Aldactone

1 INDICATIONS AND USAGE ALDACTONE is 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 ). • 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 ). • 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 ). • Treatment of primary hyperaldosternism for: ( 1.4 ) o Short-term preoperative treatment o 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 1.1 Heart Failure ALDACTONE is 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. ALDACTONE is usually administered in conjunction with other heart failure therapies. 1.2 Hypertension ALDACTONE is 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 ALDACTONE is indicated for the ma …

2 DOSAGE AND ADMINISTRATION • Heart Failure: Initiate treatment at 25 mg once daily ( 2.2 ). • Hypertension: Initiate treatment at 25 to 100 mg daily in either single or divided doses ( 2.3 ). • 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 ). • 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 ). 2.1 General Considerations ALDACTONE 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 ALDACTONE 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 ALDACTONE 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 ALDACTONE in doses of 100 to 400 mg daily in preparation for surgery. For patients who are considered unsuitable for surgery, ALDACTONE can be used as long-term maintenance therapy at the lowest effective dosage determined for the individual patient.

3 DOSAGE FORMS AND STRENGTHS Tablets: 25 mg round, light yellow, film-coated, with SEARLE and 1001 debossed on one side and ALDACTONE and 25 on the other side. Tablets: 50 mg oval, light orange, scored, film-coated, with SEARLE and 1041 debossed on the scored side and ALDACTONE and 50 on the other side. Tablets: 100 mg round, peach-colored, scored, film-coated, with SEARLE and 1031 debossed on the scored side and ALDACTONE and 100 on the other side. Tablets: 25 mg, 50 mg, and 100 mg ( 3 )

4 CONTRAINDICATIONS ALDACTONE is contraindicated in the patients with: • Hyperkalemia • Addison's disease • Concomitant use of eplerenone ALDACTONE is contraindicated in patients with ( 4 ): ▪ Hyperkalemia ▪ Addison's disease ▪ Concomitant use of eplerenone

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Hyperkalemia [see Warnings and Precautions (5.1) ] • Hypotension and Worsening Renal Function [see Warnings and Precautions (5.2) ] • Electrolyte and Metabolic Abnormalities [see Warnings and Precautions (5.3) ] • Gynecomastia [see Warnings and Precautions (5.4 ] • Impaired neurological function/ coma in patients with hepatic impairment, cirrhosis and ascites [see Use in Specific Populations (8.7) ] 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. The most common adverse reaction with ALDACTONE treatment is gynecomastia ( 5.4 , 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Pfizer, Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

7 DRUG INTERACTIONS • Agents increasing serum potassium: Concomitant administration can lead to hyperkalemia ( 5.1 , 7.1 ). • Lithium: Increased risk of lithium toxicity ( 7.2 ). • NSAIDs: May reduce the diuretic, natriuretic and antihypertensive effect of ALDACTONE ( 7.3 ). • Digoxin: ALDACTONE can interfere with radioimmunologic assays of digoxin exposure ( 7.4 ). • Cholestyramine: Hyperkalemic metabolic acidosis has been reported with concomitant use ( 7.5 ). • Acetylsalicylic Acid (ASA): ASA may reduce the efficacy of ALDACTONE ( 7.6 ). • Abiraterone: May increase prostate-specific antigen (PSA) levels ( 7.7 ). • Mitotane: Avoid concomitant use of ALDACTONE and mitotane ( 7.8 ). 7.1 Drugs and Supplements Increasing Serum Potassium Concomitant administration of ALDACTONE 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 ALDACTONE [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 ALDACTONE. 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, ALDACTONE reduces the renal clearance of lithium, thus increasing the risk of lithium toxicity. Monitor lithium levels periodically when ALDACTONE is 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 ALDACTONE 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 ALDACTONE concurrently with cholestyramine. 7.6 Acetylsalicylic Acid Acetylsalicylic acid may reduce the efficacy of spironolactone. Therefore, when ALDACTONE and acetylsalicylic acid are used concomitantly, ALDACTONE 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) ] . 7.7 Abiraterone Spironolactone binds to the androgen receptor and may increase prostate-specific antigen (PSA) levels in abiraterone-treated prostate cancer patients. Concomitant use of spironolactone and abiraterone is not recommended. 7.8 Mitotane Avoid concomitant use of ALDACTONE and mitotane. Spironolactone reduces mitotane plasma levels [see Clinical Pharmacology (12.3) ] .

8 USE IN SPECIFIC POPULATIONS ▪ Pregnancy: Based on animal data, ALDACTONE may affect sex differentiation of the male during embryogenesis ( 8.1 ) 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. 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 ALDACTONE 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, ALDACTONE 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 ALDACTONE 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. ALDACTONE has known endocrine effects in animals including progestational and antiandrogenic effects. 8.2 Lactation Risk Summary Spironolactone is not present in breastmilk; however, limited data from a lactating woman at 17 days postpartum reports the presence of the active metabolite, canre …

12.1 Mechanism of Action Spironolactone and its active metabolites are specific pharmacologic antagonists of aldosterone, acting primarily through competitive binding of receptors at the aldosterone-dependent sodium-potassium exchange site in the distal convoluted renal tubule. Spironolactone causes increased amounts of sodium and water to be excreted, while potassium is retained. Spironolactone acts both as a diuretic and as an antihypertensive drug by this mechanism. It may be given alone or with other diuretic agents that act more proximally in the renal tubule.

11 DESCRIPTION ALDACTONE oral tablets contain 25 mg, 50 mg, or 100 mg of the aldosterone antagonist spironolactone, 17-hydroxy-7α-mercapto-3-oxo-17α-pregn-4-ene-21-carboxylic acid γ-lactone acetate, which has the following structural formula: Spironolactone is practically insoluble in water, soluble in alcohol, and freely soluble in benzene and in chloroform. Inactive ingredients include calcium sulfate, corn starch, flavor, hypromellose, iron oxide, magnesium stearate, polyethylene glycol, povidone, and titanium dioxide. Chemical Structure

10 OVERDOSAGE The oral LD 50 of ALDACTONE 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. Treatment: Induce vomiting or evacuate the stomach by lavage. There is no specific antidote. Treatment is supportive to maintain hydration, electrolyte balance, and vital functions. Patients who have renal impairment may develop hyperkalemia. In such cases, discontinue ALDACTONE.

16 HOW SUPPLIED/STORAGE AND HANDLING ALDACTONE 25 mg tablets are round, light yellow, film-coated, with SEARLE and 1001 debossed on one side and ALDACTONE and 25 on the other side, supplied as: NDC Number Size 0025-1001-31 bottle of 100 ALDACTONE 50 mg tablets are oval, light orange, scored, film-coated, with SEARLE and 1041 debossed on the scored side and ALDACTONE and 50 on the other side, supplied as: NDC Number Size 0025-1041-31 bottle of 100 ALDACTONE 100 mg tablets are round, peach-colored, scored, film-coated, with SEARLE and 1031 debossed on the scored side and ALDACTONE and 100 on the other side, supplied as: NDC Number Size 0025-1031-31 bottle of 100 Store below 77°F (25°C).