Edecrin 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, crystalline powder, very slightly soluble in water, but soluble in most organic solvents such as alcohols, chloroform, and benzene. Its empirical formula is C13 H12 Cl2 O4 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 C13 H11 Cl2 NaO4 and its structural formula is:

EDECRIN is supplied as 25 mg tablets for oral use. The tablets contain the following inactive ingredients: colloidal silicon dioxide, lactose, magnesium stearate, starch and talc. Intravenous SODIUM EDECRIN (Ethacrynate Sodium) is a sterile freeze-dried powder and is supplied in a vial containing:

Ethacrynate sodium equivalent
to ethacrynic acid...............................................................................50.0 mg

Inactive ingredient:
Mannitol..............................................................................................62.5 mg

Edecrin Precautions

General

Weakness, muscle cramps, paresthesias, thirst, anorexia, and signs of hyponatremia, hypokalemia, and/or hypochloremic alkalosis may occur following vigorous or excessive diuresis and these may be accentuated by rigid salt restriction. Rarely, tetany has been reported following vigorous diuresis. During therapy with ethacrynic acid, liberalization of salt intake and supplementary potassium chloride are often necessary.

When a metabolic alkalosis may be anticipated, e.g., in cirrhosis with ascites, the use of potassium chloride or a potassium-sparing agent before and during therapy with EDECRIN may mitigate or prevent the hypokalemia.

Loop diuretics have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.

The safety and efficacy of ethacrynic acid in hypertension have not been established. However, the dosage of coadministered antihypertensive agents may require adjustment.

Orthostatic hypotension may occur in patients receiving other antihypertensive agents when given ethacrynic acid.

EDECRIN has little or no effect on glomerular filtration or on renal blood flow, except following pronounced reductions in plasma volume when associated with rapid diuresis. A transient increase in serum urea nitrogen may occur. Usually, this is readily reversible when the drug is discontinued.

As with other diuretics used in the treatment of renal edema, hypoproteinemia may reduce responsiveness to ethacrynic acid and the use of salt-poor albumin should be considered.

A number of drugs, including ethacrynic acid, have been shown to displace warfarin from plasma protein; a reduction in the usual anticoagulant dosage may be required in patients receiving both drugs.

EDECRIN may increase the risk of gastric hemorrhage associated with corticosteroid treatment.

Laboratory Tests

Frequent serum electrolyte, CO2 and BUN determinations should be performed early in therapy and periodically thereafter during active diuresis. Any electrolyte abnormalities should be corrected or the drug temporarily withdrawn.

Increases in blood glucose and alterations in glucose tolerance tests have been observed in patients receiving EDECRIN.

Lithium generally should not be given with diuretics because they reduce its renal clearance and add a high risk of lithium toxicity. Read circulars for lithium preparations before use of such concomitant therapy.

EDECRIN may increase the ototoxic potential of other drugs such as aminoglycoside and some cephalosporin antibiotics. Their concurrent use should be avoided.

A number of drugs, including ethacrynic acid, have been shown to displace warfarin from plasma protein; a reduction in the usual anticoagulant dosage may be required in patients receiving both drugs.

In some patients, the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when EDECRIN and non-steroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

There was no evidence of a tumorigenic effect in a 79-week oral chronic toxicity study in rats at doses up to 45 times the human dose.

Ethacrynic acid had no effect on fertility in a two-litter study in rats or a two-generation study in mice at 10 times the human dose.

Pregnancy

Pregnancy Category B: Reproduction studies in the mouse and rabbit at doses up to 50 times the human dose showed no evidence of external abnormalities of the fetus due to EDECRIN.

In a two-litter study in the dog and rat, oral doses of 5 or 20 mg/kg/day (2½ or 10 times the human dose), respectively, did not interfere with pregnancy or with growth and development of the pups. Although there was reduction in the mean body weights of the fetuses in a teratogenic study in the rat at a dose level of 100 mg/kg (50 times the human dose), there was no effect on mortality or postnatal development. Functional and morphologic abnormalities were not observed.

There are, however, no adequate and well-controlled studies in pregnant women. Since animal reproduction studies are not always predictive of human response, EDECRIN should be used during pregnancy only if clearly needed.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from EDECRIN, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

There are no well-controlled clinical trials in pediatric patients. The information on oral dosing in pediatric patients, other than infants, is supported by evidence from empiric use in this age group.

For information on oral use in pediatric patients, other than infants, see INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION.

Safety and effectiveness of oral and parenteral use in infants have not been established (see CONTRAINDICATIONS).

Safety and effectiveness of intravenous use in pediatric patients have not been established (see DOSAGE AND ADMINISTRATION, Intravenous Use).

Geriatric Use

Of the total number of subjects in clinical studies of EDECRIN/SODIUM EDECRIN, approximately 224 patients (21%) were 65 to 74 years of age, while approximately 100 patients (9%) were 75 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. (See WARNINGS.)

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. (See CONTRAINDICATIONS.)

Edecrin 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 and the intravenous LD50 of ethacrynate sodium is 175 mg/kg.