Furosemide-darnitsa

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FUROSEMID-DARNITSA (FUROSEMID-DARNITSA)

Composition:

Active substance: furosemide;

One tablet contains 40 mg of furosemide;

Excipients: potato starch, lactose monohydrate, sodium croscarmellose, sodium lauryl sulfate, magnesium stearate.

Pharmaceutical form. Tablets.

Main physico-chemical properties: flat cylindrical tablets of white or white with a creamy shade color.

Pharmacotherapeutic group. High-ceiling diuretics. Simple sulfonamide agents. Furosemide. ATC code C03CA01.

Pharmacological properties.

Pharmacodynamics.

Furosemide is a loop diuretic with rapid onset of action and relatively potent, short-term diuretic effect. Furosemide inhibits the Na⁺K⁺2Cl⁻ cotransporter located in the basolateral membranes of cells in the thick ascending limb of Henle’s loop. Thus, the saluretic efficacy of furosemide depends on the delivery of the drug to the tubular lumen via an anion transport mechanism. The diuretic effect results from inhibition of sodium chloride reabsorption in this segment of Henle’s loop. As a result, fractional excretion of sodium may reach up to 35% of the glomerular filtration rate of sodium. Secondary effects of increased sodium excretion include enhanced water excretion (due to osmotically bound water) and increased distal tubular secretion of potassium. Excretion of calcium and magnesium ions is also increased.

Furosemide induces dose-dependent stimulation of the renin-angiotensin-aldosterone system. In heart failure, furosemide causes acute reduction in cardiac preload (by constricting capacitance venous vessels). This early vascular effect is prostaglandin-mediated and occurs when renal function is adequate, with activation of the renin-angiotensin system and intact prostaglandin synthesis. In addition, due to its intrinsic natriuretic effect, furosemide reduces the elevated vascular reactivity to catecholamines observed in patients with arterial hypertension.

The antihypertensive efficacy of furosemide is explained by increased sodium excretion, reduced blood volume, and decreased responsiveness of vascular smooth muscle to stimulation by vasoconstrictors or vasoconstricting agents.

The onset of diuretic effect occurs within 1 hour after oral administration of the drug.

Dose-dependent increases in diuresis and natriuresis have been observed in healthy subjects receiving furosemide at doses of 10–100 mg. The duration of action in healthy individuals is approximately 3–6 hours after oral administration of 40 mg furosemide.

The effect of furosemide is reduced when there is impaired tubular secretion or when the drug interacts with albumin within the tubules.

Pharmacokinetics.

Furosemide is rapidly absorbed from the gastrointestinal tract. Maximum absorption occurs within 1 to 1.5 hours. Absorption of the drug shows considerable individual variability.

The bioavailability of furosemide in healthy volunteers is approximately 50–70% for tablets. In patients, various factors, including underlying diseases, may influence the bioavailability of the drug. For example, in nephrotic syndrome, bioavailability may decrease to as low as 30%.

Concomitant food intake may affect the absorption of furosemide.

The volume of distribution of furosemide ranges from 0.1 to 0.2 liters per kg of body weight. The volume of distribution may be higher depending on the disease state.

Furosemide (>98%) forms strong complexes with plasma proteins, particularly albumin.

Furosemide is primarily excreted unchanged via secretion into the proximal tubule.

The metabolite of furosemide—glucuronide—accounts for 10–20% of the drug-related substances found in urine. The residual dose is excreted in feces, likely via biliary secretion.

Furosemide passes into breast milk; it crosses the placental barrier and slowly enters the fetus. Furosemide is detected in the fetus or newborn at the same concentrations as in the mother.

Renal disease.

In renal insufficiency, elimination of furosemide is slowed and the elimination half-life is prolonged; the terminal half-life may extend up to 24 hours in patients with severe renal impairment.

In nephrotic syndrome, reduced plasma protein concentrations lead to increased levels of unbound (free) furosemide. On the other hand, the efficacy of furosemide in these patients is reduced due to binding with intratubular albumin and decreased tubular secretion.

Furosemide is poorly dialyzable in patients undergoing hemodialysis, peritoneal dialysis, or continuous ambulatory peritoneal dialysis.

Hepatic insufficiency.

In hepatic insufficiency, the elimination half-life of furosemide increases by 30–90%, primarily due to an increased volume of distribution. In this patient group, there is wide variability in all pharmacokinetic parameters.

Congestive heart failure, severe arterial hypertension, elderly patients.

Due to reduced renal function in these patients, elimination of furosemide is slowed.

Preterm and term infants.

Depending on the degree of renal maturation, elimination of furosemide may be delayed. Drug metabolism is also reduced in infants with impaired glucuronidation capacity. The terminal elimination half-life is less than 12 hours in fetuses older than 33 weeks post-conception. In infants older than 2 months, terminal clearance is similar to that in adult patients.

Clinical characteristics.

Indications.

• Edema in chronic congestive heart failure (if treatment with diuretics is required).
• Edema in nephrotic syndrome (if treatment with diuretics is required).
• Edema in chronic renal failure.
• Acute renal failure, including in pregnant women or during childbirth.
• Edema in liver diseases (if necessary, to supplement treatment with aldosterone antagonists).
• Arterial hypertension.

Contraindications.

• Hypersensitivity to furosemide or to any of the excipients of the medicinal product. Cross-sensitivity to furosemide may occur in patients with allergy to sulfonamides (e.g., sulfonamide antibiotics or sulfonylureas).
• Hypovolemia or dehydration.
• Renal failure manifesting as anuria unresponsive to furosemide therapy.
• Renal failure due to poisoning with nephrotoxic or hepatotoxic agents.
• Severe hypokalemia.
• Severe hyponatremia.
• Pre-comatose and comatose states associated with hepatic encephalopathy.
• Addison's disease.
• Digitalis intoxication.
• Breastfeeding.

Interaction with other medicinal products and other forms of interaction.

Not recommended combinations.

In some cases, administration of furosemide within 24 hours after use of chloral hydrate may cause flushing, excessive sweating, agitation, nausea, increased blood pressure, and tachycardia. Therefore, concomitant use of furosemide and chloral hydrate is not recommended.

Furosemide may potentiate the ototoxicity of aminoglycosides and other ototoxic medicinal products. Since this may lead to irreversible damage, these medicinal products should not be used concomitantly with furosemide. Furosemide may reduce serum levels of vancomycin.

Concomitant use of furosemide with antihistamine medicinal products may cause hypokalemia and increase the risk of cardiac toxicity.

Combinations requiring precautions.

When cisplatin and furosemide are used concomitantly, there is a risk of ototoxic effects. In addition, the nephrotoxicity of cisplatin may be enhanced if furosemide is not administered in low doses (e.g., 40 mg in patients with normal renal function) and with a positive fluid balance, as used to achieve forced diuresis during cisplatin therapy.

Oral furosemide and sucralfate should not be administered within less than 2 hours of each other, as sucralfate reduces intestinal absorption of furosemide, thereby diminishing its effect.

Furosemide reduces the excretion of lithium salts and may lead to increased serum lithium levels, resulting in an increased risk of lithium toxicity, including a higher risk of cardiotoxic and neurotoxic effects. Therefore, careful monitoring of serum lithium levels is recommended in patients receiving this combination therapy.

Patients receiving diuretics may experience severe arterial hypotension and worsening of renal function, including renal failure, particularly upon initial administration of an angiotensin-converting enzyme inhibitor (ACE inhibitor) or angiotensin II receptor antagonist, or upon initial administration of these medicinal products at increased doses. Consideration should be given to whether furosemide should be temporarily discontinued or at least its dose reduced 3 days prior to initiating treatment, or increasing the dose of the ACE inhibitor or angiotensin II receptor antagonist.

Antipsychotics: Furosemide-induced hypokalemia increases the risk of cardiac toxicity. Avoid concomitant use with pimozide; increased risk of ventricular arrhythmias when used with * amisulpride* or sertindole. Enhanced hypotensive effect when used with phenothiazine derivatives (chlorpromazine).

Risperidone: Exercise caution and carefully weigh the risks and benefits before deciding on combined therapy or concomitant use with furosemide or other potent diuretics.

Levothyroxine: High doses of furosemide may suppress thyroid hormone binding to carrier proteins, thus initially causing a transient increase in free fractions of thyroid hormones, followed by an absolute decrease in total thyroid hormone levels.

Thyroid hormone levels should be monitored.

Combinations with warnings.

Concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid, may reduce the efficacy of furosemide. In patients with dehydration or hypovolemia, NSAIDs may lead to acute heart failure. Salicylate toxicity may be increased under the influence of furosemide.

Indomethacin and ketorolac may antagonize the effects of furosemide. In patients with dehydration or hypovolemia, NSAIDs may cause acute renal failure.

Reduced efficacy of furosemide may occur following concomitant use with phenytoin.

Increased risk of hyponatremia when the medicinal product is taken together with carbamazepine.

The use of corticosteroids, carbenoxolone, liquorice root in high doses and prolonged use of laxatives increases the risk of hypokalemia.

Certain electrolyte imbalances (such as hypokalemia, hypomagnesemia) may enhance the toxicity of certain other medicinal products (e.g., digitalis preparations and medicinal products causing QT interval prolongation syndrome).

If antihypertensive agents, diuretics, or other medicinal products that lower blood pressure are used concomitantly with furosemide, an additional reduction in blood pressure (BP) should be expected.

Probenecid, methotrexate, and other medicinal products that, like furosemide, undergo significant tubular secretion in the kidneys, may reduce the effectiveness of furosemide. Conversely, furosemide may reduce renal excretion of these medicinal products. Concurrent use of high doses (of both furosemide and other medicinal products) may lead to increased serum levels and an increased risk of adverse effects caused by furosemide or concomitant therapy.

The efficacy of antidiabetic agents and sympathomimetics that have the property of increasing blood pressure (e.g., epinephrine, norepinephrine) may be reduced.

The action of curare-like muscle relaxants or theophylline may be enhanced.

The harmful effect of nephrotoxic medicinal products on the kidneys may be intensified.

Renal dysfunction may develop in patients receiving concomitant therapy with furosemide and high doses of certain cephalosporins.

Concomitant use of cyclosporine A and furosemide is associated with an increased risk of gouty arthritis secondary to hyperuricemia caused by furosemide and impaired renal excretion of urates caused by cyclosporine.

Aliskiren reduces plasma concentrations of orally administered furosemide. Reduced effect of furosemide may be observed in patients receiving both aliskiren and furosemide orally; therefore, monitoring for reduced diuretic effect is recommended, and dosage adjustment should be made accordingly.

In patients at high risk of nephropathy due to radiocontrast agents, treatment with furosemide has been associated with a higher frequency of worsening renal function after radiocontrast administration compared to patients at high risk who received only intravenous hydration prior to radiocontrast administration.

Consumption of alcohol – increases the risk of potassium loss.

Special precautions for use.

During treatment with furosemide, continuous urine flow must be ensured. Patients with partial obstruction of urine outflow require close monitoring, especially during the initial stages of therapy.

Treatment with furosemide requires regular medical supervision. Particularly careful monitoring is necessary in:

• Patients with arterial hypotension;
• Patients at high risk of significant reduction in arterial pressure, such as those with severe coronary or cerebral vascular stenosis;
• Patients with latent or overt diabetes mellitus;
• Patients with gout;
• Patients with hepatorenal syndrome, i.e., functional renal insufficiency associated with severe liver disease;
• Patients with hypoproteinaemia associated with nephrotic syndrome (the effect of furosemide may be reduced while ototoxicity may be potentiated); careful dose titration is required;
• Premature infants (risk of developing nephrocalcinosis/nephrolithiasis); monitoring of renal function and renal ultrasound are required.

Regular monitoring of serum sodium, potassium, and creatinine levels is recommended during furosemide therapy. Patients at high risk of developing electrolyte imbalances or those with significant additional fluid loss (e.g., due to vomiting, diarrhoea, or profuse sweating) require particularly close monitoring. Hypovolaemia or dehydration, as well as any significant disturbances in electrolyte and acid-base balance, should be corrected. This may require temporary discontinuation of furosemide therapy.

Factors influencing the development of electrolyte imbalances include underlying diseases (e.g., liver cirrhosis, heart failure), concomitant use of medicinal products, and diet. For example, potassium deficiency may occur as a result of vomiting or diarrhoea.

When administering furosemide, it is advisable to recommend the patient to consume potassium-rich foods (e.g., baked potatoes, bananas, tomatoes, spinach, dried fruits). It should be remembered that potassium supplementation may be required during furosemide therapy.

Concomitant use with risperidone. In placebo-controlled studies of risperidone involving elderly patients with dementia, a higher mortality rate was observed in patients receiving both furosemide and risperidone compared to those receiving risperidone alone or furosemide alone.

Caution and careful assessment of risks and benefits are required before deciding to use this combination or concurrent treatment with other potent diuretics. Dehydration should be avoided.

The medicinal product should be discontinued prior to performing a glucose tolerance test.

Important information about excipients.

The medicinal product contains lactose monohydrate; therefore, patients with known intolerance to certain sugars should consult their physician before taking this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy. Furosemide crosses the placental barrier. The drug should not be administered during pregnancy except in cases of clear medical necessity. Treatment during pregnancy requires monitoring of fetal growth.

Breastfeeding period. Furosemide passes into breast milk and may suppress lactation. Women should discontinue breastfeeding during furosemide treatment.

Ability to influence the speed of reaction when driving vehicles or operating machinery.

Some adverse effects (e.g., unexpected, significant reduction in blood pressure) may impair a patient's ability to concentrate and slow reaction time; therefore, patients should refrain from driving vehicles or operating machinery during treatment.

Method of Administration and Dosage.

The dosage regimen is determined individually by a physician depending on the severity of water-electrolyte imbalance, glomerular filtration rate, and the patient's clinical condition. The medicinal product is generally taken on an empty stomach.

The maximum total daily dose of Furosemide-Darnitsya for adults should not exceed 1500 mg.

Special Dosage Recommendations for Adults.

For edema due to chronic congestive heart failure: The recommended initial oral dose is 40 mg once daily. The dose may be adjusted as needed according to the patient's therapeutic response. It is recommended to divide the daily dose into 2 or 3 administrations.

For edema due to chronic renal failure: The dose should be carefully titrated to ensure gradual initial fluid loss. In adults, this means administering a dose that results in a daily weight reduction of approximately 2 kg (approximately 280 mmol Na+). The recommended initial oral daily dose is 40–80 mg. The dose may be adjusted as needed based on the patient's therapeutic response. The total daily dose may be given as a single dose or divided into 2 doses. For patients undergoing hemodialysis, the total daily oral dose ranges from 250 to 1500 mg.

For acute renal failure: Prior to initiating furosemide therapy, hypovolemia, hypotension, and significant electrolyte and acid-base imbalances should be corrected. Transition from intravenous to oral administration should be performed as soon as possible.

For edema associated with nephrotic syndrome: The recommended initial oral dose is 40–80 mg per day. The dose may be adjusted as needed according to the patient's therapeutic response. The total daily dose may be administered as a single dose or divided into several doses.

For edema due to liver disease: Furosemide-Darnitsya is prescribed as an adjunct to therapy with aldosterone antagonists when treatment with aldosterone antagonists alone is insufficient. To prevent complications such as orthostatic hypotension or disturbances in electrolyte and acid-base balance, the dose should be carefully titrated to ensure gradual initial fluid loss. In adult patients, this means administering a dose that results in a daily weight reduction of approximately 0.5 kg. The recommended initial oral daily dose is 40–80 mg. The dose may be adjusted as needed according to the patient's therapeutic response. The total daily dose may be administered as a single dose or divided into several doses.

For children unable to take the oral dosage form (e.g., premature infants and newborns), parenteral formulations should be considered. The recommended oral dose of furosemide in children is 2 mg/kg of body weight; however, the maximum daily dose should not exceed 40 mg. The dose should be adjusted according to body weight.

Children.

This medicinal product in the given dosage form is indicated for children with body weight exceeding 10 kg (see section "Method of Administration and Dosage").

Overdose.

Symptoms: The clinical picture of acute or chronic overdose primarily depends on the degree and consequences of fluid and electrolyte loss, and includes signs such as hypovolemia, dehydration, hemoconcentration, cardiac arrhythmias (including atrioventricular block and ventricular fibrillation). Symptoms of these disturbances may include severe arterial hypotension (progressing to shock), acute renal failure, thrombosis, delirium, peripheral paralysis, apathy, and confusion.

In patients with cirrhosis, overdose may lead to hepatic encephalopathy.

Treatment: There are no specific antidotes for furosemide. Treatment is symptomatic and should focus on fluid replacement and correction of electrolyte imbalances.

Adverse Reactions

The following classification is used to assess the frequency of adverse reactions: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10,000 and < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from the available data).

Eye disorders:

Rare: visual disturbances, decreased visual acuity, blurred vision.

Ear and labyrinth disorders:

Uncommon: hearing disturbances, usually transient, particularly in patients with renal insufficiency, hypoproteinaemia (e.g., in nephrotic syndrome), and/or in cases of too rapid intravenous administration of furosemide. Cases of deafness, sometimes irreversible, have been reported following oral administration or intravenous injection of furosemide.

Rare: tinnitus.

Gastrointestinal disorders:

Uncommon: nausea;

Rare: vomiting, diarrhoea;

Very rare: acute pancreatitis;

Frequency not known: dry mouth, intestinal motility disorders, constipation.

Hepatobiliary disorders:

Very rare: cholestasis, increased transaminase levels.

Renal and urinary disorders:

Common: increased urine volume;

Rare: tubulointerstitial nephritis;

Frequency not known:

• increased urinary sodium excretion;
• increased urinary chloride excretion, urinary retention (in patients with partial obstruction to urinary outflow);
• nephrocalcinosis/nephrolithiasis in premature infants;
• renal failure;
• urinary incontinence;
• increased blood creatinine levels.

Metabolism and nutrition disorders:

Very common: electrolyte imbalance (including with clinical manifestations), dehydration and hypovolemia, particularly in elderly patients, increased blood triglyceride levels;

Common: hyponatremia, hypochloremia, hypokalemia, increased blood cholesterol levels, increased blood urea levels, gout attacks;

Uncommon: decreased glucose tolerance, progression of latent diabetes mellitus to overt diabetes, tetany;

Frequency not known: hypocalcemia, hypomagnesemia, increased blood uric acid levels, metabolic alkalosis, pseudobartter syndrome due to incorrect and/or prolonged use of furosemide.*

Nervous system disorders:

Rare: paraesthesia, headache;

Common: hepatic encephalopathy in patients with hepatocellular insufficiency;

Frequency not known: dizziness, loss of consciousness (due to symptomatic hypotension).

Cardiovascular system disorders:

Very common (when administered as intravenous infusion): hypotension, including orthostatic arterial hypotension;

Rare: vasculitis;

Frequency not known: thrombosis.

Blood and lymphatic system disorders:

Common: hemoconcentration;

Uncommon: thrombocytopenia;

Rare: leukopenia, eosinophilia;

Very rare: agranulocytosis, aplastic anemia, or hemolytic anemia.

Immune system disorders:

Rare: severe anaphylactic or anaphylactoid reactions (including those accompanied by shock);

Frequency not known: possible exacerbation or activation of systemic lupus erythematosus.

Skin and subcutaneous tissue disorders:

Uncommon: pruritus, urticaria, rash, bullous dermatitis, erythema multiforme, pemphigoid, exfoliative dermatitis, purpura, photosensitivity reaction;

Frequency not known: Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, and DRESS syndrome (drug reaction with eosinophilia and systemic symptoms).

Musculoskeletal and connective tissue disorders:

Rare: muscle weakness, muscle cramps;

Frequency not known: rhabdomyolysis, often on the background of severe hypokalemia (see section "Contraindications").

General disorders and administration site conditions:

Rare: increased body temperature.

Congenital and hereditary/genetic disorders:

Frequency not known: increased risk of patent ductus arteriosus not closing if furosemide is administered to premature infants during the first weeks of life.

*Potassium deficiency manifests with neuromuscular symptoms (muscle weakness, paralysis), gastrointestinal symptoms (vomiting, constipation, and flatulence), renal symptoms (polyuria), and cardiac symptoms. Severe hypokalemia may lead to coma.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions via the national reporting system.

Shelf life. 3 years.

Storage conditions.

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

Keep out of the reach and sight of children.

Packaging.

10 tablets in a blister pack; 5 blister packs in a carton.

Prescription category. Prescription only.

Manufacturer.

JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's address and place of business.

13, Boryspilska Street, Kyiv, 02093, Ukraine.