Spironolactone

Spironolactone tablets are an aldosterone antagonist indicated for:

• •The treatment of NYHA Class III-IV heart failure and reduced ejection fraction to increase survival, manage edema, and to reduce the need for hospitalization for heart failure (
  1.1 Heart Failure

  Spironolactone tablets are indicated for treatment of NYHA Class III-IV heart failure and reduced ejection fraction to increase survival, manage edema, and reduce the need for hospitalization for heart failure.

  Spironolactone tablets are usually administered in conjunction with other heart failure therapies.
  ).
• •Use as an add-on therapy for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions (
  1.2 Hypertension

  Spironolactone tablets are indicated as add-on therapy for the treatment of hypertension, to lower blood pressure in patients who are not adequately controlled on other agents. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes.

  Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

  Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

  Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

  Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.
  ).
• •The management of edema in adult patients who are cirrhotic when edema is not responsive to fluid and sodium restrictions and in the setting of nephrotic syndrome when treatment of the underlying disease, restriction of fluid and sodium intake, and the use of other diuretics produce an inadequate response (
  1.3 Edema Associated with Hepatic Cirrhosis or Nephrotic Syndrome

  Spironolactone tablets are indicated for the management of edema in the following settings:

  • •Cirrhosis of the liver when edema is not responsive to fluid and sodium restriction.
  • •Nephrotic syndrome when treatment of the underlying disease, restriction of fluid and sodium intake, and the use of other diuretics produce an inadequate response.

  Because it increases serum potassium, spironolactone tablets may be useful for treating edema when administration of other diuretics has caused hypokalemia.
  ).
• •Treatment of primary hyperaldosternism for: (
  1.4 Primary Hyperaldosteronism

  Spironolactone tablets are indicated in the following settings:

  • •Short-term preoperative treatment of patients with primary hyperaldosteronism.
  • •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).
  ).
  • •Short-term preoperative treatment
  • •Long-term maintenance for patients with discrete aldosterone-producing adrenal adenomas who are not candidates for surgery and patients with bilateral micro or macronodular adrenal hyperplasia

• •Heart Failure: Initiate treatment at 25 mg once daily (
  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

  [ see Warnings and Precautions (5.1)]

  . In patients with an eGFR between 30 and 50 mL/min/1.73 m², consider initiating therapy at 25 mg every other day because of the risk of hyperkalemia [

  see Use in Specific Populations (8.6 )].
  ).
• •Hypertension: Initiate treatment at 25 to 100 mg daily in either single or divided doses (
  2.3 Treatment of Essential Hypertension

  The recommended initial daily dose is 25 to 100 mg of spironolactone tablets 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.
  ).
• •Edema: Initiate therapy in a hospital setting and titrate slowly. The recommended initial daily dose is 100 mg in single or divided doses (
  2.4 Treatment of Edema

  In patients with cirrhosis, initiate therapy in a hospital setting and titrate slowly

  [ see Use in Specific Populations (8.7)]

  . The recommended initial daily dosage is 100 mg of spironolactone tablets administered in either single or divided doses, but may range from 25 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.
  ).
• •Primary hyperaldosteronism: Initiate treatment at 100 to 400 mg in preparation for surgery. In patients unsuitable for surgery use the lowest effective dosage determined for the individual patient (
  2.5 Treatment of Primary Hyperaldosteronism

  Administer spironolactone tablets in doses of 100 to 400 mg daily in preparation for surgery. For patients who are considered unsuitable for surgery, spironolactone tablets can be used as long-term maintenance therapy at the lowest effective dosage determined for the individual patient.
  ).

Tablets: 25 mg white, round, unscored, debossed MP 35

Tablets: 50 mg white, round, film coated, scored, debossed MP 542

Tablets: 100 mg white, oval shape, film coated, scored, debossed MP 303

• •Pregnancy: Based on animal data, spironolactone tablets may affect sex differentiation of the male during embryogenesis (
  8.1 Pregnancy

  Risk Summary

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

  (see Data)

  . 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.

  Clinical Considerations

  Disease-Associated 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.

  Data

  Animal Data

  Teratology studies with spironolactone tablets 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 tablets 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 13 and 21 (late embryogenesis and fetal development), feminization of male fetuses was observed. Offspring exposed during late pregnancy to 50 and 100 mg/kg/day doses of spironolactone tablets 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 tablets has known endocrine effects in animals including progestational and antiandrogenic effects.
  ).

• •Hyperkalemia: Monitor serum potassium within one week of initiation and regularly thereafter (
  5.1 Hyperkalemia

  Spironolactone tablets can cause hyperkalemia. This risk is increased by impaired renal function or concomitant potassium supplementation, potassium-containing salt substitutes or drugs that increase potassium, such as angiotensin converting enzyme inhibitors and angiotensin receptor blockers

  [see Drug Interactions (7.1)]

  .

  Monitor serum potassium within 1 week of initiation or titration of spironolactone tablets and regularly thereafter. More frequent monitoring may be needed when spironolactone tablets are given with other drugs that cause hyperkalemia or in patients with impaired renal function.

  If hyperkalemia occurs, decrease the dose or discontinue spironolactone tablets and treat hyperkalemia.
  ).
• •Hypotension and Worsening Renal Function: Monitor volume status and renal function periodically (
  5.2 Hypotension and Worsening Renal Function

  Excessive diuresis may cause symptomatic dehydration, hypotension and worsening renal function, particularly in salt-depleted patients or those taking angiotensin converting enzyme inhibitors and angiotensin II receptor blockers. Worsening of renal function can also occur with concomitant use of nephrotoxic drugs (e.g., aminoglycosides, cisplatin, and NSAIDs). Monitor volume status and renal function periodically.
  ). Electrolyte and Metabolic Abnormalities: Monitor serum electrolytes, uric acid and blood glucose periodically (
  5.3 Electrolyte and Metabolic Abnormalities

  In addition to causing hyperkalemia, spironolactone tablets can cause hyponatremia, hypomagnesemia, hypocalcemia, hypochloremic alkalosis, and hyperglycemia. Asymptomatic hyperuricemia can occur and rarely gout is precipitated. Monitor serum electrolytes, uric acid and blood glucose periodically.
  ).
• •Gynecomastia: Spironolactone tablets can cause gynecomastia (
  5.4 Gynecomastia

  Spironolactone tablets can cause gynecomastia. In the Randomized Spironolactone Evaluation Study, patients with heart failure treated with a mean dose of 26 mg of spironolactone once daily, about 9% of the male subjects developed gynecomastia. The risk of gynecomastia increases in a dose-dependent manner with an onset that varies widely from 1-2 months to over a year. Gynecomastia is usually reversible.
  ).