Fusix

Furosemide.

Tablet: Each tablet contains: Frusemide 40 mg. Injection: Contains: Frusemide 20 mg/2mL.
Free from foreign impurity and particulate matter.

Pharmacology: Pharmacodynamics: Mode or Mechanisms of Action: Frusemide inhibits the reabsorption of electrolytes in the ascending limb of the loop of Henle. The drug also decreases reabsorption of sodium and chloride and increases potassium excretion in the distal renal tubule and exerts a direct effect on electrolyte transport at the proximal tubule.
Frusemide diuresis results in enhanced excretion of sodium, chloride, potassium, hydrogen, calcium, magnesium, ammonium, bicarbonate, and possibly phosphate.
Frusemide has some renal vasodilator effect. Renal vascular resistance decreases and renal blood flow increases following administration of the drug. When large doses of frusemide are administered to patients with chronic renal insufficiency, glomerular filtration rate may be increased temporarily. A fall in renal blood flow and glomerular filtration rate may occur if excessive drug-induced diuresis results in a reduction in plasma volume.
Pharmacokinetics: Absorption: Tablet: About 60% of single 80-mg oral dose of frusemide was absorbed from GI tract. When administered to fasting adults in this dosage, the drug appeared in the serum within 10 minutes, reached a peak concentration of 2.3 μg/ml in 60-70 minutes, and was almost completely cleared from the serum in 4 hours. When the same dose was given after a meal, the serum concentration of frusemide increased slowly to a peak of about 1 μg/ml after 2 hours and similar concentrations were present 4 hours after ingestion. The diuretic effect of orally administered frusemide is apparent within 30 minutes to 1 hour and is maximal in the first or second hour. The duration of action is usually 6-8 hours. The maximum hypotension effect may not be apparent until several days after frusemide therapy is begun. In patients with severely impaired renal function , the diuretic response may be prolonged.
Injection: After IV administration of frusemide, diuresis occurs within 5 minutes, reaches a maximum within 20-60 minutes, and persists for approximately 2 hours. After IM administration, peak plasma concentrations are attained within 30 minutes. Onset of diuresis occurs somewhat later than after IV administration. In patients with severely impaired renal function, the diuretic response may be prolonged.
Distribution: The drug crosses the placenta and is distributed into milk. Frusemide is approximately 95% bound to plasma proteins in both normal and azotemic patients.
Elimination: Plasma concentrations of frusemide decline in a biphasic manner.
In patients with normal renal function, a small amount of frusemide is metabolized in the liver to the defurfurylated derivative, 4-chloro-5-sulfamoylanthranilic acid. Frusemide and its metabolite are rapidly excreted in urine by glomerular filtration and by secretion from the proximal tubule. In patients with normal renal function, approximately 50% of an oral dose is excreted in the urine within 24 hours. 69-97% of these amounts is excreted in the first 4 hours. The remainder of the drug is eliminated by nonrenal mechanisms including degradation in the liver and excretion of unchanged drug in the feces. In patients with marked renal impairment without liver disease, nonrenal clearance of frusemide is increased so that up to 98% of the drug is removed from the plasma within 24 hours. Frusemide is not removed by hemodialysis.
Tablet: The elimination half-life was more prolonged in 1 patient with concomitant liver disease.

Frusemide is indicated in the treatment of edema associated with congestive heart failure, hepatic cirrhosis and renal disease (including nephrotic syndrome).
Tablet: It is also indicated in the treatment of mild to moderate hypertension, usually in combination with other antihypertensive agents.
Injection: It is also indicated as an adjunct in the treatment of acute pulmonary edema and hypertensive crisis.

Tablet: In the treatment of edema, the usual initial dose is 40 mg once daily by mouth, adjusted as necessary according to response. Mild cases may response to 20 mg daily or 40 mg on alternate days. Some patients may require doses of 80 mg or more daily given as one or two doses daily, or intermittently. Severe cases may require gradual titration of the frusemide dosage up to 600 mg daily. If necessary further doses may be given, increasing by 20 mg increments and not give more often than every 2 hours.
For children, the usual dose by mouth is 1 to 3 mg per kg body-weight daily up to a maximum of 40 mg daily. In the treatment of hypertension, frusemide is given in doses of 40 to 80 mg daily, either alone, or in conjunction with other antihypertensive agents.
High-dose therapy: Patients who do not respond to a dose of 1 g probably require dialysis. If the response to either method of administration is satisfactory, the effective dose (of up to 1 g) may then be repeated every 24 hours. Dosage adjustments should subsequently be made according to the patient's response. Alternatively, treatment may be maintained by mouth; 500 mg should be given by mouth for each 250 mg required by injection.
In the treatment of chronic renal insufficiency, an initial dose of 250mg may be given by mouth, increased, if necessary in steps of 250mg every 4 to 6hours to a maximum of 1.5g in 24hours; in exceptional cases up to 2.0g in 24hours, may be given.
Dosage adjustments should subsequently be made according to the patient's response.
During treatment with these high-dose forms of frusemide therapy, careful laboratory control is essential. Fluid balance and electrolytes should be carefully controlled and, in particular, in patients with shock, measures should be taken to correct the blood pressure and circulating blood volume, before commencing this type of treatment. High dose frusemide therapy is contra-indicated in renal failure caused by nephrotoxic or hepatotoxic agents, and in renal failure associated with hepatic coma.
Injection: In an emergency or when oral therapy cannot be given, the equivalent of 20 to 50 mg of frusemide may be administered by intramuscular or slow intravenous injection as the sodium salt at a rate not exceeding 4 mg per minute. If necessary further doses may be given, increasing by 20 mg increments and not given more often than every 2 hours. If doses greater than 50 mg are required it is recommended that they be given by slow intravenous infusion. For pulmonary oedema, sources in the USA have recommended that if an initial slow intravenous injection of 40 mg (over 1 to 2 minutes) does not produce a satisfactory response within one hour, the dose may be increased to 80 mg given slowly intravenously.
For children, suggested doses by injection are 0.5 to 1.5 mg per kg daily up to a maximum of 20 mg daily, although doses of up to 6 mg per kg have been suggested.
ln the treatment of hypertension, frusemide is given in doses of 40 to 80 mg daily, either alone, or in conjunction with other antihypertensive agents.
High-dose therapy: In the management of oliguria in acute or chronic renal failure where the glomerular filtration rate is less than 20 ml per minute frusemide 250 mg diluted to 250 ml in a suitable diluent is infused over one hour. If urine output is insufficient within the next hour, this dose may be followed by 500 mg added to an appropriate infusion fluid, the total volume of which must be governed by the patient's state of hydration, and infused over approximately 2 hours. If a satisfactory urine output has still not been achieved within one hour of the end of the second infusion then a third dose of 1 g may be infused over approximately 4 hours. The rate of infusion should never exceed 4 mg per minute. ln oliguric or anuric patients with significant fluid overload, the injection may be given without dilution directly into the vein, using a constant-rate infusion pump with a micrometer screw-gauge adjustment; the rate of administration should still never exceed 4 mg per minute.
Patients who do not respond to a dose of 1 g probably require dialysis. If the response to either method of administration is satisfactory, the effective dose (of up to 1 g) may then be repeated every 24 hours.
Dosage adjustments should subsequently be made according to the patient's response. Alternatively, treatment may be maintained by mouth; 500 mg should be given by mouth for each 250 mg required by injection.
During treatment with these high-dose forms of frusemide therapy, careful laboratory control is essential. Fluid balance and electrolytes should be carefully controlled and, in particular, in patients with shock, measures should be taken to correct the blood pressure and circulating blood volume, before commencing this type of treatment. High dose frusemide therapy is contra-indicated in renal failure caused by nephrotoxic or hepatotoxic agents, and in renal failure associated with hepatic coma.

Symptoms and treatment for overdose and antidotes: Overdose will lead to fluid and salt depletion subsequent to initial excessive diuresis. Medical help must be called in without delay so as to ensure immediate measures for an adequate restoration of water and electrolytes balances.

Frusemide is contraindicated in patients with anuria. The drug contraindicated for further use if increasing azotemia and/or oliguria occur during the treatment of severe, progressive renal disease. In patients with hepatic coma or electrolyte depletion, therapy should not be instituted until the basic condition is improved or corrected. Frusemide is also contraindicated in patients with a history of hypersensitivity to the drug and to sulphonamides.

Although frusemide is used in high doses for oliguria due to chronic or acute renal insufficiency it should not be given in anuria or in renal failure due to nephrotoxic or hepatotoxic drugs nor in renal failure associated with hepatic coma. Frusemide should not be given in pre-comatose states associated with hepatic cirrhosis. It should be used with care in patients with prostatic hypertrophy or impairment of micturition since it can precipitate acute urinary retention.
Use in Pregnancy: Frusemide should be used with caution in pregnancy.
Use in Lactation: Frusemide passes into breast milk, and inhibit lactation. Therefore, it must not be given during breast feeding.

Pregnancy: Frusemide should be used with caution in pregnancy.
Lactation: Frusemide passes into breast milk, and inhibit lactation. Therefore, it must not be given during breast feeding.

The most common side-effect associated with frusemide therapy is fluid and electrolyte imbalance including hyponatraemia, hypokalaemia, and hypochloraemic alkalosis, particularly after large doses or prolonged administration. Unlike the thiazide diuretics, it increases the urinary excretion of calcium.
Nephrocalcinosis has been reported when frusemide has been used to treat preterm infants. Frusemide may provoke hyperglycaemia and glycosuria, but probably to a lesser extent than the thiazide diuretics. It may cause hyperuricaemia and precipitate attacks of gout in some patients.
Diuresis (strong): The most commonly encountered adverse effects attributable to frusemide are fluid depletion and electrolyte disturbance arising from frusemide's diuretic actions.
Levels of serum lipids: Most studies into the effects of diuretics on bloods-lipids concentrations have used thiazides and long-term studies have suggested that adverse effects on blood lipids may be transitory, although the complete lipid-lipoprotein analysis necessary for full evaluation of the effects has generally not been performed. The few studies into the effects of frusemide suggest that it may adversely influence blood-lipid concentrations during short-term administration.
Adverse dermatologic and/or hypersensitivity reactions to frusemide include purpura, photosensitivity, rash, urticaria, pruritus, exfoliative dermatitis, erythema multiforme, and necrotizing angiitis (vasculitis, cutaneous vasculitis). Patients with known sulfonamide sensitivity may show allergic reactions to frusemide. Anaphylaxis, manifested as urticaria, angioedema, and hypotension, occurred with 5 minutes after IV administration of frusemide in at least one patient; subsequent intradermal skin testing showed sensitivity to frusemide and other sulfonamides.

Frusemide may enhance the nephrotoxicity of cephalosporin antibiotics such as cephalothin. It can enhance the ototoxicity of aminoglycoside antibiotics. Like other diuretics, frusemide enhances the hypotensive action of antihypertensive drugs. Particular care should be taken with ACE inhibitors since combination with frusemide can result in marked reduction in blood pressure.
Cisplatin: The concomitant administration of cisplatin and frusemide carries the risk of inducing hearing defects, the 2 drugs should not be used simultaneously.
Steroids: When a glucocorticoid is administered during diuretic treatment the potassium-lowering effect of the steroid should be borne in mind.
Lithium: Concurrent use with loop diuretics may provoke lithium toxicity because of reduced renal clearance and is not recommended unless patient can be closed monitored.
Phenytoin: Phenytoin significantly reduces absorption, plasma levels and renal response of frusemide.
NSAIDS: May antagonize the natriuresis and increase in plasma renin activity (PRA) caused by loop diuretics; indomethacine, and possibly other NSAIDs with the exception of diflunisal, may also reduce the increase in urine volume caused by loop diuretics, possibly by inhibiting renal prostaglandin synthesis and/ or by causing sodium and fluid retention.
In addition, concurrent use of NSAIDs with a diuretic may increase the risk of renal failure secondary to a decrease in renal blood flow caused by inhibition of renal prostaglandin synthesis. In the premature neonate, administration of 1 mg/kg of frusemide immediately following indomethacin has been shown to prevent or reduce indomethacin-reduced adverse renal effects without interfering with ductus arteriosus closure.
Probenecid: Probenecid has been found to increase serum concentrations of frusemide by inhibiting active renal tubular secretion.

Injection: Do not use if solution is yellow. Frusemide injection is a mildly buffered alkaline solution and should not be mixed with highly acidic solutions.

Tablet: Store below 30°C in closed container.
Protect from direct light and heat.
Injection: Store below 30°C.
Protect from light and freezing.
Shelf-Life: 3 years.

Diuretics

C03CA01 - furosemide ; Belongs to the class of high-ceiling sulfonamide diuretics.

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