INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FUROSEMIDE (FUROSEMIDE)

Composition:

Active substance: furosemide.

1 ml of solution contains furosemide 10 mg;

Excipients: sodium chloride, sodium hydroxide, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless or slightly yellowish liquid.

Pharmacotherapeutic group. High-ceiling diuretics. Sulfonamide agents.

ATC code C03CA01.

Pharmacological properties.

Pharmacodynamics.

Furosemide is a rapidly acting loop diuretic that produces a relatively strong and short-lived 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. Thus, the saluretic efficacy of furosemide 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 excretion of sodium may reach up to 35% of glomerular filtration of sodium. Secondary effects of increased sodium excretion include enhanced urine output (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 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 reactivity to catecholamines, which is elevated 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 vasoconstrictive agents.

The onset of diuretic effect occurs within 15 minutes after intravenous administration of the drug.

Dose-dependent increases in diuresis and natriuresis have been observed in healthy volunteers receiving furosemide at doses of 10–100 mg. The duration of effect in healthy volunteers is approximately 3 hours after intravenous administration of 20 mg furosemide.

In patients, the relationship between intratubular concentrations of unbound (free) furosemide (determined based on the rate of furosemide excretion in urine) and natriuretic effect follows a sigmoidal curve, with a minimal effective rate of furosemide excretion of approximately 10 micrograms per minute. Therefore, continuous infusion of furosemide is more effective than repeated bolus injections. Moreover, beyond a certain bolus dose, no significant increase in effect is observed. The effect of furosemide is reduced if tubular secretion is impaired or if the drug binds to albumin within the tubules.

Pharmacokinetics.

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

Furosemide is excreted primarily in unchanged form via secretion into the proximal tubule. After intravenous administration, 60% to 70% of the dose is excreted in this manner. The metabolite of furosemide—glucuronide—accounts for 10–20% of substances found in urine. The remainder is excreted in feces, likely via biliary secretion.

The terminal half-life of furosemide after intravenous administration is approximately 1 to 1.5 hours.

Furosemide crosses into breast milk, crosses the placental barrier, and slowly reaches the fetus. Furosemide is detected in the fetus or newborn at the same concentrations as in the mother.

Patients with kidney disease. In renal insufficiency, elimination of furosemide is slowed and the 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 impaired tubular secretion.

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

Patients with hepatic insufficiency. In hepatic insufficiency, the 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.

Patients with congestive heart failure, severe arterial hypertension, and 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 term infants. Depending on the degree of renal maturation, elimination of furosemide may be delayed. Metabolism of the drug is also reduced if infants have impaired glucuronidation capacity. The terminal half-life is less than 12 hours in fetuses from 33 weeks post-conception. In infants aged 2 months, terminal clearance is similar to that in adult patients.

Clinical characteristics.

Indications.

Edema in chronic congestive heart failure (when treatment with diuretics is required).

Edema in acute congestive heart failure.

Edema in chronic renal failure.

Acute renal failure, including in pregnant women or during childbirth.

Edema in liver diseases (when necessary, as adjunctive therapy with aldosterone antagonists).

Hypertensive crisis (as supportive therapy).

Support of forced diuresis.

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 with anuria, if no therapeutic response to furosemide is observed.

Renal failure due to poisoning with nephrotoxic or hepatotoxic medicinal products.

Severe hypokalemia.

Severe hyponatremia.

Pre-comatose or comatose states associated with hepatic encephalopathy. Breastfeeding.

For use during pregnancy, see section "Use during pregnancy or breastfeeding".

Interaction with other medicinal products and other forms of interaction.

Not recommended combinations.

In some cases, intravenous administration of furosemide within 24 hours after chloral hydrate may cause flushing, excessive sweating, restlessness, 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 be used concomitantly with furosemide only when there is a clear medical need.

Combinations requiring precautions.

When cisplatin and furosemide are used concomitantly, there is a risk of ototoxic effects. In addition, nephrotoxicity of cisplatin may be enhanced if furosemide is used in high doses (e.g., 40 mg for patients with normal renal function) during cisplatin therapy to achieve forced diuresis, particularly in the presence of positive fluid balance (fluid intake exceeds fluid output).

Furosemide reduces lithium excretion 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 such combination therapy.

Patients receiving diuretics may experience severe hypotension and worsening of renal function, including renal failure, particularly upon initial administration of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor antagonist, or upon first administration of increased doses of these medicinal products. Consideration should be given to temporarily discontinuing furosemide or at least reducing its dose three days before initiating therapy with an ACE inhibitor or angiotensin II receptor antagonist, or before increasing the dose of these medicinal products.

Risperidone: caution and careful assessment of risks and benefits should be exercised before deciding on concomitant use with furosemide or other potent diuretics. See section "Special warnings and precautions for use" regarding increased mortality in elderly patients with dementia who received risperidone and furosemide concomitantly. Levothyroxine: high doses of furosemide may inhibit the binding of thyroid hormones to carrier proteins, thus initially causing a transient increase in free fractions of thyroid hormones, followed by a general decrease in levels of all thyroid hormone fractions. Thyroid hormone levels should be monitored.

Combinations with warnings.

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

Reduced efficacy of furosemide may occur when used concomitantly with phenytoin.

Administration of corticosteroids, carbenoxolone, licorice root in high doses, and prolonged use of laxatives increases the risk of hypokalemia. Some electrolyte imbalances (such as hypokalemia, hypomagnesemia) may enhance the toxicity of certain other medicinal products (e.g., digitalis glycosides and drugs causing QT interval prolongation syndrome). When antihypertensive drugs, diuretics, or other agents with blood pressure-lowering properties are used concomitantly with furosemide, an additional reduction in blood pressure should be expected.

Probenecid, methotrexate, and other medicinal products, like furosemide, subject to significant tubular secretion in the kidneys, may reduce the efficacy of furosemide. Conversely, furosemide may reduce renal excretion of these medicinal products. Treatment with high doses (both furosemide and other medicinal products) may lead to increased serum levels and an increased risk of adverse effects. Efficacy of antidiabetic agents and sympathomimetics with blood pressure-raising properties (e.g., adrenaline, noradrenaline) may be reduced. The effect 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 furosemide concomitantly with 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 due to cyclosporine. In patients at high risk of nephropathy due to administration of radiographic contrast agents, treatment with furosemide was associated with a higher frequency of worsening renal function after contrast administration compared to patients at high risk who received only intravenous hydration prior to contrast administration.

Special precautions for use.

During administration of furosemide, a continuous urine flow should be ensured. In patients with partial obstruction of urine outflow (e.g., patients with impaired bladder emptying, benign prostatic hyperplasia, or urethral stricture), increased urine production may cause or exacerbate symptoms related to such conditions. Therefore, these patients require close monitoring, especially during the initial stages of treatment. Treatment with furosemide requires continuous medical supervision. Particular careful monitoring is necessary in the following patient groups:

Patients with arterial hypotension;
Patients at particular risk due to significant reduction in arterial pressure, for example, patients with severe coronary artery stenosis or stenosis of blood vessels supplying the brain;
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, particularly 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 ultrasonography should be performed.

In general, during furosemide therapy, serum levels of sodium, potassium, and creatinine should be monitored regularly. Patients at high risk of developing 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.

Concomitant use with risperidone. In placebo-controlled trials of risperidone involving elderly patients with dementia, a higher mortality rate was observed in patients receiving furosemide concomitantly with risperidone (7.3%; mean age 89 years, age range 75–97 years), compared to patients receiving risperidone alone (3.1%; mean age 84 years, age range 70–96 years) or furosemide alone (4.1%; mean age 80 years, age range 67–90 years). Concomitant use of risperidone with other diuretics (mostly low-dose thiazide diuretics) did not result in such an effect. No pathophysiological mechanism has been identified to explain these findings, and no consistent patterns regarding causes of death in patients were observed. However, caution should be exercised and risks versus benefits carefully weighed before deciding to use this combination or concomitant treatment with other potent diuretics. Regardless of treatment, dehydration was a common risk factor for mortality; therefore, dehydration should be avoided in elderly patients with dementia (see section "Contraindications"). There is a possibility of exacerbation or activation of systemic lupus erythematosus.

Concomitant intake of alcohol and the medicinal product Furosemide should be avoided.

Use during pregnancy or breastfeeding.

Pregnancy. Furosemide crosses the placental barrier. It should not be administered during pregnancy except when treatment is required for life-threatening conditions. Treatment with furosemide during pregnancy requires monitoring of fetal growth and development.

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

Ability to influence reaction speed when driving or operating machinery.

When using the medicinal product Furosemide, certain adverse effects (e.g., unexpected marked decrease 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 is determined individually by a physician depending on the severity of water-electrolyte imbalances, glomerular filtration rate, and the patient's clinical condition. During treatment, water-electrolyte parameters should be adjusted according to diuresis and the patient’s overall clinical dynamics.

Furosemide should be administered intravenously only when oral administration is inappropriate or ineffective (e.g., due to impaired intestinal absorption) or when a rapid effect is required. When intravenous therapy is used, a prompt transition to oral furosemide should be made as soon as possible. For optimal efficacy and to counteract compensatory mechanisms, continuous intravenous infusion of furosemide is generally preferred over repeated bolus injections.

When continuous infusion of furosemide is not feasible for further treatment after one or several bolus doses, a subsequent treatment regimen using lower doses administered at short intervals (approximately every 4 hours) is preferred over larger bolus doses given at longer intervals.

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

For children, the recommended dose for parenteral administration is 1 mg/kg body weight, but the maximum daily dose should not exceed 20 mg.

Dosage Recommendations.

The following dosage recommendations apply to adults.

Edema in chronic congestive heart failure. The recommended initial dose is 20 to 50 mg daily. The dose may be adjusted according to the patient’s therapeutic response. The daily dose should be divided into 2 or 3 administrations.

Edema in acute congestive heart failure. The recommended initial dose is 20 to 40 mg administered as a bolus injection. The dose may be adjusted according to the patient’s therapeutic response. 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. In patients with chronic renal failure, the dose should be carefully titrated to ensure gradual initial fluid loss. For adult patients, this means administering a dose that results in a daily body weight reduction of approximately 2 kg (approximately 280 mmol Na+).

In case of intravenous administration, the furosemide dose can be determined as follows: treatment starts with a continuous intravenous infusion of 0.1 mg per minute, and the infusion rate is increased every 30 minutes depending on the patient’s response.

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

A prompt transition from intravenous to oral administration is recommended.

The recommended initial dose is 40 mg administered as an intravenous injection. If this dose does not produce the desired increase in fluid excretion, continuous intravenous infusion of furosemide may be used, starting at a rate of 50 to 100 mg per hour.

Edema in liver disease. Furosemide is prescribed as an adjunct to aldosterone antagonist therapy 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. For adult patients, this means administering a dose that results in a daily body weight reduction of approximately 0.5 kg. If intravenous administration is absolutely necessary, the initial single dose is 20–40 mg.

Hypertensive crisis. The recommended initial dose of 20 to 40 mg is administered as an intravenous bolus injection. The dose may be adjusted according to the patient’s therapeutic response.

Forced diuresis in poisoning. Furosemide is administered intravenously in addition to electrolyte solution infusions. The dose depends on the patient’s response to furosemide. Fluid and electrolyte losses should be monitored and managed before and during treatment. In cases of poisoning with acidic or alkaline substances, fluid excretion can be enhanced by alkalinizing or acidifying the urine, respectively. The recommended initial dose is 20 to 40 mg administered intravenously.

Special Administration Instructions.

Intravenous injection/infusion: When administered intravenously, furosemide should be given as a slow injection or infusion at a rate not exceeding 4 mg per minute. In patients with severe hepatic dysfunction (serum creatinine > 5 mg/dL), the infusion rate should not exceed 2.5 mg per minute. Intramuscular injection: Intramuscular administration should be limited to exceptional cases when oral and intravenous routes are inappropriate. It should be noted that intramuscular administration is not indicated for the treatment of acute conditions such as pulmonary edema.

Furosemide infusion must not be administered simultaneously with other medicinal products!

Furosemide is a solution with a pH ranging from 8.8 to 9.8 and has no buffering capacity. Therefore, the active ingredient may precipitate at pH values below 7. When diluting the solution, ensure that the pH of the diluted solution remains between slightly alkaline and neutral.

0.9% sodium chloride solution may be used as a diluent. Diluted solutions should be used as soon as possible.

Children.

The dose for children should be adjusted according to body weight (see section "Dosage and Administration").

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, and cardiac arrhythmias (including atrioventricular block and ventricular fibrillation). Symptoms of these disturbances 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. Clinically significant disturbances in water and electrolyte balance require correction. Along with prevention and treatment of serious complications caused by such imbalances and other systemic effects, these corrective measures may necessitate comprehensive and specialized intensive monitoring and therapeutic interventions.

Adverse Reactions

The frequency of adverse reactions was determined based on clinical studies in which furosemide was administered to a total of 1387 patients at any dose and for any indication. If the same adverse drug reaction was categorized into different frequency categories in different sources, the highest frequency category was selected.

Frequency categories defined by the Council for International Organizations of Medical Sciences (CIOMS):

very common: ≥ 10 %;
common: ≥ 1 % — < 10 %;
uncommon: ≥ 0.1 % — < 1 %;
rare: ≥ 0.01 % — < 0.1 %;
very rare: < 0.01 %;
frequency not known — cannot be estimated from available data.

Metabolism and nutritional disorders (see section "Special warnings and precautions for use"):

Very common: electrolyte imbalance (including symptomatic), dehydration, hypovolemia, especially in elderly patients, increased blood creatinine levels, increased blood triglyceride levels.

Common: hyponatremia, hypochloremia, hypokalemia, increased blood cholesterol levels, increased blood uric acid levels and gout attacks.

Uncommon: impaired glucose tolerance. Latent diabetes mellitus may become manifest (see section "Special warnings and precautions for use").

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

Vascular disorders:

Very common (when administered as intravenous infusion): arterial hypotension, including orthostatic (see section "Special warnings and precautions for use").

Rare: vasculitis.

Frequency not known: thrombosis.

Gastrointestinal disorders:

Uncommon: nausea.

Rare: vomiting, diarrhea.

Very rare: acute pancreatitis.

Hepatobiliary and biliary disorders:

Very rare: cholestasis, increased transaminase levels.

Auditory and vestibular disorders:

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

Rare: tinnitus.

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 (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), lichenoid reactions.

Immune system disorders:

Rare: severe anaphylactic or anaphylactoid reactions (e.g., associated with shock).

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

Renal and urinary disorders:

Common: increased urine volume.

Rare: tubulointerstitial nephritis.

Frequency not known:

increased urinary sodium levels, increased urinary chloride levels, urinary retention (in patients with partial obstruction of urinary outflow, see section "Special warnings and precautions for use");
nephrocalcinosis/nephrolithiasis in premature infants (see section "Special warnings and precautions for use");
renal failure (see section "Interaction with other medicinal products and other forms of interaction").

Nervous system disorders:

Rare: paresthesia.

Common: hepatic encephalopathy in patients with hepatocellular insufficiency (see section "Contraindications").

Frequency not known: dizziness, fainting or loss of consciousness, headache.

Blood and lymphatic system disorders:

Common: hemoconcentration.

Uncommon: thrombocytopenia.

Rare: leukopenia, eosinophilia.

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

Musculoskeletal and connective tissue disorders:

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

Congenital and hereditary/genetic disorders:

Frequency not known: increased risk of failure of arterial duct closure if furosemide is administered to premature infants during the first weeks of life.

General disorders and administration site conditions:

Frequency not known: local reactions after intramuscular injection, e.g., pain.

Rare: increased body temperature.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after marketing authorization of a medicinal product is important. It allows continuous monitoring of the benefit-risk ratio of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions via the national pharmacovigilance system.

Shelf life. 3 years.

Storage conditions.

Store in original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Incompatibilities.

Furosemide may be mixed with other medicinal products only with the diluent (0.9 % sodium chloride solution) specified in the section "Dosage and method of administration".

Packaging.

2 ml in ampoules, 5 ampoules in a blister pack, 2 blister packs in a carton.

Prescription status. Prescription only.

Manufacturer. Subsidiary enterprise "FARMATREYD"

Manufacturer's address and place of business.

82100, Drohobych, Lviv region, Sambirska St., 85.