Spironolactone

Spironolactone
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]

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Black Box Warning

WARNING See full prescribing information for complete Boxed Warning. Spironolactone has been shown to be a tumorigen in chronic toxicity studies in rats (see Precautions). Spironolactone tablets should be used only in those conditions described under Indications and Usage. Unnecessary use of this drug should be avoided.

Overview

Spironolactone is {{{aOrAn}}} Aldosterone antagonist that is FDA approved for the {{{indicationType}}} of Primary hyperaldosteronism,edematous conditions of congestive heart failure, cirrhosis of the liver accompanied by edema and/or ascites, nephrotic syndrome, essential hypertension. There is a Black Box Warning for this drug as shown here. Common adverse reactions include gynecomastia, diarrhea, nausea and vomiting,[somnolence]],disorder of menstruation, impotence.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

<h4>Condition 1</h4>

• Dosing Information

(Dosage)

Off-Label Use and Dosage (Adult)

Non–Guideline-Supported Use

Acne vulgaris

• Dosing information

• 50-200 mg PO
• optimal dosage: 150-200 mg PO

Ascites of patients in cirrhosis of liver

• Dosing information

• 100-400 mg/day (300-600 mg/day satisfies 50%-90% patients)
• recommended initial dosage: 100-200 mg PO qd
• 225 mg/day

Proteinuria in Chronic renal failure

• Dosing information

• 25 mg/day

Proteinuria in diabetic nephropathy

• Dosing information

• 25 mg in addition to an ACE inhibitor or angiotensin II receptor antagonist

Hirsutism

• Dosing information

• spironolactone plus cyproterone/ethinyl estradiol or flutamide alone were both significantly effective for the treatment of women with moderate to severe hirsutism in a prospective, randomized, clinical trial

Idiopathic edema

• Dosing information

• spironolactone 50-200 mg every morning or hydrochlorothiazide 25 mg every morning

Myocardial infarction

• Dosing information

• 25 mg/day

Prophylaxis of osteopenia; - Polycystic ovary syndrome

• Dosing information

• 100 mg PO qd

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Spironolactone FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Non–Guideline-Supported Use

Primary aldosteronism

• Dosing information

• initial dosage: 400 mg/day with gradual reduction to 200 mg/day

Contraindications

Spironolactone tablets are contraindicated for patients with anuria, acute renal insufficiency, significant impairment of renal excretory function, hypercalcemia, hyperkalemia, Addison's disease or other conditions associated with hyperkalemia,and with concomitant use of eplerenone.

Warnings

WARNING See full prescribing information for complete Boxed Warning. Spironolactone has been shown to be a tumorigen in chronic toxicity studies in rats (see Precautions). Spironolactone tablets should be used only in those conditions described under Indications and Usage. Unnecessary use of this drug should be avoided.

Potassium supplementation, either in the form of medication or as a diet rich in potassium, should not ordinarily be given in association with ALDACTAZIDE therapy. Excessive potassium intake may cause hyperkalemia in patients receiving ALDACTAZIDE (see Precautions: General).

Concomitant administration of ALDACTAZIDE with the following drugs or potassium sources may lead to severe hyperkalemia:

• other potassium-sparing [[diuretics]]
• ACE inhibitors
• angiotensin II receptor antagonists
• aldosterone blockers
• non-steroidal anti-inflammatory drugs (NSAIDs), e.g., indomethacin
• heparin and low molecular weight heparin
• other drugs known to cause hyperkalemia
• potassium supplements
• diet rich in potassium
• salt substitutes containing potassium

Spironolactone tablets should not be administered concurrently with other potassium-sparing diuretics. Spironolactone tablets, when used with ACE inhibitors or indomethacin, even in the presence of a diuretic, have been associated with severe hyperkalemia. Extreme caution should be exercised when spironolactone tablets are given concomitantly with these drugs. Hyperkalemia in patients with severe heart failure Hyperkalemia may be fatal. It is critical to monitor and manage serum potassium in patients with severe heart failure receiving 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 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 Clinical Studies: Severe heart failure, and Dosage and Administration: Severe heart failure.) Spironolactone tablets 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 Precautions: Drug interactions). PRECAUTIONS General 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 spironolactone tablets. 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, spironolactone tablets should be discontinued immediately. With severe hyperkalemia, the clinical situation dictates the procedures to be employed. These may 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 spironolactone tablets are 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. Spironolactone therapy may cause a transient elevation of BUN, especially in patients with pre-existing renal impairment. Spironolactone tablets may cause mild acidosis. 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 spironolactone tablets are discontinued. In rare instances some breast enlargement may persist when spironolactone tablets are discontinued. Somnolence and dizziness have been reported to occur in some patients. Caution is advised when driving or operating machinery until the response to initial treatment has been determined.

Adverse Reactions

Clinical Trials Experience

• Digestive: Gastric bleeding, ulceration, gastritis, diarrhea and cramping, nausea, vomiting.
  
• Reproductive: Gynecomastia (see Precautions), inability to achieve or maintain erection, irregular menses or amenorrhea, postmenopausal bleeding, breast pain. Carcinoma of the breast has been reported in patients taking spironolactone but a cause and effect relationship has not been established.
  
• Hematologic: Leukopenia (including agranulocytosis), thrombocytopenia.
  
• Hypersensitivity: Fever, urticaria, maculopapular or erythematous cutaneous eruptions,
  anaphylactic reactions, vasculitis.
• Metabolism: Hyperkalemia, electrolyte disturbances (see Warnings and Precautions).
  
• Musculoskeletal: Leg cramps.
  
• Nervous system/psychiatric: Lethargy, mental confusion, ataxia, dizziness, headache, drowsiness.
  
• Liver/biliary: A very few cases of mixed cholestatic/hepatocellular toxicity, with one reported fatality, have been reported with spironolactone administration.
  
• Renal: Renal dysfunction (including renal failure).
  
• Skin: Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms (DRESS), alopecia, pruritus.
  

Postmarketing Experience

There is limited information regarding Spironolactone Postmarketing Experience in the drug label.

Drug Interactions

ACE inhibitors, Angiotensin II receptor antagonists, aldosterone blockers, potassium supplements, heparin, low molecular weight heparin, and other drugs known to cause hyperkalemia:

• Concomitant administration may lead to severe hyperkalemia.
• Alcohol, barbiturates, or narcotics: Potentiation of orthostatic hypotension may occur.
• Antidiabetic drugs (e.g., oral agents, insulin): Dosage adjustment of the antidiabetic drug may be required (see Precautions).
• Corticosteroids, ACTH: Intensified electrolyte depletion, particularly hypokalemia, may occur.
• Pressor amines (e.g., norepinephrine): Both spironolactone and hydrochlorothiazide reduce 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 ALDACTAZIDE.
• Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine): Possible increased responsiveness to the muscle relaxant may result.
• Lithium: Lithium generally should not be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity.
• Nonsteroidal anti-inflammatory drugs (NSAIDs): In some patients, the administration of an NSAID can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing, and thiazide diuretics. Combination of NSAIDs, e.g., indomethacin, with potassium-sparing diuretics has been associated with severe hyperkalemia. Therefore, when ALDACTAZIDE and NSAIDs are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.
• Digoxin: Spironolactone has been shown to increase the half-life of digoxin. This may result in increased serum digoxin levels and subsequent digitalis toxicity. Monitor serum digoxin levels and adjust dose accordingly. Thiazide-induced electrolyte disturbances, i.e. hypokalemia, hypomagnesemia, increase the risk of digoxin toxicity, which may lead to fatal arrhythmic events (see Precautions).
• Cholestyramine: Hyperkalemic metabolic acidosis has been reported in patients given spironolactone concurrently with cholestyramine.

Drug/Laboratory test interactions

• Thiazides should be discontinued before carrying out tests for parathyroid function (see Precautions: General). Thiazides may also decrease serum PBI levels without evidence of alteration of thyroid function.
• 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.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): C Teratology studies with spironolactone have been carried out in mice and rabbits at doses of up to 20 mg/kg/day. On a body surface area basis, this dose in the mouse is substantially below the maximum recommended human dose and, in the rabbit, approximates the maximum recommended human dose. No teratogenic or other embryotoxic effects were observed in mice, but the 20 mg/kg dose caused an increased rate of resorption and a lower number of live fetuses in rabbits. Because of its antiandrogenic activity and the requirement of testosterone for male morphogenesis, spironolactone may have the potential for adversely affecting sex differentiation of the male during embryogenesis. When administered to rats at 200 mg/kg/day between gestation days 13 and 21 (late embryogenesis and fetal development), feminization of male fetuses was observed. Offspring exposed during late pregnancy to 50 and 100 mg/kg/day doses of spironolactone exhibited changes in the reproductive tract including dose-dependent decreases in weights of the ventral prostate and seminal vesicle in males, ovaries and uteri that were enlarged in females, and other indications of endocrine dysfunction, that persisted into adulthood. There are no adequate and well-controlled studies with spironolactone and hydrochlorothiazide tablets in pregnant women. Spironolactone has known endocrine effects in animals including progestational and antiandrogenic effects. The antiandrogenic effects can result in apparent estrogenic side effects in humans, such as gynecomastia. Therefore, the use of spironolactone and hydrochlorothiazide tablets in pregnant women requires that the anticipated benefit be weighed against the possible hazards to the fetus.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Spironolactone in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Spironolactone during labor and delivery.

Nursing Mothers

Canrenone, a major (and active) metabolite of spironolactone, appears in human breast milk. Because spironolactone has been found to be tumorigenic in rats, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother. If use of the drug is deemed essential, an alternative method of infant feeding should be instituted.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatic Use

There is no FDA guidance on the use of Spironolactone in geriatric settings.

Gender

There is no FDA guidance on the use of Spironolactone with respect to specific gender populations.

Race

There is no FDA guidance on the use of Spironolactone with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Spironolactone in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Spironolactone in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Spironolactone in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Spironolactone in patients who are immunocompromised.

Administration and Monitoring

Administration

Primary hyperaldosteronism

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

Long test

Spironolactone tablets are administered at a daily dosage of 400 mg for three to four weeks. Correction of hypokalemiaand of hypertension provides presumptive evidence for the diagnosis of primary hyperaldosteronism.

Short test

Spironolactone tablets are administered at a daily dosage of 400 mg for four days. If serum potassium increases during spironolactone administration but drops when spironolactone tablets are discontinued, a presumptive diagnosis of primary hyperaldosteronism should be considered. After the diagnosis of hyperaldosteronism has been established by more definitive testing procedures, spironolactone tablets may be administered in doses of 100 to 400 mg daily in preparation for surgery. For patients who are considered unsuitable for surgery, spironolactone tablets 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 spironolactone tablets 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, spironolactone tablets 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 spironolactone tablets has not occurred, a second diuretic that acts more proximally in the renal tubule may be added to the regimen. Because of the additive effect of spironolactone tablets 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 spironolactone tablets should remain unchanged when other diuretic therapy is added.

Essential hypertension

For adults, an initial daily dosage of 50 to 100 mg of spironolactone tablets administered in either single or divided doses is recommended. Spironolactone tablets may also be given with diuretics that act more proximally in the renal tubule or with other antihypertensive agents. Treatment with spironolactone tablets 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

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

Severe heart failure in conjunction with standard therapy (NYHA class III – IV)

Treatment should be initiated with spironolactone 25 mg once daily if the patient's serum potassium is ≤5.0 mEq/L and the patient's serum creatinine is ≤ 2.5 mg/dL. Patients who tolerate 25 mg once daily may have their dosage increased to 50 mg once daily as clinically indicated. Patients who do not tolerate 25 mg once-daily dose may have their dosage reduced to 25 mg every other day. See Warnings: Hyperkalemia in patients with severe heart failureSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactoneSpironolactone for advice on monitoring serum potassium and serum creatinine.

Monitoring

There is limited information regarding Spironolactone Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Spironolactone and IV administrations.

Overdosage

The oral LD50 of spironolactone is greater than 1,000 mg/kg in mice, rats, and rabbits. Acute overdosage of 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.

Treatment

Induce vomiting or evacuate the stomach by lavage. There is no specific antidote. Treatment is supportive to maintain hydration, electrolyte balance, and vital functions. Patients who have renal impairment may develop spironolactone-induced hyperkalemia. In such cases, spironolactone tablets should be discontinued immediately. With severe hyperkalemia, the clinical situation dictates the procedures to be employed. These may 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.

Pharmacology

There is limited information regarding Spironolactone Pharmacology in the drug label.

Mechanism of Action

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. Spironolactone causes increased amounts of sodium and water to be excreted, while potassium is retained. Spironolactone acts both as a diuretic and as an antihypertensive drug by this mechanism. It may be given alone or with other diuretic agents that act more proximally in the renal tubule.

Structure

There is limited information regarding Spironolactone Structure in the drug label.

Pharmacodynamics

There is limited information regarding Spironolactone Pharmacodynamics in the drug label.

Pharmacokinetics

There is limited information regarding Spironolactone Pharmacokinetics in the drug label.

Nonclinical Toxicology

There is limited information regarding Spironolactone Nonclinical Toxicology in the drug label.

Clinical Studies

There is limited information regarding Spironolactone Clinical Studies in the drug label.

How Supplied

There is limited information regarding Spironolactone How Supplied in the drug label.

Storage

There is limited information regarding Spironolactone Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Spironolactone Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Spironolactone interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Spironolactone Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Spironolactone Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.