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Manufacturer
ACCORD HEALTHCA
SKU
16729022616

spironolactone 50 mg tablet (generic aldactone)

Generic
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Product Information

Uses

Edema

Spironolactone is used in the management of edema associated with excessive aldosterone excretion such as idiopathic edema and edema accompanying cirrhosis of the liver, nephrotic syndrome, and heart failure, usually in conjunction with other diuretics. Careful etiologic diagnosis should precede the use of any diuretic. Although thiazides and chlorthalidone are more rapidly acting and more effective diuretics, spironolactone does not cause potassium depletion or affect glucose metabolism or uric acid excretion as may result from thiazide or chlorthalidone therapy. In addition, spironolactone is a useful adjunct to thiazide therapy when diuresis is inadequate or reduction of potassium excretion is necessary. When used in conjunction with a thiazide diuretic in the treatment of edema associated with cirrhosis of the liver, spironolactone should be given for 2-3 days prior to administration of the thiazide diuretic in order to prevent potassium depletion and precipitation of hepatic coma.

Hypertension

Spironolactone is used in the management of hypertension, usually in conjunction with other diuretics or hypotensive agents. Used alone, spironolactone produces a modest lowering of blood pressure in most patients with hypertension, and blood pressure returns to within normal limits in about 20% of patients. Because of established clinical benefits (e.g., reductions in overall mortality and in adverse cardiovascular, cerebrovascular, and renal outcomes), angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics generally are considered the preferred drugs for the initial management of hypertension in adults; however, aldosterone antagonists (e.g., spironolactone, eplerenone) may be considered as add-on therapy if goal blood pressure cannot be achieved with the recommended drugs. Aldosterone antagonists may be particularly useful in selected patients with heart failure or following myocardial infarction; the American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) recommend the addition of an aldosterone antagonist (i.e., spironolactone or eplerenone) in selected patients with heart failure or following myocardial infarction when left ventricular ejection fraction (LVEF) is reduced and the patient is already receiving an agent to inhibit the renin-angiotensin system (e.g., ACE inhibitor, angiotensin II receptor antagonist) and a β-adrenergic blocking agent (β-blocker). For information on antihypertensive therapy for patients with heart failure or following myocardial infarction, see and also

Spironolactone may be useful to decrease the potassium loss caused by other diuretics and potentiate the hypotensive effects of those agents or other more potent hypotensive agents. In addition, the drug may be useful in hypertensive patients with gout or diabetes mellitus that may be aggravated by thiazide diuretics. Potassium-sparing diuretics should be avoided in patients with renal insufficiency and in those with hyperkalemia who have serum potassium concentrations exceeding 5 mEq/L while not receiving drug therapy.

For additional information on the role of aldosterone antagonists in the management of hypertension in patients with underlying cardiovascular risk factors and information on overall principles and expert recommendations for treatment of hypertension,

Heart Failure

Spironolactone is used in the management of severe heart failure (New York Heart Association [NYHA] functional class III-IV) in conjunction with standard therapy for heart failure to increase survival and reduce heart failure-related hospitalizations.

Current guidelines for the management of heart failure in adults generally recommend a combination of drug therapies to reduce morbidity and mortality, including neurohormonal antagonists (e.g., ACE inhibitors, angiotensin II receptor antagonists, angiotensin receptor-neprilysin inhibitors [ARNIs], β-blockers, aldosterone receptor antagonists) that inhibit the detrimental compensatory mechanisms in heart failure. Additional agents (e.g., cardiac glycosides, diuretics, sinoatrial modulators [i.e., ivabradine]) added to a heart failure treatment regimen in selected patients have been associated with symptomatic improvement and/or reduction in heart failure-related hospitalizations. For additional information on the management of heart failure, , , and . ACCF and AHA recommend the addition of an aldosterone antagonist (i.e., spironolactone or eplerenone) in selected patients with heart failure and reduced LVEF who are already receiving a β-blocker and an agent to inhibit the renin-angiotensin-aldosterone (RAA) system (e.g., ACE inhibitor, angiotensin II receptor antagonist, ARNI); careful patient selection is required to minimize the risk of hyperkalemia and renal insufficiency.(See Cautions: Electrolyte and Metabolic Effects.)

Aldosterone receptor antagonists are also recommended, unless contraindicated, in conjunction with other heart failure therapy to reduce morbidity and mortality following acute myocardial infarction in patients with reduced LVEF who develop symptoms of heart failure or who have a history of diabetes mellitus. ACCF and AHA state that there are limited data to support or refute whether spironolactone and eplerenone are interchangeable. The perceived difference between eplerenone and spironolactone is attributed to the selectivity of aldosterone receptor antagonism and not the effectiveness of mineralocorticoid-blocking activity.(See Pharmacology.)

The concomitant use of spironolactone and an ACE inhibitor had been considered relatively contraindicated because of the potential for developing severe hyperkalemia. In addition, it was believed that ACE inhibitors would inhibit formation of aldosterone, a hormone associated with the pathophysiology of heart failure, by suppressing the RAA system. However, results of several studies have indicated that ACE inhibitors only transiently inhibit the production of aldosterone, and the addition of spironolactone to ACE inhibitor therapy may augment the suppressive effect of ACE inhibitors on aldosterone.(See Pharmacology: Cardiovascular Effects.)

Results of a randomized, multicenter, controlled study (Randomized Aldactone Evaluation Study [RALES]) in 1663 patients with moderate or severe heart failure (NYHA functional class III or IV) and LVEF of 35% or less indicate that addition of low-dose (25-50 mg daily) spironolactone to standard therapy (e.g., an ACE inhibitor and a loop diuretic with or without a cardiac glycoside was associated with decreases in overall mortality and hospitalization (for worsening heart failure) rates of approximately 30 and 35%, respectively, compared with standard therapy and placebo. The reduction in mortality and hospitalization rates was observed within 2-3 months of initiation of combined therapy and continued throughout the study (mean follow-up: 24 months). The combined therapy also was associated with an improvement in NYHA functional class in about 41% of patients. Because interim analysis of this study after a mean follow-up of 24 months revealed that morbidity and death were reduced significantly in patients receiving spironolactone concomitantly with standard therapy compared with those receiving standard therapy and placebo, the study was discontinued.

Spironolactone also is used for the management of edema and sodium retention in patients with heart failure who do not respond adequately to or are intolerant of other therapeutic measures.(See Uses: Edema.)

Primary Hyperaldosteronism

Spironolactone is used in the diagnosis of primary hyperaldosteronism; however, test results may be equivocal and more complete diagnostic studies are often required.

Spironolactone is also used for the short-term preoperative treatment of primary hyperaldosteronism and for long-term maintenance therapy in patients with discrete aldosterone-producing adrenal adenomas who cannot undergo adrenalectomy or who decline surgery. The drug is also used for long-term maintenance therapy for patients with bilateral micronodular or macronodular adrenal hyperplasia (idiopathic hyperaldosteronism).

Hypokalemia

Spironolactone is used in the treatment of hypokalemia when oral potassium supplements or other measures are considered inappropriate or inadequate. The drug is also used for the prophylaxis of hypokalemia in patients taking cardiac glycosides when other measures are considered inappropriate or inadequate.

Precocious Puberty

Spironolactone is used for its antiandrogenic effects in combination with testolactone in the management of certain forms of gonadotropin releasing hormone (GnRH)-independent (peripheral) precocious puberty (e.g., familial male precocious puberty [ testotoxicosis]). Such therapy has effectively controlled acne, spontaneous erections, and aggressive behavior and slowed accelerated growth and skeletal maturation, at least in the short term (e.g., 2 years), in boys with familial precocious puberty. Neither drug alone effectively controls pubertal characteristics nor the rate of growth and skeletal maturation in boys with this condition, although some benefit (e.g., on height velocity) with testolactone alone may be apparent. Testolactone generally prevents the gynecomastia that may be associated with spironolactone. Testolactone also has been used in combination with other antiandrogens (e.g., flutamide) in the management of this condition, but experience is less extensive. While spironolactone currently is the most widely used antiandrogenic drug in familial male precocious puberty, alternative antiandrogenic drugs (e.g., flutamide) that avoid some of the potentially serious adverse effects of spironolactone therapy (e.g., mineralocorticoid-antagonist effects) are being studied for this condition and congenital adrenal hyperplasia. However, concerns about potential hepatotoxic effects of flutamide may limit the use of this drug in such precocious puberty. A gradual escape from the beneficial effects of combined therapy with spironolactone and testolactone may occur during long-term therapy because of the development of secondary GnRH-dependent precocity or pubertal increases in gonadotropins. In such cases, a GnRH analog has been added to the regimen to restore effective control of puberty progression. Additional study and experience are needed to elucidate further the optimum regimens for the management of these forms of precocious puberty and the long-term effects of such therapy, and such patients should be managed in consultation with experts in the diagnosis and treatment of these conditions. Combinations of testolactone with flutamide or with spironolactone also have been studied as a component in the complex regimen of therapy for boys and girls with congenital adrenal hyperplasia caused by steroid 21-hydroxylase or 11-hydroxylase deficiency; the rationale for the addition of such therapy to the therapeutic regimen was similar to that for familial male precocious puberty (i.e., to control androgenic effects and accelerated growth and skeletal maturation).

Other Uses

Spironolactone has been used effectively in the treatment of hirsutism in women with polycystic ovary syndrome or idiopathic hirsutism. In the treatment of hirsutism, spironolactone appears to exert its therapeutic effects by interfering with ovarian androgen secretion and peripheral androgen activity.

Spironolactone has also been used as an adjunct in the treatment of myasthenia gravis and familial periodic paralysis.

Dosage and Administration

Administration

Spironolactone is administered orally. For administration in children, spironolactone tablets may be pulverized and administered as an oral suspension in cherry syrup.

Although it has frequently been recommended that spironolactone be administered in 3 or 4 doses daily, more recent information suggests that 1 or 2 doses daily may be adequate.

Dosage

Edema

The usual initial adult dosage of spironolactone in the management of edema is 100 mg daily administered as a single dose or in divided doses, but initial dosage may range from 25-200 mg daily. For the management of edema associated with heart failure in adults, some experts recommend initiating spironolactone at a low dosage (e.g., 12.5-25 mg once daily) and increasing the dosage (maximum of 50 mg daily; higher dosages may be used with close monitoring) until urine output increases and weight decreases, generally by 0.5-1 kg daily. Experts state that diuretics should be administered at a dosage sufficient to achieve optimal volume status and relieve congestion without inducing an excessively rapid reduction in intravascular volume, which could result in hypotension, renal dysfunction, or both.

A dosage of 3.3 mg/kg daily administered as a single dose or in divided doses has been suggested in children. Alternatively, an initial pediatric dosage of 60 mg/m daily administered in divided doses has been suggested.

When used alone for the management of edema, spironolactone should be administered in the usual initial dosage for at least 5 days. If a satisfactory response is obtained, dosage may be adjusted to the optimal therapeutic or maintenance dosage. If, after 5 days of therapy, results are not satisfactory, a diuretic that acts at a more proximal site in the renal tubule (e.g., a thiazide or loop diuretic) may be added to the regimen. Dosage of spironolactone should not be adjusted when other diuretic therapy is given concomitantly.

Hypertension

Spironolactone Therapy

For the management of hypertension, the usual initial adult dosage of spironolactone recommended by the manufacturers is 50-100 mg daily administered as a single dose or in divided doses. Some experts recommend a usual dosage range of 25-50 mg daily.

For the management of hypertension in children, some experts recommend a usual initial spironolactone dosage of 1 mg/kg daily administered as a single dose or in 2 divided doses. Dosage may be increased as necessary to a maximum dosage of 3.3 mg/kg (up to 100 mg) daily given as a single dose or in 2 divided doses. For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients,

Spironolactone should be administered for a minimum of 2 weeks in order to assess its effectiveness in the management of hypertension in a specific patient. Subsequent dosage should be determined by the response of the patient.

Spironolactone/Hydrochlorothiazide Fixed-combination Therapy

When concomitant therapy with spironolactone and hydrochlorothiazide is required, the commercially available preparations containing the drugs in fixed combination should not be used initially. Dosage should first be adjusted by administering each drug separately. If it is determined that the optimum maintenance dosage corresponds to the ratio in the commercial combination preparation, the fixed combination may be used. However, whenever dosage adjustment is necessary, each drug should be administered separately.

Blood Pressure Monitoring and Treatment Goals

Careful monitoring of blood pressure during initial titration or subsequent upward adjustment in dosage of spironolactone is recommended.

The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure; specific target levels of blood pressure should be individualized based on consideration of multiple factors, including patient age and comorbidities, and the currently available evidence from clinical studies.

For additional information on initiating and adjusting spironolactone dosage in the management of hypertension,

Heart Failure

For the management of severe heart failure, the manufacturer recommends an initial spironolactone dosage of 25 mg once daily in adults who have a serum potassium concentration of 5 mEq/L or less and a serum creatinine concentration of 2.5 mg/dL or less. In patients who tolerate this initial dosage, dosage may be increased to 50 mg once daily as clinically indicated; those who do not tolerate the initial dosage may receive 25 mg once every other day. Alternatively, the American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) recommend an initial spironolactone dosage of 12.5-25 mg once daily and a maintenance dosage (after 4 weeks of therapy) of 25 mg once or twice daily in patients who have a serum potassium concentration of 5 mEq/L or less and adequate renal function (estimated glomerular filtration rate [eGFR] at least 50 mL/minute per 1.73 m).

The manufacturer recommends that serum potassium and renal function be monitored 1 week after initiation or increase in spironolactone dosage, monthly for the first 3 months, then quarterly for a year, and then every 6 months. ACCF and AHA recommend that serum potassium and renal function be checked within 2-3 days and again 7 days after initiation of an aldosterone antagonist. Subsequent monitoring should be performed as needed based upon the stability of renal function and fluid status but should occur at least monthly for the first 3 months and then every 3 months thereafter. The manufacturer states that treatment with spironolactone should be discontinued or interrupted if the patient's serum potassium concentration exceeds 5 mEq/L or if serum creatinine exceeds 4 mg/dL. ACCF and AHA recommend withholding therapy with an aldosterone receptor antagonist if the patient's serum potassium concentration exceeds 5.5 mEq/L or if renal function worsens; therapy may be resumed at a reduced dosage after confirming resolution (for at least 72 hours) of hyperkalemia (i.e., serum potassium decreases to less than 5 mEq/L) and of renal insufficiency. ACCF and AHA state that patients should also be specifically instructed to stop taking an aldosterone receptor antagonist if they have diarrhea or are dehydrated or if therapy with a concomitant loop diuretic is interrupted.

Primary Hyperaldosteronism

In the diagnosis of primary hyperaldosteronism, if serum potassium does not rise to normal following administration of 80-160 mEq of supplemental potassium daily for 5 days, the patient should be placed on a normal diet with normal sodium and potassium intake (150 mEq of sodium and 75-100 mEq of potassium daily). Spironolactone is then administered in a dosage of 400 mg daily for 3-4 weeks. A rise in serum potassium concentration to within normal limits and correction of hypertension provides presumptive evidence for the diagnosis of primary hyperaldosteronism. Alternatively, 400 mg of spironolactone may be administered daily for 4 days. If serum potassium concentration increases during spironolactone therapy but decreases when the drug is discontinued, a presumptive diagnosis of primary hyperaldosteronism should be considered. In the diagnosis of primary hyperaldosteronism, children may receive spironolactone 125-375 mg/m in divided doses over 24 hours.

A test which seems to differentiate between patients who will respond to adrenalectomy and those who will not has been used. In this test, spironolactone was administered in doses of 100 mg 4 times daily for 3-5 weeks. Potassium, sodium, chloride, and bicarbonate concentrations of all patients returned to normal, but only those patients who subsequently had a successful response to adrenalectomy had a return of blood pressure to within normal limits.

After the diagnosis of hyperaldosteronism has been established, 100-400 mg of spironolactone may be administered daily for short-term preoperative therapy. When spironolactone is used for the treatment of primary hyperaldosteronism in patients unable or unwilling to undergo surgery, dosage has been initiated at 400 mg daily and maintained at 100-300 mg daily. The lowest effective dosage should be used for long-term maintenance therapy in these patients.

Hypokalemia

For the treatment of diuretic-induced hypokalemia when oral potassium supplements or other potassium-sparing regimens are considered inappropriate or inadequate, the usual dosage of spironolactone is 25-100 mg daily.

Other Uses

For the treatment of hirsutism in women with polycystic ovary syndrome or idiopathic hirsutism, the usual dosage of spironolactone is 50-200 mg daily. Regression of hirsutism is generally evident within 2 months, maximal within 6 months, and has been maintained up to at least 16 months with continued treatment.

Dosage in Renal Impairment

The manufacturer states that spironolactone use is contraindicated in patients with anuria, acute renal insufficiency, or substantial impairment of renal excretory function. ACCF and AHA state that the dosage of spironolactone should be reduced in heart failure patients with marginal renal function (eGFR 30-49 mL/minute per 1.73 m); an initial dosage of 12.5 mg once daily or every other day and a maintenance dosage of 12.5-25 mg once daily (after 4 weeks of therapy and if serum potassium is 5 mEq/L or less) has been recommended. The use of an aldosterone antagonist may be harmful in patients with an eGFR less than 30 mL/minute per 1.73 m because of potentially life-threatening hyperkalemia or renal insufficiency.(See Cautions: Electrolyte and Metabolic Effects.)

Cautions

In general, adverse effects with recommended dosage of spironolactone are mild and respond to withdrawal of the drug.

Electrolyte and Metabolic Effects

The most serious adverse effect of spironolactone therapy is hyperkalemia, which occurs most frequently in patients receiving potassium supplements concomitantly and in patients with renal insufficiency. Hyperkalemia can cause cardiac irregularities which may be fatal. Hyperkalemia can be treated promptly by rapid IV administration of 20-50% glucose with 0.25-0.5 units of insulin injection per gram of glucose; this is a temporary measure and should be repeated as necessary.

Reversible hyperchloremic metabolic acidosis, usually in association with hyperkalemia, has occurred in some patients with decompensated hepatic cirrhosis, even in the presence of normal renal function. Mild acidosis has also occurred during spironolactone therapy.

Dehydration and hyponatremia manifested by a low serum sodium concentration, dry mouth, thirst, drowsiness, and lethargy may occur during spironolactone therapy, especially when spironolactone is used concomitantly with other diuretics. In patients with severe cirrhosis, dehydration and hyponatremia may be followed by further hepatic decompensation and asterixis. Hyponatremia occurs most frequently in patients with advanced cirrhosis and may be prevented by restriction of water intake, administration of corticosteroids, or administration of mannitol.

GI Effects

Anorexia, nausea, vomiting, diarrhea, abdominal cramping, gastritis, gastric bleeding, and ulceration have occurred during spironolactone therapy.

Nervous System Effects

Headache, drowsiness, lethargy, ataxia, mental confusion, and fever have occurred during spironolactone therapy. In addition, severe fatigue and lassitude have been associated with the rapid and profound weight loss that occurs at the start of high-dose spironolactone therapy in patients with primary hyperaldosteronism.

Dermatologic and Sensitivity Reactions

Maculopapular and erythematous rashes (sometimes accompanied by eosinophilia), anaphylactic reaction, vasculitis, and urticaria have been reported rarely in patients receiving spironolactone. Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms (DRESS), alopecia, and pruritus have also been reported in patients receiving spironolactone therapy.

Endocrine Effects

Adverse effects related to the steroid-like structure of spironolactone include painful gynecomastia, decreased libido, and relative impotence in males, and menstrual irregularities, amenorrhea, postmenopausal bleeding, and breast soreness in females. Gynecomastia appears to be related to both dosage and duration of therapy and is usually reversible following discontinuance of spironolactone; however, some breast enlargement may rarely persist. Carcinoma of the breast has been reported in patients receiving spironolactone; however, a causal relationship to the drug has not been established. Androgen-like adverse effects such as hirsutism and deepening of the voice have also been reported.

Other Adverse Effects

Increased BUN concentrations (especially in patients with preexisting renal impairment), leg cramps, leukopenia (including agranulocytosis), and thrombocytopenia have been reported during spironolactone therapy.

Precautions and Contraindications

When spironolactone is used as a fixed-combination preparation that includes hydrochlorothiazide, the cautions, precautions, and contraindications associated with thiazide diuretics must be considered in addition to those associated with spironolactone.

Unless spironolactone is given concomitantly with another diuretic and a corticosteroid, the concurrent use of potassium supplements should be avoided. Serum electrolytes should be monitored periodically during spironolactone therapy, especially early in the course of therapy. Patients should be warned to avoid excessive ingestion of potassium-rich foods or salt substitutes. If hyperkalemia occurs during spironolactone therapy, the drug should be discontinued and potassium intake, including dietary potassium, restricted.

It is critically important to monitor and manage serum potassium concentrations in patients with severe heart failure receiving spironolactone as fatal hyperkalemia may occur. Spironolactone should not be administered concurrently with other potassium-sparing diuretics, and the use of oral potassium supplements should be avoided in patients with a serum potassium concentration exceeding 3.5 mEq/L.

Spironolactone should be used with caution in patients with impaired renal function or hepatic disease, and the drug is contraindicated in patients with rapidly deteriorating renal function, anuria, acute renal insufficiency, substantial impairment of renal excretory function, or hyperkalemia. Some clinicians consider spironolactone to be contraindicated in patients whose serum creatinine or BUN concentration is more than twice normal. Spironolactone is also contraindicated in patients with Addison's disease or with concomitant use of eplerenone.

Pediatric Precautions

The manufacturer states that safety and efficacy of spironolactone have not been established in pediatric patients.

Mutagenicity and Carcinogenicity

Canrenone, a major metabolite of spironolactone, and canrenoic acid are the major metabolites of potassium canrenoate. In tests using bacteria or yeast and in an in vivo mammalian system, potassium canrenoate was not mutagenic; however, it did produce a mutagenic effect in several in vitro tests in mammalian cells following metabolic activation.

Spironolactone has been shown to be tumorigenic in chronic toxicity studies in rats. Studies in rats using spironolactone dosages 25-250 times the usual human dosage resulted in a dose-related increase in benign adenomas of the thyroid and testes, a dose-related increase in proliferative changes in the livers of male rats, and an increase in malignant mammary tumors in female rats. At dosages 250 times the usual human dosage, hepatocellular carcinoma, hepatocytomegaly, and hyperplastic nodules were reported in rats. At dosages greater than 20 mg/kg daily, a dose-related incidence of myelocytic leukemia was observed in rats receiving potassium canrenoate in their diet for one year. In rats receiving potassium canrenoate for 2 years, myelocytic leukemia and hepatic, thyroid, testicular, and mammary tumors were observed. In chronic toxicity studies in rats using spironolactone dosages up to 250 times the usual human dosage, an increased incidence of leukemia was not observed.

Although a causal relationship has not been established, carcinoma of the breast has been reported in patients receiving spironolactone.

Pregnancy and Lactation

Pregnancy

Safe use of spironolactone during pregnancy has not been established. The drug should be used during pregnancy only when the potential benefits outweigh the possible risks to the fetus. The routine use of diuretics is contraindicated in pregnant women with mild edema who are otherwise healthy. Spironolactone may be indicated during pregnancy when edema is the result of pathologic causes, but diuretics are not generally indicated for the treatment of edema which is the result of hypervolemia, or restriction of venous return by the expanded uterus. Rarely, when edema associated with hypervolemia is extremely uncomfortable and not relieved by recumbency, a short course of a diuretic may be appropriate. Diuretics do not prevent the development of toxemia of pregnancy, and there is no satisfactory evidence that the drugs are useful in the treatment of developing toxemia.

Lactation

Since canrenone, a metabolite of spironolactone, is distributed into milk, spironolactone should not be used in nursing women. If use of spironolactone is deemed essential, nursing should be discontinued and an alternative method of infant feeding should be instituted.

Drug Interactions

Drugs that Block the Renin-Angiotensin System

Concomitant administration of spironolactone and an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor antagonist may cause severe hyperkalemia.

Drugs or Foods that Increase Serum Potassium Concentration

Concomitant use of spironolactone, potassium supplements or other substances containing potassium (e.g., salt substitutes, low-salt milk), or potassium-rich diets may increase the risk of severe hyperkalemia as compared with spironolactone therapy alone.

Spironolactone should not be used concurrently with another potassium-sparing agent (e.g., amiloride, triamterene) or aldosterone receptor antagonist (e.g., eplerenone) since concomitant therapy with these drugs may increase the risk of severe hyperkalemia as compared with spironolactone alone. Concomitant use of spironolactone and other drugs that are known to cause hyperkalemia, including heparin or low molecular weight heparin, may cause severe hyperkalemia.

Antihypertensive and Hypotensive Agents

When used in conjunction with other diuretics or hypotensive agents, spironolactone may be additive with or may potentiate the action of these drugs. Therefore, dosage of these drugs, particularly ganglionic blocking agents, may need to be reduced by at least 50% when concomitant spironolactone therapy is instituted.

Cardiac Glycosides

In clinical studies, spironolactone has been shown to increase the half-life of digoxin, resulting in increased serum digoxin concentrations and subsequent cardiac glycoside toxicity. The manufacturer recommends that patients receiving spironolactone concomitantly with a cardiac glycoside be monitored and maintenance and digitalization dosages adjusted to avoid over- and underdigitalization.

Cholestyramine

Hyperkalemic metabolic acidosis has been reported in patients who received spironolactone concurrently with cholestyramine.

CNS Depressants

Concomitant use of spironolactone and CNS depressants, including alcohol, barbiturates, and opiate agonists, may potentiate orthostatic hypotension.

Corticosteroids

Concomitant use of spironolactone and corticosteroids may intensify electrolyte depletion, particularly hypokalemia.

Nondepolarizing Neuromuscular Blocking Agents

Concomitant use of spironolactone and nondepolarizing neuromuscular blocking agents (e.g., tubocurarine) may potentially increase the neuromuscular blockade.

Nonsteroidal Anti-inflammatory Agents

Concomitant use of spironolactone and nonsteroidal anti-inflammatory agents (NSAIAs) (e.g., indomethacin) may cause severe hyperkalemia. NSAIAs, including aspirin, have also been shown to slightly reduce the natriuretic effect of spironolactone in healthy individuals, possibly by reducing active renal tubular secretion of canrenone, the active metabolite of spironolactone. However, the hypotensive effect of spironolactone and its effect on urinary potassium excretion in hypertensive patients are apparently not affected. Patients receiving both drugs should be monitored for signs and symptoms of decreased clinical response to spironolactone.

Vasopressors

Spironolactone reportedly reduces vascular responsiveness to norepinephrine, and regional or general anesthesia should be used with caution in patients receiving spironolactone.

Pharmacokinetics

Absorption

Absorption of spironolactone from the GI tract depends on the formulation in which it is administered. Currently available formulations of spironolactone are well absorbed from the GI tract and bioavailability of the drug exceeds 90% when compared to an optimally absorbed spironolactone solution in polyethylene glycol 400. Following a single oral dose of spironolactone, peak serum concentrations of the drug occur within 1-2 hours, and peak serum concentrations of its principal metabolites are attained within 2-4 hours. When spironolactone is administered concomitantly with food, peak serum concentrations and areas under the serum concentration-time curves (AUCs) of the drug and, to a lesser degree, its principal metabolites are increased substantially compared with the fasting state; however, the clinical importance of these findings is not known.

When administered alone, spironolactone has a gradual onset of diuretic action with the maximum effect being reached on the third day of therapy. The delay in onset may result from the time required for adequate concentrations of the drug or metabolites to accumulate. It has been suggested that a loading dose 2-3 times the usual daily dose be administered on the first day of therapy to overcome the delay in onset of action. After withdrawal of spironolactone, diuresis persists for 2 or 3 days. When a thiazide diuretic is used concomitantly with spironolactone, diuresis usually occurs on the first day of therapy.

Distribution

Spironolactone and canrenone, a major metabolite of the drug, are both more than 90% bound to plasma proteins.

Spironolactone or its metabolites may cross the placenta. Canrenone, a major metabolite of spironolactone, is distributed into milk.

Elimination

Spironolactone is rapidly and extensively metabolized. Spironolactone undergoes deacetylation at its sulfur group to form 7α-thiospironolactone ( 7α-thiospirolactone), which then undergoes further metabolism. 7α-Thiospironolactone is dethiolated to form canrenone and subsequently other non-sulfur-containing metabolites. 7α-Thiospironolactone also undergoes thiomethylation to form 7α-thiomethylspironolactone ( 7α-thiomethylspirolactone), which undergoes 6β-hydroxylation and subsequent metabolism to other sulfur-containing metabolites. Canrenone, 7α-thiospironolactone, and 7α-thiomethylspironolactone are pharmacologically active but substantially less so than the parent drug. Canrenone has long been believed to be the major metabolite of spironolactone, but recent studies using more specific assay methods indicate that 7α-thiomethylspironolactone is the major metabolite, at least after single doses of the drug. Further studies are needed to evaluate the metabolism of spironolactone. Spironolactone metabolites are excreted principally in urine, but also in feces via biliary elimination.

Following a single oral dose in healthy adults, the half-life of spironolactone averages 1.3-2 hours, and the half-life of 7α-thiomethylspironolactone averages 2.8 hours. The half-life of canrenone reportedly ranges from 13-24 hours. In multiple-dose studies, the steady-state plasma elimination half-life of canrenone averaged 19.2 hours when 200 mg of spironolactone was administered daily as a single dose and averaged 12.5 hours when 200 mg of the drug was administered daily in 4 equally divided doses.

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