Class: Mineralocorticoid (Aldosterone) Receptor Antagonists
VA Class: CV704
CAS Number: 52-01-7
Brands: Aldactone, Aldactazide
Tumorigenic in chronic toxicity studies in rats.256 265 Use for FDA-approved indications; avoid unnecessary use.256 265
Spironolactone/hydrochlorothiazide fixed combination not indicated for initial therapy of edema or hypertension.256 Individualize dosage.256 If the fixed combination represents the dosage so determined, its use may be more convenient in patient management.256 The treatment of hypertension and edema is not static but must be reevaluated as conditions in each patient warrant.256 (See Dosage and Administration.)
Introduction
Aldosterone antagonist; a potassium-sparing diuretic.256 265
Uses for Spironolactone
Edema
Management of edema associated with excessive aldosterone including cirrhosis of the liver and nephrotic syndrome.256
Used as an adjunct to thiazide therapy when diuresis is inadequate or reduction of potassium excretion is necessary.a
Hypertension
Management of hypertension (alone or in combination with other classes of antihypertensive agents);256 262 265 used for patients who cannot be treated adequately with other agents or for whom other agents are considered inappropriate.265
One of several initial preferred therapies in hypertensive patients with heart failure and in those with ischemic heart disease (e.g., MI).262
Can be used as monotherapy for initial management of uncomplicated hypertension; however, thiazide diuretics are preferred by JNC 7.262
CHF
Management of edema and sodium retention in CHF in patients only partially responsive to, or intolerant of, other therapeutic measures.265
Has been used in conjunction with ACE inhibitors, loop diuretics, and occasionally cardiac glycosides in patients with severe CHF whose condition was inadequately controlled by an ACE inhibitor and a loop diuretic.215 216 217 226 247
Consider adding spironolactone to standard therapy in patients with severe (i.e., NYHA class IV) CHF.246 247
Safety and efficacy in mild or moderate CHF not determined.246 247
Primary Aldosteronism
Diagnosis of primary aldosteronism by therapeutic trial;265 test results may be equivocal and additional diagnostic studies often required.a
Short-term preoperative treatment of primary aldosteronism.265
Long-term maintenance therapy in patients with discrete aldosterone-producing adrenal adenomas who cannot undergo adrenalectomy or who decline surgery.265
Long-term maintenance therapy for patients with bilateral micronodular or macronodular adrenal hyperplasia (idiopathic hyperaldosteronism).265
Hypokalemia
Treatment of hypokalemia when oral potassium supplements or other measures are inappropriate or inadequate.265 a
Prophylaxis of hypokalemia in patients taking digitalis when other measures are inappropriate or inadequate.265
Precocious Puberty
Management of certain forms of gonadotropin releasing hormone (GnRH)-independent (peripheral) precocious puberty† (e.g., familial male precocious puberty [testotoxicosis]).203 204 205 206 207 208 211 213
Hirsutism
Treatment of hirsutism† in women with polycystic ovary syndrome or idiopathic hirsutism.a
Spironolactone Dosage and Administration
Administration
Administer orally.256 265
Oral Administration
Administer as single or divided doses; 2 doses daily may be adequate.262 265 a
For administration in children†, tablets may be pulverized and administered as an oral suspension in cherry syrup.a
When used with a thiazide diuretic in edema associated with cirrhosis of the liver, administer spironolactone for 2–3 days prior to the thiazide diuretic in order to prevent potassium depletion and precipitation of hepatic coma.a
Dosage
Pediatric Patients
Edema†
Oral
3.3 mg/kg (up to 100 mg) daily as a single dose or in divided doses.a
Alternatively, initial dosage of 60 mg/m2 daily in divided doses.a
Hypertension†
Oral
Initially, 1 mg/kg daily as a single dose or in 2 divided doses.269 Increase dosage as necessary up to a maximum of 3.3 mg/kg (up to 100 mg) daily as a single dose or in 2 divided doses.269
Primary Aldosteronism†
Diagnosis
Oral
125–375 mg/m2 in divided doses over 24 hours.a
If serum potassium concentration increases during therapy but decreases when the drug is discontinued, a presumptive diagnosis of primary aldosteronism should be considered.265
Adults
Edema
Oral
Initially, 100 mg daily.265 Range: 25–200 mg daily.265
As monotherapy, administer usual initial dosage for ≥5 days; if response is satisfactory, titrate dosage to optimal dosage.265
If response is not satisfactory after initial 5 days of therapy, add a thiazide or loop diuretic.265 Do not adjust spironolactone dosage during combined diuretic therapy.265
Spironolactone in combination with hydrochlorothiazide: spironolactone 100 mg daily and hydrochlorothiazide 100 mg daily as a single dose or in divided doses.256 Range: spironolactone 25–200 mg daily and hydrochlorothiazide 25–200 mg daily as a single dose or in divided doses.256
Initial use of fixed-combination preparations is not recommended; adjust by administering each drug separately, then use the fixed combination if the optimum maintenance dosage corresponds to the ratio of drugs in the combination preparation.256 Administer separately for subsequent dosage adjustment.256
Hypertension
Lower dosage and combination therapy recommended by JNC 7; higher spironolactone dosage may result in intolerable adverse effects.262
Carefully monitor BP during initial titration or subsequent upward adjustment in dosage.214 262
Adjust dosage at approximately monthly intervals.214 262
Monotherapy
Oral
Usual initial dosage: 50–100 mg daily as a single dose or in divided doses.265 Full hypotensive response may require 2 weeks.265
Usual dosage recommended by JNC 7: 25–50 mg daily.262
Spironolactone/Hydrochlorothiazide Combination Therapy
Oral
Spironolactone 50–100 mg daily and hydrochlorothiazide 50–100 mg daily as a single dose or in divided doses.256
Initial use of fixed-combination sprionolactone/hydrochlorothiazide preparations is not recommended; adjust by administering each drug separately, then use the fixed combination if the optimum maintenance dosage corresponds to the ratio of drugs in the combination preparation.256 Administer separately for subsequent dosage adjustment.256
CHF
Oral
Initially, 12.5–25 mg daily used in patients receiving an ACE inhibitor and a loop diuretic with or without a cardiac glycoside.215 216 246 247
Increase to 50 mg daily after 8 weeks in patients who exhibit signs and symptoms of progressive heart failure and have serum potassium concentrations <5.5 mEq/L.215
Decrease to 25 mg every other day if hyperkalemia occurs.215 216
Primary Aldosteronism
Diagnosis
Oral
400 mg daily for 3–4 weeks.265 Correction of hypokalemia and hypertension provides presumptive evidence for the diagnosis of primary aldosteronism.265
Alternatively, 400 mg daily for 4 days.265 If serum potassium concentration increases during spironolactone therapy but decreases when the drug is discontinued, consider presumptive diagnosis of primary aldosteronism.265
Medical Therapy Prior to Adrenalectomy
Oral
Patients with a definitive diagnosis: 100–400 mg daily before surgery.265
Treatment Of Primary Aldosteronism
Oral
Initially, 400 mg daily.265
Maintenance dosage: 100–300 mg daily.265 Use lowest effective dosage for long-term maintenance therapy.265
Hypokalemia
Oral
25–100 mg daily.265
Hirsutism†
Oral
50–200 mg daily.a Regression of hirsutism evident within 2 months, maximal within 6 months, and has been maintained for ≥16 months with continued therapy.a
Prescribing Limits
Pediatric Patients
Hypertension†
Oral
Maximum 3.3 mg/kg (up to 100 mg) daily.269
Cautions for Spironolactone
Contraindications
Anuria.265
Acute renal insufficiency265
Substantial impairment of renal excretory function.265
Hyperkalemia.265
Known hypersensitivity to spironolactone or any ingredient in the formulation.265
Warnings/Precautions
Warnings
Hyperkalemia
Avoid concurrent use of potassium supplements.256 265 (See Specific Drugs, Foods, and Laboratory Tests under Interactions.)
Hyperkalemia reported in patients with excess potassium intake and in those with renal insufficiency; hyperkalemia may cause potentially fatal cardiac irregularities.256
If hyperkalemia suspected (paresthesia, muscle weakness, fatigue, flaccid paralysis of the extremities, bradycardia, shock), obtain an ECG and monitor serum potassium concentrations.256
If hyperkalemia occurs, immediately discontinue and treat as indicated with parenteral calcium chloride, sodium bicarbonate, and/or oral or parenteral glucose with a rapid acting insulin preparation.256 Consider cationic exchange resins (e.g., sodium polystyrene sulfonate).256 Persistent hyperkalemia may require dialysis.256
Concomitant ACE Inhibitor Therapy
Combined therapy with spironolactone and an ACE inhibitor has been considered relatively contraindicated because of the potential for developing severe hyperkalemia and inhibition of aldosterone formation;215 217 218 222 however, clinical studies in patients with moderate or severe CHF indicate 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) decreases mortality and hospitalization.218 219 246 247 251 252 253 254
Tumorigenic Effects
Tumorigenic in animals; proliferative effects observed in liver and endocrine organs.256 265 (See Boxed Warning.)
Sensitivity Reactions
Anaphylaxis
Anaphylaxis reported.256 265
Major Toxicities
Fluid and Electrolyte Imbalance
Observe for signs of fluid and electrolyte imbalance (e.g., dry mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, nausea, vomiting).256
Monitor serum and urine electrolyte concentrations periodically, especially if the patient is vomiting excessively or receiving parenteral fluid therapy.256 265
Minor alterations of fluid and electrolyte balance may precipitate hepatic coma in patients with impaired hepatic function.256 (See Hepatic Impairment under Cautions.)
General Precautions
Dilutional Hyponatremia
Dilutional hyponatremia (dry mouth, thirst, lethargy, and drowsiness) reported; diagnosis confirmed by a low serum sodium concentration.256
Increased risk when spironolactone combined with other diuretics, in edematous patients during hot weather, and in patients with advanced cirrhosis.256 a
Gynecomastia
Gynecomastia reported; appears related to dose and duration of therapy.256 Generally reversible upon discontinuance.256
Use of Fixed Combinations
When spirolactone is used in fixed combination with hydrochlorothiazide, consider the cautions, precautions, and contraindications associated with hydrochlorothiazide.256
Specific Populations
Pregnancy
Category C.265
Lactation
Metabolite distributed into milk.265 Discontinue nursing or the drug.265
Pediatric Use
Safety and efficacy not fully established.265
Geriatric Use
Monitor serum and urine electrolyte concentrations.265
Hepatic Impairment
Use with caution in patients with impaired hepatic function; minor alterations of fluid and electrolyte balance may precipitate hepatic coma.265
Monitor serum and urine electrolyte concentrations.256 265
Reversible hyperchloremic metabolic acidosis (usually in association with hyperkalemia) reported in patients with decompensated hepatic cirrhosis, even in the presence of normal renal function.265
Renal Impairment
Hyperkalemia reported in patients with impaired renal function.265 (See Contraindications under Cautions.)
Monitor serum and urine electrolyte concentrations periodically.256 265
Transient elevations of BUN reported.265
Common Adverse Effects
Hyperkalemia, hyponatremia, anorexia, nausea, vomiting, diarrhea, abdominal cramping, gastritis, gastric bleeding, ulceration, headache, drowsiness, lethargy, ataxia, mental confusion, fever, rash, anaphylaxis, vasculitis, urticaria, gynecomastia, decreased libido, relative impotence in males, menstrual irregularities, amenorrhea, postmenopausal bleeding, increased BUN concentrations.256 265 a
Interactions for Spironolactone
Drug, Food, or Test | Interaction | Comments |
|---|---|---|
ACE inhibitor | Increased risk of hyperkalemia265 | Monitor serum potassium frequently265 (See CHF under Uses and also under Dosage and Administration) |
Alcohol | Potentiation of orthostatic hypotension265 | |
Antihypertensive and hypotensive agents | Additive antihypertensive effectsa | Reduce dosage of antihypertensive agent, especially ganglionic blocking agents, by at least 50% when spirolactone initiateda |
Barbiturates | Potentiation of orthostatic hypotension265 | |
Corticosteroids/ACTH | Possible additive electrolyte depletion, especially potassium265 | Monitor serum electrolytes265 |
Digoxin | Increased serum concentrations of digoxin; possible toxicity265 | Monitor for digitalis toxicity; adjust digoxin dosage (maintenance and digitalization)265 |
Diuretics, potassium-sparing (e.g. amiloride, triamterene) | Increased risk of hyperkalemiaa | Concomitant use contraindicateda |
Lithium | Reduced renal clearance of lithium; increased risk of lithium toxicity 265 | Concomitant use generally contraindicated; if concomitant therapy is necessary, monitor serum lithium concentrations closely and adjust dosage 265 |
Nondepolarizing neuromuscular blocking agents (e.g., tubocurarine chloride) | Potential increase in neuromuscular blockade265 | |
NSAIAs (e.g., indomethacin, aspirin) | Possible decreased diuretic, natriuretic, and antihypertensive effect; increased risk of hyperkalemia265 | Use with caution, monitor for diuretic effects265 a Monitor for hyperkalemia265 |
Opiate agonists | Potentiation for orthostatic hypotension265 | |
Potassium supplements and/or foods containing potassium (e.g., salt substitutes, low-salt milk) | Increased risk of hyperkalemia 265 | Concomitant use generally not recommended265 |
Test, aldosterone (urinary) | Most methods appear unaffected; metabolites may interfere with radioimmunoassay proceduresa | |
Test, digoxin (serum) | Possible false elevations with radioimmunoassay procedures; possibly assay specific265 | Clinical relevance not fully known265 |
Tests, steroids Cortisol (17-hydroxycorticosteroids, plasma and urinary) 17-hydroxycorticosteroids (urinary, Porter-Silber technique) 17-ketosteroids, 17-ketogenic steroids, (urinary, Klendshoj, Feldstein and Sprague technique) | Spironolactone metabolites fluoresce; may interfere with fluorometric analysisa | Clinical relevance not fully known265 |
Vasopressors (e.g. norepinephrine) | Possible decreased vascular response265 | Use anesthesia (regional or general) with caution265 |
Spironolactone Pharmacokinetics
Absorption
Well absorbed following oral administration; peak serum concentrations of spironolactone usually attained within 1–2 hours;200 201 peak serum concentrations of the principal metabolites200 201 usually attained within 2–4 hours.a
Bioavailability
>90%.a
Onset
Gradual; maximum diuretic effect reached on third day.a
Spironolactone in fixed combination with hydrochlorothiazide: diuresis usually occurs on the first day.a
Duration
Diuresis persists for 2–3 days after discontinuance.a
Food
Food increases peak serum concentrations and AUC; clinical importance not known.200
Distribution
Extent
Spironolactone and its metabolites crosses the placenta.
Canrenone, a major active metabolite, is distributed into milk.256 a
Plasma Protein Binding
Spironolactone and canrenone: >90%.265
Elimination
Metabolism
Rapidly and extensively metabolized; canrenone and/or 7α-thiomethylspironolactone appear to be major active metabolites.200 201 256
Undergoes hepatic deacetylation, thiomethylation, and hydroxylation.200 201
Elimination Route
Excreted principally in urine as metabolites and to a lesser extent in bile.265
Half-life
Spironolactone: 1.4 hours.265
Metabolites: 13.8–16.5 hours.265
Stability
Storage
Oral
Tablets
<25°C.256 265
Suspension
Extemporaneously prepared oral suspensions in cherry syrup reported to be stable for 1 month at 2–8°C.a
ActionsActions
Synthetic steroid mineralocorticoid receptor antagonist (aldosterone antagonist).215 256 265 266
Exhibits magnesium- and potassium-sparing,224 230 233 natriuretic,232 247 diuretic,224 232 and hypotensive215 224 225 227 effects by competitively inhibiting the physiologic effects of the adrenocorticortical hormone aldosterone on the distal renal tubules, myocardium,225 226 228 232 and vasculature.232 233 265
Generally does not cause potassium depletion or affect glucose metabolism or uric acid excretion.265
Androgen and progesterone receptor antagonist.206 208 209 210 211 215 256 265 266 267 268
Advice to Patients
Importance of advising patient to avoid excessive ingestion of potassium supplements, potassium-rich foods, or salt substitutes.256
Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.265
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs as well as concomitant illnesses.265
Importance of informing patients of other important precautionary information.265 (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 25 mg* | Aldactone (with povidone) | Pfizer |
Spironolactone Tablets | Mutual, Mylan, Sandoz, UDL, United Research | |||
50 mg* | Aldactone (with povidone; scored) | Pfizer | ||
Spironolactone Tablets | Mutual, Mylan, Purepac, United Research | |||
100 mg* | Aldactone (with povidone; scored) | Pfizer | ||
Spironolactone Tablets | Mutual, Mylan, Purepac, United Research |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 25 mg Spironolactone and Hydrochlorothiazide 25 mg* | Aldactazide (with povidone) | Pfizer |
Spironolactone and Hydrochlorothiazide Tablets | Mutual, Mylan, United Research | |||
50 mg Spironolactone and Hydrochlorothiazide 50 mg | Aldactazide (with povidone; scored) | Pfizer |
Comparative Pricing
This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.
Aldactazide 25-25MG Tablets (PFIZER U.S.): 30/$40.99 or 90/$98.97
Aldactazide 50-50MG Tablets (PFIZER U.S.): 30/$64.99 or 90/$176.97
Aldactone 100MG Tablets (PFIZER U.S.): 30/$89.99 or 90/$249.98
Aldactone 25MG Tablets (PFIZER U.S.): 30/$39.99 or 90/$96.97
Aldactone 50MG Tablets (PFIZER U.S.): 30/$61.99 or 90/$160.96
Spironolactone 100MG Tablets (ACTAVIS ELIZABETH): 30/$34.99 or 90/$81.97
Spironolactone 25MG Tablets (ACTAVIS ELIZABETH): 30/$15.99 or 60/$22.98
Spironolactone 50MG Tablets (QUALITEST): 30/$21.99 or 90/$46.97
Spironolactone-HCTZ 25-25MG Tablets (MYLAN): 30/$16.99 or 60/$22.98
Disclaimer
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The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.
AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions October 2005. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
References
Only references cited for selected revisions after 1984 are available electronically.
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