FDA Label for Ethacrynic Acid

Other

Ethacrynic acid is a potent diuretic which, if given in excessive amounts, may lead to 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

Ethacrynic acid is an unsaturated ketone derivative of an aryloxyacetic acid. It is designated chemically as [2,3-dichloro-4-(2-methylene-1-oxobutyl)phenoxy] acetic acid, and has a molecular weight of 303.14. Ethacrynic acid is a white, or practically white, odor less or practically odorless, crystalline powder, freely soluble in alcohol, chloroform and ether, very slightly soluble in water. Its empirical formula is C₁₃H₁₂Cl₂O₄ and its structural formula is:

Chemical Structure - ethacrynic 01

Ethacrynic Acid Tablets USP are supplied as 25 mg tablets for oral use. The tablets contain the following inactive ingredients: lactose monohydrate, pregelatinized starch (corn), colloidal silicon dioxide, talc and calcium stearate.

FDA approved dissolution specification differs from the USP dissolution specification.

Indications And Usage

Ethacrynic Acid Tablets, USP are indicated for treatment of edema when an agent with greater diuretic potential than those commonly employed is required.

• Treatment of the edema associated with congestive heart failure, cirrhosis of the liver, and renal disease, including the nephrotic syndrome.
• Short-term management of ascites due to malignancy, idiopathic edema, and lymphedema.
• Short-term management of hospitalized pediatric patients, other than infants, with congenital heart disease or the nephrotic syndrome.

Contraindications

All diuretics, including ethacrynic acid, are contraindicated in anuria. If increasing electrolyte imbalance, azotemia, and/or oliguria occur during treatment of severe, progressive renal disease, the diuretic should be discontinued.

In a few patients this diuretic has produced severe, watery diarrhea. If this occurs, it should be discontinued and not used again.

Until further experience in infants is accumulated, therapy with oral and parenteral ethacrynic acid is contraindicated.

Hypersensitivity to any component of this product.

Warnings

The effects of ethacrynic acid on electrolytes are related to its renal pharmacologic activity and are dose dependent. The possibility of profound electrolyte and water loss may be avoided by weighing the patient throughout the treatment period, by careful adjustment of dosage, by initiating treatment with small doses, and by using the drug on an intermittent schedule when possible. When excessive diuresis occurs, the drug should be withdrawn until homeostasis is restored. When excessive electrolyte loss occurs, the dosage should be reduced or the drug temporarily withdrawn.

Initiation of diuretic therapy with ethacrynic acid in the cirrhotic patient with ascites is best carried out in the hospital. When maintenance therapy has been established, the individual can be satisfactorily followed as an outpatient.

Ethacrynic acid should be given with caution to patients with advanced cirrhosis of the liver, particularly those with a history of previous episodes of electrolyte imbalance or hepatic encephalopathy. Like other diuretics it may precipitate hepatic coma and death.

Too vigorous a diuresis, as evidenced by rapid and excessive weight loss, may induce an acute hypotensive episode. In elderly cardiac patients, rapid contraction of plasma volume and the resultant hemoconcentration should be avoided to prevent the development of thromboembolic episodes, such as cerebral vascular thromboses and pulmonary emboli which may be fatal. Excessive loss of potassium in patients receiving digitalis glycosides may precipitate digitalis toxicity. Care should also be exercised in patients receiving potassium-depleting steroids.

A number of possibly drug-related deaths have occurred in critically ill patients refractory to other diuretics. These generally have fallen into two categories: (1) patients with severe myocardial disease who have been receiving digitalis and presumably developed acute hypokalemia with fatal arrhythmia; (2) patients with severely decompensated hepatic cirrhosis with ascites, with or without accompanying encephalopathy, who were in electrolyte imbalance and died because of intensification of the electrolyte defect.

Deafness, tinnitus, and vertigo with a sense of fullness in the ears have occurred, most frequently in patients with severe impairment of renal function. These symptoms have been associated most often with intravenous administration and with doses in excess of those recommended. The deafness has usually been reversible and of short duration (one to 24 hours). However, in some patients the hearing loss has been permanent. A number of these patients were also receiving drugs known to be ototoxic. Ethacrynic acid may increase the ototoxic potential of other drugs (see PRECAUTIONS, Drug Interactions).

Lithium generally should not be given with diuretics (see PRECAUTIONS, Drug Interactions).

Adverse Reactions

Gastrointestinal
Anorexia, malaise, abdominal discomfort or pain, dysphagia, nausea, vomiting, and diarrhea have occurred. These are more frequent with large doses or after one to three months of continuous therapy. A few patients have had sudden onset of profuse, watery diarrhea. Discontinue Ethacrynic Acid Tablets, USP if diarrhea is severe and do not give it again. Gastrointestinal bleeding has occurred in some patients. Rarely, acute pancreatitis has been reported.

Metabolic
Reversible hyperuricemia and acute gout have been reported. Acute symptomatic hypoglycemia with convulsions occurred in two uremic patients who received doses above those recommended. Hyperglycemia has been reported. Rarely, jaundice and abnormal liver function tests have been reported in seriously ill patients receiving multiple drug therapy, including Ethacrynic Acid Tablets, USP.

Hematologic
Agranulocytosis or severe neutropenia has been reported in a few critically ill patients also receiving agents known to produce this effect. Thrombocytopenia has been reported rarely. Henoch-Schönlein purpura has been reported rarely in patients with rheumatic heart disease receiving multiple drug therapy, including Ethacrynic Acid Tablets, USP.

Special Senses (see WARNINGS)
Deafness, tinnitus and vertigo with a sense of fullness in the ears, and blurred vision have occurred.

Central Nervous System
Headache, fatigue, apprehension, confusion.

Miscellaneous
Skin rash, fever, chills, hematuria.

Overdosage

Overdosage may lead to excessive diuresis with electrolyte depletion and dehydration.

In the event of overdosage, symptomatic and supportive measures should be employed. Emesis should be induced or gastric lavage performed. Correct dehydration, electrolyte imbalance, hepatic coma, and hypotension by established procedures. If required, give oxygen or artificial respiration for respiratory impairment.

In the mouse, the oral LD₅₀ of ethacrynic acid is 627 mg/kg.

Dosage And Administration

Dosage must be regulated carefully to prevent a more rapid or substantial loss of fluid or electrolyte than is indicated or necessary. The magnitude of diuresis and natriuresis is largely dependent on the degree of fluid accumulation present in the patient. Similarly, the extent of potassium excretion is determined in large measure by the presence and magnitude of aldosteronism.

Oral Use
Ethacrynic Acid Tablets, USP are available for oral use as 25 mg tablets.

Dosage: To Initiate Diuresis

In Adults: The smallest dose required to produce gradual weight loss (about 1 pound to 2 pounds per day) is recommended. Onset of diuresis usually occurs at 50 mg to 100 mg for adults. After diuresis has been achieved, the minimally effective dose (usually from 50 mg to 200 mg daily) may be given on a continuous or intermittent dosage schedule. Dosage adjustments are usually in 25 mg to 50 mg increments to avoid derangement of water and electrolyte excretion.

The patient should be weighed under standard conditions before and during the institution of diuretic therapy with this compound. Small alterations in dose should effectively prevent a massive diuretic response. The following schedule may be helpful in determining the smallest effective dose.

•  Day 1 — 50 mg once daily after a meal
•  Day 2 — 50 mg twice daily after meals, if necessary
•  Day 3 — 100 mg in the morning and 50 mg to 100 mg following the afternoon or evening meal, depending upon response to the morning dose.

A few patients may require initial and maintenance doses as high as 200 mg twice daily. These higher doses, which should be achieved gradually, are most often required in patients with severe, refractory edema.

In Pediatric Patients (excluding infants, see CONTRAINDICATIONS): The initial dose should be 25 mg. Careful stepwise increments in dosage of 25 mg should be made to achieve effective maintenance.

Maintenance Therapy
It is usually possible to reduce the dosage and frequency of administration once dry weight has been achieved.

Ethacrynic Acid Tablets, USP may be given intermittently after an effective diuresis is obtained with the regimen outlined above. Dosage may be on an alternate daily schedule or more prolonged periods of diuretic therapy may be interspersed with rest periods. Such an intermittent dosage schedule allows time for correction of any electrolyte imbalance and may provide a more efficient diuretic response.

The chloruretic effect of this agent may give rise to retention of bicarbonate and a metabolic alkalosis. This may be corrected by giving chloride (ammonium chloride or arginine chloride). Ammonium chloride should not be given to cirrhotic patients.

Ethacrynic Acid Tablets, USP has additive effects when used with other diuretics. For example, a patient who is on maintenance dosage of an oral diuretic may require additional intermittent diuretic therapy, such as an organomercurial, for the maintenance of basal weight. The intermittent use of Ethacrynic Acid Tablets, USP orally may eliminate the need for injections of organomercurials. Small doses of Ethacrynic Acid Tablets, USP may be added to existing diuretic regimens to maintain basal weight. This drug may potentiate the action of carbonic anhydrase inhibitors, with augmentation of natriuresis and kaliuresis. Therefore, when adding ethacrynic acid the initial dose and changes of dose should be in 25 mg increments, to avoid electrolyte depletion. Rarely, patients who failed to respond to ethacrynic acid have responded to older established agents.

While many patients do not require supplemental potassium, the use of potassium chloride or potassium sparing agents, or both, during treatment with Ethacrynic Acid Tablets, USP is advisable, especially in cirrhotic or nephrotic patients and in patients receiving digitalis.

Salt liberalization usually prevents the development of hyponatremia and hypochloremia. During treatment with Ethacrynic Acid Tablets, USP salt may be liberalized to a greater extent than with other diuretics. Cirrhotic patients, however, usually require at least moderate salt restriction concomitant with diuretic therapy.

How Supplied

Ethacrynic Acid Tablets, USP 25 mg, are white, capsule shaped scored (functional scoring) tablets debossed with 'SG' on scored side and '334' on the other side and supplied as

Bottles of 30 tablets: NDC 50228-334-30
Bottles of 100 tablets: NDC 50228-334-10
Bottles of 1000 tablets: NDC 50228-334-01

Principal Display Panel

NDC 50228-334-30

Ethacrynic Acid
Tablets, USP

25 mg

30 Tablets          Rx only

ScieGen Pharmaceuticals Inc.

PRINCIPAL DISPLAY PANEL - 30 Tablet Bottle Label - ethacrynic 02

NDC 50228-334-10

Ethacrynic Acid
Tablets, USP

25 mg

100 Tablets          Rx only

ScieGen Pharmaceuticals Inc.

NDC 50228-334-01

Ethacrynic Acid
Tablets, USP

25 mg

1,000 Tablets          Rx 0nly

ScieGen Pharmaceuticals Inc.