INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FUROSEMIDE

Composition:

Active substance: furosemide;

1 ml of solution contains 10 mg of furosemide;

Excipients: sodium chloride, 1 M sodium hydroxide solution, water for injections.

Pharmaceutical form. Injection solution.

Main physico-chemical properties: clear, colorless or slightly yellowish solution.

Pharmacotherapeutic group. High-ceiling diuretics. Sulfonamide agents.

ATC code C03CA01.

Pharmacological properties.

Pharmacodynamics.

Furosemide is a rapidly acting loop diuretic with a relatively potent 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 the loop of Henle. Thus, the efficacy of furosemide's saluretic action 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 the loop of Henle. As a result, fractional excretion of sodium 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 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 an 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. In addition, due to its inherent natriuretic effect, furosemide reduces vascular smooth muscle responsiveness to stimulation by 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 15 minutes after intravenous administration of furosemide.

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

In patients, the relationship between concentrations of unbound (free) furosemide within the tubular lumen (assessed based on the rate of urinary furosemide excretion) and the natriuretic effect follows a sigmoidal curve, with a minimal effective excretion rate of furosemide 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 diminishes 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 L 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. After intravenous administration, 60–70% of the administered 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 the placental barrier, penetrates into breast milk, 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 failure, elimination of furosemide is delayed 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.

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

Chronic heart failure, severe arterial hypertension, elderly patients. Elimination of furosemide is delayed due to reduced renal function in patients with chronic heart failure, severe arterial hypertension, and in elderly patients.

Preterm and full-term neonates. Depending on the degree of renal maturation, elimination of furosemide may be delayed. Drug metabolism is also reduced if neonates 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 necessary).

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 (if 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.

Patients with allergy to sulfonamides (e.g., sulfonamide antibiotics or sulfonylureas) may exhibit cross-sensitivity to furosemide.

Hypovolemia or dehydration.

Renal failure manifested as anuria, when no therapeutic response to furosemide is observed.

Renal failure due to nephrotoxic or hepatotoxic agents.

Severe hypokalemia.

Severe hyponatremia.

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 concomitantly with furosemide.

Combinations requiring precautions.

Concomitant use of cisplatin and furosemide increases the risk of ototoxic effects. In addition, 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 positive fluid balance, when the drug is used to achieve forced diuresis during cisplatin therapy.

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 this 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 inhibitor (ACE inhibitor) or angiotensin II receptor antagonist, or upon initial administration of increased doses of these medicinal products. Consideration should be given to whether furosemide should be temporarily discontinued or at least the dose of furosemide reduced three days before starting treatment or increasing the dose of an ACE inhibitor or angiotensin II receptor antagonist.

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

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 lead to acute heart failure. Toxicity of salicylates may be increased under the influence of furosemide.

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

Administration 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 enhance the toxicity of certain other medicinal products (e.g., digitalis preparations and drugs causing QT interval prolongation syndrome).

When antihypertensive drugs, diuretics, or other medicinal products 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 that, like furosemide, undergo 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 (of both furosemide and other medicinal products) may lead to increased serum levels of these drugs and an increased risk of adverse effects caused by furosemide or concomitant therapy.

The efficacy of antidiabetic drugs and sympathomimetics with blood pressure-increasing properties (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 nephropathy due to radiographic contrast agents, 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 agents.

Special precautions for use.

During treatment with the drug, a constant urine outflow must be ensured. Patients with partial obstruction of urine flow require close monitoring, especially during the initial stages of treatment.

Treatment with furosemide requires continuous medical supervision.

Particular careful monitoring is necessary for:

Patients with arterial hypotension;
Patients at high risk of significant reduction in arterial pressure, e.g. 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, 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 ultrasound should be performed.

Monitoring of serum sodium, potassium, and creatinine levels is generally 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 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 medication use, and diet. For example, potassium deficiency may occur as a result of vomiting or diarrhoea.

When using the drug, it is advisable to recommend the patient to consume foods rich in potassium (baked potatoes, bananas, tomatoes, spinach, dried fruits). It should be remembered that potassium supplementation may be required during furosemide treatment.

A higher mortality rate has been observed among elderly patients with dementia who received furosemide in combination with risperidone, compared to patients receiving risperidone alone or furosemide alone.

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

Concomitant use of alcohol and furosemide should be avoided.

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e. it is practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy. Furosemide crosses the placental barrier. It should not be administered during pregnancy except when strictly indicated for life-threatening conditions. Treatment with the drug 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 furosemide treatment.

Ability to affect reaction speed when driving or operating machinery. When using the drug, certain adverse effects (e.g. unexpected marked decrease in arterial pressure) may impair the patient's ability to concentrate and reaction speed.

Therefore, during treatment with the drug, patients should refrain from driving or operating machinery.

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. During treatment, water-electrolyte parameters should be monitored and 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 therapy is recommended.

For optimal efficacy and to prevent counter-regulatory mechanisms, continuous intravenous infusion of furosemide is generally preferred over repeated bolus injections.

When continuous infusion of furosemide is not feasible for continued treatment after one or more bolus doses, a 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.

The recommended dose of furosemide for parenteral administration in children is 1 mg/kg body weight; however, the maximum daily dose should not exceed 20 mg.

Dosage Recommendations

Dosage for adults is generally based on the recommendations listed below.

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 divide the daily dose into 2 or 3 administrations.

Edema in acute congestive heart failure. The recommended initial dose is 20–40 mg administered as a bolus injection. The dose may be adjusted based on 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. In adults, this corresponds to a dose resulting in a daily body weight reduction of approximately 2 kg (approximately 280 mmol Na+).

When administered intravenously, the furosemide dose can be determined as follows: treatment begins with a continuous intravenous infusion of 0.1 mg over 1 minute, followed by incremental increases in infusion rate 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 diuresis, furosemide may be administered as a continuous intravenous infusion, starting at 50–100 mg per hour.

Edema in liver disease. Furosemide should be used as an adjunct to aldosterone antagonist therapy when monotherapy with aldosterone antagonists 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 adults, this corresponds to a dose resulting 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 20–40 mg should be administered as an intravenous bolus injection. The dose may be adjusted according to the patient’s therapeutic response.

Forced diuresis in poisoning. Furosemide should be administered intravenously in addition to electrolyte-containing infusion solutions. The dose depends on the therapeutic response to furosemide. Fluid and electrolyte losses should be monitored and replaced before and during treatment. In cases of poisoning with acidic or alkaline substances, diuresis may be enhanced by alkalinizing or acidifying the urine, respectively.

The recommended initial dose is 20–40 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 of furosemide should be limited to exceptional cases when oral and intravenous routes are not feasible. It should be noted that intramuscular injection of furosemide 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 of approximately 9 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 must be adjusted according to body weight (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 electrolyte and fluid loss, and includes signs such as hypovolemia, dehydration, hemoconcentration, cardiac arrhythmias (including AV 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. Treatment is symptomatic.

Adverse reactions.

Metabolic and nutritional disorders: electrolyte imbalance (including with clinical manifestations), dehydration and hypovolemia, especially 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 (diabetes mellitus may progress from latent to overt form), hypocalcemia, hypomagnesemia, increased blood urea levels, metabolic alkalosis, pseudo-Bartter syndrome due to incorrect and/or prolonged use of furosemide.

Symptomatic electrolyte imbalance and metabolic alkalosis may progress to a gradually increasing electrolyte deficiency. In patients with normal liver function, administration of higher furosemide doses may lead to acute worsening of the patient's condition due to significant electrolyte loss.

Warning signs of electrolyte imbalance include increased thirst, headache, confusion, muscle cramps, tetany, muscle weakness, cardiac arrhythmias, and gastrointestinal symptoms.

Significant reduction in body fluid volume may enhance blood coagulation processes, with a tendency toward thrombosis.

Cardiovascular system disorders: arterial hypotension, including orthostatic hypotension (when administered as intravenous infusion), vasculitis, thrombosis. Furosemide may cause arterial hypotension, which in turn may lead to symptoms such as impaired concentration and responsiveness, delirium, sensation of pressure in the head, headache, dizziness, somnolence, weakness, visual disturbances, dry mouth, orthostatic hypotension.

Renal and urinary tract disorders: increased urine volume, tubulointerstitial nephritis, elevated urinary sodium levels, elevated 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, elevated transaminase levels.

Auditory and vestibular disorders: hearing disturbances, usually transient, particularly in patients with renal insufficiency, hypoproteinemia (e.g., in nephrotic syndrome), and/or with too rapid intravenous administration of furosemide; tinnitus; cases of deafness, sometimes irreversible, have been reported following oral or intravenous administration of furosemide.

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 associated with shock).

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.

Congenital and hereditary/genetic disorders: 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: increased body temperature, local reactions, e.g., pain after intramuscular injection.

Shelf life. 3 years.

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

Keep out of reach of children.

Incompatibility. The furosemide solution should not be mixed in the same container with other medicinal products.

Furosemide should not be administered simultaneously with other medicinal products.

Packaging. 2 ml in ampoules, 10 in a pack; 10, 5x2 in blisters in a pack.

Prescription category. Prescription only.

Manufacturer.

Limited Liability Company "Research Plant "GNCLS".

LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVIYA".

Manufacturer's address and place of business.

8 Vorobiova Street, Kharkiv, Kharkiv Oblast, Ukraine.

(Limited Liability Company "Research Plant "GNCLS")

22 Shevchenka Street, Kharkiv, Kharkiv Oblast, 61013, Ukraine.

(LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVIYA")