EPLERENONE

Eplerenone Tablets contain eplerenone, a blocker of aldosterone binding at the mineralocorticoid receptor. Eplerenone is chemically described as Pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy-17-hydroxy-3-oxo-, γ-lactone, methyl ester, (7α,11α, 17α)-. Its empirical formula is C 24 H 30 O 6 and it has a molecular weight of 414.50. The structural formula of eplerenone is represented below: eplerenone Eplerenone is an odorless, white to off-white crystalline powder. It is very slightly soluble in water, with its solubility essentially pH-independent. The octanol/water partition coefficient of eplerenone is approximately 7.1 at pH 7.0. Eplerenone Tablets for oral administration contain 25 mg or 50 mg of eplerenone and the following inactive ingredients: croscarmellose sodium, D&C Yellow No. 10, FD&C Yellow No. 6, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, red iron oxide, sodium lauryl sulfate, talc, titanium dioxide, and yellow iron oxide. Chemical Structure

Eplerenone Tablets are an aldosterone antagonist indicated for: The treatment of hypertension in adults, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions ( 1.2 ). 1.2 Hypertension Eplerenone Tablets are indicated for the treatment of hypertension in adults, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular (CV) events, primarily strokes and MI. 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 CV 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 CV 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 CV outcome benefit has been a reduction in the risk of stroke, but reductions in MI and CV mortality also have been seen regularly. Elevated systolic or diastolic pressure causes increased CV 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.

Hypertension: 50 mg once daily, For inadequate response, increase to 50 mg twice daily. Higher dosages are not recommended. ( 2.2 ) For all patients: Measure serum potassium before starting Eplerenone Tablets and periodically thereafter. ( 2.3 ) 2.2 Hypertension The recommended starting dose of Eplerenone Tablets is 50 mg administered once daily. The full therapeutic effect of Eplerenone Tablets is apparent within 4 weeks. For patients with an inadequate blood pressure response to 50 mg once daily increase the dosage of eplerenone tablets to 50 mg twice daily. Higher dosages of Eplerenone Tablets are not recommended because they have no greater effect on blood pressure than 100 mg and are associated with an increased risk of hyperkalemia [see Clinical Studies (14.2) ]. 2.3 Recommended Monitoring Measure serum potassium before initiating eplerenone tablets therapy, within the first week, and at one month after the start of treatment or dose adjustment. Assess serum potassium periodically thereafter. Check serum potassium and serum creatinine within 3-7 days of a patient initating a moderate CYP3A inhibitor, angiotensin-II blockers or non-steroidal-anti-inflammatories. 2.4 Dose Modification for Use with Moderate CYP3A Inhibitors In patients with hypertension receiving a moderate CYP3A inhibitor, initiate at 25 mg once daily. For inadequate blood pressure response, dosing may be increased to a maximum of 25 mg twice daily [see Drug Interactions (7.1) ].

For all patients: Serum potassium >5.5 mEq/L at initiation ( 4 ) Creatinine clearance ≤30 mL/min ( 4 ) Concomitant use with strong CYP3A inhibitors ( 4 , 7.1 ) For the treatment of hypertension: Type 2 diabetes with microalbuminuria ( 4 ) Serum creatinine >2.0 mg/dL in males, >1.8 mg/dL in females ( 4 ) Creatinine clearance <50 mL/min ( 4 ) Concomitant use of potassium supplements or potassium-sparing diuretics ( 4 ) For All Patients Eplerenone Tablets are contraindicated in all patients with: serum potassium >5.5 mEq/L at initiation, creatinine clearance ≤30 mL/min, or concomitant administration of strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, and nelfinavir) [see Drug Interactions (7.1) , Clinical Pharmacology (12.3) ]. For Patients Treated for Hypertension Eplerenone Tablets are contraindicated for the treatment of hypertension in patients with: type 2 diabetes with microalbuminuria, serum creatinine >2.0 mg/dL in males or >1.8 mg/dL in females, creatinine clearance <50 mL/min, or concomitant administration of potassium supplements or potassium-sparing diuretics (e.g., amiloride, spironolactone, or triamterene) [see Warnings and Precautions (5.1) , Adverse Reactions (6.2) , Drug Interactions (7) , and Clinical Pharmacology (12.3) ].

The following adverse reactions are discussed in greater detail in other sections of the labeling: Hyperkalemia [see Warnings and Precautions (5.1) ] Hypertension: In clinical studies, adverse reactions with eplerenone were uncommon. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Breckenridge Pharmaceutical, Inc. at 1-800-367-3395 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. Hypertension Eplerenone has been evaluated for safety in 3091 patients treated for hypertension. A total of 690 patients were treated for over 6 months and 106 patients were treated for over 1 year. In placebo-controlled studies, the overall rates of adverse events were 47% with Eplerenone Tablets and 45% with placebo. Adverse events occurred at a similar rate regardless of age, gender, or race. Therapy was discontinued due to an adverse event in 3% of patients treated with Eplerenone Tablets and 3% of patients given placebo. The most common reasons for discontinuation of Eplerenone Tablets were headache, dizziness, angina pectoris/MI, and increased GGT. Gynecomastia and abnormal vaginal bleeding were reported with eplerenone but not with placebo. The rates increased with increasing duration of therapy. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of eplerenone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin: angioedema, rash 6.3 Clinical Laboratory Test Findings Hypertension Potassium: In placebo-controlled fixed-dose studies, the mean increases in serum potassium were dose-related and are shown in Table 4 along with the frequencies of values >5.5 mEq/L. Table 4. Increases in Serum Potassium in the Placebo-Controlled, Fixed-Dose Hypertension Studies of Eplerenone Tablets Mean Increase mEq/L % >5.5 mEq/L Daily Dosage n Placebo 194 0 1 25 97 0.08 0 50 245 0.14 0 100 193 0.09 1

CYP3A Inhibitors: In patients with hypertension, initiate at 25 mg once daily. For inadequate blood pressure response, dosing may be increased to a maximum of 25 mg twice daily. ( 2.4 , 7.1 , 12.3 ) 7.1 CYP3A Inhibitors Eplerenone metabolism is predominantly mediated via CYP3A. Do not use eplerenone with drugs that are strong inhibitors of CYP3A [see Contraindications (4) and Clinical Pharmacology (12.3) ]. In patients with hypertension taking a moderate CYP3A inhibitor, initiate at 25 mg once daily. For inadequate blood pressure response, dosing may be increased to a maximum of 25 mg twice daily [see Dosage and Administration (2.3 , 2.4) and Clinical Pharmacology (12.3) ]. 7.2 Angiotensin II Receptor Antagonists The risk of hyperkalemia increases when eplerenone is used in combination with an ARB. A close monitoring of serum potassium and renal function is recommended, especially in patients at risk for impaired renal function, e.g., the elderly [see Warnings and Precautions (5.1) ]. 7.3 Lithium A drug interaction study of eplerenone with lithium has not been conducted. Lithium toxicity has been reported in patients receiving lithium concomitantly with diuretics. Serum lithium levels should be monitored frequently if Eplerenone Tablets are administered concomitantly with lithium. 7.4 Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) A drug interaction study of eplerenone with an NSAID has not been conducted. The administration of other potassium-sparing antihypertensives with NSAIDs has been shown to reduce the antihypertensive effect in some patients and result in severe hyperkalemia in patients with impaired renal function. Therefore, when eplerenone and NSAIDs are used concomitantly, monitor blood pressure and serum potassium levels.

Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [See USP Controlled Room Temperature].