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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section and/or refer to product labeling for additional detail.
Medication Safety Issues
Sound-alike/look-alike issues:
Aldactone® may be confused with Aldactazide®
International issues:
Aldactone®: Brand name for potassium canrenoate in Austria, Czech Republic, Germany, and Hungary
Pronunciation
(speer on oh LAK tone)
U.S. Brand Names
Generic Available
Yes
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use
Management of edema associated with excessive aldosterone excretion; hypertension; congestive heart failure; primary hyperaldosteronism; hypokalemia; cirrhosis of liver accompanied by edema or ascites
Use: Unlabeled/Investigational
Female acne (adjunctive therapy); hirsutism; hypertension (pediatric); diuretic (pediatric)
Pregnancy Risk Factor
C/D in pregnancy-induced hypertension (per expert analysis)
Pregnancy Implications
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. Diuretics are generally avoided in pregnancy due to the theoretical risk that decreased plasma volume may cause placental insufficiency. Diuretics should not be used during pregnancy in the presence of reduced placental perfusion (eg, pre-eclampsia, intrauterine growth restriction).
Lactation
Enters breast milk/not recommended (AAP rates “compatible”)
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
Hypersensitivity to spironolactone or any component of the formulation; anuria; acute renal insufficiency; significant impairment of renal excretory function; hyperkalemia; pregnancy (pregnancy-induced hypertension - per expert analysis)
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.
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.
Adverse Reactions
Incidence of adverse events is not always reported. (Mean daily dose: 26 mg)
Cardiovascular: Edema (2%, placebo 2%)
Central nervous system: Disorders (23%, placebo 21%) which may include drowsiness, lethargy, headache, mental confusion, drug fever, ataxia, fatigue
Dermatologic: Maculopapular, erythematous cutaneous eruptions, urticaria, hirsutism, eosinophilia
Endocrine & metabolic: Gynecomastia (men 9%; placebo 1%), breast pain (men 2%; placebo 0.1%), serious hyperkalemia (2%, placebo 1%), hyponatremia, dehydration, hyperchloremic metabolic acidosis in decompensated hepatic cirrhosis, inability to achieve or maintain an erection, irregular menses, amenorrhea, postmenopausal bleeding
Gastrointestinal: Disorders (29%, placebo 29%) which may include anorexia, nausea, cramping, diarrhea, gastric bleeding, ulceration, gastritis, vomiting
Genitourinary: Disorders (12%, placebo 11%)
Hematologic: Agranulocytosis
Hepatic: Cholestatic/hepatocellular toxicity
Renal: Increased BUN concentration
Respiratory: Disorders (32%, placebo 34%)
Miscellaneous: Deepening of the voice, anaphylactic reaction, breast cancer
Drug Interactions
ACE inhibitors can cause hyperkalemia, especially in patients with renal impairment, potassium-rich diets, or on other drugs causing hyperkalemia; avoid concurrent use or monitor closely.
Cholestyramine can cause hyperchloremic acidosis in cirrhotic patients; avoid concurrent use.
Digoxin's positive inotropic effect may be reduced; serum levels of digoxin may increase.
Mitotane loses its effect; avoid concurrent use.
Potassium supplements may increase potassium retention and cause hyperkalemia; avoid concurrent use.
Salicylates and NSAIDs may interfere with the natriuretic action of spironolactone.
Ethanol/Nutrition/Herb Interactions
Food: Food increases absorption.
Herb/Nutraceutical: Avoid natural licorice (due to mineralocorticoid activity)
Storage
Protect from light.
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 of action: 2-3 days
Protein binding: 91% to 98%
Metabolism: Hepatic to multiple metabolites, including canrenone (active)
Half-life elimination: 78-84 minutes
Time to peak, serum: 1-3 hours (primarily as the active metabolite)
Excretion: Urine and feces
Dosage
To reduce delay in onset of effect, a loading dose of 2 or 3 times the daily dose may be administered on the first day of therapy. 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, hypokalemia: 25-200 mg/day in 1-2 divided doses
Hypertension (JNC 7): 25-50 mg/day in 1-2 divided doses
Diagnosis of primary aldosteronism: 100-400 mg/day in 1-2 divided doses
Acne in women (unlabeled use): 25-200 mg once daily
Hirsutism in women (unlabeled use): 50-200 mg/day in 1-2 divided doses
CHF, severe (with ACE inhibitor and a loop diuretic ± digoxin): 12.5-25 mg/day; maximum daily dose: 50 mg (higher doses may occasionallly be used). In the RALES trial, 25 mg every other day was the lowest maintenance dose possible.
Note: If potassium >5.4 mEq/L, consider dosage reduction.
Elderly: Initial: 25-50 mg/day in 1-2 divided doses, increasing by 25-50 mg every 5 days as needed.
Dosing interval in renal impairment:
Clcr 10-50 mL/minute: Administer every 12-24 hours.
Clcr <10 mL/minute: Avoid use.
Monitoring Parameters
Blood pressure, serum electrolytes (potassium, sodium), renal function, I & O ratios and daily weight throughout therapy
CHF: Potassium levels and renal function should be checked in 3 days and 1 week after initiation, then every 2-4 weeks for 3-12 months, then every 3-6 months.
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 as directed, with meals. Avoid any potassium supplements (vitamin/mineral products), potassium-containing salt substitutes, natural licorice, or extra dietary intake of potassium. Weigh yourself weekly at the same time, in the same clothes, and report weight loss >5 lb/week. May cause dizziness, drowsiness, confusion, or headache (use caution when driving or engaging in tasks requiring alertness until response to drug is known); nausea, vomiting, or dry mouth (small, frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help); or decreased sexual ability, gynecomastia, impotence, menstrual irregularities (reversible with discontinuing of medication). 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; or respiratory difficulty; breast tenderness or increased body hair in females; breast enlargement or inability to achieve erection in males. Pregnancy precaution: Do not get pregnant while taking this medication. Consult prescriber for appropriate contraceptive measures.
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, 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 concurrent ACE inhibitor therapy.
Cardiovascular Considerations
Heart Failure: The ACC/AHA 2005 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 2005 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 >5.4 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 and antihypertensive effect may be delayed 2-3 weeks (see Dosing for loading dose recommendations). Assess potential for interactions with other pharmacological agents patient may be taking (eg, anything that will increase risk of hyperkalemia). Assess serum electrolytes and hepatic function on a regular basis during therapy. Monitor effectiveness (fluid status) and adverse reactions periodically (eg, CNS changes [drowsiness, headache, confusion], rash, gynecomastia, dehydration, hyperkalemia, jaundice). Teach patient appropriate use, possible side effects/appropriate interventions and symptoms to report.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet: 25 mg, 50 mg, 100 mg
Pricing: U.S. (www.drugstore.com)
Tablets (Aldactone)
25 mg (30): $33.99
50 mg (30): $51.99
100 mg (30): $79.99
Tablets (Spironolactone)
25 mg (30): $15.99
50 mg (30): $21.99
100 mg (30): $34.99
Extemporaneously Prepared
A 25 mg/mL oral suspension can be prepared by crushing one hundred twenty (120) 25 mg tablets in a mortar (reducing to a fine powder), and then mixing in 20 mL of vehicle (a 1:1 combination of Ora-Sweet® or Ora-Sweet® SF and Ora-Plus®) to create a uniform paste. Continue to add vehicle in geometric amounts (while mixing) until near-final volume is achieved. Transfer to a graduate and add sufficient quantity to make 120 mL. Label “shake well” and “refrigerate.” Refrigerated stability is 60 days.
Allen LV Jr and Erickson MA III, “Stability of Ketoconazole, Metolazone, Metronidazole, Procainamide Hydrochloride, and Spironolactone in Extemporaneously Compounded Oral Liquids,” Am J Health Syst Pharm, 1996, 53:2073-8.
Nahata MC, Morosco RS, and Hipple TF, 4th ed, Pediatric Drug Formulations, Cincinnati, OH: Harvey Whitney Books Co, 2000.
References
American Academy of Pediatrics Committee on Drugs, “The 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, "ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure)," available at http://www.acc.org/qualityandscience/clinical/guidelines/failure/update/index.pdf.
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.
“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.
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 2008
Content last modified May 2008
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