ETHACRYNIC SODIUM- ethacrynate sodium injection, powder, lyophilized, for solution
Mylan Institutional LLC
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).
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 molecular 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 molecular formula is C13 H11 Cl2 NaO4 and its structural formula is:
Intravenous ethacrynate sodium for injection is a sterile freeze-dried powder and is supplied in a vial containing ethacrynate sodium equivalent to ethacrynic acid 50 mg. The inactive ingredient is mannitol, 62.5 mg.
Pharmacokinetics and Metabolism
Ethacrynic acid acts on the ascending limb of the loop of Henle and on the proximal and distal tubules. Urinary output is usually dose dependent and related to the magnitude of fluid accumulation. Water and electrolyte excretion may be increased several times over that observed with thiazide diuretics, since ethacrynic acid inhibits reabsorption of a much greater proportion of filtered sodium than most other diuretic agents. Therefore, ethacrynic acid is effective in many patients who have significant degrees of renal insufficiency (see WARNINGS concerning deafness). Ethacrynic acid 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.
The electrolyte excretion pattern of ethacrynic acid varies from that of the thiazides and mercurial diuretics. Initial sodium and chloride excretion is usually substantial and chloride loss exceeds that of sodium. With prolonged administration, chloride excretion declines, and potassium and hydrogen ion excretion may increase. Ethacrynic acid is effective whether or not there is clinical acidosis or alkalosis.
Although ethacrynic acid, in carefully controlled studies in animals and experimental subjects, produces a more favorable sodium/potassium excretion ratio than the thiazides, in patients with increased diuresis excessive amounts of potassium may be excreted.
Onset of action is rapid, usually within 30 minutes after an oral dose of ethacrynic acid or within 5 minutes after an intravenous injection of ethacrynate sodium for injection. After oral use, diuresis peaks in about 2 hours and lasts about 6 to 8 hours.
The sulfhydryl binding propensity of ethacrynic acid differs somewhat from that of the organomercurials. Its mode of action is not by carbonic anhydrase inhibition.
Ethacrynic acid does not cross the blood-brain barrier.
INDICATIONS AND USAGE
Ethacrynic acid is 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.
- Intravenous ethacrynate sodium for injection 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 oral and parenteral ethacrynic acid 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, 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 (1 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).
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