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Aldactone®
(spironolactone)


DESCRIPTIONCLINICAL PHARMACOLOGYINDICATIONS AND USAGECONTRAINDICATIONSWARNINGSPRECAUTIONSADVERSE REACTIONSDOSAGE AND ADMINISTRATIONHOW SUPPLIED


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WARNING

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

DESCRIPTION

Aldactone oral tablets contain 25 mg, 50 mg, or 100 mg of the aldosterone antagonist spironolactone, 17-hydroxy-7alpha-mercapto-3-oxo-17alpha-pregn-4-ene-21-carboxylic acid gamma-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, hydroxypropyl methylcellulose, iron oxide, magnesium stearate, polyethylene glycol, povidone, and titanium dioxide.


CLINICAL PHARMACOLOGY

Mechanism of action: Aldactone (spironolactone) is a specific pharmacologic antagonist of aldosterone, acting primarily through competitive binding of receptors at the aldosterone-dependent sodium-potassium exchange site in the distal convoluted renal tubule. Aldactone causes increased amounts of sodium and water to be excreted, while potassium is retained. Aldactone acts both as a diuretic and as an antihypertensive drug by this mechanism. It may be given alone or with other diuretic agents which act more proximally in the renal tubule.

Aldosterone antagonist activity: 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 provides effective therapy for the edema and ascites in those conditions. Aldactone counteracts secondary aldosteronism induced by the volume depletion and associated sodium loss caused by active diuretic therapy.

Aldactone 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 inhibits the exchange of sodium for potassium in the distal renal tubule and helps to prevent potassium loss.

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

Pharmacokinetics: Spironolactone is rapidly and extensively metabolized. Sulfur-containing products are the predominant metabolites and are thought to be primarily responsible, together with 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 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.

Accumulation Factor:
AUC (0-24 hr,
day 15/AUC
(0-24 hr, day 1)
Mean Peak Serum Concentration Mean (SD) Post-Steady State Half-Life
7-alpha-(thiomethyl) spirolactone (TMS) 1.25 391 ng/mL at 3.2 hr 13.8 hr (6.4) (terminal)
6-beta-hydroxy-7-alpha-(thiomethyl) spirolactone (HTMS) 1.50 125 ng/mL at 5.1 hr 15.0 hr (4.0) (terminal)
Canrenone (C) 1.41 181 ng/mL at 4.3 hr 16.5 hr (6.3) (terminal)
Spironolactone 1.30 80 ng/mL at 2.6 hr Approximately 1.4 hr (0.5) (beta half-life)

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-alpha-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 in vivo activities.

Both spironolactone and canrenone 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 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.


INDICATIONS AND USAGE

Aldactone (spironolactone) is indicated in the management of:

Primary hyperaldosteronism for:

Edematous conditions for patients with:

Essential hypertension

Hypokalemia

Usage in Pregnancy. The routine use of diuretics in an otherwise healthy woman is inappropriate and exposes mother and fetus to unnecessary hazard. Diuretics do not prevent development of toxemia of pregnancy, and there is no satisfactory evidence that they are useful in the treatment of developing toxemia.

Edema during pregnancy may arise from pathologic causes or from the physiologic and mechanical consequences of pregnancy.

Aldactone is indicated in pregnancy when edema is due to pathologic causes just as it is in the absence of pregnancy (however, see Warnings section). Dependent edema in pregnancy, resulting from restriction of venous return by the expanded uterus, is properly treated through elevation of the lower extremities and use of support hose; use of diuretics to lower intravascular volume in this case is unsupported and unnecessary. There is hypervolemia during normal pregnancy which is not harmful to either the fetus or the mother (in the absence of cardiovascular disease), but which is associated with edema, including generalized edema, in the majority of pregnant women. If this edema produces discomfort, increased recumbency will often provide relief. In rare instances, this edema may cause extreme discomfort which is not relieved by rest. In these cases, a short course of diuretics may provide relief and may be appropriate.


CONTRAINDICATIONS

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


WARNINGS

Potassium supplementation, either in the form of medication or as a diet rich in potassium, should not ordinarily be given in association with Aldactone therapy. Excessive potassium intake may cause hyperkalemia in patients receiving Aldactone (see Precautions section). Aldactone should not be administered concurrently with other potassium-sparing diuretics. Aldactone, when used with ACE inhibitors, even in the presence of a diuretic, has been associated with severe hyperkalemia. Extreme caution should be exercised when Aldactone is given concomitantly with ACE inhibitors (see Precautions: Drug interactions).

Spironolactone has been shown to be a tumorigen in chronic toxicity studies performed in rats, with its proliferative effects manifested on endocrine organs and the liver. In one study using 25, 75, and 250 times the usual daily human dose (2 mg/kg) there was a statistically significant dose-related increase in benign adenomas of the thyroid and testes. In female rats there was a statistically significant increase in malignant mammary tumors at the mid-dose only. In male rats there was a dose-related increase in proliferative changes in the liver. At the highest dosage level (500 mg/kg) the range of effects included hepatocytomegaly, hyperplastic nodules, and hepatocellular carcinoma; the last was not statistically significant at a value of p = 0.05. A dose-related (above 20 mg/kg/day) incidence of myelocytic leukemia was observed in rats fed daily doses of potassium canrenoate for a period of one year. In long-term (two-year) oral carcinogenicity studies of potassium canrenoate in the rat, myelocytic leukemia and hepatic, thyroid, testicular, and mammary tumors were observed. Potassium canrenoate did not produce a mutagenic effect in tests using bacteria or yeast. It did produce a positive mutagenic effect in several in vitro tests in mammalian cells following metabolic activation. In an in vivo mammalian system potassium canrenoate was not mutagenic. Canrenone and canrenoic acid are the major metabolites of potassium canrenoate. Spironolactone is also metabolized to canrenone. An increased incidence of leukemia was not observed in chronic rat toxicity studies conducted with spironolactone at doses up to 500 mg/kg/day.


PRECAUTIONS

General: Because of the diuretic action of Aldactone (spironolactone), patients should be carefully evaluated for possible disturbances of fluid and electrolyte balance. 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. Hyperkalemia can be treated promptly by the rapid intravenous administration of glucose (20% to 50%) and regular insulin, using 0.25 to 0.5 units of insulin per gram of glucose. This is a temporary measure to be repeated as required. Aldactone use should be discontinued and potassium intake (including dietary potassium) restricted.

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.

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 is administered in combination with other diuretics.

Gynecomastia may develop in association with the use of 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 is discontinued. In rare instances some breast enlargement may persist when Aldactone is discontinued.

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

A determination of serum electrolytes to detect possible electrolyte imbalance should be performed at periodic intervals.

Drug interactions: When used in combination with other diuretics or antihypertensive agents, Aldactone potentiates their effects. Therefore, the dosage of such drugs, particularly the ganglionic blocking agents, should be reduced by at least 50% when Aldactone is added to the regimen.

Concomitant administration of potassium-sparing diuretics with ACE inhibitors or indomethacin has been associated with severe hyperkalemia.

Spironolactone reduces the vascular responsiveness to norepinephrine. Therefore, caution should be exercised in the management of patients subjected to regional or general anesthesia while they are being treated with Aldactone.

Spironolactone has been shown to increase the half-life of digoxin. This may result in increased serum digoxin levels and subsequent digitalis toxicity. It may be necessary to reduce the maintenance and digitalization doses when spironolactone is administered, and the patient should be carefully monitored to avoid over- or underdigitalization.

Drug/Laboratory test interactions: Several reports of possible interference with digoxin radioimmunoassays by spironolactone, or its metabolites, have appeared in the literature. Neither the extent nor the potential clinical significance of its interference (which may be assay-specific) has been fully established.

Usage in pregnancy: Spironolactone or its metabolites may cross the placental barrier. Therefore, the use of Aldactone in pregnant women requires that the anticipated benefit be weighed against possible hazard to the fetus.

Nursing mothers: Canrenone, a metabolite of spironolactone, appears in breast milk. If use of the drug is deemed essential, an alternative method of infant feeding should be instituted.


ADVERSE REACTIONS

Gynecomastia is observed not infrequently. A few cases of agranulocytosis have been reported in patients taking spironolactone. Other adverse reactions that have been reported in association with Aldactone are: gastrointestinal symptoms including cramping and diarrhea, drowsiness, lethargy, headache, maculopapular or erythematous cutaneous eruptions, urticaria, mental confusion, drug fever, ataxia, inability to achieve or maintain erection, irregular menses or amenorrhea, postmenopausal bleeding, hirsutism, deepening of the voice, gastric bleeding, ulceration, gastritis, vomiting, and anaphylactic reactions. Carcinoma of the breast has been reported in patients taking spironolactone, but a cause and effect relationship has not been established. A very few cases of mixed cholestatic/hepatocellular toxicity, with one reported fatality, have been reported with spironolactone administration.

Adverse reactions are usually reversible upon discontinuation of the drug.


DOSAGE AND ADMINISTRATION

Primary hyperaldosteronism. Aldactone may be employed as an initial diagnostic measure to provide presumptive evidence of primary hyperaldosteronism while patients are on normal diets.

After the diagnosis of hyperaldosteronism has been established by more definitive testing procedures, Aldactone may be administered in doses of 100 to 400 mg daily in preparation for surgery. For patients who are considered unsuitable for surgery, Aldactone may be employed for long-term maintenance therapy at the lowest effective dosage determined for the individual patient.

Edema in adults (congestive heart failure, hepatic cirrhosis, or nephrotic syndrome). An initial daily dosage of 100 mg of Aldactone administered in either single or divided doses is recommended, but may range from 25 to 200 mg daily. When given as the sole agent for diuresis, Aldactone should be continued for at least five days at the initial dosage level, after which it may be adjusted to the optimal therapeutic or maintenance level administered in either single or divided daily doses. If, after five days, an adequate diuretic response to Aldactone has not occurred, a second diuretic which acts more proximally in the renal tubule may be added to the regimen. Because of the additive effect of Aldactone when administered concurrently with such diuretics, an enhanced diuresis usually begins on the first day of combined treatment; combined therapy is indicated when more rapid diuresis is desired. The dosage of Aldactone should remain unchanged when other diuretic therapy is added.

Edema in children. The initial daily dosage should provide approximately 1.5 mg of Aldactone per pound of body weight (3.3 mg/kg) administered in either single or divided doses.

Essential hypertension. For adults, an initial daily dosage of 50 to 100 mg of Aldactone administered in either single or divided doses is recommended. Aldactone may also be given with diuretics which act more proximally in the renal tubule or with other antihypertensive agents. Treatment with Aldactone should be continued for at least two weeks, since the maximum response may not occur before this time. Subsequently, dosage should be adjusted according to the response of the patient.

Hypokalemia. Aldactone in a dosage ranging from 25 mg to 100 mg daily is useful in treating a diuretic-induced hypokalemia, when oral potassium supplements or other potassium-sparing regimens are considered inappropriate.


HOW SUPPLIED

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

NDC Number Size
0025-1001-31 bottle of 100
0025-1001-51 bottle of 500
0025-1001-52 bottle of 1000
0025-1001-55 bottle of 2500
0025-1001-34 carton of 100 unit dose

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

NDC Number Size
0025-1041-31 bottle of 100
0025-1041-34 carton of 100 unit dose

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

NDC Number Size
0025-1031-31 bottle of 100
0025-1031-34 carton of 100 unit dose

Store below 77°F (25°C).

Caution: Federal law prohibits dispensing without prescription.

11/18/96

G.D. Searle & Co.
Chicago IL 60680 USA

©1996, G.D. Searle & Co.


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