Aldactone (Spironolactone) has been shown to be a tumorigen in chronic toxicity studies in rats (see ). Aldactone (Spironolactone) should be used only in those conditions described under . Unnecessary use of this drug should be avoided.

Aldactone (Spironolactone) oral tablets contain 25 mg, 50 mg, or 100 mg of the aldosterone antagonist spironolactone, 17-hydroxy-7α-mercapto-3-oxo-17α-pregn-4-ene-21-carboxylic acid γ-lactone acetate, which has the following structural formula:

Spironolactone is practically insoluble in water, soluble in alcohol, and freely soluble in benzene and in chloroform.

Inactive ingredients include calcium sulfate, corn starch, flavor, hypromellose, iron oxide, magnesium stearate, polyethylene glycol, povidone, and titanium dioxide.

Increased levels of the mineralocorticoid, aldosterone, are present in primary and secondary hyperaldosteronism. Edematous states in which secondary aldosteronism is usually involved include congestive heart failure, hepatic cirrhosis, and the nephrotic syndrome. By competing with aldosterone for receptor sites, Aldactone (Spironolactone) provides effective therapy for the edema and ascites in those conditions. Aldactone (Spironolactone) counteracts secondary aldosteronism induced by the volume depletion and associated sodium loss caused by active diuretic therapy.

Aldactone (Spironolactone) is effective in lowering the systolic and diastolic blood pressure in patients with primary hyperaldosteronism. It is also effective in most cases of essential hypertension, despite the fact that aldosterone secretion may be within normal limits in benign essential hypertension.

Through its action in antagonizing the effect of aldosterone, Aldactone (Spironolactone) inhibits the exchange of sodium for potassium in the distal renal tubule and helps to prevent potassium loss.

Aldactone (Spironolactone) has not been demonstrated to elevate serum uric acid, to precipitate gout, or to alter carbohydrate metabolism.

Aldactone (Spironolactone) is rapidly and extensively metabolized. Sulfur-containing products are the predominant metabolites and are thought to be primarily responsible, together with Aldactone (Spironolactone) , for the therapeutic effects of the drug. The following pharmacokinetic data were obtained from 12 healthy volunteers following the administration of 100 mg of spironolactone (Aldactone (Spironolactone) film-coated tablets) daily for 15 days. On the 15th day, spironolactone was given immediately after a low-fat breakfast and blood was drawn thereafter.

The pharmacological activity of spironolactone metabolites in man is not known. However, in the adrenalectomized rat the antimineralocorticoid activities of the metabolites C, TMS, and HTMS, relative to spironolactone, were 1.10, 1.28, and 0.32, respectively. Relative to spironolactone, their binding affinities to the aldosterone receptors in rat kidney slices were 0.19, 0.86, and 0.06, respectively.

In humans the potencies of TMS and 7-α-thiospirolactone in reversing the effects of the synthetic mineralocorticoid, fludrocortisone, on urinary electrolyte composition were 0.33 and 0.26, respectively, relative to spironolactone. However, since the serum concentrations of these steroids were not determined, their incomplete absorption and/or first-pass metabolism could not be ruled out as a reason for their reduced activities.

Spironolactone and its metabolites are more than 90% bound to plasma proteins. The metabolites are excreted primarily in the urine and secondarily in bile.

The effect of food on spironolactone absorption (two 100 mg Aldactone (Spironolactone) tablets) was assessed in a single-dose study of 9 healthy, drug-free volunteers. Food increased the bioavailability of unmetabolized spironolactone by almost 100%. The clinical importance of this finding is not known.

Aldactone (Spironolactone) is indicated in the management of:

Establishing the diagnosis of primary hyperaldosteronism by therapeutic trial.

Short-term preoperative treatment of patients with primary hyperaldosteronism.

Long-term maintenance therapy for patients with discrete aldosterone-producing adrenal adenomas who are judged to be poor operative risks or who decline surgery.

Long-term maintenance therapy for patients with bilateral micro or macronodular adrenal hyperplasia (idiopathic hyperaldosteronism).

Aldactone (Spironolactone) is contraindicated for patients with anuria, acute renal insufficiency, significant impairment of renal excretory function, or hyperkalemia.

Potassium supplementation, either in the form of medication or as a diet rich in potassium, should not ordinarily be given in association with Aldactone (Spironolactone) therapy.

Excessive potassium intake may cause hyperkalemia in patients receiving Aldactone (Spironolactone) (see ). Aldactone (Spironolactone) should not be administered concurrently with other potassium-sparing diuretics. Aldactone (Spironolactone) , when used with ACE inhibitors or indomethacin, even in the presence of a diuretic, has been associated with severe hyperkalemia. Extreme caution should be exercised when Aldactone (Spironolactone) is given concomitantly with these drugs.

Hyperkalemia may be fatal. It is critical to monitor and manage serum potassium in patients with severe heart failure receiving Aldactone (Spironolactone) . Avoid using other potassium-sparing diuretics. Avoid using oral potassium supplements in patients with serum potassium > 3.5 mEq/L. RALES excluded patients with a serum creatinine > 2.5 mg/dL or a recent increase in serum creatinine > 25%. The recommended monitoring for potassium and creatinine is one week after initiation or increase in dose of Aldactone (Spironolactone) , monthly for the first 3 months, then quarterly for a year, and then every 6 months. Discontinue or interrupt treatment for serum potassium > 5 mEq/L or for serum creatinine > 4 mg/dL. (See , and .)

Aldactone (Spironolactone) should be used with caution in patients with impaired hepatic function because minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

Lithium generally should not be given with diuretics (see ).

All patients receiving diuretic therapy should be observed for evidence of fluid or electrolyte imbalance, e.g., hypomagnesemia, hyponatremia, hypochloremic alkalosis, and hyperkalemia.

Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance, irrespective of cause, include dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting. Hyperkalemia may occur in patients with impaired renal function or excessive potassium intake and can cause cardiac irregularities, which may be fatal. Consequently, no potassium supplement should ordinarily be given with Aldactone (Spironolactone) .

Concomitant administration of potassium-sparing diuretics and ACE inhibitors or nonsteroidal anti-inflammatory drugs (NSAIDs), e.g., indomethacin, has been associated with severe hyperkalemia.

If hyperkalemia is suspected (warning signs include paresthesia, muscle weakness, fatigue, flaccid paralysis of the extremities, bradycardia and shock), an electrocardiogram (ECG) should be obtained. However, it is important to monitor serum potassium levels because mild hyperkalemia may not be associated with ECG changes.

If hyperkalemia is present, Aldactone (Spironolactone) should be discontinued immediately. With severe hyperkalemia, the clinical situation dictates the procedures to be employed. These include the intravenous administration of calcium chloride solution, sodium bicarbonate solution and/or the oral or parenteral administration of glucose with a rapid-acting insulin preparation. These are temporary measures to be repeated as required. Cationic exchange resins such as sodium polystyrene sulfonate may be orally or rectally administered. Persistent hyperkalemia may require dialysis.

Reversible hyperchloremic metabolic acidosis, usually in association with hyperkalemia, has been reported to occur in some patients with decompensated hepatic cirrhosis, even in the presence of normal renal function.

Dilutional hyponatremia, manifested by dryness of the mouth, thirst, lethargy, and drowsiness, and confirmed by a low serum sodium level, may be caused or aggravated, especially when Aldactone (Spironolactone) is administered in combination with other diuretics, and dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction rather than administration of sodium, except in rare instances when the hyponatremia is life-threatening.

Aldactone (Spironolactone) therapy may cause a transient elevation of BUN, especially in patients with preexisting renal impairment. Aldactone (Spironolactone) may cause mild acidosis.

Gynecomastia may develop in association with the use of Aldactone (Spironolactone) ; physicians should be alert to its possible onset. The development of gynecomastia appears to be related to both dosage level and duration of therapy and is normally reversible when Aldactone (Spironolactone) is discontinued. In rare instances some breast enlargement may persist when Aldactone (Spironolactone) is discontinued.

Orally administered Aldactone (Spironolactone) has been shown to be a tumorigen in dietary administration studies performed in rats, with its proliferative effects manifested on endocrine organs and the liver. In an 18-month study using doses of about 50, 150 and 500 mg/kg/day, there were statistically significant increases in benign adenomas of the thyroid and testes and, in male rats, a dose-related increase in proliferative changes in the liver (including hepatocytomegaly and hyperplastic nodules). In a 24-month study in which the same strain of rat was administered doses of about 10, 30, 100 and 150 mg Aldactone (Spironolactone) /kg/day, the range of proliferative effects included significant increases in hepatocellular adenomas and testicular interstitial cell tumors in males, and significant increases in thyroid follicular cell adenomas and carcinomas in both sexes. There was also a statistically significant, but not dose-related, increase in benign uterine endometrial stromal polyps in females.

A dose-related (above 20 mg/kg/day) incidence of myelocytic leukemia was observed in rats fed daily doses of potassium canrenoate (a compound chemically similar to Aldactone (Spironolactone) and whose primary metabolite, canrenone, is also a major product of Aldactone (Spironolactone) in man) for a period of one year. In two-year studies in the rat, oral administration of potassium canrenoate was associated with myelocytic leukemia and hepatic, thyroid, testicular and mammary tumors.

Neither Aldactone (Spironolactone) nor potassium canrenoate produced mutagenic effects in tests using bacteria or yeast. In the absence of metabolic activation, neither Aldactone (Spironolactone) nor potassium canrenoate has been shown to be mutagenic in mammalian tests In the presence of metabolic activation, Aldactone (Spironolactone) has been reported to be negative in some mammalian mutagenicity tests and inconclusive (but slightly positive) for mutagenicity in other mammalian tests In the presence of metabolic activation, potassium canrenoate has been reported to test positive for mutagenicity in some mammalian tests inconclusive in others, and negative in still others.

In a three-litter reproduction study in which female rats received dietary doses of 15 and 50 mg Aldactone (Spironolactone) /kg/day, there were no effects on mating and fertility, but there was a small increase in incidence of stillborn pups at 50 mg/kg/day. When injected into female rats (100 mg/kg/day for 7 days, i.p.), Aldactone (Spironolactone) was found to increase the length of the estrous cycle by prolonging diestrus during treatment and inducing constant diestrus during a two-week post-treatment observation period. These effects were associated with retarded ovarian follicle development and a reduction in circulating estrogen levels, which would be expected to impair mating, fertility and fecundity. Aldactone (Spironolactone) (100 mg/kg/day), administered i.p. to female mice during a two-week cohabitation period with untreated males, decreased the number of mated mice that conceived (effect shown to be caused by an inhibition of ovulation) and decreased the number of implanted embryos in those that became pregnant (effect shown to be caused by an inhibition of implantation), and at 200 mg/kg, also increased the latency period to mating.

The following adverse reactions have been reported and, within each category (body system), are listed in order of decreasing severity.

The oral LD of Aldactone (Spironolactone) is greater than 1,000 mg/kg in mice, rats, and rabbits.

Acute overdosage of Aldactone (Spironolactone) may be manifested by drowsiness, mental confusion, maculopapular or erythematous rash, nausea, vomiting, dizziness, or diarrhea. Rarely, instances of hyponatremia, hyperkalemia, or hepatic coma may occur in patients with severe liver disease, but these are unlikely due to acute overdosage. Hyperkalemia may occur, especially in patients with impaired renal function.

Aldactone (Spironolactone) 25 mg tablets are round, light yellow, film-coated, with SEARLE and 1001 debossed on one side and Aldactone (Spironolactone) and 25 on the other side, supplied as:

Aldactone (Spironolactone) 50 mg tablets are oval, light orange, scored, film-coated, with SEARLE and 1041 debossed on the scored side and Aldactone (Spironolactone) and 50 on the other side, supplied as:

Aldactone (Spironolactone) 100 mg tablets are round, peach-colored, scored, film-coated, with SEARLE and 1031 debossed on the scored side and Aldactone (Spironolactone) and 100 on the other side, supplied as:

Store below 77°F (25°C).

NDC 0025-1001-31

NDC 0025-1041-31

NDC 0025-1031-31