Eplerenone Drug Information
Generic name: EPLERENONE
Aldosterone Antagonist [EPC]
Uses of Eplerenone
Heart Failure Post-Myocardial Infarction Eplerenone tablets are indicated to improve survival of
stable patients with symptomatic heart failure with reduced ejection fraction (≤40%) (HFrEF) after an acute myocardial infarction (MI).
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). 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.
Eplerenone tablets may be used alone or in combination with other antihypertensive agents.
Dosage & Administration of Eplerenone
| less than 5.0 | 25 mg every other day to 25 mg once daily |
|---|---|
| 25 mg once daily to 50 mg once daily | |
| 5.0 to 5.4 | No adjustment |
| 5.5 to 5.9 | 50 mg once daily to 25 mg once daily |
| 25 mg once daily to 25 mg every other day | |
| 25 mg every other day to withhold | |
| greater than or equal to 6.0 | Withhold and restart at 25 mg every other day when potassium levels fall to less than 5.5 mEq/L |
Side Effects of Eplerenone
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. Heart Failure Post-Myocardial Infarction In EPHESUS, safety was evaluated in 3,307 patients treated with eplerenone and 3,301 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.
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
Clinical 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 , the frequencies of patients with changes in potassium (less than 3.5 mEq/L or greater than 5.5 mEq/L or greater than or equal to 6.0 mEq/L) receiving eplerenone compared with placebo are displayed in Table 2. Table 2. Hypokalemia (less than 3.5 mEq/L) or Hyperkalemia (greater than 5.5 or greater than or equal to 6.0 mEq/L) in EPHESUS Potassium (mEq/L) Eplerenone (N=3,251) n (%) Placebo (N=3,237) n (%) Rates of hyperkalemia increased with decreasing renal function. less than 3.5 273 424 greater than 5.5 508 363 Greater than or equal to 6.0 180 126 Table 3. Rates of Hyperkalemia (greater than 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 (%) less than or equal to 30 mL/min 160 82 31 mL/min to 50 mL/min 122 46 51mL/min to 70 mL/min 86 48 greater than 70 mL/min 56 32 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 greater than 5.5 mEq/L. Table 4. Increases in Serum Potassium in the Placebo-Controlled, Fixed-Dose Hypertension Studies of Eplerenone Mean Increase mEq/L % greater than 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
Warnings & Cautions for Eplerenone
Hyperkalemia
The risk of hyperkalemia is higher in patients with impaired renal function, proteinuria, diabetes and those concomitantly treated with ACEs, ARBs, NSAIDs and moderate CYP3A inhibitors. Minimize the risk of hyperkalemia with proper patient selection and monitoring. Monitor patients for the development of hyperkalemia until the effect of eplerenone is established.
Patients who develop hyperkalemia (5.5 mEq/L 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..
Drug Interactions with Eplerenone
CYP3A Inhibitors Eplerenone metabolism is predominantly mediated via
CYP3A. Do not use eplerenone with drugs that are strong inhibitors of CYP3A. 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.
ACE Inhibitors and Angiotensin II Receptor Antagonists
The risk of hyperkalemia increase 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.
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 and ACE inhibitors. Serum lithium levels should be monitored frequently if eplerenone is administered concomitantly with lithium.
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.
Pregnancy Safety for Eplerenone
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 2-4% and 15-20%, 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.
Pediatric Use of Eplerenone
Pediatric Use In a 10-week study of 304 hypertensive pediatric patients age 4 to 16 years treated with eplerenone up to 100 mg per day, doses that produced exposure similar to that in adults, eplerenone did not lower blood pressure effectively. In this study and in a 1-year pediatric safety study in 149 patients (age range 5 to 17 years), the incidence of reported adverse events was similar to that of adults. Eplerenone has not been studied in hypertensive patients less than 4 years old because the study in older pediatric patients did not demonstrate effectiveness.
Eplerenone has not been studied in pediatric patients with heart failure.
Contraindications for Eplerenone
- For all patients: Serum potassium greater than 5.5 mEq/L at initiation Creatinine clearance less than or equal to 30 mL/min Concomitant use with strong CYP3A inhibitors For the treatment of hypertension: Type 2 diabetes with microalbuminuria Serum creatinine greater than 2.0 mg/dL in males, greater than 1.8 mg/dL in females Creatinine clearance less than 50 mL/min Concomitant use of potassium supplements or potassium-sparing diuretics For all patients: Eplerenone is contraindicated in all patients with: serum potassium greater than 5.5 mEq/L at initiation, creatinine clearance less than or equal to 30 mL/min, or concomitant administration of strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, and nelfinavir), For Patients Treated for Hypertension Eplerenone is contraindicated for the treatment of hypertension in patients with: type 2 diabetes with microalbuminuria, serum creatinine greater than 2.0 mg/dL in males or greater than 1.8 mg/dL in females, creatinine clearance less than 50 mL/min, or concomitant administration of potassium supplements or potassium-sparing diuretics (e.g., amiloride, spironolactone, or triamterene).
Overdosage Information for Eplerenone
No cases of human overdosage with eplerenone have been reported. Lethality was not observed in mice, rats, or dogs after single oral doses that provided C max exposures at least 25 times higher than in humans receiving eplerenone 100 mg/day. Dogs showed emesis, salivation, and tremors at a C max 41 times the human therapeutic C max, progressing to sedation and convulsions at higher exposures.
The most likely manifestation of human overdosage would be anticipated to be hypotension or hyperkalemia. Eplerenone cannot be removed by hemodialysis. Eplerenone has been shown to bind extensively to charcoal.
If symptomatic hypotension should occur, supportive treatment should be instituted. If hyperkalemia develops, standard treatment should be initiated.
Clinical Studies of Eplerenone
Heart Failure Post-Myocardial Infarction
The eplerenone post-acute myocardial infarction heart failure efficacy and survival study (EPHESUS) was a multinational, multicenter, double-blind, randomized, placebo-controlled study in patients clinically stable 3 to 14 days after an acute MI with LV dysfunction (as measured by left ventricular ejection fraction less than or equal to 40%) and either diabetes or clinical evidence of HF (pulmonary congestion by exam or chest x-ray or S3). Patients with HF of valvular or congenital etiology, patients with unstable post-infarct angina, and patients with serum potassium greater than 5.0 mEq/L or serum creatinine greater than 2.5 mg/dL were to be excluded. Patients were allowed to receive standard post-MI drug therapy and to undergo revascularization by angioplasty or coronary artery bypass graft surgery. Patients randomized to eplerenone were given an initial dose of 25 mg once daily and titrated to the target dose of 50 mg once daily after 4 weeks if serum potassium was less than 5.0 mEq/L. Dosage was reduced or suspended anytime during the study if serum potassium levels were greater than or equal to 5.5 mEq/L. EPHESUS randomized 6,632 patients (9.3% U.S.) at 671 centers in 27 countries.
The study population was primarily white (90%, with 1% Black, 1% Asian, 6% Hispanic, 2% other) and male (71%). The mean age was 64 years (range, 22 to 94 years). The majority of patients had pulmonary congestion (75%) by exam or x-ray and were Killip Class II (64%). The mean ejection fraction was 33%. The average time to enrollment was 7 days post-MI. Medical histories prior to the index MI included hypertension (60%), coronary artery disease (62%), dyslipidemia (48%), angina (41%), type 2 diabetes (30%), previous MI (27%), and HF (15%). The mean dose of eplerenone was 43 mg/day. Patients also received standard care including aspirin (92%), ACE inhibitors (90%), beta-blockers (83%), nitrates (72%), loop diuretics (66%), or HMG-CoA reductase inhibitors (60%). Patients were followed for an average of 16 months (range, 0 to 33 months). The ascertainment rate for vital status was 99.7%. The co-primary endpoints for EPHESUS were the time to death from any cause, and the time to first occurrence of either cardiovascular mortality or CV hospitalization (defined as hospitalization for progression of HF, ventricular arrhythmias, acute MI, or stroke). For the co-primary endpoint for death from any cause, there were 478 deaths in the eplerenone group (14.4%) and 554 deaths in the placebo group (16.7%). The risk of death with eplerenone was reduced by 15%. Kaplan-Meier estimates of all-cause mortality are shown in Figure 1 and the components of mortality are provided in Table 5. Figure 1. Kaplan-Meier Estimates of All-Cause Mortality Table 5. Components of All-Cause Mortality in EPHESUS Eplerenone (N=3,319) n (%) Placebo (N=3,313) n (%) Hazzard Ratio p-value Death from any cause 478 554 0.85 0.008 CV Death 407 483 0.83 0.005 Non-CV Death 60 54 Unknown or unwitnessed death 11 17 Most CV deaths were attributed to sudden death, acute MI, and HF. The time to first event for the co-primary endpoint of CV death or hospitalization, as defined above, was longer in the eplerenone group (hazard ratio 0.87, 95% confidence interval 0.79 to 0.95, p = 0.002). An analysis that included the time to first occurrence of CV mortality and all CV hospitalizations (atrial arrhythmia, angina, CV procedures, progression of HF, MI, stroke, ventricular arrhythmia, or other CV causes) showed a smaller effect with a hazard ratio of 0.92 (95% confidence interval 0.86 to 0.99; p = 0.028). The combined endpoints, including combined all-cause hospitalization and mortality were driven primarily by CV mortality. The combined endpoints in EPHESUS, including all-cause hospitalization and all-cause mortality, are presented in Table 6. Table 6. Rates of Death or Hospitalization in EPHESUS Event Eplerenone n (%) Placebo n (%) CV death or hospitalization for progression of HF, stroke, MI or ventricular arrhythmia Co-Primary Endpoint. 885 993 Death 407 483 Hospitalization 606 649 CV death or hospitalization for progression of HF, stroke, MI,ventricular arrhythmia, atrial arrhythmia, angina, CV procedures, or other CV causes (PVD; Hypotension) 1,516 1,610 Death 407 483 Hospitalization 1,281 1,307 All-cause death or hospitalization 1,734 1,833 Death 478 554 Hospitalization 1,497 1,530 Mortality hazard ratios varied for some subgroups as shown in Figure 2. Mortality hazard ratios appeared favorable for eplerenone for both genders and for all races or ethnic groups, although the numbers of non-Caucasians were low (648, 10%). Patients with diabetes without clinical evidence of HF and patients greater than 75 years did not appear to benefit from the use of eplerenone.
Such subgroup analyses must be interpreted cautiously. Analyses conducted for a variety of CV biomarkers did not confirm a mechanism of action by which mortality was reduced.
Hypertension
The safety and efficacy of eplerenone have been evaluated alone and in combination with other antihypertensive agents in clinical studies of 3,091 hypertensive patients. The studies included 46% women, 14% Blacks, and 22% elderly (age ≥65). The studies excluded patients with elevated baseline serum potassium (greater than 5.0 mEq/L) and elevated baseline serum creatinine (generally greater than 1.5 mg/dL in males and greater than 1.3 mg/dL in females). Two fixed-dose, placebo-controlled, 8- to 12-week monotherapy studies in patients with baseline diastolic blood pressures of 95 mm Hg to 114 mm Hg were conducted to assess the antihypertensive effect of eplerenone. In these two studies, 611 patients were randomized to eplerenone and 140 patients to placebo.
Patients received eplerenone in doses of 25 mg to 400 mg daily as either a single daily dose or divided into two daily doses. The mean placebo-subtracted reductions in trough cuff blood pressure achieved by eplerenone in these studies at doses up to 200 mg are shown in Figures 3 and 4. Figure 3. Eplerenone Dose Response – Trough Cuff SBP Placebo-Subtracted Adjusted Mean Change from Baseline in Hypertension Studies Figure 4. Eplerenone Dose Response – Trough Cuff DBP Placebo-Subtracted Adjusted Mean Change from Baseline in Hypertension Studies Patients treated with eplerenone 50 mg to 200 mg daily experienced significant decreases in sitting systolic and diastolic blood pressure at trough with differences from placebo of 6 mm Hg to 13 mm Hg (systolic) and 3 mm Hg to 7 mm Hg (diastolic). These effects were confirmed by assessments with 24-hour ambulatory blood pressure monitoring (ABPM). In these studies, assessments of 24-hour ABPM data demonstrated that eplerenone, administered once or twice daily, maintained antihypertensive efficacy over the entire dosing interval. However, at a total daily dose of 100 mg, eplerenone administered as 50 mg twice per day produced greater trough cuff (4/3 mm Hg) and ABPM (2/1 mm Hg) blood pressure reductions than 100 mg given once daily.
Blood pressure lowering was apparent within 2 weeks from the start of therapy with eplerenone, with maximal antihypertensive effects achieved within 4 weeks. Stopping eplerenone following treatment for 8 to 24 weeks in six studies did not lead to adverse event rates in the week following withdrawal of eplerenone greater than following placebo or active control withdrawal. Blood pressures in patients not taking other antihypertensives rose 1 week after withdrawal of eplerenone by about 6/3 mm Hg, suggesting that the antihypertensive effect of eplerenone was maintained through 8 to 24 weeks.
Blood pressure reductions with eplerenone in the two fixed-dose monotherapy studies and other studies using titrated doses, as well as concomitant treatments, were not significantly different when analyzed by age, gender, or race with one exception. In a study in patients with low renin hypertension, blood pressure reductions in Blacks were smaller than those in whites during the initial titration period with eplerenone. Eplerenone has been studied concomitantly with treatment with ACE inhibitors, ARB, calcium channel blockers, beta-blockers, and hydrochlorothiazide.
When administered concomitantly with one of these drugs eplerenone usually produced its expected antihypertensive effects.
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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