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Spironolactone

Pronunciation

(speer on oh LAK tone)

Index Terms

  • Carospir

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Suspension, Oral:

CaroSpir: 25 mg/5 mL (118 mL, 473 mL) [contains saccharin sodium; banana flavor]

Tablet, Oral:

Aldactone: 25 mg

Aldactone: 50 mg, 100 mg [scored]

Generic: 25 mg, 50 mg, 100 mg

Brand Names: U.S.

  • Aldactone
  • CaroSpir

Pharmacologic Category

  • Antihypertensive
  • Diuretic, Potassium-Sparing
  • Mineralocorticoid (Aldosterone) Receptor Antagonists

Pharmacology

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

Metabolism

Rapid and extensive; hepatic to multiple metabolites, including active metabolites canrenone, 7-alpha-spirolactone, and 6-beta-hydroxy-7-alpha

Excretion

Urine (primarily as metabolites) and bile (secondary)

Time to Peak

Serum:

Tablet: 2.6 to 4.3 hours (primarily as active metabolites)

Suspension: Spironolactone: 0.5 to 1.5 hours; Canrenone: 2.5 to 5 hours

Duration of Action

Tablet: 2 to 3 days

Half-Life Elimination

Tablet: Spironolactone: ~1.4 hours; Canrenone: 16.5 hours (terminal); 7-alpha-spirolactone: 13.8 hours (terminal)

Suspension: Spironolactone: 1 to 2 hours; Canrenone, 7-alpha-spirolactone, and 6-beta-hydroxy-7-alpha: 10 to 35 hours

Protein Binding

>90%

Special Populations: Hepatic Function Impairment

Terminal half-life is increased in patients with cirrhotic ascites.

Use: Labeled Indications

Edema: Management of edema and sodium retention associated with heart failure unresponsive to other therapies; cirrhosis of liver accompanied by edema and/or ascites; or nephrotic syndrome unresponsive to other therapies.

Heart failure, severe: To increase survival and to reduce hospitalization for severe heart failure (New York Heart Association class III to IV) when used in addition to standard therapy.

Guideline recommendations: The American College of Cardiology Foundation/American Heart Association (ACCF/AHA) 2013 heart failure guidelines recommend the use of aldosterone antagonists, along with other guideline-directed medical therapies, to reduce morbidity and mortality in patients with heart failure (New York Heart Association [NYHA] class III to IV) with left ventricular ejection fraction (LVEF) 35% or less.

Hypertension: Management of hypertension unresponsive to other therapies.

Guideline recommendations: According to the Eighth Joint National Committee (JNC 8) guidelines, aldosterone antagonists are not recommended for the initial treatment of hypertension.

Hypokalemia (tablet only): Treatment of hypokalemia unresponsive to other therapies; prophylaxis of hypokalemia in patients taking digitalis.

Primary hyperaldosteronism (tablet only): Establishing the diagnosis of primary hyperaldosteronism by therapeutic trial; short-term preoperative treatment of primary hyperaldosteronism; long-term maintenance therapy for patients with discrete aldosterone-producing adrenal adenomas who are judged to be poor operative risks or who decline surgery; long-term maintenance therapy for bilateral micro- or macronodular adrenal hyperplasia (idiopathic hyperaldosteronism).

Off Label Uses

Acne vulgaris (females)

Data from a limited number of patients in a small number of randomized, placebo-controlled trials suggest that spironolactone may be beneficial in the treatment of moderate to severe acne in women. Additional trials may be necessary to further define the role of spironolactone in this condition.

Based on the American Academy of Dermatology guidelines of care for the management of acne vulgaris, spironolactone may be beneficial as therapy for the treatment of acne in select females.

Heart failure (NYHA class II; LVEF ≤35%)

Based on the American College of Cardiology Foundation/American Heart Association guidelines for the management of heart failure, spironolactone (along with other guideline directed medical therapies) is effective and recommended to reduce morbidity and mortality in patients with heart failure (NYHA class II-IV) with a left ventricular ejection fraction ≤35%.

Heart failure (post-myocardial infarction; LVEF ≤40%):

According to the 2013 ACCF/AHA guidelines for the management of ST-elevation myocardial infarction (STEMI) and the 2014 ACC/AHA guidelines for the management of non-ST-Elevation Acute Coronary Syndromes (NSTE-ACS), an aldosterone antagonist should be given to post-MI patients (without significant renal dysfunction) who are already on an ACE inhibitor and beta-blocker, who have an LVEF 40% or less and either symptomatic heart failure or diabetes mellitus.

Hirsutism

Data from systematic review of published randomized trials supports the use of spironolactone in combination with another drug used in the treatment of hirsutism [Koulouri 2008]. Additional trials may be necessary to further define the role of spironolactone in this condition.

Based on the Evaluation and Treatment of Hirsutism in Premenopausal Women: An Endocrine Society Clinical Practice guideline, spironolactone given for the treatment of hirsutism is effective and recommended in the management of this condition [Martin 2008].

Hypertension, diuretic (pediatric)

Based on the National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents guidelines, spironolactone is effective and recommended as a diuretic in the treatment of pediatric hypertension.

Post-myocardial infarction (left ventricular ejection fraction ≤40%)

Based on the American College of Cardiology Foundation/American Heart Association guidelines for the management of heart failure, spironolactone is effective and recommended post-myocardial infarction in patients with a left ventricular ejection fraction ≤40%.

Contraindications

Hyperkalemia; Addison disease; concomitant use with eplerenone.

Additional contraindications: Tablet only: Anuria; acute renal insufficiency; significant impairment of renal excretory function.

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to spironolactone or any component of the formulation; concomitant use with heparin or low molecular weight heparin.

Dosing: Adult

Note: Suspension is NOT therapeutically equivalent to tablets. In patients requiring >100 mg/dose, use tablets (>100 mg/dose of suspension may result in spironolactone concentration higher than expected).

Edema:

Tablet: Oral: 25 to 200 mg daily in single or divided doses.

Suspension: Initial: 75 mg daily in single or divided doses. Titrate slowly. When used as the sole agent for diuresis, administer ≥5 days before increasing dose to obtain desired effect.

Heart failure:

Tablet:

Severe (NYHA class III to IV): Oral: Initial: 12.5 to 25 mg once daily; maximum: 50 mg/day. If 25 mg once daily not tolerated, may reduce to 25 mg every other day (ACCF/AHA [Yancy 2013]).

NYHA class II; LVEF ≤35% (off-label use): Oral: 12.5 to 25 mg once daily; maximum: 50 mg/day (ACCF/AHA [Yancy 2013]).

Post myocardial infarction; LVEF ≤40% (off-label use): Oral: 12.5 to 25 mg once daily; maximum: 50 mg/day (ACCF/AHA [Yancy 2013]).

Note: Per the manufacturer, if potassium >5 mEq/L or serum creatinine >4 mg/dL, discontinue or interrupt therapy. Alternatively, the ACCF/AHA 2013 HF guidelines recommend withholding treatment if potassium >5.5 mEq/L or renal function worsens; hold doses until potassium is <5 mEq/L and consider restarting with a reduced dose after confirming resolution of hyperkalemia/renal insufficiency for at least 72 hours (ACCF/AHA [Yancy 2013]).

Suspension: Serum potassium ≤5 mEq/L: Initial: 20 mg once daily. May titrate to 37.5 mg once daily or decrease to 20 mg every other day as clinically indicated.

Hypokalemia: Oral: Tablet: 25 to 100 mg once daily.

Hypertension: Oral: Initial:

Tablet: 50 to 100 mg in single or divided doses; after 2 weeks, may adjust dose. In patients with resistant hypertension, an initial daily dose of 25 mg may also be added to other antihypertensive agents with an increase to 50 mg daily if needed (Vaclavik 2014; Williams 2015). Usual dosage range (ASH/ISH [Weber 2014]): 25 to 50 mg daily.

Suspension: 20 to 75 mg daily in single or divided doses; may titrate at 2-week intervals.

Primary aldosteronism: Oral: Tablet:

Manufacturer's labeling:

Diagnostic aid: Long test: 400 mg once daily for 3 to 4 weeks; short test: 400 mg once daily for 4 days Note: Clinical practice guidelines recommend using the plasma aldosterone/renin ratio (ARR) to detect potential cases of primary aldosteronism (not spironolactone); in addition, spironolactone (a mineralocorticoid receptor antagonist) should be withdrawn at least 4 weeks before ARR testing for optimal test interpretation (Funder 2016)

Maintenance until surgical correction: 100 to 400 mg once daily

Alternate recommendations:

Treatment of bilateral adrenal hypersecretion, or unilateral hypersecretion in patients unwilling or unable to undergo surgery: Initial: 12.5 to 25 mg once daily; gradually titrate upward if necessary to the lowest effective dose (maximum: 100 mg/day) (Funder 2016)

Acne vulgaris (females) (off-label use): Oral: 50 to 200 mg once daily (AAD [Zaenglein 2016]; Goodfellow 1984; Muhlemann 1986)

Ascites, due to cirrhosis (off-label dose): Initial: 100 mg once daily; titrate every 3 to 5 days as clinically indicated (usual maximum: 400 mg once daily); a spironolactone to furosemide dosing ratio of 100 mg (spironolactone) to 40 mg (furosemide) should be maintained (AASLD [Runyon 2012])

Hirsutism in women (off-label use): Oral: 50 to 200 mg daily in 1 to 2 divided doses (Koulouri 2008; Martin 2008)

Dosing: Geriatric

Hypertension: Oral: No initial dosage adjustment necessary (Aronow 2011).

Dosing: Pediatric

Edema, hypertension (off-label use): Oral: Children and Adolescents: Initial: 1 mg/kg/day divided every 12 to 24 hours (maximum dose: 3.3 mg/kg/day, up to 100 mg daily) (NHBPEP 2004)

Dosing: Renal Impairment

Manufacturer's labeling:

Tablet: Contraindicated in patients with anuria, acute renal impairment, or significant impairment of renal excretory function.

Suspension:

Edema, hypertension: There are no dosage adjustments provided in the manufacturer's labeling; spironolactone is substantially excreted by the kidney; use with caution.

Heart failure:

eGFR >50 mL/minute/1.73 m2: No dosage adjustment necessary.

eGFR 30 to 50 mL/minute/1.73 m2: Initial: 10 mg once daily.

eGFR <30 mL/minute/1.73 m2: There are no specific dosage adjustments provided in the manufacturer's labeling.

Alternate recommendations: Tablet:

Heart failure (ACCF/AHA [Yancy 2013]):

eGFR ≥50 mL/minute/1.73 m2: Initial dose: 12.5 to 25 mg once daily; Maintenance dose (after 4 weeks of treatment with potassium ≤5 mEq/L): 25 mg once or twice daily

eGFR 30 to 49 mL/minute/1.73 m2: Initial dose: 12.5 mg once daily or every other day; Maintenance dose (after 4 weeks of treatment with potassium ≤5 mEq/L): 12.5 to 25 mg once daily

eGFR <30 mL/minute/1.73 m2: Not recommended.

Patients ≥65 years: CrCl <30 mL/minute (regardless of indication): Avoid use due to risk of hyperkalemia (Beers Criteria [AGS 2015]).

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling. Use with caution; minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

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):2073-8.8870895Mathur LK and Wickman A, "Stability of Extemporaneously Compounded Spironolactone Suspensions," Am J Hosp Pharm. 1989, 46(10):2040-2.2816959Nahata MC, Morosco RS, and Hipple TF, "Stability of Spironolactone in an Extemporaneously Prepared Suspension at Two Temperatures," Ann Pharmacother. 1993, 27(10):1198-9.8251687

Administration

Solution: Shake well before administering dose. Administer with or without food; however, administer consistently with respect to food.

Dietary Considerations

Administration with food increases the bioavailability of spironolactone. Excessive potassium intake (eg, salt substitutes, low-salt foods, bananas, nuts) should be avoided.

Storage

Tablet: Store below 25°C (77°F).

Suspension: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

Abiraterone Acetate: Spironolactone may diminish the therapeutic effect of Abiraterone Acetate. Monitor therapy

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Alpha-/Beta-Agonists: Spironolactone may diminish the vasoconstricting effect of Alpha-/Beta-Agonists. Monitor therapy

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

AMILoride: May enhance the hyperkalemic effect of Spironolactone. Avoid combination

Ammonium Chloride: Potassium-Sparing Diuretics may enhance the adverse/toxic effect of Ammonium Chloride. Specifically the risk of systemic acidosis. Consider therapy modification

Amphetamines: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Angiotensin II Receptor Blockers: May enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Monitor therapy

Angiotensin-Converting Enzyme Inhibitors: Potassium-Sparing Diuretics may enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

AtorvaSTATin: May enhance the adverse/toxic effect of Spironolactone. Specifically, there is a theoretical potential for enhanced effects on reducing endogenous steroid activity. Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Brigatinib: May diminish the antihypertensive effect of Antihypertensive Agents. Brigatinib may enhance the bradycardic effect of Antihypertensive Agents. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Canagliflozin: May enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Canagliflozin may enhance the hypotensive effect of Potassium-Sparing Diuretics. 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. Monitor therapy

Cholestyramine Resin: May enhance the adverse/toxic effect of Spironolactone. Specifically, the risks of developing metabolic acidosis and hyperkalemia may be elevated with this combination. Monitor therapy

Ciprofloxacin (Systemic): Spironolactone may enhance the arrhythmogenic effect of Ciprofloxacin (Systemic). Monitor therapy

CycloSPORINE (Systemic): Potassium-Sparing Diuretics may enhance the hyperkalemic effect of CycloSPORINE (Systemic). Avoid combination

Diacerein: May enhance the therapeutic effect of Diuretics. Specifically, the risk for dehydration or hypokalemia may be increased. Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. 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. Monitor therapy

Drospirenone: May enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Monitor therapy

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. 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. Consider therapy modification

Heparin: May enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Management: Monitor serum potassium concentrations closely. The spironolactone Canadian product monograph lists its combination with heparin or low molecular weight heparins as contraindicated. Monitor therapy

Heparins (Low Molecular Weight): May enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Management: Monitor serum potassium concentrations closely. The spironolactone Canadian product monograph lists its combination with heparin or low molecular weight heparins as contraindicated. Monitor therapy

Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. Monitor therapy

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Methylphenidate: May diminish the antihypertensive effect of Antihypertensive Agents. 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. Consider therapy modification

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Neuromuscular-Blocking Agents (Nondepolarizing): Spironolactone may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing). Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nitrofurantoin: May enhance the hyperkalemic effect of Spironolactone. Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. 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. Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

Opioid Analgesics: May enhance the adverse/toxic effect of Diuretics. Opioid Analgesics may diminish the therapeutic effect of Diuretics. Monitor therapy

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Potassium Salts: May enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Consider therapy modification

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

QuiNIDine: Potassium-Sparing Diuretics may diminish the therapeutic effect of QuiNIDine. Monitor therapy

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. Consider therapy modification

Tacrolimus (Systemic): Potassium-Sparing Diuretics may enhance the hyperkalemic effect of Tacrolimus (Systemic). Avoid combination

Tolvaptan: May enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Monitor therapy

Triamterene: May enhance the hyperkalemic effect of Spironolactone. Avoid combination

Trimethoprim: May enhance the hyperkalemic effect of Spironolactone. Monitor therapy

Yohimbine: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Test Interactions

May interfere with the radioimmunoassay for digoxin; may lead to false negative aldosterone/renin ratio (ARR) (Funder 2016; Mulatero 2002)

Adverse Reactions

1% to 10%:

Endocrine & metabolic: Gynecomastia (9%)

Frequency not defined.

Cardiovascular: Vasculitis

Central nervous system: Ataxia, confusion, dizziness, drowsiness, headache, lethargy, nipple pain

Dermatologic: Alopecia, chloasma, erythematous maculopapular rash, pruritus, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria

Endocrine & metabolic: Amenorrhea, decreased libido, electrolyte disturbance, hyperkalemia, hyponatremia, hypovolemia

Gastrointestinal: Abdominal cramps, diarrhea, gastritis, gastrointestinal hemorrhage, gastrointestinal ulcer, nausea, vomiting

Genitourinary: Erectile dysfunction, impotence, irregular menses, mastalgia, postmenopausal bleeding

Hematologic & oncologic: Agranulocytosis, leukopenia, malignant neoplasm of breast, thrombocytopenia

Hepatic: Hepatotoxicity

Hypersensitivity: Anaphylaxis

Immunologic: DRESS syndrome

Neuromuscular & skeletal: Leg cramps

Renal: Increased blood urea nitrogen, renal failure, renal insufficiency

Miscellaneous: Fever

ALERT: U.S. Boxed Warning

Tumorigenic:

Spironolactone has been shown to be a tumorigen in chronic toxicity studies in rats. Use spironolactone only in those conditions for which it is indicated. Avoid unnecessary use of this drug.

Warnings/Precautions

Concerns related to adverse effects:

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving).

• Fluid/electrolyte imbalance: Fluid and electrolyte imbalance (eg, hypomagnesemia, hyponatremia, hypocalcemia, hypochloremic alkalosis, hyperglycemia, hyperkalemia, acidosis, elevated BUN) may occur; close medical supervision and dose evaluation are required. Patients with heart failure, renal disease, or cirrhosis may be particularly susceptible. Monitor and correct electrolyte disturbances; adjust dose to avoid dehydration.

• Gout: Asymptomatic hyperuricemia may occur and gout may be precipitated (rare).

• Gynecomastia: Related to dose and duration of therapy; typically is reversible following discontinuation of therapy but may persist (rare).

• Hyperkalemia: Hyperkalemia may occur; risk of hyperkalemia is increased with renal impairment, excessive potassium intake, and patients taking certain drugs (eg, ACE inhibitors, angiotensin-II blockers, NSAIDs). Monitor closely for hyperkalemia; increases in serum potassium are dose related and rates of hyperkalemia also increase with declining renal function. The concurrent use of larger doses of ACE inhibitors (eg, ≥ lisinopril 10 mg daily in adults) also increases the risk of hyperkalemia (ACCF/AHA [Yancy 2013]). Dose reduction or interruption of therapy may be necessary with development of hyperkalemia. Use is contraindicated in patients with hyperkalemia; use caution in conditions known to cause hyperkalemia.

• Tumorigenic: [US 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.

• Heart failure: When evaluating a heart failure patient for spironolactone treatment, eGFR should be >30 mL/minute/1.73 m2 or creatinine should be ≤2.5 mg/dL (men) or ≤2 mg/dL (women) with no recent worsening and potassium <5 mEq/L with no history of severe hyperkalemia (ACCF/AHA [Yancy 2013]). Serum potassium levels require close monitoring and management if elevated. The manufacturer of the tablet recommends to discontinue or interrupt therapy if serum potassium >5 mEq/L or serum creatinine >4 mg/dL. The ACCF/AHA recommends considering discontinuation upon the development of serum potassium >5.5 mEq/L or worsening renal function with careful evaluation of the entire medical regimen. Avoid routine triple therapy with the combined use of an ACE inhibitor, ARB, and spironolactone. Instruct patients with heart failure to discontinue use during an episode of diarrhea or dehydration or when loop diuretic therapy is interrupted (ACCF/AHA [Yancy 2013]).

• Hepatic impairment: Use with caution in patients with hepatic impairment; minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

• Renal impairment: Risk of hyperkalemia is increased with declining renal function and with the concurrent use of larger doses of ACE inhibitors (eg, ≥ lisinopril 10 mg daily in adults) (ACCF/AHA [Yancy 2013]). Use with caution in patients with mild renal impairment; tablets are contraindicated with anuria, acute renal insufficiency, or significant impairment of renal excretory function.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Avoid use of tablets >25 mg/day in elderly patients with heart failure or with reduced renal function (eg, CrCl <30 mL/minute or eGFR ≤30 mL/minute/1.73 m2 [Yancy 2013]).

Other warnings/precautions:

• Suspension: Suspension is NOT therapeutically equivalent to tablets. In patients requiring >100 mg/dose, use tablets (>100 mg/dose of suspension may result in spironolactone concentration higher than expected).

Monitoring Parameters

Blood pressure, serum electrolytes (potassium, sodium), renal function, I & O ratios and daily weight throughout therapy

ACCF/AHA heart failure guideline recommendations (ACCF/AHA [Yancy 2013]): Serum potassium and renal function should be checked in 3 days after initiation, at 1 week after initiation, at least monthly for the first 3 months of therapy, and every 3 months thereafter. If adding or increasing the dose of concomitant ACE inhibitors or ARBs, a new cycle of monitoring should be done. If serum potassium increases to >5.5 mEq/L or renal function worsens, hold doses until potassium is <5 mEq/L and consider restarting with a reduced dose after confirming resolution of hyperkalemia/renal insufficiency for at least 72 hours.

Pregnancy Considerations

Adverse events have been observed in some animal reproduction studies. The antiandrogen effects of spironolactone have been shown to cause feminization of the male fetus in animal studies. Spironolactone crosses the placenta (Regitz-Zagrosek 2011).

The treatment of heart failure is generally the same in pregnant and nonpregnant women; however, spironolactone should be avoided in the first trimester due to its antiandrogenic effects (Regitz-Zagrosek 2011). The use of mineralocorticoid receptor antagonists is not recommended to treat chronic uncomplicated hypertension in pregnant women and should generally be avoided in women of reproductive potential. When treatment for hypertension in pregnancy is needed, other agents are preferred (ACOG 2013). Use of diuretics to treat edema during normal pregnancies is not appropriate; use may be considered when edema is due to pathologic causes (as in the nonpregnant patient); monitor.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience diarrhea, fatigue, headache, hair loss, nausea, vomiting, or abdominal cramps. Have patient report immediately to prescriber signs of fluid and electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, dizziness, passing out, tachycardia, increased thirst, seizures, loss of strength and energy, lack of appetite, urinary retention or change in amount of urine passed, dry mouth, dry eyes, nausea, or vomiting), signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe bleeding or persistent bleeding), severe dizziness, passing out, confusion, change in balance, decreased libido, sexual dysfunction, chills, pharyngitis, burning or numbness feeling, bradycardia, menstrual changes, breast pain, or enlarged breasts (males) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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