia is a major risk associated with the use of thiazide and thiazide-like diuretics. Hypokalemia may cause muscle disorders. Cases of rhabdomyolysis, mainly associated with severe hypokalemia, have been reported. The risk of developing hypokalemia (< 3.4 mmol/L) should be anticipated in certain high-risk patient groups, such as elderly patients, poorly nourished patients, and/or those taking multiple medications, patients with cirrhosis accompanied by edema and ascites, patients with ischemic heart disease, and patients with heart failure. In these cases, hypokalemia increases the cardiotoxicity of cardiac glycosides and the risk of arrhythmias.

Patients with congenital or drug-induced prolonged QT interval are also at risk. Hypokalemia, as well as bradycardia, may predispose to severe cardiac rhythm disturbances, including torsades de pointes-type paroxysmal ventricular tachycardia, which may be fatal.

In all the above cases, more frequent monitoring of serum potassium levels is required. The first test should be performed within the first week of treatment.

If hypokalemia is detected, it should be corrected. Hypokalemia associated with low serum magnesium levels may be refractory to treatment unless serum magnesium levels are also corrected.

Serum magnesium

Thiazides and related diuretics, including indapamide, have been shown to increase urinary excretion of magnesium, which may lead to hypomagnesemia (see sections "Interaction with other medicinal products and other forms of interaction" and "Undesirable effects").

Serum calcium

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

Blood glucose

In patients with diabetes mellitus, blood glucose levels should be closely monitored, especially in the presence of hypokalemia.

Uric acid

In patients with elevated uric acid levels, there may be an increased tendency to gout attacks.

Renal function and diuretics

Thiazide and thiazide-like diuretics are most effective when renal function is normal or only slightly impaired (plasma creatinine < 25 mg/L, i.e., < 220 µmol/L in adults). In elderly patients, plasma creatinine should be within the range corresponding to age, body weight, and sex. Hypovolemia due to water and sodium loss caused by diuretic therapy at the beginning of treatment may lead to a reduction in glomerular filtration rate. This may result in increased blood urea and creatinine levels. This transient functional renal insufficiency has no consequences in individuals with normal kidney function, but may worsen pre-existing renal impairment.

In athletes, indapamide may lead to a positive result in doping tests.

Choroidal effusion, acute myopia, and secondary angle-closure glaucoma. Medicinal products containing sulfonamide or sulfonamide derivatives may induce an idiosyncratic reaction leading to choroidal effusion with visual field defects, transient myopia, and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or eye pain and typically occur within hours to weeks after initiating the drug. Untreated acute angle-closure glaucoma may lead to permanent vision loss. The primary treatment is prompt discontinuation of the drug. If intraocular pressure remains uncontrolled, medical or surgical interventions may be necessary. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

Use during pregnancy or breastfeeding.

Pregnancy

Data on the use of indapamide in pregnant women are lacking or limited (fewer than 300 cases). Prolonged use of a thiazide diuretic during the third trimester of pregnancy may reduce the pregnant woman's circulating blood volume and uteroplacental perfusion, potentially leading to fetoplacental ischemia and delayed fetal development. Animal studies have not revealed any direct or indirect toxic effects on fertility. As a precautionary measure, indapamide should be avoided during pregnancy.

Breastfeeding

Data on the passage of indapamide/metabolites into breast milk are insufficient. Hypersensitivity to sulfonamide derivatives and hypokalemia may develop. Risk to newborns/infants cannot be excluded. Indapamide belongs to the group of thiazide-like diuretics, the use of which during breastfeeding is associated with reduced or even suppressed 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 affect reaction speed when driving or operating machinery.

ARIFON® RETARD does not affect alertness. However, if adverse reactions occur (see section "Undesirable effects"), including symptoms related to reduced blood pressure, especially at the beginning of treatment or when used in combination with other antihypertensive agents, the ability to drive or operate machinery may be impaired.

Dosage and Administration

Route of Administration

For oral use.

Dosage

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

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

Special Patient Groups

Renal Impairment (see sections "Special Precautions" and "Contraindications")

The use of the drug is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min). Thiazide and thiazide-like diuretics are most effective when renal function is normal or only slightly impaired.

Elderly Patients (see section "Special Precautions")

In elderly patients, plasma creatinine levels should be within the range corresponding to age, body weight, and gender. ARIFON® RETARD may be prescribed to elderly patients if renal function is normal or only slightly impaired.

Hepatic Impairment (see sections "Special Precautions" and "Contraindications")

Treatment with the drug is contraindicated in cases of severe hepatic dysfunction.

Children

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

Overdose

Symptoms

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

Treatment

Emergency measures include rapid removal of the drug by gastric lavage and/or administration of activated charcoal, followed by restoration of water-electrolyte balance under hospital conditions.

Adverse reactions.

The most frequently reported adverse reactions were: hypokalemia, hypersensitivity reactions, predominantly dermatological, in individuals predisposed to allergic and asthmatic reactions, and maculopapular rashes.

The following adverse events have been observed during treatment with indapamide, with the following frequency of occurrence: 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 not known (cannot be estimated from the available data).

Description of individual adverse reactions

During phase II and III studies comparing 1.5 mg and 2.5 mg of indapamide, analysis of plasma potassium levels revealed 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 mm0l/L in 4 % of patients after 4–6 weeks of treatment. After 12 weeks of treatment, the mean decrease in plasma potassium level 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 level was 0.41 mmol/L.

Shelf life.

2 years.

Storage conditions.

Store at a temperature not exceeding 30 °C.

Keep out of reach and sight of children.

Packaging.

30 tablets in a blister; 1 blister per cardboard box (for manufacturer ANPHARM Przedsiębiorstwo Farmaceutyczne S.A., Poland).

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

Prescription status.

Prescription only.

Manufacturer.

Laboratoires Servier Industrie /
Les Laboratoires Servier Industrie.

Address of manufacturer and location of its operations.

905 route de Saran, 45520 Gidy, France.

Manufacturer.

Servier (Ireland) Industries Ltd.

Address of manufacturer and location of its operations.

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

Manufacturer.

ANPHARM Przedsiębiorstwo Farmaceutyczne S.A. /
ANPHARM Pharmaceutical Enterprise S.A.

Address of manufacturer and location of its operations.

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

Marketing Authorization Holder.

LES LABORATOIRES SERVIER.

Address of Marketing Authorization Holder.

50 rue Carnot, 92284 Suresnes cedex, France.

For any questions regarding this medicinal product, please contact the Marketing Authorization Holder's representative in Ukraine, LLC "Servier Ukraine", by phone: (044) 490 3441, fax: (044) 490 3440.