Furosemide

FUROSEMIDE- furosemide tablet
DAVA Pharmaceuticals, Inc.

WARNING: Furosemide is a potent diuretic which, if given in excessive amounts, can lead to a profound diuresis with water and electrolyte depletion. Therefore, careful medical supervision is required, and dose and dose schedule must be adjusted to the individual patient’s needs. (See “ DOSAGE AND ADMINISTRATION “.)

DESCRIPTION

Furosemide is a diuretic which is an anthranilic acid derivative. Chemically, it is 4-chloro-N -furfuryl-5-sulfamoylanthranilic acid. Furosemide is a white to slightly yellow odorless, crystalline powder. It is practically insoluble in water, sparingly soluble in alcohol, freely soluble in dilute alkali solutions and insoluble in dilute acids.

The structural formula is as follows:

Furosemide Structural Formula
(click image for full-size original)

Furosemide is supplied as round, white to off-white, 20mg, 40mg and 80mg oral tablets and meets USP DISSOLUTION TEST 1.

Inactive ingredients: corn starch, lactose monohydrate NF, magnesium stearate, microcrystalline cellulose, povidone and sodium lauryl sulfate.

CLINICAL PHARMACOLOGY

Investigations into the mode of action of furosemide have utilized micropuncture studies in rats, stop flow experiments in dogs, and various clearance studies in both humans and experimental animals. It has been demonstrated that furosemide inhibits primarily the reabsorption of sodium and chloride not only in the proximal and distal tubules but also in the loop of Henle. The high degree of efficacy is largely due to this unique site of action. The action on the distal tubule is independent of any inhibitory effect on carbonic anhydrase and aldosterone.

Recent evidence suggests that furosemide glucuronide is the only or at least the major biotransformation product of furosemide in man. Furosemide is extensively bound to plasma proteins, mainly to albumin. Plasma concentrations ranging from 1 to 400 µg/mL are 91 to 99% bound in healthy individuals. The unbound fraction averages 2.3 to 4.1% at therapeutic concentrations.

The onset of diuresis following oral administration is within one hour. The peak effect occurs within the first or second hour. The duration of diuretic effect is 6 to 8 hours.

In fasted normal men, the mean bioavailability of furosemide from furosemide tablets and furosemide oral solution has been shown to be about 60% of that from an intravenous injection of the drug. Although furosemide is more rapidly absorbed from the oral solution than from the tablet, peak plasma levels and area under the plasma concentration-time curves do not differ significantly. Peak plasma concentrations of furosemide increase with increasing dose but times-to-peak do not differ among doses. The terminal half-life of furosemide is approximately 2 hours.

Significantly more furosemide is excreted in urine following the IV injection than after the tablet or oral solution. There are no significant differences between the two oral formulations in the amount of unchanged drug excreted in urine.

Geriatric Population

Furosemide binding to albumin may be reduced in elderly patients. Furosemide is predominantly excreted unchanged in the urine. The renal clearance of Furosemide after intravenous administration in older healthy male subjects (60-70 years of age) is statistically significantly smaller than in younger healthy male subjects (20-35 years of age.) The initial diuretic effect of Furosemide in older subjects is decreased relative to younger subjects. (See PRECAUTIONS: Geriatric Use.)

INDICATIONS AND USAGE

Edema: Furosemide is indicated in adults, infants, and children for the treatment of edema associated with congestive heart failure, cirrhosis of the liver, and renal disease, including the nephrotic syndrome. Furosemide is particularly useful when an agent with greater diuretic potential is desired.

Hypertension: Oral furosemide may be used in adults for the treatment of hypertension alone or in combination with other antihypertensive agents. Hypertensive patients who cannot be adequately controlled with thiazides will probably also not be adequately controlled with furosemide alone.

CONTRAINDICATIONS

Furosemide is contraindicated in patients with anuria and in patients with a history of hypersensitivity to furosemide.

WARNINGS

In patients with hepatic cirrhosis and ascites, furosemide therapy is best initiated in the hospital. In hepatic coma and in states of electrolyte depletion, therapy should not be instituted until the basic condition is improved. Sudden alteration of fluid and electrolyte balance in patients with cirrhosis may precipitate hepatic coma; therefore, strict observation is necessary during the period of diuresis. Supplemental potassium chloride and, if required, an aldosterone antagonist are helpful in preventing hypokalemia and metabolic alkalosis.

If increasing azotemia and oliguria occur during treatment of severe progressive renal disease, furosemide should be discontinued.

Cases of tinnitus and reversible or irreversible hearing impairment have been reported. Usually, reports indicate that furosemide ototoxicity is associated with rapid injection, severe renal impairment, doses exceeding several times the usual recommended dose, or concomitant therapy with aminoglycoside antibiotics, ethacrynic acid, or other ototoxic drugs. If the physician elects to use high dose parenteral therapy, controlled intravenous infusion is advisable (for adults, an infusion rate not exceeding 4 mg furosemide per minute has been used).

PRECAUTIONS

General:

Excessive diuresis may cause dehydration and blood volume reduction with circulatory collapse and possible vascular thrombosis and embolism, particularly in elderly patients. As with any effective diuretic, electrolyte depletion may occur during furosemide therapy, especially in patients receiving higher doses and a restricted salt intake. Hypokalemia may develop with furosemide, especially with brisk diuresis, inadequate oral electrolyte intake, when cirrhosis is present or during concomitant use of corticosteroids or ACTH. Digitalis therapy may exaggerate metabolic effects of hypokalemia, especially myocardial effects.

All patients receiving furosemide therapy should be observed for these signs or symptoms of fluid or electrolyte imbalance (hyponatremia, hypochloremic alkalosis, hypokalemia, hypomagnesemia or hypocalcemia): dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, arrhythmia, or gastrointestinal disturbances such as nausea and vomiting.

Increases in blood glucose and alterations in glucose tolerance tests (with abnormalities of the fasting and 2-hour postprandial sugar) have been observed, and rarely, precipitation of diabetes mellitus has been reported.

Asymptomatic hyperuricemia can occur and gout may rarely be precipitated.

Patients allergic to sulfonamides may also be allergic to furosemide.

The possibility exists of exacerbation or activation of systemic lupus erythematosus.

As with many other drugs, patients should be observed regularly for the possible occurrence of blood dyscrasias, liver or kidney damage or other idiosyncratic reactions.

Information for Patients:

Patients receiving furosemide should be advised that they may experience symptoms from excessive fluid and/or electrolyte losses. The postural hypotension that sometimes occurs can usually be managed by getting up slowly. Potassium supplements and/or dietary measures may be needed to control or avoid hypokalemia.

Patients with diabetes mellitus should be told that furosemide may increase blood glucose levels and thereby affect urine glucose tests. The skin of some patients may be more sensitive to the effects of sunlight while taking furosemide.

Hypertensive patients should avoid medications that may increase blood pressure, including over-the-counter products for appetite suppression and cold symptoms

Laboratory Tests:

Serum electrolytes, (particularly potassium), CO2 , creatinine and BUN should be determined frequently during the first few months of furosemide therapy and periodically thereafter. Serum and urine electrolyte determinations are particularly important when the patient is vomiting profusely or receiving parenteral fluids. Abnormalities should be corrected or the drug temporarily withdrawn. Other medications may also influence serum electrolytes.

Reversible elevations of BUN may occur and are associated with dehydration which should be avoided, particularly in patients with renal insufficiency.

Urine and blood glucose should be checked periodically in diabetics receiving furosemide, even in those suspected of latent diabetes.

Furosemide may lower serum levels of calcium (rarely cases of tetany have been reported) and magnesium. Accordingly, serum levels of these electrolytes should be determined periodically.

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