Furosemide sofarma

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FUROSEMID SOPHARMA (FUROSEMID SOPHARMA)

Composition:

Active substance: furosemide;

1 tablet contains 40 mg of furosemide;

Excipients: lactose monohydrate, wheat starch, colloidal anhydrous silicon dioxide, magnesium stearate, talc.

Pharmaceutical form. Tablets.

Main physicochemical properties: round, biconvex tablets, 6 mm in diameter, white to almost white in color.

Pharmacotherapeutic group.

Diuretics. High-ceiling loop diuretics.

ATC code C03CA01.

Pharmacological properties.

Pharmacodynamics.

Furosemide is a loop diuretic that inhibits the reabsorption of sodium and chloride ions in the ascending limb of Henle's loop, as well as in the proximal and distal tubules of the nephron. Its high efficacy is due to a unique mechanism of action. The effect in the distal tubules is independent of carbonic anhydrase inhibition or the influence of aldosterone. The pharmacological action of furosemide is limited to the kidneys. The main mechanism of furosemide's action consists in the inhibition of active chloride transport in the ascending limb of Henle's loop. Reabsorption of sodium chloride in the nephron is reduced, resulting in the formation of hypo- or isotonic urine.

It has been established that furosemide administration affects prostaglandin synthesis and the renin-angiotensin system. Furosemide also influences glomerular permeability to serum proteins.

The onset of diuretic effect occurs approximately 1 hour after oral administration. Maximum therapeutic effect is achieved between the 1st and 2nd hour. The duration of diuretic action lasts more than 4 hours.

Pharmacokinetics.

Absorption. Furosemide is rapidly but incompletely absorbed (approximately 60–70%) after oral administration. Following oral intake, the drug is significantly reabsorbed in the upper part of the duodenum at pH 5.0. Its effect lasts more than 4 hours after oral administration and averages about 2 hours after parenteral administration.

Distribution. Furosemide is characterized by a high degree of plasma protein binding, primarily to albumin. In healthy subjects, plasma concentrations range from 1 to 400 μg/mL, with 91–99% of furosemide bound to plasma proteins. Furosemide crosses the placental barrier and slowly enters the fetal circulation.

Metabolism. The glucuronide conjugate of furosemide is the sole or at least the main metabolite of its biotransformation in humans. Small amounts are metabolized via side chain cleavage.

Excretion. Elimination occurs mainly via the kidneys into urine (glomerular filtration and proximal tubular secretion), accounting for approximately 50% of the administered dose after oral administration, and up to 80–90% after intravenous or intramuscular administration. About 10–15% of the active substance is excreted in feces within 24 hours. A small portion is excreted via bile.

Patients with renal/hepatic impairment.

In liver disease, biliary excretion is reduced by 50%. Renal impairment has minimal effect on the elimination rate of furosemide; however, when residual renal function is less than 20%, a significant prolongation of elimination half-life is observed.

Elderly patients.

In the presence of renal insufficiency, furosemide elimination is slowed.

Clinical characteristics.

Indications.

• Edema in chronic congestive heart failure (if treatment with diuretics is required);
• edema in chronic renal failure;
• edema in nephrotic syndrome (if treatment with diuretics is required);
• acute renal failure, including in pregnant women or during childbirth;
• edema in liver diseases (if necessary, as adjunctive therapy with aldosterone antagonists);
• arterial hypertension.

Contraindications.

• Hypersensitivity to furosemide or to any of the excipients of the medicinal product;
• allergy to sulfonamides (e.g., sulfonamide antibiotics or sulfonylureas) due to possible cross-sensitivity to furosemide;
• hypovolemia or dehydration;
• anuria or impaired kidney function (creatinine clearance below 30 mL/min), renal failure with anuria if no therapeutic response to furosemide is observed;
• renal failure due to nephrotoxic or hepatotoxic agents;
• severe hypokalemia;
• severe hyponatremia;
• pre-comatose and comatose states associated with hepatic encephalopathy;
• digitalis intoxication;
• concomitant use of potassium supplements or potassium-sparing diuretics.

Interaction with other medicinal products and other forms of interaction.

Antihypertensive agents. When antihypertensive agents, diuretics, or other medicinal products with blood pressure-lowering properties are used concomitantly with furosemide, an enhanced antihypertensive effect and further reduction in blood pressure should be expected. In patients receiving diuretics, severe arterial hypotension and worsening of renal function up to renal failure may occur when combined with ACE inhibitors or angiotensin II receptor antagonists, especially when initiating therapy or using high doses. Consideration should be given to temporarily discontinuing furosemide or at least reducing its dose for 3 days before starting or increasing the dose of ACE inhibitors or angiotensin II receptor antagonists.

Other diuretics. Concomitant use with thiazide diuretics increases the risk of hypokalemia. Simultaneous administration with metolazone (thiazide diuretic) may result in enhanced diuresis.

Antiarrhythmic agents. (including amiodarone, disopyramide, flecainide, and sotalol) – risk of cardiac toxicity (due to furosemide-induced hypokalemia). The effects of lidocaine, tocainide, or mexiletine may be antagonized by furosemide.

Drugs associated with QT prolongation. Certain electrolyte imbalances (such as hypokalemia and hypomagnesemia) may increase the toxicity of digitalis and of medicinal products that cause QT prolongation syndrome.

Cardiac glycosides. Furosemide increases myocardial sensitivity to the effects of cardiac glycosides.

Vasodilators. Enhanced hypotensive effect of nitrates, tiamoxamine, or hydralazine.

Renin inhibitors. Aliskiren reduces plasma concentrations of furosemide after oral administration. Reduced furosemide effect may occur in patients receiving both aliskiren and furosemide orally; therefore, monitoring for reduced diuretic effect is recommended, with appropriate dose adjustments.

Lithium. Furosemide reduces the excretion of lithium salts and may lead to increased lithium serum levels and increased risk of toxicity of lithium preparations, including their cardio- and neurotoxic effects. For this reason, careful monitoring of lithium levels is required in patients receiving this combination.

Sucralfate. Concomitant administration of sucralfate and furosemide may suppress its diuretic and antihypertensive effects, requiring a minimum interval of two hours between administration of the two medicinal products.

Non-steroidal anti-inflammatory and anti-rheumatic agents. Indomethacin, acetylsalicylic acid, and ketorolac in combination with furosemide may significantly reduce the diuretic and antihypertensive effects of furosemide. In patients with dehydration or hypovolemia, NSAIDs may cause acute renal failure and lead to acute heart failure.

Salicylates. Under the influence of furosemide, the toxicity of salicylates may increase.

Antibiotics. Furosemide may potentiate the ototoxicity of aminoglycosides, polymyxin, or vancomycin and other ototoxic medicinal products. Since this may lead to irreversible damage, these medicinal products should not be used concomitantly with furosemide, or only if strongly indicated.

Increased risk of nephrotoxicity with aminoglycosides or cephaloridine. Furosemide may reduce serum levels of vancomycin after cardiac surgery. Increased risk of hyponatremia with trimethoprim. Concomitant use of furosemide with high doses of certain cephalosporins may lead to impaired renal function.

Antidepressants. Enhanced hypotensive effect with MAO inhibitors; increased risk of postural hypotension with tricyclic antidepressants; increased risk of hypokalemia with reboxetine.

Oral antidiabetic agents. Furosemide may reduce their therapeutic effect.

Insulin. Furosemide may reduce its therapeutic effect. Insulin requirements in diabetic patients may increase.

Antiepileptic agents. Combined use with carbamazepine may increase the risk of hyponatremia. The effect of furosemide is reduced (diuretic effect is diminished) by phenytoin and phenobarbital.

Antihistamines. Hypokalemia with increased risk of cardiac toxicity.

Antifungal agents. Concomitant use with furosemide may lead to severe reduction in plasma potassium levels and nephrotoxicity with amphotericin.

Anxiolytics and hypnotics. Enhanced hypotensive effect. In individual cases, administration of furosemide within 24 hours after chloral hydrate may cause flushing, increased sweating, agitation, nausea, elevated blood pressure, and tachycardia. Therefore, concomitant use of furosemide and chloral hydrate is not recommended.

Antipsychotic agents. Furosemide-induced hypokalemia increases the risk of cardiac toxicity; increased risk of ventricular arrhythmias with amisulpride or sertindole; enhanced hypotensive effect with phenothiazines.

Risperidone. Particular caution is required when using furosemide concomitantly with risperidone as combination or adjunctive therapy, and a careful benefit-risk assessment should be performed.

CNS stimulants (medicinal products used in ADHD (attention deficit hyperactivity disorder)) – hypokalemia increases the risk of ventricular arrhythmias. Enhanced hypotensive effect with levodopa.

Corticosteroids. Cause potassium loss. When used concomitantly with furosemide, they may lead to severe reduction in plasma potassium levels and may cause sodium retention.

Cisplatin. There is a risk of ototoxic and nephrotoxic effects when used concomitantly with cisplatin, unless furosemide is administered in low doses (40 mg in patients with normal renal function) or with positive fluid balance to achieve forced diuresis during cisplatin therapy.

Immunomodulators. Concomitant use with cyclosporine A is associated with an increased risk of secondary gouty arthritis due to furosemide-induced hyperuricemia and impaired renal excretion of urates by cyclosporine. Increased risk of hyperkalemia with cyclosporine and tacrolimus; enhanced hypotensive effect with aldesleukin.

Muscle relaxants. Furosemide may enhance the action of muscle relaxants (curare-like type), potentiate the hypotensive effect of baclofen, tizanidine, and theophylline.

General anesthetics. They may enhance the hypotensive effect of furosemide.

Estrogens. Antagonism of diuretic effect.

Progestogens. Increased risk of hyperkalemia.

Prostaglandins. Enhanced hypotensive effect with alprostadil.

Levothyroxine. High doses of furosemide in combination with levothyroxine may suppress thyroid hormone binding to carrier protein, 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.

Sympathomimetics. Furosemide may reduce the therapeutic effect of sympathomimetics with blood pressure-raising properties (e.g., epinephrine, norepinephrine); use of high-dose β2-sympathomimetics may increase the risk of hypokalemia.

Probenecid, methotrexate. Like furosemide itself, these are eliminated via tubular secretion and may therefore reduce the effect of furosemide. Conversely, furosemide may reduce renal excretion of these medicinal products. When used in high doses, their plasma concentrations increase, thereby increasing the risk of adverse reactions caused by furosemide or concomitant therapy.

Carbenoxolone, liquorice, reboxetine. May increase the risk of hypokalemia.

Laxatives. Prolonged use may increase the risk of hypokalemia.

High-dose use of liquorice root may increase the risk of hypokalemia.

Cholestyramine. Patients prescribed cholestyramine should take this medicinal product at least one hour after furosemide.

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

Special precautions for use

Excessively aggressive diuresis may lead to orthostatic hypotension, as well as acute hypotensive episodes.

Serum levels of sodium, potassium, calcium, chloride, magnesium, and creatinine should be monitored, especially in patients at high risk of developing electrolyte imbalance or significant fluid loss. Factors influencing the development of electrolyte disturbances include pre-existing conditions (e.g., hepatic cirrhosis, heart failure), concomitant medication use, and diet. For example, potassium deficiency may occur due to vomiting or diarrhea. When using furosemide, it is advisable to recommend a diet rich in potassium (baked potatoes, bananas, tomatoes, spinach, dried fruits). It should be remembered that potassium supplementation may become necessary during furosemide therapy.

Hypovolemic states or dehydration, as well as disturbances in acid-base balance or significant electrolyte imbalances, must be corrected before initiating treatment or, if already underway, treatment should be temporarily discontinued.

An adequate route for urine elimination from the body must be ensured. In patients with partial urinary obstruction, symptoms may be provoked or existing ones exacerbated. Patients with urinary voiding disorders (prostate hyperplasia or urinary tract obstruction) may develop acute urinary retention if the bladder has not been previously emptied.

Treatment with furosemide requires regular medical supervision.

The following patients require particular caution and monitoring:

• Patients with hypotension or at increased risk of a sudden drop in arterial pressure (e.g., patients with severe coronary or cerebral vascular stenosis);
• Patients in whom latent diabetes may become overt or patients with diabetes requiring increased insulin;
• Patients with gout. Furosemide reduces uric acid excretion and may provoke gout attacks;
• Patients with hepatorenal syndrome, i.e., functional renal insufficiency associated with severe liver disease;
• Patients with hypoproteinemia due to nephrotic syndrome (the diuretic effect of furosemide is reduced, but its ototoxicity is potentiated); careful dose titration is required;
• Premature newborns – risk of developing nephrocalcinosis/nephrolithiasis; monitoring of renal function and ultrasound surveillance are required;
• Patients with acute porphyria – the use of diuretics is considered potentially hazardous;
• Patients receiving concomitant risperidone.

In placebo-controlled trials involving elderly patients with dementia, higher mortality was observed in patients treated concomitantly with furosemide and risperidone, compared to those treated with furosemide alone or risperidone alone. In such cases, the benefit-risk ratio must be carefully evaluated before initiating such combination therapy. There are no reports of increased mortality in patients receiving other diuretics (mainly low-dose thiazide diuretics) as concomitant treatment with risperidone.

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

Concomitant use of alcohol and furosemide should be avoided.

The medicinal product contains wheat starch as an excipient, which may contain only trace amounts of gluten and is considered safe for individuals with celiac disease.

The medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Use of the drug may cause exacerbation or activation of systemic lupus erythematosus.

Use during pregnancy or breastfeeding

Pregnancy

Furosemide crosses the placental barrier. It should not be administered during pregnancy except in cases where treatment is life-saving. Furosemide therapy during pregnancy requires monitoring of fetal growth and development.

Breastfeeding

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

Furosemide may reduce concentration and impair the ability to drive or operate machinery. Some adverse effects of furosemide (e.g., sudden, significant drop in blood pressure) may affect the patient's ability to concentrate and reaction speed.

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

Method of Administration and Dosage.

Furosemide is taken orally, usually during or on an empty stomach.

The dosage regimen is determined individually by a physician according to the patient's therapeutic response, using the lowest effective dose. It can be administered once daily or on alternate days.

Adults.

The recommended initial single dose for adults is 40 mg. Additional dose adjustments may be required until a maintenance dose is achieved. In mild cases, a dose of 40 mg every other day may be sufficient. In cases of resistant edema, the usual daily dose is 80 mg or more, administered once or twice daily, or as needed. In severe conditions caused by edema, gradual dose escalation may be necessary, up to 600 mg per day.

The maximum daily dose of furosemide should not exceed 1500 mg.

Special Dosage Recommendations.

Edema in Chronic Congestive Heart Failure.

The recommended initial oral dose is 20–40 mg daily. The dose may be adjusted as needed according to the patient's therapeutic response. It is recommended to administer the daily dose divided into 2 or 3 doses.

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 effectiveness of a given dose cannot be precisely predicted. For 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 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 according to the patient's therapeutic response. The total daily dose can 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, significant electrolyte imbalances, and acid-base disturbances should be corrected before initiating furosemide therapy.

It is recommended to switch from intravenous administration to oral intake as soon as possible.

Edema in Nephrotic Syndrome.

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

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. For adult patients, this means administering a dose that results 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 as needed according to the patient's therapeutic response. The total daily dose can be administered as a single dose or divided into several doses. If intravenous administration is absolutely necessary, the initial single dose is 20–40 mg.

Children.

The tablet form of the drug is prescribed for children with body weight over 10 kg.

The recommended dose of furosemide for oral administration is 2 mg/kg body weight per day; however, the maximum daily dose should not exceed 40 mg per day.

Elderly Patients.

There are no specific dosage recommendations. Furosemide is eliminated more slowly in elderly patients. The dose should be titrated to achieve the desired therapeutic effect.

Children.

For children, the dose must be adjusted according to body weight (see section "Method of Administration and Dosage").

For children unable to take the oral dosage form, such as preterm infants and newborns, consideration should be given to using a parenteral formulation.

Overdose.

Symptoms.

The clinical picture of acute or chronic overdose primarily depends on the degree and consequences of fluid and electrolyte loss, and manifests as hypovolemia, dehydration, hemoconcentration, and cardiac arrhythmias (including AV block and ventricular fibrillation) due to enhanced diuresis. Overdose of furosemide most commonly presents as severe arterial hypotension (progressing to shock), cardiac arrhythmia, orthostatic collapse, or other signs of hypovolemia (acute renal failure, thrombosis, delirious states, hallucinations, peripheral paralysis, apathy, confusion).

Treatment.

Drug administration should be immediately discontinued, and electrolyte solutions should be administered as needed to restore circulating volume and water-electrolyte balance. Intensive treatment and close monitoring of the patient may be required for the prevention and management of these disturbances. Following recent ingestion of the drug, gastric lavage and administration of activated charcoal should be performed to limit systemic absorption of the active substance.

There is no specific antidote. Treatment is symptomatic.

Adverse Reactions

Metabolic and nutritional disorders. Furosemide causes increased excretion from the body of sodium and chloride, and consequently of fluid. This leads to reduced levels of sodium and chloride in the blood (hyponatremia, hypochloremia). In addition, excretion of other electrolytes is enhanced (particularly potassium, calcium, magnesium), leading to decreased levels of these in the blood – hypokalemia, hypocalcemia, hypomagnesemia. Symptomatic disturbances of electrolyte balance, metabolic alkalosis, and pseudo-Bartter syndrome (due to incorrect and/or prolonged use of furosemide) may progress into a gradually increasing electrolyte deficiency. In patients with normal liver function, administration of higher doses of furosemide may result in acute worsening of condition due to excessive loss of electrolytes.

Warning signs of electrolyte imbalance include: increased sensation of thirst, headache, confusion, muscle cramps, tetany, muscle weakness, cardiac arrhythmias, and gastrointestinal symptoms. Significant potassium deficiency may lead to paralytic ileus or confusion progressing to coma.

The diuretic effect of furosemide may lead to or contribute to hypovolemia and dehydration, particularly in elderly patients. A significant reduction in body fluid volume may enhance blood coagulation processes, with a tendency toward thrombosis.

Furosemide treatment may lead to transient increases in blood creatinine and urea levels, as well as to a decrease in HDL cholesterol and an increase in cholesterol and triglyceride levels in blood serum. Serum uric acid levels may rise, potentially triggering gout attacks.

Glucose tolerance may be reduced during furosemide therapy. In patients with diabetes mellitus, this may lead to deterioration of metabolic control; latent diabetes may become overt.

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

There have been reports of bone marrow suppression, requiring immediate discontinuation of furosemide therapy.

Immune system disorders: severe anaphylactic or anaphylactoid reactions, very rarely progressing to shock; exacerbation or activation of systemic lupus erythematosus.

Nervous system disorders: paresthesia, delirium, hyperosmolar coma, dizziness, syncope, and loss of consciousness (caused by symptomatic hypotension).

Eye disorders: visual disturbances.

Ear and labyrinth disorders: tinnitus, hearing impairment. These are usually transient. They occur more frequently in patients with renal insufficiency, hypoproteinemia (as in nephrotic syndrome), and with rapid intravenous administration of furosemide.

Cases of deafness, sometimes irreversible, have been reported following oral or intravenous administration of furosemide.

Cardiovascular system disorders: arterial hypotension (in severe cases associated with symptoms of reduced concentration, slowed reactions, dizziness, sensation of pressure in the head, headache, drowsiness, weakness, dry mouth), orthostatic hypotension (orthostatic collapse), cardiac arrhythmias. Increased predisposition to thrombosis and vasculitis.

Gastrointestinal disorders: loss of appetite, gastrointestinal disturbances such as diarrhea, nausea, vomiting, flatulence, thirst, intestinal motility disorders, constipation; however, these are usually not severe enough to discontinue treatment.

Liver and biliary system disorders: intrahepatic cholestasis, elevated liver transaminase levels, acute pancreatitis. Hepatic encephalopathy (in patients with hepatocellular insufficiency or acute pancreatitis).

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

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

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

Congenital, familial and genetic disorders: increased risk of persistent patent ductus arteriosus when furosemide is administered to premature infants during the first weeks of life.

General disorders: fever, fatigue, malaise.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is of great importance. It allows continuous monitoring of the benefit-risk ratio of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 5 years.

Storage conditions.

Keep out of reach of children.

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

Packaging.

10 tablets in a blister pack made of PVC film and aluminum foil. Two blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

JSC "Sofarma".

Manufacturer's address and location of business operations.

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