Eplerenone
Quick Facts
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Heart failure post-acute MI — to improve survival in stable adult patients with symptomatic HFrEF (LVEF ≤40%) | Adults; initiate after clinical stabilization (3–14 days post-MI in EPHESUS) | Adjunctive to standard post-MI/HF therapy | FDA Approved |
| Hypertension — to lower blood pressure | Adults | Monotherapy or in combination | FDA Approved |
The current FDA-approved indications for eplerenone are limited to two populations: stable post-MI patients with HFrEF, and adult hypertension. Approval in post-MI HFrEF was based on EPHESUS, which demonstrated a 15% relative reduction in all-cause mortality (14.4% vs. 16.7% with placebo; HR 0.85, p=0.008) when added to standard care. In hypertension, eplerenone produces dose-dependent blood pressure reductions of approximately 6–13 mmHg systolic and 3–7 mmHg diastolic at doses of 50–200 mg/day. Despite robust trial evidence in chronic mildly symptomatic heart failure, eplerenone is not FDA-approved for that population — clinicians should be aware of this regulatory boundary even when guideline-supported.
Chronic HFrEF, NYHA class II — supported by EMPHASIS-HF, which showed a 37% relative reduction in CV death or HF hospitalization (HR 0.63) in patients with LVEF ≤30% (or ≤35% with QRS >130 ms). Recommended as foundational therapy in major HF guidelines (AHA/ACC/HFSA 2022; ESC 2021). Evidence: high (single pivotal RCT).
Chronic HFrEF, NYHA class III–IV — extrapolated from spironolactone (RALES). Spironolactone is generally preferred unless the patient is intolerant due to antiandrogenic effects. Evidence: indirect / extrapolated.
Resistant hypertension — fourth-line agent per AHA scientific statement when BP remains uncontrolled on three drugs including a diuretic. Spironolactone remains first-choice MRA. Evidence: moderate.
Primary aldosteronism (medical management) — alternative to spironolactone when antiandrogenic effects are problematic. Spironolactone is generally more potent at lowering BP in this population. Evidence: moderate.
Spironolactone-induced gynecomastia — substitution can preserve MRA effect while avoiding sex-hormone–related adverse effects. Evidence: low (small case series).
Dosing
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Post-MI HFrEF (LVEF ≤40%) — FDA-labeled | 25 mg once daily | 50 mg once daily (target) | 50 mg/day | Titrate to target within 4 weeks if tolerated and K⁺ <5.0 mEq/L EPHESUS mean achieved dose was 43 mg/day |
| Hypertension — FDA-labeled | 50 mg once daily | 50 mg once or twice daily | 50 mg twice daily (100 mg/day total) | Allow 4 weeks for full effect before titrating; doses >100 mg/day are not recommended (no greater BP effect, more hyperkalemia) |
| Chronic HFrEF NYHA II (off-label, EMPHASIS-HF protocol) | 25 mg once daily | 50 mg once daily | 50 mg/day | Titrate after 4 weeks if K⁺ <5.0 and eGFR adequate Reduce to 25 mg every other day if eGFR 30–49 mL/min/1.73 m² |
| HF (any) with moderate CYP3A inhibitor (erythromycin, fluconazole, verapamil, saquinavir) | 25 mg once daily | 25 mg once daily | 25 mg/day | Do not exceed 25 mg daily (FDA labeling) Strong CYP3A inhibitors are contraindicated |
| HTN with moderate CYP3A inhibitor | 25 mg once daily | 25 mg once or twice daily | 25 mg twice daily (50 mg/day total) | Halve the usual maximum dose |
Potassium-Guided Dose Adjustment (Post-MI HFrEF, per FDA Labeling)
| Serum K⁺ (mEq/L) | Action |
|---|---|
| <5.0 | Increase: 25 mg every other day → 25 mg once daily; or 25 mg once daily → 50 mg once daily |
| 5.0–5.4 | No adjustment |
| 5.5–5.9 | Reduce: 50 mg once daily → 25 mg once daily; or 25 mg once daily → 25 mg every other day; or 25 mg every other day → withhold |
| ≥6.0 | Withhold; restart at 25 mg every other day when K⁺ falls to <5.5 mEq/L |
Renal Adjustment
| Renal Function | Heart Failure (FDA-labeled post-MI use) | Hypertension |
|---|---|---|
| CrCl >50 mL/min | Standard dosing | Standard dosing |
| CrCl 31–50 mL/min | Use with closer K⁺ surveillance; consider 25 mg every other day | Contraindicated per FDA labeling |
| CrCl ≤30 mL/min | Contraindicated | Contraindicated |
Hepatic Adjustment
No dose adjustment required for moderate hepatic impairment (Child-Pugh B): steady-state Cmax and AUC increased by 3.6% and 42% respectively at a 400 mg dose, neither of which is clinically meaningful at therapeutic doses. Eplerenone has not been studied in severe hepatic impairment (Child-Pugh C); use with caution or avoid.
Pediatric, Geriatric, Pregnancy & Lactation
Safety and effectiveness in pediatric patients have not been established for any indication. In a 10-week study of 304 hypertensive children aged 4–16, eplerenone did not lower blood pressure effectively. In older adults, AUC and Cmax are approximately 45% and 22% higher than in younger subjects; the FDA label notes that EPHESUS subgroup analysis suggested patients older than 75 years did not appear to benefit. Hyperkalemia risk is elevated due to age-related declines in renal function. Pregnancy data are limited; animal studies showed no teratogenicity at exposures 31–32 times the human therapeutic AUC. Eplerenone is present in rat milk; human data are unavailable.
The mortality benefit in EPHESUS was achieved with a target dose of 50 mg once daily (mean achieved 43 mg/day). The 25 mg starting dose is a titration step, not a target. If serum potassium and renal function permit, titrate to 50 mg within 4 weeks. Conversely, do not initiate when baseline potassium exceeds 5.0 mEq/L — first address contributors (concurrent ACEi/ARB dose, NSAID use, potassium supplements) before re-evaluating.
Pharmacology
Mechanism of Action
Eplerenone binds to the mineralocorticoid receptor (MR) and competitively blocks the binding of aldosterone, a key effector of the renin-angiotensin-aldosterone system. Aldosterone normally activates MR in epithelial tissues such as the distal nephron — driving sodium reabsorption, potassium secretion, and a rise in blood pressure — as well as in non-epithelial tissues including the heart, blood vessels, and brain. By antagonising MR, eplerenone produces modest natriuresis and potassium retention, and increases plasma renin and serum aldosterone via loss of negative feedback; these compensatory rises do not overcome the receptor blockade.
Eplerenone is selective for the human MR over recombinant glucocorticoid, progesterone, and androgen receptors. This selectivity — absent in spironolactone — is the drug’s defining clinical advantage: it produces meaningfully fewer sex-hormone-related adverse effects (gynecomastia, breast pain, menstrual irregularity) at the cost of weaker MR potency and a shorter half-life requiring daily dosing.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Absolute oral bioavailability 69%; Tmax ~1.5–2 h; absorption not affected by food | May be taken without regard to meals; once-daily dosing is acceptable for both indications despite the short half-life |
| Distribution | Vd 42–90 L at steady state; protein binding ~50%, primarily to α1-acid glycoprotein; does not preferentially bind erythrocytes | Modest tissue distribution; protein binding low enough that displacement interactions are clinically insignificant |
| Metabolism | Hepatic, predominantly CYP3A4-mediated; no active metabolites identified in human plasma; not a substrate or inhibitor of P-glycoprotein at clinically relevant doses | Strong CYP3A inhibitors are contraindicated; moderate inhibitors require dose reduction; CYP3A inducers reduce efficacy |
| Elimination | t½ 3–6 h; less than 5% recovered as unchanged drug; ~67% urinary and ~32% fecal as metabolites; steady state in ~2 days; not removed by hemodialysis | Short half-life means missed doses lose effect quickly; hemodialysis is not a rescue option in overdose; renal impairment increases AUC by ~38% in severe CKD |
Side Effects
Frequencies below are drawn directly from the FDA prescribing information (EPHESUS post-MI HFrEF data, n=3251 vs 3237; pooled placebo-controlled hypertension studies, n=3091) and from the EMPHASIS-HF publication (chronic NYHA II HFrEF; off-label population). Hyperkalemia rates differ substantially between heart failure and hypertension populations because of differences in renal function, diabetes prevalence, and concurrent ACEi/ARB use.
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Hyperkalemia (K⁺ >5.5 mEq/L) — laboratory finding, EPHESUS | 15.6% | vs. 11.2% placebo. Risk concentrated in patients with reduced creatinine clearance, diabetes, or proteinuria |
| Hyperkalemia (K⁺ >5.5 mEq/L) — laboratory finding, EMPHASIS-HF (off-label NYHA II) | 11.8% | vs. 7.2% placebo (p<0.001). Reflects the chronic mild HF population |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Hyperkalemia (K⁺ ≥6.0 mEq/L) — EPHESUS lab finding | 5.5% | vs. 3.9% placebo. Threshold at which the FDA label requires drug to be withheld |
| Hyperkalemia — reported as adverse reaction (EPHESUS) | 3.4% | vs. 2.0% placebo. The principal AE attributable to eplerenone in post-MI HFrEF |
| Increased serum creatinine (rise >0.5 mg/dL) — EPHESUS | 6.5% | vs. 4.9% placebo. Often modest; investigate larger rises for AKI triggers |
| Increased creatinine — reported as adverse reaction (EPHESUS) | 2.4% | vs. 1.5% placebo |
| Hypokalemia (K⁺ <3.5 mEq/L) — EPHESUS lab finding | 8.4% | vs. 13.1% placebo (less common with eplerenone — a benefit, not adverse effect) |
| Headache, dizziness (HTN trials) | Uncommon | FDA PI does not give specific numerator percentages but lists these among the most common reasons for HTN trial discontinuation |
| Gynecomastia / mastodynia (men, long-term use) | ~0.5–1.6% | Pooled controlled trials ≥6 months: gynecomastia 0.7%, mastodynia 1.3%, either 1.6%. Substantially less than spironolactone (~10% in RALES) |
| Abnormal vaginal bleeding (women) | ~0.8% | Reported in HTN trials; rates increase with treatment duration |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Severe hyperkalemia (K⁺ ≥6.0) with cardiac arrhythmia | ~5.5% (post-MI HF); ~1% (HTN) | Days to weeks; peak risk during dose escalation or after addition of interacting drugs | Withhold; ECG; treat per ACLS hyperkalemia algorithm; resume only at reduced dose with close lab follow-up |
| Acute kidney injury | Uncommon (specific rate not quantified in PI) | Within first weeks; risk persists with intercurrent illness | Hold drug; address volume status, NSAID use, and contrast exposure; consider permanent discontinuation if eGFR drop >30% from baseline |
| Symptomatic hypotension | Uncommon | Days to weeks | Reduce concomitant loop diuretic; reassess background RAAS-blocker dosing; eplerenone usually does not need to be stopped |
| Angioedema | Rare (postmarketing report) | Any time during therapy | Permanent discontinuation; treat per anaphylaxis protocol |
| Rash | Rare (postmarketing report) | Variable | Discontinue if severe; evaluate for alternative etiology |
Postmarketing adverse reactions identified in the FDA label are limited to angioedema and rash. Other class-attributed events (hepatotoxicity, severe cutaneous reactions) are not listed in current FDA labeling.
Hyperkalemia Risk by Baseline Renal Function (EPHESUS)
| Baseline CrCl (Cockcroft-Gault) | K⁺ >5.5 — Eplerenone | K⁺ >5.5 — Placebo |
|---|---|---|
| ≤30 mL/min | 32% | 23% |
| 31–50 mL/min | 24% | 13% |
| 51–70 mL/min | 17% | 13% |
| >70 mL/min | 11% | 9% |
Rates were also elevated in patients with proteinuria (16% vs 11%), diabetes (18% vs 13%), and both (26% vs 16%). These data underpin the FDA’s CrCl ≤30 mL/min absolute contraindication.
Hyperkalemia drives the great majority of clinically meaningful adverse events with eplerenone. Mitigation is structured: confirm K⁺ <5.0 mEq/L and CrCl >30 mL/min (or >50 mL/min for the hypertension indication) before starting; recheck K⁺ within 1 week, at 1 month, then periodically — and within 3–7 days of starting any moderate CYP3A inhibitor, ACE inhibitor, ARB, or NSAID. Counsel patients to avoid potassium-containing salt substitutes and large daily portions of high-potassium foods. If K⁺ rises to 5.5–5.9, reduce the dose; if ≥6.0, hold and treat acutely.
Drug Interactions
Eplerenone is metabolised almost exclusively by CYP3A4 and is neither an inhibitor nor a meaningful inducer of major CYP enzymes. Clinically significant interactions therefore cluster into two groups: agents that modify CYP3A activity (changing eplerenone exposure) and agents that independently elevate serum potassium or impair renal handling of potassium (additive hyperkalemia risk).
Monitoring
-
Serum Potassium
Baseline → within 1 week → 1 month → periodically thereafter
Routine FDA-mandated monitoring schedule. Single most important parameter. Recheck within 3–7 days after starting a moderate CYP3A inhibitor, ACE inhibitor, ARB, or NSAID, and after any dose change or hospitalization. -
Serum Creatinine / eGFR
Baseline → with each K⁺ check
Routine Expect a small bump (~0.1–0.3 mg/dL) on initiation. Investigate any drop in eGFR >30% from baseline and look for AKI triggers. -
Blood Pressure
Baseline → 2–4 weeks → periodically (HTN); each visit (HF)
Routine Full antihypertensive effect within 4 weeks. In HF, watch for symptomatic hypotension; usually resolves with loop diuretic reduction rather than stopping eplerenone. -
HF symptoms / Weight
Each clinical visit
Routine Track NYHA class, daily weights, JVP, and orthopnea to confirm clinical benefit and detect fluid status shifts that may alter electrolyte balance. -
Serum Sodium
With each electrolyte panel
Routine Mean sodium decrease in trials was small (0.7–1.7 mmol/L at therapeutic doses). Symptomatic hyponatremia warrants discontinuation. -
Lithium level (if applicable)
Within 1 week of starting eplerenone in patients on lithium
Trigger-based FDA labeling specifically calls for frequent lithium monitoring during co-administration. -
ECG
If K⁺ >5.5 or symptomatic arrhythmia
Trigger-based Look for peaked T-waves, PR prolongation, QRS widening — markers of cardiac toxicity from hyperkalemia.
FDA-aligned schedule: K⁺ and creatinine at baseline, within 1 week, at 1 month, and periodically thereafter. Add an interval check within 3–7 days of any dose change, hospitalization, or initiation of a moderate CYP3A inhibitor, ACE inhibitor, ARB, or NSAID. This pattern catches the great majority of preventable hyperkalemia events.
Contraindications & Cautions
Absolute Contraindications — All Patients
- Serum potassium >5.5 mEq/L at initiation.
- Creatinine clearance ≤30 mL/min.
- Concomitant administration of strong CYP3A inhibitors (ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir).
Additional Contraindications — Hypertension Indication Only
- 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.
- Concomitant potassium supplements or potassium-sparing diuretics (amiloride, spironolactone, triamterene).
Relative Contraindications (Specialist Input Recommended)
- Severe hepatic impairment (Child-Pugh C) — pharmacokinetics not characterised; specialist guidance preferred.
- CrCl 31–50 mL/min in heart failure — cardiology input advised; consider 25 mg every other day with weekly K⁺ checks initially.
- Combined ACEi + ARB + eplerenone — discouraged outside specialist settings; hyperkalemia and AKI rates rise sharply.
- Older adults (≥75 years) with multiple risk factors for hyperkalemia. Note that EPHESUS subgroup analysis suggested no clear mortality benefit in patients older than 75.
Use with Caution
- Diabetes mellitus with proteinuria — both substantially increase hyperkalemia risk.
- Volume depletion or dehydration — heightens AKI risk; address before initiation.
- Patients on chronic NSAIDs — counsel to substitute acetaminophen where possible.
- Pregnancy — limited human data; weigh maternal benefit against unknown fetal risk.
Eplerenone does not carry a boxed warning. The principal labeled warning is hyperkalemia, which can cause fatal cardiac arrhythmias. Risk is amplified by impaired renal function, proteinuria, diabetes, and concurrent ACE inhibitors, ARBs, NSAIDs, or moderate CYP3A inhibitors.
Per FDA labeling: minimise risk through proper patient selection and monitoring. Confirm K⁺ ≤5.5 mEq/L and CrCl >30 mL/min (or >50 mL/min for the hypertension indication) before starting. Monitor K⁺ within 1 week, at 1 month, and periodically thereafter. Patients who develop K⁺ 5.5–5.9 mEq/L may continue therapy with dose reduction; withhold if K⁺ ≥6.0 mEq/L.
Patient Counselling
Purpose of Therapy
Eplerenone protects the heart by blocking aldosterone — a hormone that drives scarring of the heart muscle and fluid retention. In patients who have had a heart attack with weakened heart function, it has been shown to reduce the chance of dying. In patients with high blood pressure, it lowers blood pressure with relatively few side effects. The benefit builds gradually over weeks to months — patients will not feel the drug working in the way they might feel a diuretic.
How to Take
Take eplerenone once daily, ideally at the same time each morning, with or without food. If a dose is missed, take it as soon as remembered the same day; if it is nearly time for the next dose, skip the missed dose entirely — never double up. Do not stop the medication without speaking with the prescribing clinician, even if blood pressure feels normal or symptoms have improved. Blood tests for potassium and kidney function are part of the prescription; missing them is not optional.
Sources
- U.S. Food and Drug Administration. INSPRA® (eplerenone) tablets — Highlights of Prescribing Information. Revised June 2025. Reference ID: 5608959. accessdata.fda.gov/drugsatfda_docs/label/2025/021437s018lbl.pdf Authoritative source for indications (post-MI HFrEF, hypertension), dosing, contraindications, and US adverse-event frequencies. Confirms that chronic NYHA II HFrEF use is not FDA-labeled.
- European Medicines Agency. Inspra (eplerenone) — Summary of Product Characteristics. ema.europa.eu EMA reference document for European labelling, which includes the chronic mild HF indication based on EMPHASIS-HF (broader than US label).
- Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction (EPHESUS). N Engl J Med. 2003;348(14):1309–1321. doi.org/10.1056/NEJMoa030207 Pivotal trial supporting the FDA post-MI HFrEF indication; demonstrated 15% relative reduction in all-cause mortality (HR 0.85, p=0.008).
- Zannad F, McMurray JJV, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms (EMPHASIS-HF). N Engl J Med. 2011;364(1):11–21. doi.org/10.1056/NEJMoa1009492 Underpins guideline-supported off-label use in chronic NYHA II HFrEF; 37% relative reduction in CV death or HF hospitalization (HR 0.63).
- Weinberger MH, Roniker B, Krause SL, Weiss RJ. Eplerenone, a selective aldosterone blocker, in mild-to-moderate hypertension. Am J Hypertens. 2002;15(8):709–716. doi.org/10.1016/S0895-7061(02)02957-6 Foundational dose-finding study supporting the 50–100 mg/day antihypertensive dosing range.
- Pitt B, White H, Nicolau J, et al. Eplerenone reduces mortality 30 days after randomization following acute myocardial infarction in patients with left ventricular systolic dysfunction and heart failure. J Am Coll Cardiol. 2005;46(3):425–431. doi.org/10.1016/j.jacc.2005.04.038 EPHESUS sub-analysis showing very early mortality benefit (within 30 days), supporting prompt initiation after stabilization.
- Eschalier R, McMurray JJV, Swedberg K, et al. Safety and efficacy of eplerenone in patients at high risk for hyperkalemia and/or worsening renal function: analyses of EMPHASIS-HF study subgroups. J Am Coll Cardiol. 2013;62(17):1585–1593. doi.org/10.1016/j.jacc.2013.04.086 Demonstrates that eplerenone retains efficacy and acceptable safety in higher-risk subgroups when monitoring is adhered to.
- Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure. Circulation. 2022;145(18):e895–e1032. doi.org/10.1161/CIR.0000000000001063 Class I recommendation for MRA use in chronic HFrEF; supports eplerenone as guideline-directed therapy (off-label in the US for NYHA II).
- McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42(36):3599–3726. doi.org/10.1093/eurheartj/ehab368 European guideline placing MRAs as part of foundational quadruple therapy for HFrEF.
- Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults. Hypertension. 2018;71(6):e13–e115. doi.org/10.1161/HYP.0000000000000065 Positions MRAs as preferred fourth-line agents in resistant hypertension.
- Carey RM, Calhoun DA, Bakris GL, et al. Resistant Hypertension: Detection, Evaluation, and Management — A Scientific Statement From the American Heart Association. Hypertension. 2018;72(5):e53–e90. doi.org/10.1161/HYP.0000000000000084 Evidence framework for off-label MRA use in resistant hypertension and selection between eplerenone and spironolactone.
- Delyani JA. Mineralocorticoid receptor antagonists: the evolution of utility and pharmacology. Kidney Int. 2000;57(4):1408–1411. doi.org/10.1046/j.1523-1755.2000.00983.x Classic review of MRA pharmacology and the rationale for selectivity that drove eplerenone’s development.
- Garthwaite SM, McMahon EG. The evolution of aldosterone antagonists. Mol Cell Endocrinol. 2004;217(1–2):27–31. doi.org/10.1016/j.mce.2003.10.005 Compares spironolactone and eplerenone receptor binding profiles, explaining the differential endocrine adverse-event rates.
- Cook CS, Berry LM, Bible RH, Hribar JD, Hajdu E, Liu NW. Pharmacokinetics and metabolism of [14C]eplerenone after oral administration to humans. Drug Metab Dispos. 2003;31(11):1448–1455. doi.org/10.1124/dmd.31.11.1448 Definitive ADME study describing eplerenone bioavailability, CYP3A4 metabolism, and elimination pattern.
- Ravis WR, Reid S, Sica DA, Tolbert DS. Pharmacokinetics of eplerenone after single and multiple dosing in subjects with and without renal impairment. J Clin Pharmacol. 2005;45(7):810–821. doi.org/10.1177/0091270005277936 Underpins the renal dosing thresholds and the absolute contraindication at CrCl ≤30 mL/min.
- Antoniou T, Gomes T, Mamdani MM, et al. Trimethoprim-sulfamethoxazole-induced hyperkalemia in elderly patients receiving spironolactone: nested case-control study. BMJ. 2011;343:d5228. doi.org/10.1136/bmj.d5228 Class-effect evidence informing the major interaction between MRAs and trimethoprim-containing antibiotics.