Ethacrynic Acid (Page 2 of 3)

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 Any electrolyte abnormalities should be corrected or the drug temporarily withdrawn.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 ethacrynic acid.

Drug Interactions

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.

Ethacrynic acid 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 ethacrynic acid 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 ethacrynic acid.

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, ethacrynic acid 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 ethacrynic acid, 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 use in infants have not been established (see CONTRAINDICATIONS).

Geriatric Use

Of the total number of subjects in clinical studies of ethacrynic acid, 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).

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 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.

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.

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.

To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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.

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 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 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. 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 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 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, 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 orally may eliminate the need for injections of organomercurials. Small doses of ethacrynic acid tablets 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 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 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, 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.