Furosemide

FUROSEMIDE- furosemide tablet
FUROSEMIDE- furosemide solution

Rx only

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 schedule must be adjusted to the individual patient’s needs. (See “DOSAGE AND ADMINISTRATION”.)

DESCRIPTION

Each tablet for oral administration contains:

Furosemide . . . . . . . . . . . . . . . . 20 mg, 40 mg and 80 mg

Each mL of Oral Solution for oral administration contains:

Furosemide . . . . . . . . . . . . . . . . 10 mg, or 8 mg (40 mg per 5 mL)

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 CAS Registry Number is 54-31-9.

The structural formula is as follows:

Image from Drug Label Content

C12 H11 CIN2 O5 S M.W. 330.74

Each tablet for oral administration contains 20 mg, 40 mg, or 80 mg of furosemide. The tablets meet USP Dissolution Test 1. Furosemide Oral Solution is available in two strengths: 40 mg per 5 mL, and 10 mg per mL.

Inactive Ingredients:

The tablets contain colloidal silicon dioxide, NF, corn starch, NF, lactose monohydrate, NF, microcrystalline cellulose, NF, pregelatinized starch, NF, sodium lauryl sulfate, NF, sodium starch glycolate, NF and stearic acid, NF.

The oral solutions contain D and C Yellow No. 10, FD and C Yellow No. 6, flavors, potassium carbonate 1 1/2 hydrate, propylene glycol, USP, sorbitol solution, USP and water. The 10 mg/mL solution is orange flavored and the 40 mg/5 mL solution is pineapple-peach flavored. The 10 mg/mL oral solution also contains saccharin sodium, USP.

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 absorption 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 the 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 1 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 is 64% and 60%, respectively, of that from an intravenous injection of the drug. Although furosemide is somewhat more rapidly absorbed from the oral solution (50 minutes) than from tablets (87 minutes), peak plasma levels and area under the plasma concentration-time curves do not differ significantly. Peak plasma concentrations 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 and pediatric patients 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 alterations 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 possibly 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 dyscrasia, liver or kidney damage, or other idiosyncratic reactions.

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