Spironolactone: Package Insert and Label Information

SPIRONOLACTONE- spironolactone tablet, film coated
Mylan Institutional Inc.

1 INDICATIONS AND USAGE

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.

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.

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.

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).

2 DOSAGE AND ADMINISTRATION

2.1 General Considerations

Spironolactone tablets can be taken with or without food, but should be taken consistently with respect to food [see Clinical Pharmacology (12.3)] .

2.2 Treatment of Heart Failure

In patients with serum potassium ≤ 5.0 mEq/L and eGFR > 50 mL/min/1.73 m 2 , 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 m 2 , consider initiating therapy at 25 mg every other day because of the risk of hyperkalemia [see Use in Specific Populations (8.6)].

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.

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.

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.

3 DOSAGE FORMS AND STRENGTHS

Spironolactone Tablets, USP are available containing 25 mg, 50 mg or 100 mg of spironolactone, USP.

  • The 25 mg tablets are white, film-coated, round, unscored tablets debossed with M over 146 on one side of the tablet and blankon the other side.
  • The 50 mg tablets are white, film-coated, round tablets debossed with M over 243 on one side of the tablet and scored on the other side.
  • The 100 mg tablets are white, film-coated, round tablets debossed with M over 437 on one side of the tablet and scored on the other side.

4 CONTRAINDICATIONS

Spironolactone tablets are contraindicated in the patients with:

  • Hyperkalemia
  • Addison’s disease
  • Concomitant use of eplerenone

5 WARNINGS AND PRECAUTIONS

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.

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.

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.

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.

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

The following adverse reactions associated with the use of spironolactone were identified in clinical trials or postmarketing reports. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency, reliably, or to establish a causal relationship to drug exposure.

Digestive: Gastric bleeding, ulceration, gastritis, diarrhea and cramping, nausea, vomiting.

Reproductive: Decreased libido, inability to achieve or maintain erection, irregular menses or amenorrhea, postmenopausal bleeding, breast and nipple pain.

Hematologic: Leukopenia (including agranulocytosis), thrombocytopenia.

Hypersensitivity: Fever, urticaria, maculopapular or erythematous cutaneous eruptions, anaphylactic reactions, vasculitis.

Metabolism: Hyperkalemia, electrolyte disturbances [see Warnings and Precautions ( 5.1, 5.3)] , hyponatremia, hypovolemia.

Musculoskeletal: Leg cramps.

Nervous system/psychiatric: Lethargy, mental confusion, ataxia, dizziness, headache, drowsiness.

Liver/biliary: A very few cases of mixed cholestatic/hepatocellular toxicity, with one reported fatality, have been reported with spironolactone administration.

Renal: Renal dysfunction (including renal failure).

Skin: Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms (DRESS), alopecia, pruritis.

7 DRUG INTERACTIONS

7.1 Drugs and Supplements Increasing Serum Potassium

Concomitant administration of spironolactone tablets with potassium supplementation or drugs that can increase potassium may lead to severe hyperkalemia. In general, discontinue potassium supplementation in heart failure patients who start spironolactone tablets [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)] . Check serum potassium levels when ACE inhibitor or ARB therapy is altered in patients receiving spironolactone tablets.

Examples of drugs that can increase potassium include:

  • ACE inhibitors
  • angiotensin receptor blockers
  • non-steroidal anti-inflammatory drugs (NSAIDs)
  • heparin and low molecular weight heparin
  • trimethoprim

7.2 Lithium

Like other diuretics, spironolactone tablets reduce the renal clearance of lithium, thus increasing the risk of lithium toxicity. Monitor lithium levels periodically when spironolactone tablets are coadministered [see Clinical Pharmacology (12.3)] .

7.3 Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

In some patients, the administration of an NSAID can reduce the diuretic, natriuretic, and antihypertensive effect of diuretics. Therefore, when spironolactone tablets and NSAIDs are used concomitantly, monitor closely to determine if the desired effect of the diuretic is obtained [see Clinical Pharmacology (12.3)] .

7.4 Digoxin

Spironolactone and its metabolites interfere with radioimmunoassays for digoxin and increase the apparent exposure to digoxin. It is unknown to what extent, if any, spironolactone may increase actual digoxin exposure. In patients taking concomitant digoxin, use an assay that does not interact with spironolactone.

7.5 Cholestyramine

Hyperkalemic metabolic acidosis has been reported in patients given spironolactone tablets concurrently with cholestyramine.

7.6 Acetylsalicylic Acid

Acetylsalicylic acid may reduce the efficacy of spironolactone. Therefore, when spironolactone tablets and acetylsalicylic acid are used concomitantly, spironolactone tablets may need to be titrated to higher maintenance dose and the patient should be observed closely to determine if the desired effect is obtained [see Clinical Pharmacology (12.3)] .

8 USE IN SPECIFIC POPULATIONS

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 [see Clinical Considerations] . 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.

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