spironolactone

1 INDICATIONS AND USAGE Spironolactone oral suspension is an antagonist of aldosterone indicated for: • the treatment of NYHA Class III to lV 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 cirrhotic patients when edema is not responsive to fluid and sodium restrictions ( 1.3 ) 1.1 Heart Failure Spironolactone oral suspension is indicated for treatment of NYHA Class III to IV heart failure and reduced ejection fraction in adult patients to increase survival, manage edema, and to reduce the need for hospitalization for heart failure. Spironolactone oral suspension is usually administered in conjunction with other heart failure therapies. 1.2 Hypertension Spironolactone oral suspension is indicated as an add-on therapy for the treatment of hypertension, to lower blood pressure in adult 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 caused by Cirrhosis Spironolactone oral suspension is indicated for the management of edema in adult cirrhotic patients when edema is not responsive to fluid and sodium restriction.

2 DOSAGE AND ADMINISTRATION • Spironolactone oral suspension is not therapeutically equivalent to Aldactone ( 2.1 ) • Heart Failure: Initiate treatment at 20 mg once daily. ( 2.2 ) • Hypertension: Initiate treatment at 20 to 75 mg daily in either single or divided doses ( 2.3 ) • Edema associated with Hepatic Cirrhosis: Initiate therapy in a hospital setting and titrate slowly. The initial recommended daily dose is 75 mg in either single or divided doses ( 2.4 ) 2.1 General Considerations Spironolactone oral suspension is not therapeutically equivalent to Aldactone. Follow dosing instructions given here. In patients requiring a dose greater than 100 mg, use another formulation. Doses of the suspension greater than 100 mg may result in spironolactone concentrations higher than expected [see Clinical Pharmacology ( 12.3 )] . Spironolactone oral suspension 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/1.73m 2 , initiate treatment at 20 mg (4 mL) once daily. Patients who tolerate 20 mg (4 mL) once daily may have their dosage increased to 37.5 mg (7.5 mL) once daily as clinically indicated. Patients who develop hyperkalemia on 20 mg (4 mL) once daily may have their dosage reduced to 20 mg (4 mL) every other day [see Warnings and Precautions ( 5.1 )] . In patients with an eGFR between 30 and 50 mL/min/1.73m 2 , consider initiating treatment at 10 mg (2 mL) 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 20 mg (4 mL) to 75 mg (15 mL) administered in either single or divided doses. Dosage can be titrated at two-week intervals. Doses >75 mg/day generally do not provide additional reductions in blood pressure. 2.4 Treatment of Edema Associated with Hepatic Cirrhosis In patients with cirrhosis, initiate therapy in a hospital setting and titrate slowly [see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )] . The recommended initial daily dose is 75 mg (15 mL) administered in either single or divided doses. In patients requiring titration above 100 mg, use another formulation [see Dosage and Administration ( 2.1 )] . When given as the sole agent for diuresis, administer for at least five days before increasing dose to obtain desired effect.

3 DOSAGE FORMS AND STRENGTHS Spironolactone Oral Suspension: 25 mg/5 mL (5 mg/mL); white to off-white, banana flavored suspension. Oral suspension, 25 mg/5 mL

4 CONTRAINDICATIONS Spironolactone oral suspension is contraindicated for patients with the following conditions: • Hyperkalemia • Addison’s disease • Concomitant use of eplerenone Spironolactone oral suspension 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 : Gynecomastia [see Warnings and Precautions ( 5.4 )], 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, chloasma. The most common adverse reaction (incidence > 5%) with spironolactone treatment is gynecomastia ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Hetero Labs Limited at 1-866-495-1995 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 spironolactone oral suspension ( 7.3 ) • Digoxin: Spironolactone oral suspension 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 spironolactone ( 7.6 ) 7.1 Drugs and Supplements Increasing Serum Potassium Concomitant administration of spironolactone oral suspension 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 oral suspension [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 oral suspension. Examples of drugs that can increase potassium include: • ACE inhibitors • angiotensin receptor blockers • aldosterone blockers • non-steroidal anti-inflammatory drugs (NSAIDs) • heparin and low molecular weight heparin • trimethoprim 7.2 Lithium Like other diuretics, spironolactone oral suspension reduces the renal clearance of lithium, thus increasing the risk of lithium toxicity. Monitor lithium levels periodically when spironolactone oral suspension 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 loop, potassium-sparing, and thiazide diuretics. Therefore, when spironolactone oral suspension 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 increase the apparent exposure to digoxin. In patients taking concomitant digoxin, measure serum digoxin concentrations before initiating spironolactone using an assay that does not interact with spironolactone. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring [see Clinical Pharmacology ( 12.3 )] . 7.5 Cholestyramine Hyperkalemic metabolic acidosis has been reported in patients given spironolactone concurrently with cholestyramine. 7.6 Acetylsalicylic Acid Acetylsalicylic acid may reduce the efficacy of spironolactone. Therefore, when spironolactone oral suspension and acetylsalicylic acid are used concomitantly, spironolactone oral suspension 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 CYP2C8 and CYP3A Substrates Spironolactone is an irreversible inhibitor for CYP2C8 and CYP3A4/5 in vitro [see Clinical Pharmacology ( 12.3 )] . Therefore, spironolactone may increase the exposure of other coadministered drugs that are metabolized by CYP2C8 and CYP3A4/5. Dosage adjustments of the drugs metabolized by CYP2C8 (e.g., repaglinide) and CYP3A4/5 (e.g., midazolam, sirolimus and tacrolimus) may be necessary if they are given concurrently with spironolactone.

8 USE IN SPECIFIC POPULATIONS • Pregnancy; Based on animal data, spironolactone 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 Clinical Pharmacology ( 12.1 )] . 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 congenital anomalies 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 congenital anomalies and miscarriage in the clinically recognized pregnancies is 2% to 4% and 15% to 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 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 embryo toxic 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 oral suspension may have the potential for adversely affecting sex differentiation of the male during embryogenesis. When administered to rats at 200 mg/kg/day, a dose 10 times the human dose of 200 mg/day, when based on body surface area, 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 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 oral suspension has known endocrine effects in animals including progestational and antiandrogenic effects. 8.2 La …

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 Spironolactone oral suspension contains 25 mg of the aldosterone antagonist spironolactone USP, 17-hydroxy-7α-mercapto-3-oxo-17α-pregn-4-ene-21-carboxylic acid γ-lactone acetate per 5 mL, which has the following structural formula: Molecular formula: C 24 H 32 O 4 S Molecular weight: 416.57 Spironolactone, USP is white or light cream color to light tan powder. It is practically insoluble in water, soluble in ethanol (96 %). Inactive ingredients include ammonium glycyrrhizate, art banana flavour (contains flavour and propylene glycol), dibasic sodium phosphate anyhydrous, glycerin, malic acid, microcrystalline cellulose and carboxy methyl cellulose sodium, potassium sorbate, purified water, saccharin sodium, simethicone emulsion, and sorbic acid. spironolactone-structure

10 OVERDOSAGE The oral LD50 of spironolactone is greater than 1000 mg/kg in mice, rats, and rabbits. Acute overdosage of spironolactone oral suspension 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 spironolactone oral suspension.

16 HOW SUPPLIED/STORAGE AND HANDLING Spironolactone Oral Suspension 25 mg/5 mL is a white to off-white, opaque, banana-flavored suspension. It is available in a 118 mL bottle (NDC 0574-1133-04), a 473 mL bottle (NDC 0574-1133-16), and a 5 mL unit dose cup (NDC 0574-1133-05) available in a 10 count carton (NDC 0574-1133-10). Store at 20° to 25°C (68° to 77°F). Excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature] . Shake well before use. Dispense in a tight container as defined in the USP.