Eplerenone

1 INDICATIONS AND USAGE Eplerenone is an aldosterone antagonist indicated 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 infarctio( 1.2 ) 1.2 Hypertension Eplerenone tablets are indicated for the treatment of hypertension, 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).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.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.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 press…

2 DOSAGE AND ADMINISTRATION 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 are 50 mg administered once daily. The full therapeutic effect of eplerenone tablet 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 to 7 days of a patient initating a moderate CYP3A inhibitor, angiotensin-II blockers or non-steroidal-anti-inflammatories. 2.4 Dose Modifications 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) .]

5 WARNINGS AND PRECAUTIONS Hyperkalemia: Patients with decreased renal function diabetes, proteinuria or patients who are taking ARBs, NSAIDs or moderate CYP3A inhibitors are at increased risk. Monitor serum potassium levels and adjust dose as needed. ( 5.1 ) 5.1 Hyperkalemia The risk of hyperkalemia is higher in patients with impaired renal function, proteinuria , diabetes and those concomitantly treated with ARBs, NSAIDs and moderate CYP3A inhibitors. Minimize the risk of hyperkalemia with proper patient selection and monitoring [See Contraindications (4) , Adverse Reactions (6.2) and Drug Interactions (7) ] . Monitor patients for the development of hyperkalemia until the effect of eplerenone is established. Patients who develop hyperkalemia (5.5 to 5.9 mEq/L) may continue eplerenone therapy with proper dose adjustment. Dose reduction decreases potassium levels. Patients on moderate CYP3A inhibitors that cannot be avoided should have their dose of eplerenone reduced. [See Drug Interactions (7.2) ].

4 CONTRAINDICATIONS 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) .]

7 DRUG INTERACTIONS 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 post-MI HFrEF patients taking a moderate CYP3A inhibitor, do not exceed 25 mg once daily. 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. Serum lithium levels should be monitored frequently if eplerenone is 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.

8.1 Pregnancy Risk Summary The available data from published case reports on eplerenone use during pregnancy are insufficient to establish a drug-associated risk of major birth defects, miscarriage, adverse maternal or fetal outcomes (see Clinical Considerations). In animal studies, no adverse developmental effects were observed when eplerenone was administered to pregnant rats and rabbits during organogenesis at exposures 32 and 31 times, respectively the human exposure at the 100 mg/day therapeutic dose. The estimated background risk of major birth defects and miscarriage for the indicated population are unknown. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk 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. Pregnant women with hypertension should be carefully monitored and managed accordingly. Pregnant women with 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. Data Animal Data Embryo-fetal development studies were conducted with doses up to 1000 mg/kg/day in rats and 300 mg/kg/day in rabbits (exposures up to 32 and 31 times the human AUC for the 100 mg/day therapeutic dose, respectively) administered during organogenesis. No teratogenic effects were seen in rats or rabbits, although decreased rat fetal weights were observed, and decreased body weight in maternal rabbits and increased rabbit fetal resorptions and post-implantation loss were observed at the highest administered dosages. In a pre-and postnatal development study pregnant rats were administered eplerenone at doses up to 1000 mg/kg/day from Gestation Day 6 through Lactation Day 20. Decreased pup weights were observed beginning at birth at 1000 mg/kg/day.

8.2 Lactation Risk Summary There are no human data available on whether eplerenone is present in human milk, or has effects on breastfed infants or on milk production. Eplerenone was present in the milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. 8.3 Females and Males of Reproductive Potential Infertility based on animal data, use of eplerenone may compromise male fertility. In mature rats, male fertility was decreased with eplerenone exposure at 17 times the 100 mg/day human therapeutic dose. Reversibility of effects was not evaluated [See Nonclinical Toxicology (13.1) ].

6 ADVERSE REACTIONS 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 Accord Healthcare Inc at 1-866-941-7875 or www.accordhealthcare.us 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 3,091 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 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 and 3% of patients given placebo. The most common reasons for discontinuation of eplerenone 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: angioneurotic edema, 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 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