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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(speer on oh LAK tone)
Generic Available (U.S.)
Yes
U.S. Brand Names
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Management of edema associated with excessive aldosterone excretion; hypertension; primary hyperaldosteronism; hypokalemia; cirrhosis of liver accompanied by edema or ascites; nephritic syndrome; severe heart failure (NYHA class III-IV) to increase survival and reduce hospitalization when added to standard therapy
Use: Unlabeled/Investigational
Female acne (adjunctive therapy); hirsutism; hypertension (pediatric); diuretic (pediatric)
Pregnancy Risk Factor
C
Pregnancy Considerations
Teratogenic effects were not observed in animal studies; however, doses used were less than or equal to equivalent doses in humans. The antiandrogen effects of spironolactone have been shown to cause feminization of the male fetus in animal studies. Two case reports did not demonstrate this effect in humans however, the authors caution that adequate data is lacking. Use of diuretics during normal pregnancies is not appropriate; use may be considered when edema is due to pathologic causes (as in the nonpregnant patient); monitor.
Lactation
Enters breast milk/not recommended (AAP rates “compatible”; AAP 2001 update pending)
Breast-Feeding Considerations
The active metabolite of spironolactone has been found in breast milk. Effects to humans are not known; however, this metabolite was found to be carcinogenic in rats. The manufacturer recommends discontinuing spironolactone or using an alternative method of feeding.
Contraindications
Anuria; acute renal insufficiency; significant impairment of renal excretory function; hyperkalemia
Warnings/Precautions
Boxed warnings:
• Tumorigenic: See “Concerns related to adverse effects” below.
Concerns related to adverse effects:
• Fluid/electrolyte loss: Excess amounts can lead to profound diuresis with fluid and electrolyte loss; close medical supervision and dose evaluation are required. Watch for and correct electrolyte disturbances; adjust dose to avoid dehydration.
• Gynecomastia: Related to dose and duration of therapy.
• Tumorigenic: [U.S. Boxed Warning]: Shown to be a tumorigen in chronic toxicity animal studies. Avoid unnecessary use.
Disease-related concerns:
• Adrenal vein catheterization: Discontinue use prior to adrenal vein catheterization.
• Cirrhosis: In cirrhosis, avoid electrolyte and acid/base imbalances that might lead to hepatic encephalopathy.
• Heart failure: When evaluating a heart failure patient for spironolactone treatment, creatinine should be ≤2.5 mg/dL in men or ≤2 mg/dL in women and potassium <5 mEq/L. Serum potassium levels require close monitoring and management if elevated. Discontinue or interrupt therapy if serum potassium >5 mEq/L or serum creatinine >4 mg/dL. Avoid concurrent use of ACEIs, ARBs, and spironolactone (Hunt, 2005).
Concurrent drug therapy issues:
• Potassium supplements: Avoid potassium supplements, potassium-containing salt substitutes, a diet rich in potassium, or other drugs that can cause hyperkalemia (eg, other potassium-sparing diuretics, NSAIDS).
Adverse Reactions
Frequency not always defined.
Cardiovascular: Vasculitis
Central nervous system: Ataxia, confusion, drowsiness, drug fever, fatigue, headache, lethargy
Dermatologic: Eosinophilia, maculopapular or erythematous cutaneous eruptions, urticaria
Endocrine & metabolic: Gynecomastia (men 9%), breast pain (men 2%), hyperkalemia (serious; 2%), dehydration, hyperchloremic metabolic acidosis in decompensated hepatic cirrhosis, hyponatremia, impotence, irregular menses, amenorrhea, postmenopausal bleeding
Gastrointestinal: Anorexia, cramps, diarrhea, gastritis, nausea, ulceration, vomiting, xerostomia
Hematologic: Agranulocytosis
Hepatic: Cholestatic/hepatocellular toxicity
Renal: BUN increased, renal dysfunction, renal failure
Miscellaneous: Anaphylactic reaction, breast cancer, deepening of the voice
Drug Interactions
ACE Inhibitors: Potassium-Sparing Diuretics may enhance the hyperkalemic effect of ACE Inhibitors. Risk C: Monitor therapy
Alpha-/Beta-Agonists: Spironolactone may diminish the vasoconstricting effect of Alpha-/Beta-Agonists. Risk C: Monitor therapy
Amifostine: Antihypertensives may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, antihypertensive medications should be withheld for 24 hours prior to amifostine administration. If antihypertensive therapy can not be withheld, amifostine should not be administered. Risk D: Consider therapy modification
Ammonium Chloride: Potassium-Sparing Diuretics may enhance the adverse/toxic effect of Ammonium Chloride. Specifically the risk of systemic acidosis. Risk D: Consider therapy modification
Angiotensin II Receptor Blockers: May enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Risk C: Monitor therapy
Antihypertensives: May enhance the hypotensive effect of other Antihypertensives. Risk C: Monitor therapy
Cardiac Glycosides: Potassium-Sparing Diuretics may diminish the therapeutic effect of Cardiac Glycosides. In particular, the inotropic effects of digoxin appear to be diminished. Potassium-Sparing Diuretics may increase the serum concentration of Cardiac Glycosides. This particular effect may be unique to Spironolactone. Risk C: Monitor therapy
Diazoxide: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Digoxin: Spironolactone may increase the serum concentration of Digoxin. Spironolactone (and/or its metabolites) may also interfere with the assays used to determine Digoxin concentrations, falsely increasing or decreasing Digoxin concentrations. Risk C: Monitor therapy
Drospirenone: May enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Risk C: Monitor therapy
Eplerenone: May enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Management: This combination is contraindicated in patients receiving eplerenone for treatment of hypertension. Risk D: Consider therapy modification
Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Herbs (Hypotensive Properties): May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Hypotensive Agents: May enhance the adverse/toxic effect of other Hypotensive Agents. Risk C: Monitor therapy
MAO Inhibitors: May enhance the orthostatic hypotensive effect of Orthostatic Hypotension Producing Agents. Risk C: Monitor therapy
Methylphenidate: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Mitotane: Spironolactone may diminish the therapeutic effect of Mitotane. Management: Consideration should be given to discontinuing spironolactone prior to initiating mitotane in order to eliminate the risk of therapeutic failure of the mitotane. Risk D: Consider therapy modification
Neuromuscular-Blocking Agents (Nondepolarizing): Spironolactone may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing). Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: May diminish the antihypertensive effect of Potassium-Sparing Diuretics. Nonsteroidal Anti-Inflammatory Agents may enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Risk C: Monitor therapy
Pentoxifylline: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Potassium Salts: May enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Risk D: Consider therapy modification
Prostacyclin Analogues: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
QuiNIDine: Potassium-Sparing Diuretics may diminish the therapeutic effect of QuiNIDine. Risk C: Monitor therapy
RiTUXimab: Antihypertensives may enhance the hypotensive effect of RiTUXimab. Risk D: Consider therapy modification
Sodium Phosphates: Diuretics may enhance the nephrotoxic effect of Sodium Phosphates. Specifically, the risk of acute phosphate nephropathy may be enhanced. Management: Consider avoiding this combination by temporarily suspending treatment with diuretics, or seeking alternatives to oral sodium phosphate bowel preparation. If the combination cannot be avoided, hydrate adequately and monitor fluid and renal status. Risk D: Consider therapy modification
Tacrolimus: Potassium-Sparing Diuretics may enhance the hyperkalemic effect of Tacrolimus. Risk X: Avoid combination
Tolvaptan: May enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Risk C: Monitor therapy
Yohimbine: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: Increases risk of orthostasis.
Food: Food increases absorption.
Herb/Nutraceutical: Avoid natural licorice (due to mineralocorticoid activity)
Storage
Store below 25°C (77°F).
Mechanism of Action
Competes with aldosterone for receptor sites in the distal renal tubules, increasing sodium chloride and water excretion while conserving potassium and hydrogen ions; may block the effect of aldosterone on arteriolar smooth muscle as well
Pharmacodynamics/Kinetics
Duration: 2-3 days
Protein binding: 91% to 98%
Metabolism: Hepatic to multiple metabolites, including active metabolites canrenone and 7-alpha-spirolactone
Half-life elimination: Spironolactone: 78-84 minutes; Canrenone: 10-23 hours; 7-alpha-spirolactone: 7-20 hours
Time to peak, serum: 3-4 hours (primarily as the active metabolite)
Excretion: Urine and feces
Dosage
Oral:
Children:
Diuretic, hypertension (unlabeled use): Children 1-17 years: Initial: 1 mg/kg/day divided every 12-24 hours (maximum dose: 3.3 mg/kg/day, up to 100 mg/day)
Diagnosis of primary aldosteronism (unlabeled use): 125-375 mg/m2/day in divided doses
Adults:
Edema: 25-200 mg/day in 1-2 divided doses
Hypokalemia: 25-100 mg daily
Hypertension (JNC 7): 25-50 mg/day in 1-2 divided doses
Diagnosis of primary aldosteronism: Long test: 400 mg daily for 3-4 weeks; short test: 400 mg daily for 4 days; maintenance until surgical correction: 100-400 mg/day in 1-2 divided doses
Heart failure, severe (NYHA class III-IV; with ACE inhibitor and a loop diuretic ± digoxin): 12.5-25 mg/day; maximum daily dose: 50 mg. If 25 mg once daily not tolerated, reduce to 25 mg every other day was the lowest maintenance dose possible.
Note: If potassium >5 mEq/L or serum creatinine >4 mg/dL, discontinue or interrupt therapy.
Acne in women (unlabeled use): 25-200 mg once daily
Hirsutism in women (unlabeled use): 50-200 mg/day in 1-2 divided doses
Elderly: Indication specific: Initial: 12.5-50 mg/day in 1-2 divided doses, increasing by 25-50 mg every 5 days as needed; adjust for renal impairment
Dosing interval in renal impairment: Heart failure:
Clcr 31-50 mL/minute: Decrease initial dose to 12.5 mg once daily
Clcr <30 mL/minute: Not recommended
Monitoring Parameters
Blood pressure, serum electrolytes (potassium, sodium), renal function, I & O ratios and daily weight throughout therapy
HF: Potassium levels and renal function should be checked in 3 days and 1 week after initiation or increase in dose, then every 2-4 weeks for 3 months, then quarterly for a year, then every 6 months thereafter.
Test Interactions
May cause false elevation in serum digoxin concentrations measured by RIA
Dietary Considerations
Should be taken with food to decrease gastrointestinal irritation and to increase absorption. Excessive potassium intake (eg, salt substitutes, low-salt foods, bananas, nuts) should be avoided.
Patient Education
Take with meals. Avoid any potassium supplements (vitamin/mineral products), potassium-containing salt substitutes, natural licorice, or extra dietary intake of potassium. Weigh yourself weekly and report weight loss. May cause dizziness, drowsiness, confusion, headache, nausea, vomiting, dry mouth, or gynecomastia. Report mental confusion; clumsiness; persistent fatigue, chills, numbness, or muscle weakness in hands, feet, or face; acute persistent diarrhea; chest pain, rapid heartbeat, or palpitations; excessive thirst; respiratory difficulty; breast tenderness or increased body hair in females; breast enlargement; or inability to achieve erection in males.
Geriatric Considerations
When used in combination with ACE inhibitors, monitor patient for hyperkalemia.
Additional Information
Maximum diuretic effect may be delayed 2-3 days and maximum hypertensive effects may be delayed 2-3 weeks.
Anesthesia and Critical Care Concerns/Other Considerations
In severe heart failure (NYHA class III, IV), spironolactone (25 mg/day), when combined with maximal standard therapy, resulted in a striking improvement in cardiovascular outcome (N Engl J Med, 1999, 341:709-17).
Potassium levels should be monitored in patients on an aldosterone blocker, particularly in those who have underlying renal impairment or any therapy increasing the risk of hyperkalemia (eg, ACEI, ARB, potassium supplements).
Cardiovascular Considerations
Heart Failure: The ACC/AHA 2009 Heart Failure Guidelines suggest that the addition of an aldosterone antagonist is reasonable in selected patients with moderately severe to severe symptoms of heart failure (HF) and reduced LVEF who can be carefully monitored (renal function and serum potassium). When evaluating a heart failure patient for aldosterone antagonist treatment, creatinine should be ≤2.5 mg/dL in men or ≤2 mg/dL in women and potassium <5 mEq/L. Patients are not candidates for such therapy if they are unable to comply with the monitoring required. In addition, the routine combined use of an ACE inhibitor, ARB, and aldosterone antagonist is not recommended in patients with current or prior symptoms of HF and reduced LVEF. In severe heart failure, spironolactone (25 mg/day), when combined with maximal standard therapy, resulted in a striking improvement in cardiovascular outcome (Pitt B, 1999). In the RALES trial, potassium supplementation was stopped with the initiation of spironolactone unless the patient was hypokalemic.
Monitoring Issues: Recently, a group of investigators published an observational study evaluating the effect of the RALES study on hospitalization for hyperkalemia in an older (>66 years of age) heart failure population on ACE inhibitors. This study was a population-based, timed-series analysis of healthcare databases in Ontario, Canada from January 1994 through December 2001(Juurlink DN, 2004). Computerized prescription records were reviewed to identify prescriptions for spironolactone, ACE inhibitors, angiotensin receptor antagonists, beta-blockers, loop diuretics, nonsteroidal anti-inflammatory agents, potassium supplements, thiazide diuretics, or other potassium-sparing diuretics. Hospitalization records were reviewed to identify hospitalizations for hyperkalemia or heart failure. Among patients treated with ACE inhibitors who had recently been hospitalized for heart failure, the spironolactone prescription rate significantly increased after RALES publication (34 per 1000 patients in 1994 and 149 per 1000 patients in 2001). The rate of hospitalizations for hyperkalemia significantly rose from 2.4 per 1000 patients (1994) to 11 per 1000 patients (2001). The associated mortality significantly rose from 0.2 per 1000 (1994) to 2 per 1000 (2001). The authors concluded that closer laboratory monitoring may be necessary, in addition to proper prescribing of spironolactone. The ACC/AHA 2009 Heart Failure Guidelines emphasize factors to consider in minimizing the risk of hyperkalemia such as initial dosages to use, avoidance of NSAIDs, discontinuing or reducing potassium supplements, and following monitoring guidelines. They suggest that potassium levels and renal function be checked in 3 days and at 1 week after initiation of therapy and at least monthly for the first 3 months. If serum potassium increases to a level of >5.5 mEq/L while on spironolactone, dose reduction is suggested. The RALES trial used 25 mg every other day as the lowest maintenance dose possible.
Hypertension: Aldosterone antagonists may add additional antihypertensive benefits in patients who have severe LV dysfunction (NYHA class III and IV), but only after ACE inhibitors and beta-blockers have been instituted (if no contraindications or intolerances exist).
Dental Health: Effects on Dental Treatment
No significant effects or complications reported
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause drowsiness, dizziness, nervousness, or confusion
Mental Health: Effects on Psychiatric Treatment
Has been used to treat lithium-related edema
Nursing: Physical Assessment/Monitoring
Diuretic effect may be delayed 2-3 days. Assess serum electrolytes on a regular basis. Assess fluid status and monitor for CNS changes (drowsiness, headache, confusion), rash, gynecomastia, dehydration, and hyperkalemia during therapy.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, oral: 25 mg, 50 mg, 100 mg
Aldactone®: 25 mg
Aldactone®: 50 mg, 100 mg [scored]
Pricing: U.S. (www.drugstore.com)
Tablets (Aldactone)
25 mg (30): $39.99
50 mg (30): $61.99
100 mg (30): $89.99
Tablets (Spironolactone)
25 mg (30): $15.99
100 mg (30): $34.99
Extemporaneously Prepared
A 1 mg/mL oral suspension may be made with tablets. Crush ten 25 mg tablets in a mortar and reduce to a fine powder. Add a small amount of purified water and soak for 5 minutes; add 50 mL 1.5% carboxymethylcellulose, 100 mL syrup NF, and mix to a uniform paste; mix while adding purified water in incremental proportions to almost 250 mL; transfer to a calibrated bottle, rinse mortar with purified water, and add quantity of purified water sufficient to make 250 mL. Label "shake well". Stable for 3 months at room temperature or refrigerated (Nahata, 1993).
A 2.5 mg/mL oral suspension may be made with tablets. Crush twelve 25 mg tablets in a mortar and reduce to a fine powder. Add small portions of distilled water or glycerin and mix to a uniform paste; mix while adding cherry syrup to almost 120 mL; transfer to a calibrated bottle, rinse mortar with cherry syrup, and add quantity of cherry syrup sufficient to make 120 mL. Label "shake well" and "refrigerate". This method may also be used with twenty-four 25 mg tablets for a 5 mg/mL oral suspension. Both concentrations are stable for 28 days refrigerated (Mathur, 1989).
A 25 mg/mL oral suspension may be made with tablets and either a 1:1 mixture of Ora-Sweet® and Ora-Plus® or a 1:1 mixture of Ora-Sweet® SF and Ora-Plus®. Crush one-hundred-twenty 25 mg tablets in a mortar and reduce to a fine powder. Add small portions of chosen vehicle and mix to a uniform paste; mix while adding vehicle in incremental proportions to almost 120 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 120 mL. Store in amber bottles; label "shake well" and "refrigerate". Stable for 60 days refrigerated (Allen, 1996).
Allen LV Jr and Erickson MA 3rd, "Stability of Ketoconazole, Metolazone, Metronidazole, Procainamide Hydrochloride, and Spironolactone in Extemporaneously Compounded Oral Liquids," Am J Health Syst Pharm, 1996, 53(17):2073-8.
Mathur LK and Wickman A, "Stability of Extemporaneously Compounded Spironolactone Suspensions," Am J Hosp Pharm, 1989, 46(10):2040-2.
Nahata MC, Morosco RS, and Hipple TF, "Stability of Spironolactone in an Extemporaneously Prepared Suspension at Two Temperatures," Ann Pharmacother, 1993, 27(10):1198-9.
References
American Academy of Pediatrics Committee on Drugs, "Transfer of Drugs and Other Chemicals Into Human Milk," Pediatrics, 2001, 108(3):776-89.
Barrilleaux PS and Martin Jr JN, “Hypertension Therapy During Pregnancy,” Clin Obstet Gynecol, 2002, 45(1):22-34.
Bozkurt B, Agoston I, and Knowlton AA, “Complications of Inappropriate Use of Spironolactone in Heart Failure: When an Old Medicine Spirals Out of New Guidelines,” J Am Coll Cardiol, 2003, 41(2):211-4.
Chobanian AV, Bakris GL, Black HR, et al, “The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure,” JAMA, 2003, 289(19):2560-71.
Groves TD and Corenblum B, “Spironolactone Therapy During Human Pregnancy,” Am J Obstet Gynecol, 1995, 172(5):1655-6.
Hunt SA, Abraham WT, Chin MH, et al, “2009 Focused Update Incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the International Society for Heart and Lung Transplantation,” J Am Coll Cardiol, 2009, 53(15):e1-90.
Hunter MH and Carek PJ, “Evaluation and Treatment of Women With Hirsutism,” Am Fam Physician, 2003, 67(12):2565-72.
Juurlink DN, Mamdani MM, Lee DS, et al, “Rates of Hyperkalemia After Publication of the Randomized Aldactone Evaluation Study,” N Engl J Med, 2004, 351(6):543-51.
Lindenfeld J, Albert NM, Boehmer JP, et al, “HFSA 2010 Comprehensive Heart Failure Practice Guideline,” J Card Fail, 2010, 16(6):e1-194.
“National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents,” Pediatrics, 2004, 114(2 Suppl 4th Report):555-76.
Palmer BF, “Managing Hyperkalemia Caused by Inhibitors of the Renin-Angiotensin-Aldosterone System,” N Engl J Med, 2004, 351:585-92.
Pitt B, Zannad F, Remme WJ, et al, “The Effect of Spironolactone on Morbidity and Mortality in Patients With Severe Heart Failure. Randomized Aldactone Evaluation Study Investigators,” N Engl J Med, 1999, 341(10):709-17.
“Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy,” Am J Obstet Gynecol, 2000, 183(1):S1-22.
Rigo J Jr, Glaz E, and Papp Z, “Low or High Doses of Spironolactone for Treatment of Maternal Bartter's Syndrome,” Am J Obstet Gynecol, 1996, 174(1 Pt 1):297.
Runyon BA, “Management of Adult Patients With Ascites Due to Cirrhosis: An Update,” Hepatology, 2009, 49(6):2087-107.
Shaw JC, “Acne: Effect of Hormones on Pathogenesis and Management,” Am J Clin Dermatol, 2002, 3(8):571-8.
Thiboutot D and Chen W, “Update and Future of Hormonal Therapy in Acne,” Dermatology, 2003, 206(1):57-67.
International Brand Names
Lexi-Comp.com
Last full review/revision May 2011
Content last modified May 2011
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