Ethacrynate Sodium for Injection, USP 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).

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, crystalline powder, very slightly soluble in water, but soluble in most organic solvents such as alcohols, chloroform, and benzene. Its empirical formula is C13H12Cl2O4 and its structural formula is:Ethacrynate sodium, the sodium salt of ethacrynic acid, is soluble in water at 25°C to the extent of about 7 percent. Solutions of the sodium salt are relatively stable at about pH 7 at room temperature for short periods, but as the pH or temperature increases the solutions are less stable.The molecular weight of ethacrynate sodium is 325.12. Its empirical formula is C13H11Cl2NaO4 and its structural formula is:Intravenous Ethacrynate Sodium is a sterile freeze-dried powder and is supplied in a vial containing: Ethacrynate sodium equivalent to ethacrynic acid - 50 mgInactive ingredient:Mannitol - 62.5 mg

Ethacryname Sodium is indicated for treatment of edema when as agent with greater diuretic potential than those commonly employed is required.

1. Treatment of the edema associated with congestive heart failure, cirrhosis of the liver and renal disease, including the nephrotic syndrome.
2. Short-term management of ascites due to malignancy, idiopathic edema, and lymphedema.
3. Short-term management of hospitalized pediatric patients, other than infants, with congenital heart disease or the nephrotic syndrome.
4. Intravenous ethacrynate sodium is indicated when a rapid onset of diuresis is desired, e.g., in acute pulmonary edema, or when gastrointestinal absorption is impaired or oral medication is not practicable.

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 parenteral ethacrynate sodium is contraindicated.

Hypersensitivity to any component of this product.

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, byinitiating 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 drugtemporarily withdrawn.

Initiation of diuretic therapy with ethacrynate sodium 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.

Ethacrynate sodium 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 thromboembolicepisodes, 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 withfatal 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. Ethacrynate sodium may increase the ototoxic potential of other drugs (see PRECAUTIONS, Drug Interactions).

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

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 ethacrynate sodium 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 ethacrynate sodium.

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-Schӧnlein purpura has been reported rarely in patients with rheumatic heart disease receiving multiple drug therapy, including ethacrynate sodium.

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.

Ethacrynate sodium occasionally has caused local irritation and pain after intravenous use.

For medical advice about adverse reactions contact your medical professional. To report SUSPECTED ADVERSE REACTIONS, contact Leading Pharma at 1-844-740-7500 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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

In the event of overdosage; symptomatic and supportive measures should be employed. 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 and the intravenous LD50 of ethacrynate sodium is 175 mg/kg.

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 as 25 mg tablets.

Dosage: To Initiate Diuresis

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

Intravenous Use

Intravenous ethacrynate sodium is for intravenous use when oral intake is impractical or in urgent conditions, such as acute pulmonary edema.

The usual intravenous dose for the average sized adult is 50 mg, or 0.5 to 1 mg per kg of body weight. Usually only one dose has been necessary; occasionally a second dose at a new injection site, to avoid possible thrombophlebitis, may be required. A single intravenous dose not exceeding 100 mg has been used in critical situations.

Insufficient pediatric experience precludes recommendation for this age group.

To reconstitute the dry material, add 50 ml of 5 percent Dextrose Injection, or Sodium Chloride Injection to the vial. Occasionally, some 5 percent Dextrose Injection solutions may have a low pH (below 5). The resulting solution with such a diluent may be hazy or opalescent. Intravenous use of such a solution is not recommended. Inspect the vial containing Intravenous ethacrynate sodium for particulate matter and discoloration before use.

The solution may be given slowly through the tubing of a running infusion or by direct intravenous injection over a period of several minutes. Do not mix this solution with whole blood or its derivatives. Discard unused reconstituted solution after 24 hours.

Ethacrynate sodium should not be given subcutaneously or intramuscularly because of local pain and irritation.

Ethacrynate sodium for injection is a dry white material either in a plug form or as a powder.

NDC 69315-701-50: Ethacrynate sodium equivalent to 50 mg of ethacrynic acid, in a single dose vial.

Storage

Store in a tightly closed container at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].

Rx only

Made in Italy

Manufactured for:

VPI Pharmaceuticals Inc.

Kirkland, Quebec, Canada,

H9H 4R9

Distributed by:

Leading Pharma, LLC

Fairfield, New Jersey 07004

Version: June 2020