Indications:
Acute pulmonary oedema.
Oedema associated with heart, liver, renal problems, and other oedemas.
Kidney disease-induced hypertension.
Hypercalcemia.
Dosage and administration:
Administration: Oral administration.
Dosage:
Adults and children over 12 years:
Treatment of oedema: The usual initial dose is 40 mg daily. Dosage adjustment may be necessary depending on the individual response. Mild cases may respond to 20 mg daily or 40 mg on alternative days. In some cases, the dose may be increased to 80 mg or more, in one or two divided doses per day. In severe cases, the dose of furosemide may be carefully titrated up to 600 mg/day.
Treatment of hypertension: Furosemide is not the main medicine used for the treatment of hypertension and it may be used in combination with other antihypertensive agents in patients with renal impairment.
The oral dose is 40 – 80 mg daily, given alone or in combination with other antihypertensive drugs.
Treatment of hypercalcemia: 120 mg daily, once or divided into 2 or 3 smaller doses.
Children under 12 years of age: From 1 to 3 mg/kg body weight.
Some special attention on the handling of the medicine before and after use:
There are no special requirements for handling this medicine after use.
Contraindications:
Hypersensitivity to furosemide, sulphonamide derivatives, such as sulfonamide treatment of diabetes mellitus as well as any of the excipients of the medicine.
Electrolyte disturbances (severe hyponatremia, severe hypokalaemia, hypovolaemia), dehydration and/or hypotension.
Comatose or pre-comatose states associated with cirrhosis.
Anuria or renal failure because of poisoning by nephrotoxic or hepatotoxic agents.
Addison’s disease.
Digitalis intoxication.
Breast-feeding women.
Warnings and precautions for use:
Conditions where caution should be taken:
Conditions should be corrected before the treatment with furosemide:
Hypotension.
Hypovolaemia.
Severe electrolyte disturbances– especially hypokalaemia, hyponatremia and acid-base disorders.
Conditions that dosage adjustment is required:
Patients with hypoproteinaemia (such as that associated with the nephotic syndrome) require careful dose titration (reduced furosemide effect, increased risk of ototoxicity).
Conditions where caution should be taken.
Impaired liver function.
Impaired renal function and hepato-renal syndrome.
Diabetes.
Elderly patients.
Patients with prostatic hypertrophy or difficult urination since furosemide can cause acute urinary retention.
Patients with gout (increased risk of hyperuricemia).
Patients at risk of hypotension.
Clinical monitoring requirements:
Regular monitoring for:
Blood dyscrasias. If these occur, stop furosemide immediately.
Liver damage.
Idiosyncratic reactions of furosemide.
Requirement of monitoring indexes of laboratory tests:
Monitoring electrolytes, especially potassium and sodium.
Renal function: BUN test (blood urea nitrogen) should be performed frequently during the first few months of furosemide therapy and periodically thereafter.
Creatinine and urea levels in the blood tend to increase during treatment.
Serum cholesterol and triglycerides may rise but usually return to normal within 6 months of
starting furosemide.
Furosemide should be stopped before a glucose test.
Pregnancy and lactation:
Pregnancy:
Thiazides, thiazide diuretics and loop diuretics cross the placental barrier, appear in cord blood and cause alterations of fluid and electrolyte balance in the fetus. Many cases of neonatal thrombocytopenia have been reported associated with thiazide and its derivatives. This risk also appears after the use of loop diuretics such as furosemide and bumetamide.
Furosemide should only be used during pregnancy when the benefits to the mother outweigh the risk to the fetus.
Lactation:
The use of furosemide during lactation may lead to the risk of inhibiting breast milk production. Furosemide is not recommended during lactation.
Effects on ability to drive and use machines:
Information on effects of furosemide on ability to drive and use machines has not been reported; however, caution should be exercised during the treatment with furosemide because side effects may occur, including headache, hypotension, and muscle cramp. Furosemide may reduce alertness and affects the ability to drive and operate machines.
Interactions, incompatibilities of medicine:
Interaction with other medicinal products and other forms of interaction:
Antihypertensives enhanced hypotensive effect. If coadministration of furosemide and antihypertensives is required, dosage should be adjusted. Particularly, concurrent use with angiotensin-converting enzyme inhibitors can result in marked fall in blood pressure.
Anti-arrhythmics (including amiodarone, disopyramide, flecanaide and sotalol) – risk of cardiac toxicity (because of furosemide-induced hypokalaemia). The effects of lidocaine, tocainide or mexiletine may be antagonised by furosemide.
Drugs that prolong QT interval: Increased risk of cardiac toxicity with furosemide-induced hypokalaemia and/or hypomagnesemia.
Cardiac glycosides: Furosemide-induced hypokalaemia may increase the risk of cardiac toxicity.
Blood potassium levels and ECG should be monitored.
Vasodilators enhanced hypotensive effect with moxisylyte (thymoxamine) or hydralazine.
Renin inhibitors: Aliskiren reduced plasma concentrations of furosemide.
Nitrates enhanced hypotensive effect.
Other diuretics: Increased effect of furosemide, increased risk of hypokalaemia with thiazide. Concurrent use of potassium sparing diuretics and furosemide may reduce potassium depletion (positive).
Antibiotics: Cephalosporin increased renal toxicity; aminoglycosides increased the toxicity to the ears and kidneys; polymyxins and vancomycin increase the toxicity to the ears. Furosemide can reduce serum vancomycin concentrations after cardiac surgery.
Antifungals increased risk of hypokalaemia with amphotericin.
Lithium salts: Serum lithium levels may be increased when lithium is given concomitantly with furosemide, resulting in increased lithium toxicity. Therefore, it is recommended that concurrent use of furosemide with lithium should be avoided if lithium levels may not be carefully monitored.
Nonsteroidal anti-inflammatory drugs: Increased risk of nephrotoxicity, reduced effect of diuretics. Indomethacin and ketorolac may antagonise the effects of furosemide. In patients with dehydration or blood volume depletion, nonsteroidal anti-inflammatory drugs may cause acute renal failure.
Corticosteroids increased risk of hypokalaemia, diuretic effect antagonized by corticosteroids.
Salicylates: Effects may be potentiated by furosemide.
Antidiabetics: Furosemide reduces hypoglycemic effect of antidiabetic medicines, which should be monitored and the dosage should be adjusted.
Nondepolarizing muscle relaxants increased muscle relaxant effect.
Anticoagulant increased anticoagulant effect.
Sucralfate may decrease the absorption of furosemide from the gastrointestinal tract. The intake of furosemide and sucralfate should be separated by at least two hours.
Cholestyramine, colestipol may reduce the absorption of furosemide. The intake of furosemide and cholestyramine or colestipol should be separated by 2-3 hours.
Cisplatin increased toxicicity to the ears and kidneys.
Antiepileptics: Effect of furosemide is reduced by phenytoin. Hyponatraemia is decreased with carbamazepine.
Antipsychotics: Furosemide-induced hypokalaemia increases the risk of cardiac toxicity. Avoid concurrent use with pimozide. Increased risk of ventricular arrhythmias with amisulpride or sertindole. Enhanced hypotensive effect with phenothiazines.
Antidepressants: Enhanced hypotensive effect with MAOIs. Increased risk of postural hypotension with TCAs (tricyclic antidepressants). Increased risk of hypokalaemia with reboxetine.
Chloral hydrate: Furosemide causes flushing, tachycardia, hypertension, sweating.
Probenecid: Furosemide may reduce renal clearance of probenecid and attenuate the diuretic effect.
Central nervous system inhibitors (clopromazine, diazepam, clonazepam, halothane, ketamine) increased hypotensive effect.
CNS stimulants (drugs used for ADHD) – Hypokalaemia increases the risk of ventricular arrhythmias.
Levodopa enhanced hypotensive effect with levodopa.
Aldesleukin enhanced hypotensive effect with aldesleukin.
Oestrogens and progestogen – Diuretic effect is antagonized by estrogens and progestogen.
Prostaglandins enhanced hypotensive effect with alprostadil.
Sympathomimetics – Increased risk of hypokalaemia with high doses of beta2 sympathomimetics (eg, bambuterol, femoterol, salbutamol, salmeterol and terbutaline).
Theophylline enhanced hypotensive effect.
Anaesthetic agents – General anaesthetic agents may enhance the hypotensive effects of furosemide. The effects of curare may be enhanced by furosemide.
Alcohol enhanced hypotensive effect.
Laxatives increases the risk of potassium loss.
Liquorice – Excess intake may increase the risk of hypokalaemia
Incompatibilities:
Because there are no studies about the incompatibility of the medicine, it should not be mixed with other medicines.
Undesirable effects:
Undesirable effects mainly occur during high dose treatment; the most common side effects such as water and electrolyte imbalance, especially in patients with hepatic impairment, renal failure have been seen, after taking high doses for long term. Signs of electrolyte imbalance include headache, hypotension, dizziness, vertigo, visual disturbances, muscle cramps, dry mouth, thirst, weakness, fatigue, sleepiness, drowsiness, insomnia, oliguria, arrhythmia and digestive disorders. Hypovolemia and dehydration may occur, especially in the elderly. Because of the shorter duration of action, the risk of hypokalemia of furosemide may be less potent than that of thiazide diuretics. Unlike thiazides, furosemide increases urinary calcium excretion and nephrocalcinosis has been reported in children.
Adverse drug reactions are listed below in descending order by frequency of occurrence: Very common (≥ 1/10); common (≥ 1/100, and < 1/10); uncommon (≥ 1/1,000 and < 1/100); rare (≥ 1/10,000 and < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data).
Very common:
Vascular disorders: Hypotension (signs and symptoms may include dizziness, sensations of pressure in the head, headache, drowsiness, weakness, visual disorders, dry mouth).
Renal and urinary disorders: Nephrocalcinosis in children.
Common:
Circulation: Hypovolemia in case of high dose therapy. Postural hypotension.
Nutrition and metabolism disorders: Water and electrolyte imbalance including hypokalemia, hyponatremia, hypomagnesemia, hypocalcaemia, alkalosis, hypochloremia.
Tests: Serum creatinine and urea levels may be elevated.
Uncommon:
Digestive disorders: Dry mouth, thirst, nausea, vomiting, bowel motility disturbances, diarrhea, constipation.
Metabolism and nutrition disorders: Hyperuricemia and gout; reduction of serum HDL-cholesterol, elevation of serum LDL-cholesterol, hypertriglyceridemia; hyperglycemia.
Blood and lymphatic system disorders: Aplastic anemia.
Eye disorders: Visual disturbance, blurred vision, yellow vision.
Ear and labyrinth disorders: Deafness (sometimes irreversible).
Cardiac disorders: Cardiac arrhythmias.
Musculoskeletal and connective tissue disorders: Muscle pain, muscle weakness.
Renal and urinary disorders: Reduced diuresis, urinary incontinence, urinary tract obstruction (in patients with hyperplasia of the prostate, bladder inability to empty, urethral stricture unspecified).
General disorder: Fatigue.
Rare:
Skin and subcutaneous tissue disorders: Skin rash, paresthesias, urticaria, pruritus, purpura, exfoliative dermatitis, photosensitivity (may be severe).
Blood and lymphatic system disorders: Bone marrow depression, leukopenia, thrombocytopenia, agranulocytosis, anemia.
Vascular disorders: Vasculitis, thrombosis, shock.
Metabolism and nutrition disorders: Hyperglycaemia, hyperglucoseuria (furosemide effect may be weaker than thiazide diuretics).
Ear and labyrinth disorders: Tinnitus, hearing loss, deafness (especially when intravenous furosemide has been given too rapidly at high doses). Deafness may be irreversible, especially in patients treated with other ototoxic medications.
Neurological disorders: Paraesthesiae, confusion, headache.
Gastrointestinal disorders: Acute pancreatitis (in long-term treatment with diuretics, including furosemide).
Hepatobiliary disorders: Intrahepatic cholestasis (jaundice), abnormal liver function.
Renal and urinary disorders: Acute renal failure.
General disorders: Fatigue, fever, severe anaphylactic or anaphylactoid reactions.
Tests increased transaminase.
Very rare:
Blood and lymphatic system disorders: Hemolytic anaemia, leukopenia, thrombocytopenia.
Metabolism and nutrition disorders: Muscle cramps.
Renal and urinary disorders: Interstitial nephritis.
Guidelines for ADR management:
ECG should be monitored regularly. Potassium supplements or concurrent use of potassium-sparing diuretics in patients at high risk of hypokalemia should be indicated.
Whenever adverse reactions are moderate or severe, furosemide dosage should be reduced or therapy withdrawn.
Overdose and management:
Overdose:
Symptoms: Water and electrolyte imbalance, including headache, muscle weakness, cramps, thirst, hypotension, anorexia, tachycardia.
Management: The loss of electrolytes and water should be replenished.
Pharmacodynamics:
Pharmacotherapeutic group: Loop diuretics.
ATC code: CO3CA01.
Furosemide is a sulfonamide diuretic with a potent and rapid action, which is dose dependent. Furosemide acts at the ascending limb of Henle’s loop, so it is grouped into loop diuretics. Furosemide mainly acts by inhibitiing Na+, K+, 2Cl– cotransport system in the thick ascending limb of Henle’s loop, which increases the excretion of these electrolytes associated with increased excretion of water. There is also an increased excretion of Ca++ and Mg++. Furosemide has potent diuretic effect resulting in lowering blood pressure despite having a weak diuretic effect. In patients with pulmonary oedema, furosemide increases intravascular volume; therefore, it decreases preload on the ventricle before diuretic effect is apparent.
Pharmacokinetics:
Absorption: Furosemide is well-absorbed orally, the diuretic effect of furosemide is apparent within 30 minutes and the peak concentrations are achieved 1-2 hours after oral administration. The duration of action is 4-6 hours which resulting the antihypertensive effect persisted for a longer time. In patients with severe oedema, furosemide bioavailability is reduced, which may be directly affected by reduced gastrointestinal absorption.
Foods may prolong and reduce the absorption of furosemide.
Distribution: Furosemide is up to 99% bound to plasma albumin. The unbound fraction is found higher in patients with heart disease, renal failure, and cirrhosis.
Furosemide crosses the placental barrier and is distributed into breast milk.
Metabolism, excretion: Furosemide is mainly excreted in the urine, mostly in the non-metabolized form. Half-life elimination is from 30 minutes to 120 minutes in normal people, prolonged in infants and patients with hepatic and renal impairment.
Special subjects:
In renal/ hepatic impairment: Where liver disease is present, biliary elimination is reduced up to 50%. Renal impairment has little effect on the elimination rate of furosemide, but less than 20% residual renal function increases the elimination time.
The elderly: The elimination of furosemide is delayed in the elderly where a certain degree of renal impairment is present.
Newborn: A sustained diuretic effect is seen in the newborn, possibly due to immature tubular function.
Storage conditions, shelf life of the medicine:
Storage conditions: Protect from humidity and light, below 300C.
Shelf life: 36 months from the manufacture date.
