Furosemide

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FUROSEMIDE

Composition:

Active substance: furosemide;

1 tablet contains 40 mg of furosemide;

Excipients: lactose monohydrate, potato starch, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white tablets with a beige tint.

Pharmacotherapeutic group.

High-ceiling diuretics. Sulfonamide agents. ATC code C03CA01.

Pharmacological properties.

Pharmacodynamics.

Furosemide is a rapid-acting loop diuretic that produces a relatively strong and short-term diuretic effect. Furosemide blocks the Na+K+2Cl- cotransporter located in the basolateral membranes of cells in the thick ascending limb of Henle's loop. The efficacy of furosemide's saluretic action thus depends on whether the drug reaches 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 sodium excretion may reach up to 35% of filtered sodium. Secondary effects of increased sodium excretion include enhanced urine output (due to osmotically bound water) and increased distal tubular potassium secretion. Excretion of calcium and magnesium ions is also increased.

Furosemide causes dose-dependent activation of the renin-angiotensin-aldosterone system. In heart failure, furosemide leads to acute reduction of cardiac preload (by constricting capacitance veins). This early vascular effect is prostaglandin-mediated and requires adequate renal function with activation of the renin-angiotensin system and intact prostaglandin synthesis. Additionally, due to its inherent natriuretic effect, furosemide reduces vascular responsiveness to catecholamines, which is heightened in patients with arterial hypertension.

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

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

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 diminished tubular secretion or when the drug interacts with albumin within the tubules.

Pharmacokinetics.

Furosemide is rapidly absorbed from the gastrointestinal tract. The time to maximum absorption is between 1 and 1.5 hours. Absorption of furosemide shows considerable individual variability.

The bioavailability of furosemide in healthy volunteers is approximately 50–70% for tablets. In patients, bioavailability is influenced by various factors, including underlying diseases. Bioavailability may decrease to as low as 30% (e.g., in nephrotic syndrome).

Food intake taken simultaneously with furosemide may affect its absorption.

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

Furosemide is highly bound (>98%) to plasma proteins, particularly albumin.

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

The metabolite of furosemide—furosemide glucuronide—accounts for 10–20% of the substances found in urine. The remainder 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 concentrations similar to those in the mother.

Renal disease. In renal insufficiency, elimination of furosemide is slowed and elimination half-life is prolonged; 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, furosemide efficacy is reduced in these patients due to binding with intratubular albumin and diminished tubular secretion.

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

Hepatic insufficiency. In hepatic insufficiency, the half-life of furosemide is increased by 30–90%, primarily due to a larger volume of distribution. It should also be noted that in this patient group, there is considerable variability in all pharmacokinetic parameters.

Congestive heart failure, severe arterial hypertension, elderly patients. Elimination of furosemide is slowed due to reduced renal function in patients with congestive heart failure, severe arterial hypertension, and in elderly patients.

Preterm and full-term neonates. Depending on the degree of renal maturity, elimination of furosemide may be delayed. Metabolism of furosemide is also reduced if neonates have impaired glucuronidation capacity. Terminal half-life is less than 12 hours in fetuses from 33 weeks gestational age. In infants aged 2 months, terminal clearance is similar to that in adults.

Clinical characteristics.

Indications.

• Edema in chronic congestive heart failure (if treatment with diuretics is required).
• Edema in chronic renal failure.
• Acute renal failure, including in pregnant women or during labor.
• Edema in nephrotic syndrome (if treatment with diuretics is required).
• Edema in liver diseases (if necessary – as an adjunct to 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).
• Patients with hypovolemia or dehydration.
• Patients with renal failure due to anuria unresponsive to furosemide.
• Patients with renal failure caused by nephrotoxic or hepatotoxic agents.
• Patients with severe hypokalemia.
• Patients with severe hyponatremia.
• Patients with pre-comatose or comatose states associated with hepatic encephalopathy.

Interaction with other medicinal products and other forms of interaction.

Not recommended combinations

In some cases, administration of furosemide within 24 hours after 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 simultaneously with furosemide.

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 decreasing 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 of lithium. Therefore, careful monitoring of lithium levels is recommended in patients receiving this combination therapy.

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

Risperidone: caution should be exercised and the risk and benefit carefully weighed before deciding on combination therapy or concomitant use with furosemide or other potent diuretics.

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

Thyroid hormone levels should be monitored.

Combinations to be considered

Concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid, may reduce the effect of furosemide. In patients with dehydration or hypovolemia, NSAIDs may lead to acute heart failure. Under the influence of furosemide, salicylate toxicity may increase.

Reduced effectiveness of furosemide may occur after concomitant use of phenytoin.

Aliskiren reduces the plasma concentration of orally administered furosemide. A reduction in the effect of furosemide may be observed in patients taking both aliskiren and oral furosemide; therefore, monitoring for reduced diuretic effect is recommended, and the dose should be adjusted accordingly.

The use of corticosteroids, carbenoxolone, licorice root in high doses, and prolonged use of laxatives may increase the risk of developing hypokalemia.

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

If antihypertensive agents, diuretics, or other medicinal products that have the property of lowering blood pressure are used concomitantly with furosemide, a further reduction in blood pressure 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. Treatment with high doses (of both furosemide and other medicinal products) may lead to increased serum levels and increased risk of adverse effects caused by furosemide or concomitant therapy.

The effectiveness 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.

In patients at high risk of developing contrast-induced nephropathy, treatment with furosemide was associated with a higher frequency of worsening renal function after administration of contrast agents compared to patients at high risk who received only intravenous hydration prior to contrast agent administration.

Special precautions for use

During treatment with this medicinal product, ensure continuous urine drainage. Patients with partial obstruction of urinary outflow require close monitoring, especially during the initial stages of treatment.

Treatment with furosemide requires regular medical supervision.

Particular careful monitoring is necessary in the following cases:

• Patients with arterial hypotension;
• Patients at particular risk of significant reduction in blood pressure, for example, patients with severe coronary or cerebral vascular stenosis;
• Patients with latent or manifest diabetes mellitus;
• Patients with gout;
• Patients with hepatorenal syndrome, i.e., functional renal insufficiency associated with severe liver disease;
• Patients with hypoproteinaemia, for example, associated with nephrotic syndrome (the effect of furosemide may be reduced while ototoxicity may be potentiated); careful dose titration is required;
• Preterm infants (risk of developing nephrocalcinosis/nephrolithiasis); monitoring of renal function and renal ultrasonography are recommended.

Regular monitoring of serum sodium, potassium, and creatinine levels is generally recommended during furosemide therapy. Patients at high risk of electrolyte imbalances or those with significant additional fluid loss (e.g., due to vomiting, diarrhoea, or excessive sweating) require particularly careful 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 pre-existing conditions (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 using this medicinal product, it is advisable to recommend the patient to consume foods rich in potassium (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 elderly patients with dementia, a higher mortality rate has been observed in patients receiving furosemide plus risperidone compared to those receiving risperidone alone or furosemide alone.

Caution should be exercised, and risks and benefits should be carefully weighed before deciding to use this combination or concomitant treatment with other potent diuretics. Dehydration should be avoided.

Use of this medicinal product may lead to exacerbation or activation of systemic lupus erythematosus.

If a patient has known intolerance to certain sugars, consult a physician before taking this medicinal product.

Use during pregnancy or breastfeeding
Furosemide crosses the placental barrier. It should not be administered during pregnancy.

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

Ability to affect reaction speed when driving or operating machinery
Some adverse effects (e.g., unexpected significant drop in blood pressure) may impair a patient's ability to concentrate and reaction speed. Therefore, patients should refrain from driving or operating machinery during treatment.

Dosage and Administration

The dosage regimen should be individually determined by a physician, depending on the severity of water-electrolyte imbalance, glomerular filtration rate, and the patient's overall condition. During treatment, water-electrolyte parameters should be monitored and adjusted according to diuresis and the patient's clinical progress. The drug should generally be administered on an empty stomach.

To achieve the prescribed doses, pharmaceutical forms of furosemide with the appropriate content of active substance should be used.

The recommended maximum daily dose of furosemide for adults is 1500 mg.

Special Dosage Recommendations

Dosing for adults is generally based on the following recommendations.

Edema in Chronic Congestive Heart Failure

The recommended initial oral dose is 20–50 mg per day. The dose may be adjusted according to the patient's therapeutic response. It is recommended to take the daily dose divided into 2 or 3 administrations.

Edema in Chronic Renal Failure

The natriuretic effect of furosemide depends on several factors, including the severity of renal impairment and sodium balance. Therefore, the effective dose cannot be precisely predicted. For patients with chronic renal failure, the dose should be carefully titrated to ensure gradual initial fluid loss. In adult patients, this corresponds to a dose resulting in a daily weight reduction of approximately 2 kg (approximately 280 mmol Na+).

The recommended initial daily oral 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 administered as a single dose or divided into 2 doses. For patients undergoing hemodialysis, the total daily oral dose ranges from 250 to 1500 mg.

In acute renal failure, hypovolemia, arterial hypotension, and significant electrolyte and acid-base imbalances should be corrected before initiating furosemide therapy.

An early transition from intravenous to oral administration is recommended.

Edema in Nephrotic Syndrome

The recommended initial oral dose is 40–80 mg per day. The dose may be adjusted according to the patient's therapeutic response. The total daily dose may be administered as a single dose or divided into several administrations.

Edema in Liver Diseases

Furosemide should be 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 corresponds to a dose resulting in a daily weight reduction of approximately 0.5 kg.

The recommended initial daily oral dose is 20–80 mg. The dose may be adjusted according to the patient's therapeutic response. The total daily dose may be administered as a single dose or divided into several administrations. If intravenous administration is absolutely necessary, the initial single dose is 20–40 mg.

Children. This pharmaceutical form of the drug should be prescribed to children with body weight over 10 kg.

For children, the recommended oral dose of furosemide is 2 mg/kg body weight, but the maximum daily dose should not exceed 40 mg.

For children unable to take the oral formulation, such as premature infants and newborns, parenteral forms should be considered.

Overdose.

Symptoms: The clinical picture of acute or chronic overdose primarily depends on the degree and consequences of electrolyte and fluid loss, and includes signs such as hypovolemia, dehydration, hemoconcentration, cardiac arrhythmias (including AV 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.

Treatment: There are no specific antidotes for furosemide. Treatment is symptomatic.

Adverse Reactions

Metabolic and nutritional disorders: electrolyte imbalance (including with clinical manifestations), dehydration and hypovolemia, particularly in elderly patients, increased blood creatinine levels, increased blood triglyceride levels, hyponatremia, hypochloremia, hypokalemia, increased blood cholesterol levels, increased blood uric acid levels, gout attacks, decreased glucose tolerance (latent diabetes mellitus may progress to overt disease), hypocalcemia, hypomagnesemia, increased blood urea levels, metabolic alkalosis, pseudo-Bartter syndrome due to incorrect and/or prolonged use of furosemide.

Vascular disorders: arterial hypotension, including orthostatic hypotension (when administered as intravenous infusion), vasculitis, thrombosis.

Renal and urinary disorders: increased urine volume, tubulointerstitial nephritis, increased urinary sodium levels, increased urinary chloride levels, urinary retention (in patients with partial obstruction of urinary outflow), nephrocalcinosis/nephrolithiasis in premature infants, renal failure.

Gastrointestinal disorders: nausea, vomiting, diarrhea, acute pancreatitis.

Hepatobiliary disorders: cholestasis, increased transaminase levels.

Ear and labyrinthine disorders: hearing disturbances, which are usually transient, particularly in patients with renal impairment, hypoproteinemia (e.g., in nephrotic syndrome), and/or with too rapid intravenous administration of furosemide; cases of deafness, sometimes irreversible, have been reported after oral or intravenous administration of furosemide, tinnitus.

Skin and subcutaneous tissue disorders: pruritus, urticaria, rash, bullous dermatitis, erythema multiforme, pemphigoid, exfoliative dermatitis, purpura, photosensitivity reaction, Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis (AGEP), and DRESS syndrome (drug reaction with eosinophilia and systemic symptoms).

Immune system disorders: severe anaphylactic or anaphylactoid reactions (including those accompanied by shock), exacerbation or activation of systemic lupus erythematosus.

Nervous system disorders: paresthesia, hepatic encephalopathy in patients with hepatocellular insufficiency.

Blood and lymphatic system disorders: hemoconcentration, thrombocytopenia, leukopenia, eosinophilia, agranulocytosis, aplastic anemia, or hemolytic anemia.

Musculoskeletal and connective tissue disorders: cases of rhabdomyolysis have been reported, often in the setting of severe hypokalemia (see section "Contraindications").

Congenital and hereditary/genetic disorders: increased risk of failure of closure of the arterial duct if furosemide is administered to premature infants during the first weeks of life.

General disorders and administration site conditions: increased body temperature, local reactions, e.g., pain after intramuscular injection.

Shelf life. 4 years.

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

Keep out of reach of children.

Packaging. Tablets, 10x5 in a blister pack in a carton.

Prescription category. Prescription only.

Manufacturer.

Limited Liability Company "Research Plant 'GNCLS'".

Limited Liability Company "FARMEX GROUP".

LIMITED LIABILITY COMPANY "CORPORATION 'ZDOROVIYA'".

Manufacturer's address and place of business.

Ukraine, 61057, Kharkiv region, city of Kharkiv, Vorobiova Street, 8.

(Limited Liability Company "Research Plant 'GNCLS')

Ukraine, 08301, Kyiv region, city of Boryspil, Shevchenka Street, 100.

(Limited Liability Company "FARMEX GROUP")

Ukraine, 61013, Kharkiv region, city of Kharkiv, Shevchenka Street, 22.

(LIMITED LIABILITY COMPANY "CORPORATION 'ZDOROVIYA")