SPIRONOLACTONE (Generic for ALDACTONE)

General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 2
-NIOSH (Draft) 2020 List: Table 2
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure and require additional protective equipment. Oral liquid drugs require double chemotherapy gloves and protective gown; may require eye/face protection.

Route-Specific Administration

Oral Administration
-May be taken without regard to meals; however, should be taken consistently with respect to food.
Oral Liquid Formulations
-The commercially available spironolactone oral suspension is not therapeutically equivalent to the tablets. In patients requiring a dose more than 100 mg, another formulation should be used.
-Shake well before use.
-Measure with a calibrated oral device to ensure accurate dosing.

Extemporaneous Compounding-Oral
Extemporaneous Formulas for Oral Suspension
NOTE: The extemporaneous preparation of spironolactone is not FDA-approved.
-Several recipes resulting in DIFFERENT final concentrations have been described.
-Adherence to stated techniques for preparation is recommended to obtain uniform suspensions and to avoid problems in formulation (e.g., excessively thick suspensions) during compounding.

- Method 1 (1 mg/mL suspension)
-Pulverize ten (10) spironolactone 25 mg tablets.
-Add a small amount of Purified Water, USP and allow to dissolve for 5 minutes.
-Add 50 mL of 1.5% Carboxymethylcellulose and 100 mL of Simple Syrup NF and mix.
-Use a sufficient quantity of purified water to produce a total volume of 250 mL.
-Transfer to a glass bottle.
-Shake well.
-Storage: The resulting suspension is stable for 3 months at room temperature or refrigerated.

- Method 2 (2.5, 5, or 10 mg/mL suspension)
-Add two hundred (200) spironolactone 25 mg (for 2.5 mg/mL concentration), 50 mg (for 5 mg/mL concentration), or 100 mg (for 10 mg/mL concentration) tablets to a large glass mortar.
-Break with the pestle, and grind tablets until they and their film coats are a fine powder.
-Slowly add 100 mL of Purified Water USP, and triturate to form a fine paste; any film coat particles should dissolve at this phase.
-Gradually add 1900 mL of Cherry Syrup, NF in 3 steps as follows: 1) add about one-third of the cherry syrup to the paste, triturate well, and transfer the mortar contents to a large stainless steel container. 2) Rinse mortar with about one-third of cherry syrup and transfer contents to the stainless steel container. 3) Repeat step 2 with the remaining one-third cherry syrup.
-Homogenize for 10 minutes at high speed using a laboratory model homogenizer.
-Transfer the resulting suspension to amber glass bottles with constant stirring.
-Shake well.
-Storage: The resulting suspension is reported stable for 4 weeks at 5 and 30 degrees C.

- Method 3 (25 mg/mL suspension)
-Add one hundred twenty (120) spironolactone 25 mg tablets to a large glass mortar.
-Break with the pestle, and grind tablets into a fine powder.
-Add approximately 40 mL of the chosen vehicle and mix to a uniform paste. Vehicle choices include: 1) a 1:1 mixture of Ora-Sweet and Ora-Plus 2) a 1:1 mixture of Ora-Sweet SF and Ora-Plus 3) cherry syrup.
-Add geometric portions of the vehicle almost to volume and mix thoroughly after each addition.
-Transfer the contents to a calibrated bottle and add enough vehicle to bring to a total volume of 120 mL.
-Storage: The resulting suspension is reported stable for 60 days at 5 and 25 degrees C when protected from light.

Spironolactone causes hyperkalemia and can cause life-threatening cardiac arrhythmias. Signs and symptoms of hyperkalemia include muscle weakness, paresthesias, fatigue, flaccid paralysis of the extremities, sinus bradycardia, shock, and electrocardiogram (ECG) changes. Patients who receive potassium supplements or patients with impaired renal function who are also receiving spironolactone therapy are particularly at risk for developing hyperkalemia. Monitor serum potassium and renal function 3 days and 1 week after initiation of therapy or dose increase, monthly for 3 months, quarterly for a year, and every 6 months thereafter. If hyperkalemia occurs, decrease the dose or discontinue spironolactone. In adults, spironolactone should be discontinued if serum creatinine is greater than 4 mg/dL or serum potassium is greater than 5 mEq/L; pediatric-specific recommendations are not available. In cases of severe hyperkalemia, urgent measures such as the administration of intravenous calcium, sodium bicarbonate, glucose, and a rapid-acting insulin may be necessary; persistent hyperkalemia may require dialysis.

Spironolactone can cause hyponatremia, hypomagnesemia, hypocalcemia, hypochloremic metabolic alkalosis, and hyperglycemia. Asymptomatic hyperuricemia can also occur; rarely, gout is precipitated. Monitor serum electrolytes, uric acid, and blood glucose periodically. Electrolyte abnormalities other than hyperkalemia may be more likely when spironolactone is used in combination with other diuretic therapy. Dilutional hyponatremia, which can present as dry mouth, thirst, lethargy, and drowsiness, may also occur in edematous patients during hot weather; appropriate therapy includes water restriction rather than sodium administration except in rare cases of life-threatening hyponatremia.

A reversible hyperchloremic metabolic acidosis can occur in patients with decompensated hepatic cirrhosis who are receiving spironolactone. This effect is usually associated with hyperkalemia and can occur regardless of renal function.

Spironolactone has antiandrogenic, progestogenic, and estrogenic properties. Spironolactone may cause gynecomastia, an effect that is usually dose-related with an onset that varies widely from 1 to 2 months to over a year. Gynecomastia is usually reversible. Menstrual irregularity, breast tenderness or mastalgia, and amenorrhea may also occur.

While a cause-and-effect relationship has not been established for development of a new primary malignancy, breast cancer has been reported in adults receiving spironolactone. In addition, the tablet product label carries a boxed warning stating that spironolactone is a tumorigen in rats. However, human data are not available to describe the potential for tumorigenicity secondary to use.

Adverse GI effects reported during spironolactone therapy include nausea, vomiting, cramping, diarrhea, gastritis, abdominal pain, gastric bleeding, and ulceration.

Adverse nervous system effects that have been reported in patients receiving spironolactone therapy include headache, dizziness, drowsiness, lethargy, ataxia, and mental confusion. Muscular weakness may be a sign of drug-induced hyperkalemia.

Excessive diuresis may cause symptomatic dehydration, hypovolemia, hypotension, and worsening renal function including renal failure (unspecified). Transient increases in BUN may occur during spironolactone therapy, especially in patients with renal impairment. Monitor volume status and renal function periodically. In addition, due to the diuretic action of spironolactone, polyuria can be troublesome for some patients during therapy.

Hypersensitivity reactions such as fever, urticaria, erythema, maculopapular rash, erythematous cutaneous eruptions, vasculitis, and anaphylactoid reactions may occur during therapy with spironolactone. Stevens-Johnson syndrome, toxic epidermal necrolysis, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), alopecia, chloasma, and pruritus also have been reported with spironolactone therapy.

Leukopenia, including agranulocytosis, and thrombocytopenia have been reported during spironolactone therapy.

A few cases of mixed cholestatic/hepatocellular toxicity, including one report of hepatic failure resulting in death, have been reported with spironolactone administration.

Muscle cramps (leg cramps) have been reported in patients taking spironolactone.

Spironolactone may cross react with some enzyme linked immunosorbent assay (ELISA) kits used to screen neonates for congenital adrenal hyperplasia causing a false positive result.

Spironolactone is contraindicated in patients with hyperkalemia and Addison's disease (chronic adrenal insufficiency), and should not be administered to patients receiving other potassium-sparing agents. Spironolactone-induced hyperkalemia can cause life-threatening cardiac arrhythmias, and it is more likely to occur in patients with renal impairment (e.g., renal disease, renal failure, anuria) or diabetes mellitus. Excessive diuresis may cause symptomatic dehydration, hypotension, and worsening renal function, especially in salt-depleted patients. Monitor serum potassium within 1 week of initiation or dose titration and regularly thereafter. Patients taking other drugs that cause hyperkalemia or those with impaired renal function may require more frequent monitoring. Monitor volume status periodically. If hypokalemia occurs, decrease the dosage of or discontinue spironolactone and treat the hyperkalemia. Patients receiving spironolactone should not receive potassium supplementation or increase their dietary intake of potassium unless they have refractory hypokalemia. In adults, the risk of hyperkalemia increases progressively when serum creatinine exceeds 1.6 mg/dL; the threshold for pediatric patients is unknown.

Correct significant electrolyte imbalance and/or acid/base imbalance before spironolactone is initiated. In addition to hyperkalemia, spironolactone can cause hyponatremia, hypomagnesemia, hypocalcemia, hypochloremic metabolic alkalosis, and hyperglycemia. Asymptomatic hyperuricemia can occur; rarely, gout is precipitated. Monitor serum electrolytes, uric acid, and blood glucose periodically.

Spironolactone can cause sudden alterations of fluid and electrolyte balance which may precipitate impaired neurologic function, worsening hepatic encephalopathy, and coma in patients with hepatic disease with biliary cirrhosis and ascites. In these patients, initiate spironolactone in the hospital. Clearance of spironolactone and its metabolites is reduced in patients with cirrhosis; start with the lowest initial dose and titrate slowly in these patients.

Use spironolactone with caution in pediatric patients (infants, children, and adolescents) due to potential risks associated with its antiandrogenic, progestogenic, and estrogenic properties. Spironolactone can cause gynecomastia; risk increases in a dose-dependent manner with an onset that varies from 1 month to over a year. Gynecomastia is usually reversible.

Spironolactone has been demonstrated to be a tumorigen in chronic toxicity studies in rats. Although human data are not available, the potential for tumorigenicity or development of a new primary malignancy are potential risks to consider during spironolactone therapy.

Somnolence and dizziness have been reported to occur in some patients receiving spironolactone. Patients should not perform activities requiring coordination and concentration, such as gymnastics, riding a bicycle or for older adolescents, operation of vehicles, until they are aware of how this medication affects them.

Description: Spironolactone is a potassium-sparing diuretic used in the management of edema, hypertension, and chronic lung disease. The American Academy of Pediatrics recommends diuretics, in general, be used as add-on therapy in pediatric patients uncontrolled on other antihypertensives. Compared to thiazide or loop diuretics, spironolactone is a relatively weak agent for treating hypertension or generalized edema, although its effects can be additive with thiazide diuretics. It is often given in combination with thiazide or loop diuretics to reduce the potassium excretion associated with these drugs. In adult patients, spironolactone is a key component in the management of heart failure. It is also used in pediatric patients with heart failure; however, it has not been as rigorously studied in this population. Although not FDA-approved, spironolactone has been used in pediatric patients as young as neonates.

-NOTE: The commercially available oral suspension (CaroSpir) is not therapeutically equivalent to spironolactone tablets. CaroSpir is not FDA-approved for pediatric use and should not be substituted for dosing based on the tablets (or compounded suspension).

For the treatment of hypertension* or hypokalemia*, including that associated with hyperaldosteronism*:
Oral dosage (tablets or extemporaneous suspension):
Neonates: 1 to 3.3 mg/kg/day PO given in 1 to 2 divided doses. Doses up to 4 mg/kg/day PO given in 1 to 2 divided doses have been reported in an observational study of 100 patients (mean age 20.8 months, range 4 days to 21 years) with various indications, including co-administration with loop diuretics. Allow 72 hours between dosage adjustments due to the gradual onset of action.
Infants, Children, and Adolescents: 1 to 3.3 mg/kg/day PO given in 1 to 2 divided doses (Max: 100 mg/day). Doses up to 4 mg/kg/day PO given in 1 to 2 divided doses have been reported in an observational study of 100 patients (mean age 20.8 months, range 4 days to 21 years) with various indications, including co-administration with loop diuretics. Allow 72 hours between dosage adjustments due to the gradual onset of action.

For the treatment of heart failure* and edema* (e.g., due to nephrotic syndrome* or hepatic disease (ascites*)):
Oral dosage (tablets or extemporaneous suspension):
Neonates and Infants: 1 to 2 mg/kg/day PO given in 1 to 2 divided doses initially, and then titrate to effect (Max: 3 to 4 mg/kg/day). In 11 infants (1 to 12 months of age) with congestive heart failure secondary to congenital heart disease, 1 to 2 mg/kg/day PO divided every 12 hours was used in combination with digoxin and chlorothiazide. Significant reductions in liver size, weight, and respiratory rate were seen compared to baseline and no significant differences in electrolyte abnormalities were noted compared to a group of infants receiving therapy with potassium supplements, digoxin, and chlorothiazide. In an observational study, 1 to 4 mg/kg/day PO given in 1 to 2 divided doses was used in 100 patients (mean age 20.8 months, range 4 days to 21 years) with various indications. Allow 72 hours between dosage adjustments due to the gradual onset of action.
Children and Adolescents: 1 to 4 mg/kg/day PO given in 1 to 4 divided doses (Max: 200 mg/day PO). Allow 72 hours between dosage adjustments due to the gradual onset of action.

For the treatment of pulmonary edema* due chronic lung disease (CLD)*:
Oral dosage (tablets or extemporaneous suspension):
Neonates and Infants: 3 to 4 mg/kg/day PO divided twice daily has been used in combination with chlorothiazide or hydrochlorothiazide. Because of the potential effects on electrolytes, it may be prudent to begin with a lower dose and titrate as tolerated in patients at risk for electrolyte imbalance.

For the treatment of peripheral precocious puberty* in persons with familial male-limited precocious puberty*:
Oral dosage:
Children and Adolescents: 1.5 mg/kg/day divided every 12 hours for 7 days, then 3 mg/kg/day divided every 12 hours for 7 days, then 5.7 mg/kg/day divided every 12 hours. Max: 500 mg/day. Use spironolactone in combination with an aromatase inhibitor.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established; however, doses up to 4 mg/kg/day PO have been used off-label.
-Infants
Safety and efficacy have not been established; however, doses up to 4 mg/kg/day PO have been used off-label.
-Children
Safety and efficacy have not been established; however, doses up to 4 mg/kg/day PO (Max: 200 mg/day PO) have been used off-label for edema due to nephrotic syndrome.
-Adolescents
Safety and efficacy have not been established; however, doses up to 4 mg/kg/day PO (Max: 200 mg/day PO) have been used off-label for edema due to nephrotic syndrome.

Patients with Hepatic Impairment Dosing
In patients with cirrhosis, start with the lowest initial dose and titrate slowly. Use with caution in patients with hepatic disease; minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

Patients with Renal Impairment Dosing
CrCl 10 mL/minute/1.73 m2 or more: No dosage adjustment needed; however, monitor renal function closely as hyperkalemia is more likely to occur in patients with renal impairment.
CrCl less than 10 mL/minute/1.73 m2: Avoid use.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Spironolactone inhibits the effects of aldosterone on the distal renal tubules. Unlike amiloride and triamterene, spironolactone exhibits its diuretic effect only in the presence of aldosterone, and these effects are enhanced in patients with hyperaldosteronism. Aldosterone antagonism enhances sodium, chloride, and water excretion, and reduces the excretion of potassium, ammonium, and phosphate. Spironolactone does not inhibit renal transport mechanisms or carbonic anhydrase activity. In addition, spironolactone acts as an androgen receptor blocker by competitively inhibiting dihydrotestosterone at its receptor sites, and at high doses, spironolactone interferes with steroid synthesis in the adrenal glands and gonads. Sebum excretion rates also are reduced in a dose-dependent manner with spironolactone.

Spironolactone has modest hypotensive effects. The hypotensive mechanism of spironolactone is unknown. It is possibly due to the ability of the drug to inhibit aldosterone's effect on arteriole smooth muscle. Spironolactone also can alter the extracellular-intracellular sodium gradient across the membrane. In general, diuretics lower blood pressure by initially decreasing cardiac output and reducing plasma and extracellular fluid volume. Cardiac output and extracellular fluid volume eventually return to normal, but peripheral resistance is reduced, resulting in lower blood pressure.

Pharmacokinetics: Spironolactone is administered orally. Spironolactone is extensively metabolized, via hepatic pathways, to active metabolites. The clinical effects of spironolactone are partially due to canrenone, a metabolite. The parent drug and canrenone are greater than 90% plasma protein-bound. The duration of action after multiple doses of spironolactone is 2 to 3 days. Both unchanged drug (less than 10%) and its metabolites are excreted primarily in the urine. The remainder of a dose is excreted in the feces via biliary elimination. The half-life of spironolactone after a single dose is 1 to 2 hours. The half-life of canrenone ranges from 10 to 35 hours.

Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4/5, CYP2C8
Spironolactone is rapidly and extensively metabolized primarily by CYP3A4/5, and to a lesser extent by CYP2C8. In vitro studies also show that spironolactone is an irreversible inhibitor of CYP3A4/5 and CYP2C8.


-Route-Specific Pharmacokinetics
Oral Route
Approximately 60% to 90% of a dose of spironolactone is absorbed from the GI tract after oral administration. The peak plasma concentration of spironolactone occurs 0.5 to 1.5 hours after administration; the Cmax of the active metabolite canrenone occurs 2.5 to 5 hours after dosing. For an equivalent dose, the oral suspension results in 15% to 37% higher serum concentrations compared to the tablets; information about dose proportionality is limited, and based on comparative studies, doses of oral suspension higher than 100 mg may result in higher than expected plasma concentrations. Food will enhance absorption when given concurrently. A high fat and high calorie meal increases bioavailability of the oral suspension by about 90%. There is considerable first-pass elimination and significant enterohepatic recirculation. The onset of diuresis is gradual, with peak effects occurring on the third day after administration.


-Special Populations
Hepatic Impairment
The terminal half-life of spironolactone has been reported to be increased in patients with cirrhotic ascites.