Ravel sr

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Ravel® SR (Rawel® SR)

Composition:

Active substance: 1 prolonged-release tablet contains 1.5 mg of indapamide;

Excipients: hypromellose, celactose (containing monohydrate lactose and powdered cellulose), colloidal anhydrous silicon dioxide, magnesium stearate, Opadry Y-1-7000 (containing hypromellose, macrogol 400, and titanium dioxide (E 171)).

Pharmaceutical form. Prolonged-release tablets.

Main physicochemical properties: round, white, slightly biconvex tablets.

Pharmacotherapeutic group.

Diuretics with moderately expressed diuretic activity, excluding thiazides. Simple sulfonamides. Indapamide. ATC code C03B A11.

Pharmacological properties.

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 chlorides, and to a lesser extent potassium and magnesium, thus 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 increases. If treatment is insufficiently effective, dose escalation is not recommended.

Indapamide, when used to treat patients with arterial hypertension:

• 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.

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 absorbed drug.

Maximum plasma concentration after a single dose is reached approximately within 12 hours. Continued administration reduces fluctuations in plasma indapamide levels during the interdose interval. Individual variations exist.

Distribution

Protein binding in plasma 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 patient groups

In patients with renal impairment, pharmacokinetic parameters are not altered.

Clinical characteristics.

Indications.

Essential hypertension in adults.

Contraindications.

Hypersensitivity to indapamide, to other sulfonamides, or to any of the excipients of the medicinal product; severe renal impairment; hepatic encephalopathy or severe hepatic dysfunction; hypokalemia.

Interaction with other medicinal products and other forms of interaction.

Combinations not recommended

Lithium

Concomitant use with lithium may lead to increased plasma lithium levels and symptoms of lithium toxicity, particularly under low-sodium diet conditions (reduced renal lithium excretion). If diuretic therapy is necessary, careful monitoring of blood lithium levels is required, with dose adjustment as needed.

Combinations requiring caution

Medicinal products that may provoke ventricular tachycardia of the "torsades de pointes" type

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

Concomitant administration of indapamide with any of these agents, especially in the presence of hypokalemia, increases the risk of ventricular arrhythmias, particularly of the «torsades de pointes» type. Plasma potassium levels should be monitored and corrected prior to initiating such combination therapy. Clinical status, plasma electrolyte levels, and ECG should be closely monitored. In the presence of hypokalemia, agents not associated with risk of «torsades de pointes» should be preferred.

Nonsteroidal anti-inflammatory drugs (systemic use), including selective COX-2 inhibitors, and high-dose acetylsalicylic acid (≥3 g/day)

The antihypertensive effect of indapamide may be reduced. In dehydrated patients, there is an increased risk of acute renal failure (due to decreased glomerular filtration). Adequate hydration should be ensured, and renal function should be monitored at the start of treatment.

Angiotensin-converting enzyme (ACE) inhibitors

When used concomitantly with ACE inhibitors in patients with low sodium levels (particularly in patients with renal artery stenosis), sudden arterial hypotension and/or acute renal failure may occur at the beginning of treatment.

In patients with arterial hypertension, where prior diuretic therapy may have caused sodium depletion, the following is recommended:

• discontinue diuretic therapy 3 days before initiating ACE inhibitor therapy, and if necessary, restart potassium-wasting diuretic therapy;
• or initiate ACE inhibitor therapy with low doses and gradually increase dosage.

In patients with congestive heart failure, ACE inhibitor therapy should be initiated with very low doses, preferably after reducing the dose of potassium-wasting diuretics.

All patients should have renal function (plasma creatinine levels) monitored during the first weeks of ACE inhibitor therapy.

Other agents causing hypokalemia:

• intravenous amphotericin B,
• glucocorticoids and mineralocorticoids (systemic use),
• tetracosactide,
• stimulant laxatives.

The risk of hypokalemia is increased (additive effect). Plasma potassium levels should be monitored and corrected as needed. Concomitant use of digitalis preparations should be approached with caution. Stimulant laxatives should not be used.

Baclofen

Enhances the hypotensive effect.

Patients should maintain adequate fluid intake; renal function should be assessed at the beginning of treatment.

Cardiac glycosides

The presence of hypokalemia and/or hypomagnesemia predisposes to cardiac glycoside cardiotoxicity. Plasma potassium and magnesium concentrations and ECG parameters should be monitored and treatment adjusted as necessary.

Combinations requiring special monitoring

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

Combinations requiring attention

Potassium-sparing diuretics (amiloride, spironolactone, triamterene)

Such combinations may be acceptable for certain patients, but may lead to hyperkalemia. In particular, patients with renal impairment or diabetes mellitus are at increased risk of hyperkalemia. Plasma potassium concentration and ECG parameters should be monitored, and treatment adjusted as necessary.

Metformin

In cases of functional renal impairment associated with diuretic use—especially loop diuretics—the risk of metformin-induced lactic acidosis increases. Metformin should not be used in patients with plasma creatinine levels exceeding 15 mg/L (135 µmol/L) in men and 12 mg/L (110 µmol/L) in women.

Iodinated contrast agents

In the context of dehydration caused by diuretic use, administration of iodinated contrast agents—particularly at high doses—increases the risk of acute renal failure. Fluid balance should be restored prior to administration of iodinated contrast agents.

Imipramine-like antidepressants, neuroleptics

Enhanced hypotensive effect of indapamide and increased risk of orthostatic hypotension (additive effect).

Calcium salts

Risk of hypercalcemia due to reduced renal excretion of calcium.

Cyclosporine, tacrolimus

Risk of increased plasma creatinine concentration without changes in cyclosporine blood levels, even in the absence of fluid/sodium depletion.

Corticosteroids, tetracosactide (systemic)

May reduce the antihypertensive effect (due to fluid and sodium retention).

Special precautions for use.

Photosensitivity

Cases of photosensitivity reactions have been reported with thiazide and thiazide-like diuretics. If a photosensitivity reaction occurs during treatment, discontinuation of therapy is recommended. If re-administration of indapamide is necessary, protection of susceptible areas from sunlight or artificial ultraviolet radiation is advised.

Special warnings regarding certain excipients.

The product contains lactose. This medicine must not be used in patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

Water and electrolyte balance

Plasma sodium concentration

Plasma sodium levels should be monitored before starting treatment and regularly during therapy. Hyponatremia may initially be asymptomatic; therefore, regular monitoring is essential. Monitoring of sodium levels 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 lead to secondary compensatory metabolic alkalosis (the frequency and severity of this effect are low).

Plasma potassium concentration

Reduction in plasma potassium levels leading to hypokalemia is a major risk associated with thiazide and thiazide-like diuretics. Hypokalemia may cause muscle disorders. Cases of rhabdomyolysis have been reported, predominantly in association with severe hypokalemia. 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 patients on multiple medications, patients with cirrhosis of the liver associated with 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 interval prolongation also belong to the risk group. Hypokalemia, as well as bradycardia, may predispose to severe cardiac rhythm disturbances, including paroxysmal ventricular tachycardia of the torsades de pointes type, which may be fatal.

In all the above-mentioned 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.

Plasma magnesium concentration

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 "Side effects").

Plasma calcium concentration

Thiazide and related diuretics may reduce calcium excretion in urine and may cause a slight transient increase in plasma calcium concentration. Persistent hypercalcemia may indicate hyperparathyroidism. Therefore, diuretic treatment should be discontinued until parathyroid function has been evaluated.

Blood glucose level

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

Uric acid

In patients with hyperuricemia, there may be a tendency toward gout attacks.

Kidney function and diuretics

Thiazide and thiazide-like diuretics are most effective when kidney 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 expected for age, body weight, and sex. Hypovolemia due to water and sodium loss following diuretic use at the beginning of treatment may lead to a reduction in glomerular filtration. This may result in increased blood urea and creatinine levels. This transient functional renal impairment has no consequences in individuals with normal kidney function but may worsen pre-existing renal insufficiency.

Athletes

Athletes should be aware that Ravel® SR contains an active substance that may cause a positive doping test.

Choroidal effusion, acute myopia, and secondary angle-closure glaucoma

Sulfonamide or sulfonamide derivative drugs may cause an idiosyncratic reaction leading to 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 typically occur within hours to weeks after starting the drug. Untreated acute angle-closure glaucoma may lead to permanent vision loss. The primary treatment is prompt discontinuation of the drug. Medical or surgical intervention may need to be considered if intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

Patients with impaired liver function

In patients with impaired liver function, thiazide diuretics may precipitate encephalopathy, particularly in the presence of electrolyte imbalance, which may progress to hepatic coma. In such cases, diuretic therapy should be discontinued immediately.

Elderly patients

The drug may be prescribed to elderly patients if renal function is normal or only slightly impaired.

Use during pregnancy or breastfeeding.

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 reproductive performance. As a precautionary measure, use of indapamide during pregnancy should be avoided.

Breastfeeding

Data on the passage of indapamide/metabolites into breast milk are insufficient. Hypersensitivity to sulfonamide derivatives and hypokalemia may occur. Risk to newborns/infants cannot be excluded. Indapamide belongs to the group of thiazide-like diuretics, the use of which during breastfeeding has been 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 influence reaction speed when driving or operating machinery.

Indapamide does not affect reaction speed; however, in some cases, particularly at the beginning of treatment or when used concomitantly with other antihypertensive agents, various symptoms related to decreased blood pressure may occur. As a result, the ability to drive or operate machinery may be impaired.

Dosage and Administration.

For oral use.

The recommended dose is 1 tablet once daily, preferably in the morning. The tablet should be swallowed whole, without chewing, with a glass of water.

Maximum daily dose – 1 tablet. The duration of treatment depends on the severity and course of the disease and is determined individually by the physician.

At higher doses, the antihypertensive effect of indapamide does not increase, but diuretic and saluretic effects become more pronounced.

Elderly patients

In elderly patients, plasma creatinine levels should be adjusted according to age, body weight, and gender. Ravell® SR can be administered to such patients only if renal function is not impaired or impairment is mild.

Renal impairment

The use of the drug is contraindicated in severe renal impairment (creatinine clearance below 30 ml/min).

Thiazide and thiazide-like diuretics are most effective when renal function is normal or only mildly impaired.

Patients with hepatic impairment

The use of the drug is contraindicated in severe hepatic impairment.

Children

Ravell® SR is not recommended for use in children due to insufficient data on safety and efficacy.

Overdose.

Symptoms of acute poisoning include disturbances in water-electrolyte balance (hyponatremia, hypokalemia), manifested by nausea, vomiting, arterial hypotension, seizures, dizziness, drowsiness, confusion, polyuria, oliguria, and even anuria (due to hypovolemia).

Initial management includes rapid removal of the drug from the body by gastric lavage and/or administration of activated charcoal, followed by restoration of water-electrolyte balance under hospital conditions.

Adverse Reactions

Summary of Safety Profile

The most commonly reported adverse reactions are hypokalaemia, hypersensitivity reactions (mainly dermatological), in patients predisposed to allergic and asthmatic reactions, and maculopapular rashes.

The frequency of adverse reactions is classified as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000), including isolated case reports.

Thiazide diuretics, including indapamide, may cause the following adverse reactions:

Blood and lymphatic system disorders

Very rare: thrombocytopenia, leucopenia, agranulocytosis, aplastic anaemia, haemolytic anaemia.

Nervous system disorders

Rare: fatigue, headache, paraesthesia, dizziness (vertigo).

Frequency not known: loss of consciousness.

Eye disorders

Frequency not known: myopia, blurred vision, visual impairment, acute angle-closure glaucoma, choroidal effusion.

Cardiovascular system disorders

Very rare: arrhythmia, arterial hypotension.

Isolated reports: paroxysmal torsades de pointes-type ventricular tachycardia (which may be fatal) (see sections "Special Warnings and Precautions for Use", "Interaction with Other Medicinal Products and Other Forms of Interaction").

Gastrointestinal disorders

Uncommon: vomiting.

Rare: nausea, constipation, dry mouth.

Very rare: pancreatitis.

Metabolism and nutrition disorders

Common: hypokalaemia (see section "Special Warnings and Precautions for Use").

Uncommon: hyponatraemia (see section "Special Warnings and Precautions for Use").

Rare: hypochloraemia, hypomagnesaemia.

Very rare: hypercalcaemia.

Hepatobiliary disorders

Very rare: hepatic function abnormalities.

Isolated reports: development of hepatic encephalopathy in the presence of hepatic insufficiency (see sections "Contraindications", "Special Warnings and Precautions for Use"), hepatitis.

Renal and urinary disorders

Very rare: renal failure.

Skin and subcutaneous tissue disorders

Hypersensitivity reactions, mainly dermatological (common: maculopapular rash; uncommon: purpura), in patients predisposed to allergic and asthmatic reactions.

Very rare: angioneurotic oedema and/or urticaria, toxic epidermal necrolysis, Stevens-Johnson syndrome.

Isolated reports: possible exacerbation of pre-existing systemic lupus erythematosus.

Cases of photosensitivity have been reported (see sections "Special Warnings and Precautions for Use").

Reproductive system and breast disorders

Uncommon: erectile dysfunction.

Musculoskeletal and connective tissue disorders

Frequency not known: muscle cramps, muscle weakness, myalgia, rhabdomyolysis.

Laboratory findings

Isolated reports: prolonged QT interval on electrocardiogram (see sections "Special Warnings and Precautions for Use", "Interaction with Other Medicinal Products and Other Forms of Interaction"); increased plasma uric acid and glucose levels during treatment with thiazide and thiazide-like diuretics: the appropriateness of prescribing these diuretics should be carefully considered in patients with gout or diabetes mellitus; increased levels of liver enzymes.

Description of selected adverse reactions

In Phase II and III studies comparing indapamide 1.5 mg and 2.5 mg, plasma potassium analysis 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 mmol/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.

5 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging to protect from moisture.

Keep out of reach and sight of children.

Packaging.

10 tablets per blister, 2, 3, 6, or 9 blisters per cardboard box.

Prescription category. Prescription only.

Manufacturer.

KRKA, d.d., Novo mesto, Slovenia.

Manufacturer's address.

Šmarješka cesta 6, 8501 Novo mesto, Slovenia.