Softenzif

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SОFТENSIF (SOPHTENSIF®)

Composition:

Active substance: indapamide;

One prolonged-release tablet contains 1.5 mg of indapamide;

Excipients: hypromellose, monohydrate lactose, microcrystalline cellulose, povidone K 25, colloidal anhydrous silicon dioxide, magnesium stearate;

Film coating: Opadry II White 33G28707 (hypromellose, titanium dioxide (E 171), monohydrate lactose, macrogol 3000, triacetin).

Pharmaceutical form. Prolonged-release tablets.

Main physicochemical properties: round, biconvex tablets coated with a film, white to almost white in color, 9 mm in diameter.

Pharmacotherapeutic group.

Non-thiazide diuretics with moderately expressed diuretic activity. Simple sulfonamides. Indapamide.

ATC code C03B A11.

Pharmacological Properties.

Pharmacodynamics.

Indapamide is a sulfonamide derivative with an indole ring and pharmacologically belongs to the group of thiazide diuretics that inhibit sodium reabsorption in the cortical diluting segment. It increases the excretion of sodium and chlorides, and to a lesser extent potassium and magnesium, thereby enhancing diuresis and exerting its antihypertensive effect.

Clinical studies in phases II and III using monotherapy have demonstrated antihypertensive effects lasting up to 24 hours. The diuretic effect was moderate.

These effects lead to a reduction in total peripheral vascular and arterial resistance, resulting in decreased arterial pressure.

Indapamide reduces left ventricular hypertrophy.

When the recommended dose is exceeded, the therapeutic effect of thiazide and thiazide-like diuretics does not increase, while adverse effects continue to rise. The dose should not be increased if treatment proves ineffective.

It has been demonstrated that indapamide, during short-, medium-, and long-term treatment of patients with hypertension:

• does not affect lipid metabolism: triglycerides, LDL cholesterol, and HDL cholesterol;
• does not affect carbohydrate metabolism, even in hypertensive patients with diabetes mellitus.

Pharmacokinetics.

Softensif is formulated as a prolonged-release dosage form based on a matrix system, in which the active ingredient is dispersed within a carrier enabling sustained release of indapamide.

Absorption. The released fraction of indapamide is rapidly and completely absorbed from the gastrointestinal tract. Food slightly increases the rate of absorption but does not affect the total amount of absorbed substance. Peak plasma concentration after a single dose occurs approximately 12 hours after administration. Repeated dosing reduces serum level fluctuations between doses. There is individual variability.

Distribution. Plasma protein binding of indapamide is 79%. The elimination half-life from plasma ranges from 14 to 24 hours (average 18 hours). Steady-state concentration is reached within 7 days. Repeated administration does not lead to accumulation in the body.

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

High-risk patients. Pharmacokinetic parameters are not altered in patients with renal insufficiency.

Clinical characteristics.

Indications.

Essential hypertension.

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

Unrecommended combinations.

Lithium. Possible increase in lithium plasma levels with signs of lithium overdose, especially under a low-sodium diet (reduced urinary excretion of lithium). However, if diuretic therapy is necessary, plasma lithium levels must be closely monitored and lithium dosage adjusted accordingly.

Combinations requiring precautions during use.

Medicinal products that may induce torsades de pointes-type ventricular tachycardia:

• Class IА antiarrhythmics (quinidine, hydroquinidine, disopyramide);
• Class III antiarrhythmics (amiodarone, sotalol, dofetilide, ibutilide);
• certain antipsychotics: phenothiazines (chlorpromazine, tiaramide, levomepromazine, thioridazine, trifluoperazine), benzamides (amisulpride, sulpiride, sultopride, tiapride), butyrophenones (droperidol, haloperidol);
• others: bepridil, cisapride, diphemanil, erythromycin IV, halofantrine, mizolastine, pentamidine, sparfloxacin, moxifloxacin, vincamine IV.

Use of these agents increases the risk of ventricular arrhythmias, particularly torsades de pointes-type ventricular tachycardia (hypokalemia being a risk factor). Hypokalemia should be monitored and corrected prior to initiating such combination therapy. Clinical, plasma electrolyte, and ECG monitoring are required.

Medicinal products that do not induce torsades de pointes-type ventricular tachycardia under existing hypokalemia should be used.

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

• possible reduction in antihypertensive effect of indapamide;
• risk of acute renal failure in dehydrated patients (reduced glomerular filtration). Patients should be adequately hydrated and renal function monitored at the start of treatment.

Angiotensin-converting enzyme (ACE) inhibitors. Risk of sudden arterial hypotension and/or acute renal failure may occur at the beginning of ACE inhibitor therapy in patients with existing sodium deficiency (particularly in patients with renal artery stenosis).

In arterial hypertension, if prior diuretic therapy has caused sodium depletion, it is necessary to:

• either discontinue the diuretic 3 days before starting ACE inhibitor therapy and restart the hypokalemic diuretic if needed;
• or initiate therapy with a low dose of ACE inhibitor and gradually increase the dose.

In congestive heart failure, therapy should begin, if possible, with a very low dose of ACE inhibitor after reducing the dose of concomitantly administered hypokalemic diuretic.

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

Other agents causing hypokalemia – amphotericin B (intravenous), glucocorticoids and mineralocorticoids (for systemic use), tetracosactide, stimulant laxatives – increase the risk of hypokalemia (additive effect). Plasma potassium levels should be monitored and corrected if necessary. Particular caution is required when co-administering digitalis glycosides. Non-stimulant laxatives should be used.

Digitalis glycosides. Hypokalemia and/or hypomagnesemia may enhance the toxic effects of digitalis glycosides. Monitoring of plasma potassium and magnesium levels and ECG is required, with appropriate corrective treatment if necessary.

Baclofen. Enhances antihypertensive effect. Adequate hydration and monitoring of renal function are recommended at the beginning of treatment.

Combinations to be taken into consideration.

Potassium-sparing diuretics (amiloride, spironolactone, triamterene). While such rational combinations may be acceptable in some patients, hypokalemia (especially in patients with renal impairment or diabetes) or hyperkalemia may occur in others. Plasma potassium levels and ECG should be monitored, and treatment adjusted if necessary.

Metformin. Increased risk of metformin-associated lactic acidosis due to possible functional renal impairment associated with diuretics, particularly loop diuretics. Metformin should not be used if plasma creatinine exceeds 15 mg/L (135 µmol/L) in men and 12 mg/L (110 µmol/L) in women.

Iodinated contrast agents. In the presence of diuretic-induced dehydration, there is an increased risk of acute renal failure, especially with high doses of iodinated contrast agents. Adequate rehydration is required before administration of iodinated agents.

Tricyclic antidepressants, neuroleptics. Increased antihypertensive effect and risk of orthostatic hypotension (additive effect).

Calcium (salts). Risk of hypercalcemia due to reduced renal excretion.

Cyclosporine, tacrolimus. Risk of increased plasma creatinine without changes in circulating cyclosporine levels, even in the absence of water-sodium deficit.

Corticosteroids, tetracosactide (systemic use). Reduced antihypertensive effect (water and sodium retention caused by corticosteroids).

Special precautions for use.

Special warnings.

Patients with impaired liver function.

Thiazide diuretics may cause hepatic encephalopathy in patients with impaired liver function, particularly in the presence of electrolyte imbalance. In such cases, diuretic therapy should be discontinued immediately.

Photosensitivity.

Cases of photosensitivity reactions have been reported with thiazide and thiazide-like diuretics. If a photosensitivity reaction occurs during treatment, therapy should be discontinued. If re-treatment with a diuretic is necessary, protection of skin areas exposed to sunlight or artificial UV radiation is recommended.

Excipients.

The medicinal product contains lactose monohydrate and therefore should not be used in patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

Special precautions during use.

Water and electrolyte balance.

• Serum sodium.

Serum sodium should be measured before starting treatment and monitored periodically thereafter. Diuretic therapy may cause hyponatremia, which can sometimes have serious consequences. Hyponatremia with hypovolemia may lead to dehydration and orthostatic hypotension. Concomitant chloride loss may lead to secondary compensatory metabolic alkalosis (this phenomenon is of low frequency and severity). Initial decreases in serum sodium may be asymptomatic, making regular monitoring particularly important, especially in elderly patients or patients with liver cirrhosis.

• Serum potassium.

Potassium loss leading to hypokalemia is a major risk during treatment with thiazide and thiazide-like diuretics. The risk of hypokalemia (<3.4 mmol/L) should be anticipated in certain high-risk patient groups, such as elderly patients, those who are undernourished and/or receiving multiple medications, patients with cirrhosis, edema and ascites, and patients with ischemic heart disease or heart failure. In these patients, hypokalemia increases cardiac toxicity of digitalis preparations and the risk of arrhythmias.

Patients with prolonged QT interval, whether congenital or drug-induced, are also at risk. Hypokalemia, as well as bradycardia, are risk factors for severe cardiac rhythm disturbances and may be potentially life-threatening, particularly in the case of paroxysmal ventricular tachycardia of the torsades de pointes type.

In all the above cases, serum potassium levels should be monitored more frequently. The first serum potassium measurement should be performed during the first week of treatment.

If hypokalemia is detected, it should be corrected.

Hypokalemia associated with low serum magnesium levels may not respond to treatment unless serum magnesium levels are also corrected.

Serum magnesium.

Thiazides and their analogues, including indapamide, have been shown to increase urinary excretion of magnesium, potentially leading to hypomagnesemia (see sections «Interaction with other medicinal products and other forms of interaction» and «Adverse reactions»).

• Serum calcium.

Thiazide and thiazide-like diuretics may reduce urinary calcium excretion and cause mild and transient elevation of serum calcium levels. Marked hypercalcemia may be due to previously undiagnosed hyperparathyroidism. Treatment should be discontinued until parathyroid function has been evaluated.

Blood glucose.

Monitoring of blood glucose levels is important in diabetic patients, particularly in the presence of hypokalemia.

Uric acid.

An increased tendency to gout attacks may occur in patients with hyperuricemia.

Renal function and diuretics.

Thiazide and thiazide-like diuretics are effective only when renal function is normal or minimally impaired (plasma creatinine below 25 mg/L, i.e., 220 µmol/L in adults). In elderly patients, plasma creatinine should be assessed according to age, body weight, and sex.

Hypovolemia, secondary to water and sodium loss due to diuretic therapy, may initially reduce glomerular filtration. This may lead to increased plasma urea and creatinine levels. This transient functional renal insufficiency is generally benign in patients with normal renal function but may worsen the condition of patients with pre-existing renal impairment.

Choroidal effusion, acute myopia and secondary angle-closure glaucoma. Medicinal products containing sulfonamide or sulfonamide derivatives may induce an idiosyncratic reaction causing 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 usually occur within hours to weeks after initiating the medicinal product.

Untreated acute angle-closure glaucoma may lead to permanent vision loss. The primary treatment is immediate discontinuation of the medicinal product. If intraocular pressure remains uncontrolled, medical or surgical intervention may be required. Risk factors for developing acute angle-closure glaucoma may include a history of allergy to sulfonamides or penicillin.

Use of indapamide in athletes may lead to a positive doping test.

Use during pregnancy or breastfeeding.

Pregnancy. As a general rule, diuretics should be avoided during pregnancy; they should never be used to treat physiological edema of pregnancy. Diuretics may cause fetoplacental ischemia, with a risk of irreversible fetal damage.

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 thiazide-like diuretics, the use of which during breastfeeding has been associated with decreased or even suppressed lactation. Indapamide should not be used during breastfeeding.

Fertility. Reproductive toxicity studies showed no effect on fertility in male and female rats. A similar effect in humans is not expected.

Ability to affect reaction speed when driving or operating machinery.

Softenzif does not affect active attention; however, in some cases, particularly at the beginning of treatment or when adding another antihypertensive agent, changes in reaction time related to blood pressure reduction may occur. As a result, ability to drive vehicles or operate machinery may be impaired.

Dosage and Administration.

For oral use. One tablet every 24 hours, preferably in the morning. The tablet should be taken whole, without chewing, with water.

Antihypertensive effect of indapamide does not increase at higher doses, but diuretic effect becomes stronger.

Renal impairment.

The use of the drug is contraindicated in severe renal impairment (creatinine clearance below 30 mL/min) (see sections «Contraindications» and «Special precautions»).

Thiazide and thiazide-like diuretics are fully effective only when kidney function is normal or minimally impaired.

Elderly patients.

In elderly patients, plasma creatinine should be assessed according to age, body weight, and gender. Elderly patients may use Softenif when their kidney function is normal or minimally impaired (see section «Special precautions»).

Patients with hepatic impairment.

Softenif is contraindicated in patients with severe hepatic impairment (see sections «Contraindications» and «Special precautions»).

Children.

Softenif is not recommended for use in children (under 18 years of age) due to lack of data on safety and efficacy.

Overdose.

Symptoms. Indapamide does not exhibit toxicity when administered at doses up to 40 mg, i.e., 27 times the therapeutic dose.

Symptoms of overdose are manifested by disturbances in water-electrolyte balance (hyponatremia, hypokalemia). Clinically, nausea, vomiting, arterial hypotension, cramps, dizziness, drowsiness, confusion, polyuria or oliguria up to anuria (due to hypovolemia) may occur.

Treatment. Initial measures include rapid removal of the drug by gastric lavage and/or administration of activated charcoal, followed by restoration of water-electrolyte balance to normal in a specialized facility. Symptomatic therapy.

Adverse reactions.

Summary of safety profile

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

During Phase II and III studies comparing indapamide 1.5 mg with 2.5 mg, plasma potassium analyses demonstrated 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.

Most adverse reactions related to clinical or laboratory parameters are dose-dependent. Thiazide-like diuretics, including indapamide, may cause the following adverse reactions, classified by frequency: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), frequency not known (cannot be estimated from the available data).

Blood and lymphatic system disorders: very rare – thrombocytopenia, leukopenia, agranulocytosis, aplastic anemia, hemolytic anemia.

Nervous system disorders: rare – dizziness (vertigo), fatigue, headache, paresthesia; frequency not known – syncope.

Cardiac disorders: very rare – arrhythmia, arterial hypotension; frequency not known – paroxysmal ventricular tachycardia of the torsades de pointes type (torsades de pointes) (potentially fatal) (see sections «Interaction with other medicinal products and other forms of interaction» and «Special precautions for use»).

Eye disorders: frequency not known – myopia, blurred vision, visual disturbances, choroidal effusion.

Gastrointestinal disorders: uncommon – vomiting; rare – nausea, constipation, dry mouth; very rare – pancreatitis.

Renal and urinary disorders: very rare – renal failure.

Hepatobiliary disorders: very rare – impaired liver function; frequency not known – risk of hepatic encephalopathy in liver insufficiency (see sections «Contraindications» and «Special precautions for use»), hepatitis.

Skin and subcutaneous tissue disorders: hypersensitivity reactions, mainly skin-related, in patients predisposed to allergic and asthmatic reactions: common – maculopapular rash; uncommon – purpura; very rare – angioneurotic edema and/or urticaria, toxic epidermal necrolysis, Stevens-Johnson syndrome; frequency not known – possible exacerbation of pre-existing systemic lupus erythematosus. Cases of photosensitivity have been reported (see section «Special precautions for use»).

Investigations: frequency not known – QT interval prolongation on electrocardiogram (see section «Special precautions for use»), increased blood glucose and uric acid levels during treatment (careful consideration should be given to the suitability of these diuretics in patients with gout or diabetes), elevated liver enzymes.

Metabolism and nutrition disorders: common – hypokalemia (see section «Special precautions for use»); uncommon – hyponatremia (see section «Special precautions for use»); rare – hypochloremia, hypomagnesemia; very rare – hypercalcemia. Hyponatremia with hypovolemia may lead to dehydration and orthostatic hypotension. Concomitant loss of chloride ions may result in secondary compensatory metabolic alkalosis; the frequency and extent of this phenomenon are low.

Reproductive system and breast disorders: uncommon – erectile dysfunction.

Shelf life. 2 years.

Storage conditions.

Keep out of the reach of children.

Store in the original packaging at a temperature not exceeding 25 °C.

Packaging.

10 tablets per blister pack made of PVC film and aluminum foil; 3 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

JSC "Sofarma".

Manufacturer's name and address.

16 Iliensko Shose Str., Sofia, 1220, Bulgaria.