ALDACTONE

Spironolactone is a potassium-sparing diuretic.

It binds to mineralocorticoid receptors and functions as aldosterone antagonists.

It promotes sodium and water excretion and potassium retention.

Spironolactone was originally developed purely for this ability before other pharmacodynamic properties of the drug were discovered. 7, 10 It is indicated to treat several conditions, including heart failure, edema, hyperaldosteronism, and hypertension.

Off-label uses of spironolactone include hirsutism, female pattern hair loss, and adult acne vulgaris. 4, 11 Spironolactone was developed in 1957, marketed in 1959, and approved by the FDA on January 21, 1960.

Spironolactone is indicated for the treatment of the following conditions: NYHA Class III-Intravenous heart failure and reduced ejection fraction to increase survival, manage edema, and reduce the need for hospitalization for heart failure.

Spironolactone is usually administered in conjunction with other heart failure therapies.

Hypertension, as add-on therapy, in patients not adequately controlled by other agents. 14, 15 Edema associated with hepatic cirrhosis when edema is not responsive to fluid and sodium restriction. 14, 15 Edema associated with nephrotic syndrome when treatment of the underlying disease, restriction of fluid and sodium intake, and the use of other diuretics produce an inadequate response.

Refractory edema associated with congestive cardiac failure, malignant ascites, hepatic cirrhosis with ascites, and essential hypertension.

Short-term preoperative treatment of patients with primary hyperaldosteronism. 14, 15 Diagnosis of primary aldosteronism.

Long-term maintenance therapy for patients with discrete aldosterone-producing adrenal adenomas who are not candidates for surgery.

Long-term maintenance therapy for patients with bilateral micro or macronodular adrenal hyperplasia (idiopathic hyperaldosteronism).

As spironolactone has antiandrogenic activity, its off-label uses include the treatment of hirsutism, female pattern hair loss, and adult acne vulgaris. 4,

Spironolactone has a potassium-sparing diuretic effect.

It promotes sodium and water excretion and potassium retention.

It increases renin and aldosterone levels.

Spironolactone is a mineralocorticoid receptor antagonist and has a low affinity for the glucocorticoid receptor.

It also exhibits progestogenic and anti-androgenic actions as it binds to the androgen receptor and, to a lesser extent, estrogen and progesterone receptors. 7, 6, 11 Spironolactone exhibits anti-inflammatory effects.

The mean time to reach peak plasma concentration of spironolactone and the active metabolite, canrenone, in healthy volunteers is 2.6 and 4.3 hours, respectively.

Food increased the bioavailability of spironolactone (as measured by AUC) by approximately 95.4%.

Spironolactone is rapidly and extensively metabolized to form different metabolites.

A group of metabolites are formed when sulfur of spironolactone is removed, such as canrenone.

Sulfur is retained in another group of metabolites, including 7-alpha (α)-thiomethylspironolactone (TMS) and 6-beta (ß)-hydroxy-7-alpha (α)-thiomethylspirolactone (HTMS).

Spironolactone is firstly deacetylated to 7-α-thiospironolactone. 2, 3, 5 7-α-thiospironolactone is S-methylated to TMS, which is the primary metabolite, 7, 8, 12 or dethioacetylated to canrenone. 2, 3, 12 TMS and HTMS can be further metabolized. 2, 3, 12 In humans, the potencies of TMS and 7-α-thiospirolactone in reversing the effects of the synthetic mineralocorticoid, fludrocortisone, on urinary electrolyte composition were approximately a third relative to spironolactone.

However, since the serum concentrations of these steroids were not determined, their incomplete absorption and/or first-pass metabolism could not be ruled out as a reason for their reduced in vivo activities.

Hover over products below to view reaction partners Spironolactone 7-alpha-thiospironolactone 7-alpha-thiomethylspironolactone 6-beta-7-alpha-thiomethylspironolactone 3beta-hydroxythiomethylspironolactone 3alpha-hydroxythiomethylspironolactone Canrenone.

The metabolites are excreted primarily in the urine and secondarily in bile.

Metabolites of spironolactone are excreted in urine (42-56%) and in the feces (14.2-14.6%).

No unmetabolized spironolactone is present in the urine.

The mean half-life of spironolactone is 1.4 hours.

The mean half-life values of its metabolites, including canrenone, TMS, and HTMS are 16.5, 13.8, and 15 hours, respectively.

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The oral

LD of spironolactone is greater than 1000 mg/kg in mice, rats, and rabbits.

Acute overdosage of

ALDACTONE may be manifested by drowsiness, mental confusion, maculopapular or erythematous rash, nausea, vomiting, dizziness, or diarrhea.

Rarely, instances of hyponatremia, hyperkalemia,or hepatic coma may occur in patients with severe liver disease, but these are unlikely due to acute overdosage.

Hyperkalemia may occur, especially in patients with impaired renal function.

In case of an overdose, vomiting may be induced and gastric lavage may be instituted.

As there is no specific antidote, treatment is supportive to maintain hydration, electrolyte balance, and vital functions.

Patients who have renal impairment may develop hyperkalemia.

Spironolactone is contraindicated in the patients with: Hyperkalemia Addison’s disease Concomitant use of eplerenone Spironolactone is contraindicated in patients with: Hyperkalemia Addison’s disease Concomitant use of eplerenone.

Initiate treatment at 25 mg once daily.

Initiate treatment at to 100 mg daily in either single or divided doses.

Initiate therapy in a hospital setting and titrate slowly.

The recommended initial daily dose is 100 mg in single or divided doses.

Primary hyperaldosteronism

Initiate treatment at to 400 mg in preparation for surgery.

In patients unsuitable for surgery use the lowest effective dosage determined for the individual patient. 2.1 General Considerations Spironolactone can be taken with or without food, but should be taken consistently with respect to food. 2.2 Treatment of Heart Failure In patients with serum potassium ≤5.0 mEq/L and eGFR >50 mL/min/1.73 m², initiate treatment at 25 mg once daily.

Patients who tolerate 25 mg once daily may have their dosage increased to 50 mg once daily as clinically indicated.

Patients who develop hyperkalemia on 25 mg once daily may have their dosage reduced to 25 mg every other day.

In patients with an eGFR between and 50 mL/min/1.73 m 2, consider initiating therapy at 25 mg every other day because of the risk of hyperkalemia. 2.3 Treatment of Essential Hypertension The recommended initial daily dose is to 100 mg of spironolactone administered in either single or divided doses is recommended.

Dosage can be titrated at two-week intervals.

Doses greater than 100 mg/day generally do not provide additional reductions in blood pressure. 2.4 Treatment of Edema In patients with cirrhosis, initiate therapy in a hospital setting and titrate slowly.

The recommended initial daily dosage is 100 mg of spironolactone administered in either single or divided doses, but may range from to 200 mg daily.

When given as the sole agent for diuresis, administer for at least five days before increasing dose to obtain desired effect. 2.5 Treatment of Primary Hyperaldosteronism Administer spironolactone in doses of to 400 mg daily in preparation for surgery.

For patients who are considered unsuitable for surgery, spironolactone can be used as long-term maintenance therapy at the lowest effective dosage determined for the individual patient.

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Based on mechanism of action and findings in animal studies, spironolactone may affect sex differentiation of the male during embryogenesis.

Rat embryofetal studies report feminization of male fetuses and endocrine dysfunction in females exposed to spironolactone in utero.

Limited available data from published case reports and case series did not demonstrate an association of major malformations or other adverse pregnancy outcomes with spironolactone.

There are risks to the mother and fetus associated with heart failure, cirrhosis and poorly controlled hypertension during pregnancy.

Because of the potential risk to the male fetus due to anti-androgenic properties of spironolactone and animal data, avoid spironolactone in pregnant women or advise a pregnant woman of the potential risk to a male fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.

Maternal and/or Embryo/Fetal Risk Pregnant women with congestive heart failure are at increased risk for preterm birth.

Stroke volume and heart rate increase during pregnancy, increasing cardiac output, especially during the first trimester.

Clinical classification of heart disease may worsen with pregnancy and lead to maternal death.

Closely monitor pregnant patients for destabilization of their heart failure.

Pregnant women with symptomatic cirrhosis generally have poor outcomes including hepatic failure, variceal hemorrhage, preterm delivery, fetal growth restriction and maternal death.

Outcomes are worse with coexisting esophageal varices.

Pregnant women with cirrhosis of the liver should be carefully monitored and managed accordingly.

Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage).

Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death.

Teratology studies with spironolactone have been carried out in mice and rabbits at doses of up to 20 mg/kg/day. On a body surface area basis, this dose in the mouse is substantially below the maximum recommended human dose and, in the rabbit, approximates the maximum recommended human dose.

No teratogenic or other embryotoxic effects were observed in mice, but the 20 mg/kg dose caused an increased rate of resorption and a lower number of live fetuses in rabbits.

Because of its antiandrogenic activity and the requirement of testosterone for male morphogenesis, spironolactone may have the potential for adversely affecting sex differentiation of the male during embryogenesis.

When administered to rats at 200 mg/kg/day between gestation days and 21 (late embryogenesis and fetal development), feminization of male fetuses was observed.

Offspring exposed during late pregnancy to and 100 mg/kg/day doses of spironolactone exhibited changes in the reproductive tract including dose-dependent decreases in weights of the ventral prostate and seminal vesicle in males, ovaries and uteri that were enlarged in females, and other indications of endocrine dysfunction, that persisted into adulthood.

Spironolactone has known endocrine effects in animals including progestational and antiandrogenic effects.

Safety and effectiveness in pediatric patients have not been established.

Spironolactone is substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function.

Because elderly patients are more likely to have decreased renal function, monitor renal function.