Aldosterone Antagonist

Eplerenone

Approved 13 Jul 2017OralTablet

The FDA lists this product in 18 strengths and forms.

Indications

Eplerenone is an aldosterone antagonist indicated for: Improving survival of stable adult patients with symptomatic heart failure with reduced ejection fraction (HFrEF) after an acute myocardial infarction. (1.1) 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 )

1.1Heart Failure Post-Myocardial Infarction

Eplerenone is indicated to improve survival of stable adult patients with symptomatic heart failure with reduced ejection fraction (≤40%) (HFrEF) after an acute myocardial infarction (MI).

1.2Hypertension

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).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.

At a glance

Brand name: Eplerenone
Pharmacologic class: Aldosterone Antagonist
Route: Oral
Dosage form: Tablet
Applicant: Accord Hlthcare
Status: Prescription
FDA approval: 13 Jul 2017
Application: ANDA206922-001

Indications

1.1Heart Failure Post-Myocardial Infarction

Eplerenone is indicated to improve survival of stable adult patients with symptomatic heart failure with reduced ejection fraction (≤40%) (HFrEF) after an acute myocardial infarction (MI).

1.2Hypertension

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.

Interactions

CYP3A Inhibitors: In post-MI HFrEF patients, do not exceed 25 mg once daily when used with moderate CYP3A inhibitors (e.g., verapamil, erythromycin, saquinavir, fluconazole). 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 )

7.1CYP3A 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) ].

7.2ACE Inhibitors and Angiotensin II Receptor Antagonists

The risk of hyperkalemia increases when eplerenone is used in combination with an ACE inhibitor and/or 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) ].

7.3Lithium

A drug interaction study of eplerenone with lithium has not been conducted. Lithium toxicity has been reported in patients receiving lithium concomitantly with diuretics and ACE inhibitors. Serum lithium levels should be monitored frequently if eplerenone is administered concomitantly with lithium.

7.4Nonsteroidal 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.

Pregnancy and breastfeeding

8.1Pregnancy 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 U.S. 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.

Adverse reactions

The following adverse reactions are discussed in greater detail in other sections of the labeling: Hyperkalemia [see Warnings and Precautions (5.1) ] HFrEF Post-MI: Most common adverse reactions (>2% and more frequent than with placebo): hyperkalemia and increased creatinine. (6.1) 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 FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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. Heart Failure Post-Myocardial Infarction In EPHESUS, safety was evaluated in 3307 patients treated with eplerenone and 3301 placebo-treated patients. The overall incidence of adverse events reported with eplerenone (78.9%) was similar to placebo (79.5%).

Adverse events occurred at a similar rate regardless of age, gender, or race. Patients discontinued treatment due to an adverse event at similar rates in either treatment group (4.4% eplerenone vs. 4.3% placebo), with the most common reasons for discontinuation being hyperkalemia, MI, and abnormal renal function. Adverse reactions that occurred more frequently in patients treated with eplerenone than placebo were hyperkalemia (3.4% vs. 2.0%) and increased creatinine (2.4% vs. 1.5%).

Discontinuations due to hyperkalemia or abnormal renal function were less than 1.0% in both groups. 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.

6.2Postmarketing 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

6.3Clinical Laboratory Test Findings Heart Failure Post-Myocardial Infarction Creatinine: Increases

of more than 0.5 mg/dL were reported for 6.5% of patients administered eplerenone and for 4.9% of placebo-treated patients. Potassium: In EPHESUS [see Clinical Studies (14.1)] , the frequencies of patients with changes in potassium (<3.5 mEq/L or >5.5 mEq/L or ≥6.0 mEq/L) receiving eplerenone compared with placebo are displayed in Table 2. Table 2. Hypokalemia (<3.5 mEq/L) or Hyperkalemia (>5.5 or ≥6.0 mEq/L) in EPHESUS Potassium (mEq/L) Eplerenone (N=3251) n(%) Placebo (N=3237) n(%) <3.5 273 (8.4) 424 (13.1) >5.5 508 (15.6) 363 (11.2) ≥6.0 180 (5.5) 126 (3.9) Rates of hyperkalemia increased with decreasing renal function.

Table 3. Rates of Hyperkalemia (>5.5 mEq/L) in EPHESUS by Baseline Creatinine Clearance * * Estimated using the Cockroft-Gault formula. Baseline Creatinine Clearance Eplerenone (N=508) n(%) Placebo (N=363) n(%) ≤30 mL/min 160 (32) 82 (23) 31 to 50 mL/min 122 (24) 46 (13) 51 to 70 mL/min 86 (17) 48 (13) >70 mL/min 56 (11) 32 (9) The rates of hyperkalemia in EPHESUS in the eplerenone-treated group vs. placebo were increased in patients with proteinuria (16% vs 11%), diabetes (18% vs. 13%) or both (26% vs. 16%).

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

Eplerenone

Indications

1.1Heart Failure Post-Myocardial Infarction

1.2Hypertension

At a glance

Two medicines in one question?

Eplerenone

Indications

1.1Heart Failure Post-Myocardial Infarction

1.2Hypertension

At a glance

Two medicines in one question?

Contraindications

Warnings and precautions

5.1Hyperkalemia

Interactions

7.1CYP3A Inhibitors

7.2ACE Inhibitors and Angiotensin II Receptor Antagonists

7.3Lithium

7.4Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary

Adverse reactions

6.1Clinical Trials Experience

6.2Postmarketing Experience

6.3Clinical Laboratory Test Findings Heart Failure Post-Myocardial Infarction Creatinine: Increases

Composition

Strengths and forms

Official product information