INFORMATION FOR HEALTH PROFESSIONALS
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Frusemide in:
40mg tablets: A white, flat, bevel-edged tablet with FRUSID embossed on one face and a bisecting score on the other face. Diameter 7mm.
500mg tablets: A white, flat, bevel-edged tablet, diameter 13mm, having a score on one face.
20mg/2mL injections: A 2ml amber glass ampoule containing a clear liquid. The ampoule is marked with the trade name, approved name and strength.
40mg/2mL injections: A 2ml amber glass ampoule containing a clear liquid. The ampoule is marked with the trade name, approved name and strength.
Frusemide, an anthranilic acid derivative, is a loop diuretic having a rapid effect. Investigations into its mode of action have utilised micropuncture studies in both human and experimental animals and stop flow experiments in dogs. It is reported to exert inhibiting effects on electrolyte reabsorption in the proximal and distal renal tubules and especially in the ascending loop of Henle. The net effect is to enhance excretion of sodium, potassium and chloride ions and water. Frusemide has no effect on carbonic anhydrase. Frusemide has a steep dose-response curve and wide therapeutic range.
In addition to its diuretic actions, frusemide has been shown to increase peripheral venous capacitance and reduce forearm blood flow. It also reduces renal vascular resistance with a resultant increase in renal blood flow the degree of which is proportional to the initial resistance (see Warnings and Precautions).
Frusemide may be effective in patients with moderate renal insufficiency.
Onset of diuresis following oral administration is within one hour, with peak effect occurring between 1-2 hours. Duration of effect is 6-8 hours. After intravenous administration the onset of diuresis is within 5 minutes and somewhat later after intramuscular injection. Duration of effect is approximately 2 hours.
Approximately 60 to 70% of an oral dose of frusemide is absorbed. Peak plasma concentrations occur 60 minutes after oral administration and 30 minutes after intramuscular injection. They increase with increasing dose. Administration after food apparently delays absorption producing lower but more persistent blood concentrations. Plasma protein binding of frusemide to albumin is between 95-99%, however, the response to frusemide is determined more by the medicine concentration in the tissue compartment than that in the plasma.
Frusemide is excreted in the urine mainly as unchanged frusemide but glucuronide and free amine metabolites also appear. The site of metabolism of the glucuronide metabolite is unknown. Approximately 80% of a dose appears in the urine within 24 hours. The terminal half-life is approximately 2 hours. Non-renal elimination also occurs especially in renal failure. Frusemide crosses the placental barrier and is excreted in milk. Absorption is reduced to 43 - 46% in patients with end-stage renal disease, and is probably reduced also in patients with edematous bowel caused by congestive heart failure or nephrotic syndrome; parenteral administration may be preferable in these patients.
Frusemide is indicated for the treatment of oedema associated with congestive heart failure and renal and hepatic disorders and for the control of hypertension. Frusemide may be effective in patients unresponsive to thiazine diuretics. It may also be used to treat moderate renal insufficiency. Frusemide may be indicated in conditions where diuresis is considered necessary.
Intravenous administration is generally preferred over intramuscular administration. Intravenous administration should be at a slow, controlled rate over a one to two minute period. If high-dose parenteral therapy is indicated, administration should be by controlled intravenous infusion at a rate not exceeding 4mg per minute.
Oedema: Initially 40mg once daily reducing to 20mg daily or 40mg on alternate days. Some patients may require 80mg daily while severe cases may require gradual titration up to 600mg daily. In severe cases 20mg to 40mg may be given by intramuscular or slow intravenous injection. The next dose should be given not less than 2 hours later.
Pulmonary oedema: 40mg to 50mg by slow intravenous injection followed by a second dose one to one and a half hours later.
Hypertension: Oral, initially 40mg two times a day, the dose then being adjusted according to patient response.
Renal failure: Frusemide clearance is influenced by age, underlying disease state and drug interactions. Clearance reduces with increasing age probably due to decreasing renal function. Impaired renal function in renal or cardiac disease reduces renal clearance, although this may be compensated by increases in non-renal clearance. Hepatic failure has little impact on clearance.
Children - diuretic: Oral, initially 2mg per kg of body weight as a single dose, the dosage then being increased by an additional 1 to 2mg per kg of body weight at six to eight hour intervals until the desired response is obtained.
Doses as large as 5mg per kg may be required in some children with nephrotic syndrome. Suggested doses by injection are 0.5 to 1.5mg per kg daily to a maximum of 20mg daily.
Doses larger than 6mg per kg of body weight are not recommended. Dosing interval should be extended in neonates because of prolonged half-life.
Hypokalaemia, anuria and history of hypersensitivity to frusemide.
In patients with hepatic cirrhosis and ascites, frusemide therapy is best initiated in hospital. Therapy should not be initiated in hepatic coma or electrolyte depletion until the basic condition is improved. Sudden alterations of fluid and electrolyte balance in patients with cirrhosis may precipitate hepatic coma, therefore, strict observation is required during diuretic treatment. Supplemental potassium chloride and, if required, an aldosterone antagonist are helpful in preventing hypokalaemia and metabolic alkalosis. Increasing azotemia and oliguria occurring during therapy of severe progressive renal disease requires discontinuation of frusemide.
Frusemide should be used with caution in patients with prostatic hypertrophy or impairment of micturition since it can precipitate acute urinary retention.
At high doses and especially if serum concentrations are over 50µg/ml cases of tinnitus, and reversible or irreversible hearing loss, have been reported with frusemide therapy.
These effects have also been associated with rapid injection, severe renal impairment, doses exceeding by several times the usual recommended dose or concomitant therapy with other medicines associated with ototoxic side effects. Consideration should be given to using an alternative non-ototoxic diuretic. Excessive diuresis may lead to decreases in glomerular filtration rate and increased BUN. This can cause dehydration and blood volume reduction with circulatory collapse and possible vascular thrombosis and embolism particularly in elderly patients. The vasodilatory action of frusemide can also cause postural hypotension.
Renal failure: In the management of oliguria in acute or chronic renal failure where the glomerular filtration rate is less than 20mL per minute frusemide 250mg diluted to 250mL in a suitable diluent is infused over one hour. If urine output is insufficient within the next hour, this dose may be followed by 500mg 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 1g may be infused over approximately 4 hours. The rate of infusion should never exceed 4mg per minute. In oliguria or anuria 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 4mg per minute. Patients who do not respond to a dose of 1g probably require dialysis.
If the response to either method of administration is satisfactory, the effective dose (of up to 1g) 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; 500mg should be given by mouth for each 250mg 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 6 hours to a maximum of 1.5g in 24 hours; in exceptional cases up to 2.0g in 24 hours 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 contraindicated in renal failure caused by nephrotoxic or hepatotoxic agents, and in renal failure associated with hepatic coma.
Electrolyte depletion may occur during frusemide therapy especially in patients receiving higher doses and restricted salt intake.
Hypokalaemia may develop with frusemide therapy especially with brisk diuresis, inadequate oral electrolyte intake, when cirrhosis is present, or during concomitant use of corticosteroids or ACTH. Digitalis therapy may exaggerate the metabolic effects of hypokalaemia, especially myocardial effects.
All patients receiving frusemide therapy should be observed for signs and symptoms of: fluid and electrolyte imbalance, mouth dryness, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramp, muscular fatigue, hypotension, oliguria, tachycardia, arrhythmia, or GI disturbances. Increases in blood glucose, and alterations in glucose tolerance tests have been observed and precipitation of diabetes mellitus has been reported while on frusemide therapy.
Asymptomatic hyperuricaemia can occur and gout may be precipitated rarely. Patients allergic to sulphonamides may also be allergic to frusemide. Exacerbation or activation of systemic lupus erythematosus may also occur.
Serum electrolytes, CO2 and BUN should be determined frequently during the first few months of therapy and periodically thereafter. Urine and blood glucose should be checked periodically in both diabetics receiving frusemide and those suspected of latent diabetes. Serum calcium may be lowered and tetany has been reported rarely.
Possible skin photosensitivity; avoid unprotected exposure to the sun and use protective clothing. Patients should use a sunblock that includes protection against both UVA-caused photosensitivity reactions and UVB-caused sunburn reactions. Patients should avoid the use of a sun lamp, tanning bed or tanning booth.
The more intensive diuretic treatment is, the greater the risks of sudden withdrawal. Withdraw intensive diuretic treatment only with the utmost caution and do not attempt withdrawal at all if there is any radiological evidence of heart failure.
The LD50 of frusemide in rats, mice and dogs exceeds 1000mg/kg body weight after oral administration while it is between 300-680mg/ kg body weight after parenteral administration. The acute intragastric toxicity in neonatal rats is 7-10x that of adult rats.
Frusemide has been shown to produce unexplained maternal deaths and abortions in rabbits at doses of 2-8x the human dose expressed as mg/kg. No impairment in fertility of male or female rats was noted at doses of 100mg/kg/day.
Renal calcification has occurred in some severely premature infants treated with intravenous frusemide for oedema associated with a patent ductus arteriosus and hyaline membrane disease. There is evidence that frusemide-related renal calcifications in very low birth-weight infants may be associated with long-term impairment of kidney function.
Pregnancy and Lactation: There are no adequate controlled clinical studies of the use of frusemide in pregnant women so that it should only be used in pregnancy if its potential benefit outweighs the potential risk. Similarly since frusemide appears in breast milk caution is advised when frusemide is required for a nursing mother.
The most common adverse effects are fluid depletion and electrolyte imbalance with an occurrence of approximately 9% and 24% respectively. Other effects are uncommon but include the following:
Hypersensitivity: Photosensitivity reactions, necrotising angiitis, skin rash, exfoliative dermatitis, erythema multiforme, purpura, urticaria, and pruritus.
Gastrointestinal disturbances: Nausea, diarrhoea, anorexia, vomiting, pancreatitis, jaundice, oral and gastric irritation, cramping and constipation. These are uncommon and account for less than 1% of all adverse reactions, with normal doses.
CNS effects: Blurred vision, dizziness, headache, tinnitus and deafness, paresthesias, vertigo, xanthopsia.
Cardiovascular: Orthostatic hypotension which may be aggravated by alcohol, barbiturates and narcotics.
Haematological: Agranulocytosis, aplastic anaemia, thrombocytopenia, leucopenia and anaemia.
Biochemical: Frusemide may provoke hyperglycaemia, glycosuria, hyperuricaemia leading to gout, however, such effects are rare in comparison to thiazides.
Other effects: Pancreatitis, liver damage, weakness, muscle spasm, restlessness, urinary bladder spasm and thrombophlebitis.
Frusemide may increase the ototoxic potential of aminoglycoside antibiotics, and enhance the nephrotoxicity of cephalosporin antibiotics such as cephalothin, especially in the presence of impaired renal function.
Concomitant administration of frusemide and phenytoin may cause a reduction in the blood concentration of frusemide. The diuretic effect of frusemide has been shown to be substantially reduced by concomitant anti-convulsant therapy. The mean diuretic effect of frusemide 20mg or 40mg by mouth in patients on anti-epileptic therapy was 68% and 51% that of healthy controls respectively. The administration of non-steroidal anti-inflammatory agents may inhibit the effect of frusemide by inhibition of prostaglandin synthesis.
The concomitant administration of high doses of salicylates with frusemide may induce salicylate toxicity at lower salicylate dosage than expected because of competition at renal excretory sites.
Frusemide has been reported to enhance and prolong d-tubocurarine-induced block in anephric patients. Frusemide shortened the recovery time from pancuronium blockade in neurosurgical patients with normal renal function. Phosphodiesterase inhibition and increased pancuronium excretion were suggested as possible explanations.
Lithium generally should not be given with diuretics since they reduce the renal clearance of lithium and add a high risk of lithium toxicity.
Arterial responsiveness to noradrenaline may be decreased by frusemide, however, this does not preclude effective use of noradrenaline if required.
The concurrent use of chlorothiazide has been reported to decrease hypercalciuria and dissolve some calculi.
Nephrotoxic or ototoxic medications should be avoided since the potential for ototoxicity and nephrotoxicity may be increased especially in the presence of renal function impairment.
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.
Since frusemide can cause hypokalaemia, it may potentiate the potassium lowering effects of other medicines.
Probenecid has been found to increase serum concentrations of frusemide by inhibiting active renal tubular secretion.
Anticoagulant effects may be decreased when used concurrently with frusemide as a result of reduction of plasma volume, leading to a higher concentration of procoagulant factors in the blood; in addition diuretic-induced improvement of hepatic congestion may lead to improved hepatic function; resulting in increased procoagulant factor synthesis. Dosage adjustments may be necessary.
Frusemide may rarely increase the blood glucose concentrations or interfere with the hypoglycaemic effects of anti-diabetic agents.
Administration of chloral hydrate followed by intravenous frusemide may result in diaphoresis, hot flushes and variable blood pressure including hypertension. This is due to a hypermetabolic state caused by displacement of thyroxine from its bound state.
The combination of frusemide and mannitol may rapidly lead to acute renal failure and may potentiate the effect of curare.
The use of thiazine and loop diuretics in combination to treat resistant hypertension often causes severe deterioration in renal function. It is not clear whether this is a result of excess diuresis or excessive blood pressure reduction.
The most frequently encountered problem of overdosage is excessive depletion of blood volume that may lead to profound shock, frequently complicated by hypokalaemia. Treatment is symptomatic and directed at fluid and electrolyte replacement.
The tablets should be protected from light and moisture.
The injections should be protected from light. Do not mix with acidic solutions or infusions such as dextrose. Do not store the 40mg injection potency below 10°C as crystallisation may occur. This can be reversed by gentle heating without loss of potency.
All medicines must be kept out of reach of children.
Prescription Medicine.
Frusid 40mg tablets in packs of 30, 250 and 1000 tablets.
Frusid Forte 500mg tablets in packs of 50 tablets.
Frusid injection 20mg/2mL and 40mg/2mL in packs of 5 and 25 ampoules.
Frusemide is 4-Chloro-N-furfuryl-5-sulphamoyl anthranilic acid having a molecular formula of C12H11ClN2O5S and a molecular weight of 330.7.
Solutions for injection are prepared with sodium hydroxide giving solutions having a pH of about 9.
Other ingredients of the tablets are:
40mg tablets: Lactose, Butyl paraben, Propyl paraben Polyvinylpyrrolidinone K30, Microcrystalline cellulose, Sodium starch glycolate, Magnesium stearate and Silicon dioxide.
500mg tablets: Lactose, Microcrystalline cellulose, Sodium starch glycolate, Butyl paraben, Propyl paraben, Magnesium stearate and Polyvinylpyrrolidinone K30
Other ingredients of the injections (both strength) are: Sodium hydroxide and Water fir injection.
Douglas Pharmaceuticals Ltd
P.O. Box 45-027
AUCKLAND 8
Ph: (09) 835-0660
Fax: (09) 835-0665
16 March 1999