ETHACRYNATE SODIUM 50 mg/50mL Injection, Powder, For Solution — NDC 42023-157-01 (Billing 42023-0157-01)

WARNINGS The effects of ethacrynate sodium 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 When excessive diuresis occurs, the drug should be withdrawn until homeostasis is restored.

When excessive electrolyte loss occurs, the dosage should be reduced or the drug temporarily withdrawn.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 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 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. 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 ).

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 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-Schönlein 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 Par Health at 1-800-828-9393 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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. Ethacrynate sodium 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 ethacrynate sodium 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.

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 ethacrynate sodium 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. Ethacrynate sodium 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. Ethacrynate sodium may increase the risk of gastric hemorrhage associated with corticosteroid treatment. Laboratory Tests Frequent serum electrolyte, CO 2 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 ethacrynate sodium. 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. Ethacrynate sodium 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 ethacrynate sodium 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 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 ethacrynate sodium.

In a two-litter study in the dog and rat, oral doses of 5 or 20 mg/kg/day (2 1/2; 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 weight… [Excerpted — this section continues on DailyMed.]