Brand name: Inspra
Drug class: Steroidal Mineralocorticoid Receptor Antagonists
VA class: CV704
Chemical name: 9,11α-Epoxy-17-hydroxy-3-oxo-17α-pregn-4-ene-7α,21-dicarboxylic acid, γ-lactone, methyl ester
Molecular formula: C₂₄H₃₀O₆
CAS number: 107724-20-9

Medically reviewed by Drugs.com on Nov 16, 2023. Written by ASHP.

Introduction

Relatively selective mineralocorticoid (aldosterone) receptor antagonist.^{1 2 3 10 11}

Uses for Eplerenone

Heart Failure after Acute MI

Used to reduce the risk of mortality following acute MI in clinically stable patients with left ventricular systolic dysfunction (i.e., left ventricular ejection fraction [LVEF] ≤40%) and heart failure.^{1 17 21 524}

Therapy with an aldosterone antagonist (i.e., eplerenone or spironolactone) recommended by ACCF and AHA to reduce morbidity and mortality following acute MI in patients with reduced LVEF (≤40%) who develop symptoms of heart failure or who have a history of diabetes mellitus, unless contraindicated.⁵²⁴

Chronic Heart Failure

Has been used in the management of chronic heart failure^{† [off-label]} (NYHA class II–IV) with reduced ejection fraction in conjunction with standard therapy for heart failure to increase survival and reduce heart failure-related hospitalizations.^{524 700 721}

ACCF, AHA, and the Heart Failure Society of America (HFSA) recommend the addition of an aldosterone antagonist (i.e., eplerenone or spironolactone) in selected patients with heart failure and reduced LVEF who are already receiving an agent to inhibit the renin-angiotensin-aldosterone (RAA) system (e.g., ACE inhibitor, angiotensin II receptor antagonist, angiotensin receptor-neprilysin inhibitor [ARNI]) and a β-blocker; careful patient selection required to minimize the risk of hyperkalemia and renal insufficiency.^{524 700}

Hypertension

Management of hypertension.^{1 2 3 4 10 11 24 1200}

Used as monotherapy or in combination with other classes of antihypertensive agents.^{1 2 4 10 11}

Not considered a preferred agent for initial management of hypertension according to current evidence-based hypertension guidelines, but may be used as add-on therapy if BP not adequately controlled with the recommended antihypertensive drug classes (i.e., ACE inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, thiazide diuretics).^{501 502 503 504 1200}

Some experts state that eplerenone may be useful for the management of resistant hypertension in patients with type 2 diabetes mellitus when added to an existing treatment regimen consisting of a renin-angiotensin system inhibitor (e.g., ACE inhibitor, angiotensin II receptor antagonist), diuretic, and calcium-channel blocker.¹²¹⁵

Individualize choice of therapy; consider patient characteristics (e.g., age, ethnicity/race, comorbidities, cardiovascular risk) as well as drug-related factors (e.g., ease of administration, availability, adverse effects, cost).^{501 502 503 504 515 1200 1201}

A 2017 ACC/AHA multidisciplinary hypertension guideline classifies BP in adults into 4 categories: normal, elevated, stage 1 hypertension, and stage 2 hypertension.¹²⁰⁰ (See Table 1.)

Source: Whelton PK, Carey RM, Aronow WS et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71:e13-115.

Individuals with SBP and DBP in 2 different categories (e.g., elevated SBP and normal DBP) should be designated as being in the higher BP category (i.e., elevated BP).

The goal of hypertension management and prevention is to achieve and maintain optimal control of BP.¹²⁰⁰ However, the BP thresholds used to define hypertension, the optimum BP threshold at which to initiate antihypertensive drug therapy, and the ideal target BP values remain controversial.^{501 503 504 505 506 507 508 515 523 526 530 1200 1201 1207 1209 1222 1223 1229}

The 2017 ACC/AHA hypertension guideline generally recommends a target BP goal (i.e., BP to achieve with drug therapy and/or nonpharmacologic intervention) of <130/80 mm Hg in all adults, regardless of comorbidities or level of atherosclerotic cardiovascular disease (ASCVD) risk.¹²⁰⁰ In addition, an SBP goal of <130 mm Hg generally is recommended for noninstitutionalized ambulatory patients ≥65 years of age with an average SBP of ≥130 mm Hg.¹²⁰⁰ These BP goals are based upon clinical studies demonstrating continuing reduction of cardiovascular risk at progressively lower levels of SBP.^{1200 1202 1210}

Other hypertension guidelines generally based target BP goals on age and comorbidities.^{501 504 536} Guidelines such as those issued by the JNC 8 expert panel generally have targeted a BP goal of <140/90 mm Hg regardless of cardiovascular risk, and have used higher BP thresholds and target BPs in elderly patients^{501 504 536} compared with those recommended by the 2017 ACC/AHA hypertension guideline.¹²⁰⁰

Some clinicians continue to support previous target BPs recommended by JNC 8 due to concerns about the lack of generalizability of data from some clinical trials (e.g., SPRINT study) used to support the 2017 ACC/AHA hypertension guideline and potential harms (e.g., adverse drug effects, costs of therapy) versus benefits of BP lowering in patients at lower risk of cardiovascular disease.^{1222 1223 1224 1229}

Consider potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs when deciding a patient's BP treatment goal.^{1200 1220 1229}

For decisions regarding when to initiate drug therapy (BP threshold), the 2017 ACC/AHA hypertension guideline incorporates underlying cardiovascular risk factors.^{1200 1207} ASCVD risk assessment is recommended by ACC/AHA for all adults with hypertension.¹²⁰⁰

ACC/AHA currently recommend initiation of antihypertensive drug therapy in addition to lifestyle/behavioral modifications at an SBP ≥140 mm Hg or DBP ≥90 mm Hg in adults who have no history of cardiovascular disease (i.e., primary prevention) and a low ASCVD risk (10-year risk <10%).¹²⁰⁰

For secondary prevention in adults with known cardiovascular disease or for primary prevention in those at higher risk for ASCVD (10-year risk ≥10%), ACC/AHA recommend initiation of antihypertensive drug therapy at an average SBP ≥130 mm Hg or an average DBP ≥80 mm Hg.¹²⁰⁰

Adults with hypertension and diabetes mellitus, chronic kidney disease (CKD), or age ≥65 years are assumed to be at high risk for cardiovascular disease; such patients should have antihypertensive drug therapy initiated at a BP ≥130/80 mm Hg.¹²⁰⁰ Individualize drug therapy in patients with hypertension and underlying cardiovascular or other risk factors.^{502 1200}

In stage 1 hypertension, experts state that it is reasonable to initiate drug therapy using the stepped-care approach in which one drug is initiated and titrated and other drugs are added sequentially to achieve the target BP.¹²⁰⁰ Initiation of antihypertensive therapy with 2 first-line agents from different pharmacologic classes recommended in adults with stage 2 hypertension and average BP >20/10 mm Hg above BP goal.¹²⁰⁰

Eplerenone Dosage and Administration

General

• Measure serum potassium concentrations prior to initiation of therapy, within the first week, and at 1 month after initiation of therapy or dosage adjustment.¹

• Monitor serum potassium concentrations periodically thereafter, and modify drug dosage accordingly.¹ (See Table: Dosage Modification in Heart Failure for Serum Potassium Concentrations under Dosage and Administration.)

Monitoring and BP Treatment Goals

• Monitor BP regularly (i.e., monthly) during therapy and adjust dosage of the antihypertensive drug until BP controlled.¹²⁰⁰

• If unacceptable adverse effects occur, discontinue drug and initiate another antihypertensive agent from a different pharmacologic class.^{1200 1216}

• Assess patient's renal function and electrolytes 2–4 weeks after initiation of diuretic therapy.¹²⁰⁰

• If adequate BP response not achieved, either increase dosage of the drug or add another drug with demonstrated benefit and preferably a complementary mechanism of action (e.g., ACE inhibitor, angiotensin II receptor antagonist, calcium-channel blocker, thiazide diuretic).^{1200 1216} Many patients will require ≥2 drugs from different pharmacologic classes to achieve BP goal.^{1200 1216 1220}

Administration

Oral Administration

Administer orally^{1 2 3 11} without regard to meals.¹

Dosage

Adults

Heart Failure after Acute MI

Oral

Initially, 25 mg once daily.¹ Titrate dosage as tolerated to a target dosage of 50 mg once daily, preferably within 4 weeks of initiation of therapy in patients without hyperkalemia (defined as serum potassium concentrations ≥5.5 mEq/L).¹

ACCF/AHA recommendation: Hold eplerenone therapy if serum potassium >5.5 mEq/L or renal function worsens; consider resuming therapy at reduced dosage after resolution (for ≥72 hours) of hyperkalemia (serum potassium <5 mEq/L) and renal insufficiency.⁵²⁴

Hypertension

Oral

Initially, 50 mg once daily.^{1 3 8} If BP is not adequately controlled after 4 weeks, increase dosage to 50 mg twice daily.¹

Some experts state usual dosage range is 50–100 mg daily, given in 1 dose or 2 divided doses.¹²⁰⁰

In hypertensive patients currently receiving therapy with weak inhibitors of CYP3A4 (e.g., erythromycin, saquinavir, verapamil, fluconazole), reduce the initial dosage to 25 mg once daily.^{1 3 8}

Chronic Heart Failure† [off-label]

Oral

Has been administered at an initial dosage of 25 mg once daily and increased after 4 weeks of therapy to 50 mg once daily in patients with serum potassium ≤5 mEq/L and adequate renal function.^{524 721}

Hold eplerenone therapy if serum potassium >5.5 mEq/L or renal function worsens; consider resuming therapy at reduced dosage after resolution (for ≥72 hours) of hyperkalemia (serum potassium <5 mEq/L) and renal insufficiency.⁵²⁴

Prescribing Limits

Adults

Hypertension

Oral

50 mg twice daily.¹ No additional benefit from higher dosages (>100 mg daily) and such dosages have been associated with increased risk of hyperkalemia.¹

Special Populations

Hepatic Impairment

No adjustment in the initial dosage is necessary in those with mild-to-moderate hepatic impairment.^{1 21} (See Hepatic Impairment under Cautions.)

Renal Impairment

Heart failure patients with eGFR 30–49 mL/minute per 1.73 m²: Initially, 25 mg once every other day; maintenance dosage of 25 mg once daily (after 4 weeks of therapy and if serum potassium ≤5 mEq/L).⁵²⁴

Heart failure patients with eGFR <30 mL/minute per 1.73 m²: Use is potentially harmful.⁵²⁴

Geriatric Patients

No adjustment in the initial dosage is necessary.^{1 21}

Cautions for Eplerenone

Contraindications

• Serum potassium concentrations >5.5 mEq/L at initiation of therapy.¹

• Cl_cr ≤ 30 mL/minute.¹

• Concomitant therapy with potent CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir, any agent described as a potent CYP3A4 inhibitor in its prescribing information).^{1 4}

• In hypertensive patients having type 2 diabetes mellitus with microalbuminuria.¹

• In hypertensive patients with S_cr >2 or 1.8 mg/dL in males or females, respectively.¹

• In hypertensive patients with Cl_cr <50 mL/minute.¹

• In hypertensive patients receiving potassium supplements or potassium-sparing diuretics (e.g., amiloride, spironolactone, triamterene).^{1 4 8}

Warnings/Precautions

Warnings

Hyperkalemia

Most serious risk associated with therapy is hyperkalemia (serum potassium >5.5 mEq/L).¹ Hyperkalemia may cause serious, sometimes fatal, cardiac arrhythmias.^{1 11}

Increased risk of hyperkalemia in patients with impaired renal function or diabetes mellitus and in patients receiving concurrent agents affecting the RAA system (e.g., ACE inhibitors, angiotensin II receptor antagonists).^{1 2 4 8 11 13 21}

Monitor serum potassium concentrations periodically.^{1 21} Some experts recommend checking serum potassium and renal function within 2–3 days and again at 7 days after initiation of an aldosterone antagonist; perform subsequent monitoring as needed based upon the stability of renal function and fluid status, but monitor at least monthly for the first 3 months and every 3 months thereafter.⁵²⁴ (See Table: Dosage Modification in Heart Failure for Serum Potassium Concentrations under Dosage and Administration.)¹

Specific Populations

Pregnancy

Category B.

Lactation

Distributed into milk in animals.¹ Discontinue nursing or the drug.¹

Pediatric Use

The manufacturer states that in hypertensive pediatric patients 4–16 years of age, eplerenone in dosages up to 100 mg daily did not lower BP effectively.¹ In safety studies in patients 5–17 years of age who received eplerenone for up to 1 year, the incidence of adverse effects was similar to that in studies in adults.¹ Data on safety and efficacy of eplerenone therapy are lacking in hypertensive patients <4 years of age because the drug did not demonstrate efficacy in older pediatric patients.¹

Safety and efficacy of eplerenone not established in pediatric patients with heart failure.¹

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults.¹ Geriatric patients ≥75 years of age with CHF following an acute MI did not benefit from the addition of eplerenone to standard medical therapy.¹ Because of the greater frequency of decreased renal function, the incidence of hyperkalemia may be increased in the elderly.¹ (See Renal Impairment under Cautions.)

Hepatic Impairment

Safety and efficacy not established in patients with severe hepatic impairment.¹ Serum potassium concentrations not affected in patients with mild-to-moderate hepatic impairment.¹

Renal Impairment

Use with caution in patients with CHF following an acute MI, who have renal impairment (i.e., S_cr >2 or 1.8 mg/dL in males or females, respectively, or Cl_cr ≤50 mL/minute) or those with diabetes mellitus (including those with proteinuria).¹

Drug contraindicated in hypertensive patients with S_cr >2 or 1.8 mg/dL in males or females, respectively, and in those hypertensive patients with Cl_cr <50 mL/minute.¹

Black Patients

Initial BP reduction may be smaller in black patients compared with nonblack patients;¹ such difference does not appear to occur during continued therapy.²

Common Adverse Effects

In patients with CHF following MI: hyperkalemia,^{1 17} increased S_cr,¹ urinary tract disorders,¹⁷ adverse CNS effects,¹⁷ adverse GI effects.¹⁷

In patients with hypertension: dizziness, fatigue, flu-like symptoms, cough, diarrhea, abdominal pain, hyperkalemia, decreased serum sodium concentrations, abnormal vaginal bleeding, gynecomastia, hypercholesterolemia, hypertriglyceridemia, mastodynia, albuminuria.¹

Drug Interactions

Metabolized by CYP3A4 isoenzyme.¹

Drugs Affecting Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction (altered plasma eplerenone concentrations) with drugs that induce or inhibit CYP3A4.¹

Does not inhibit or induce the CYP isoenzymes 1A2, 3A4, 2C19, 2C9, or 2D6, suggesting that the drug is unlikely to alter the pharmacokinetics of drugs metabolized by these enzymes.^{1 21}

Specific Drugs and Food1

Eplerenone Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability 69% (100-mg oral tablet).¹

Peak plasma concentrations usually attained within 1.5–2 hours.¹ Steady-state plasma concentrations attained within 2 days.¹

Onset

During chronic therapy, hypotensive effect apparent within 2 weeks and maximum antihypertensive effect generally achieved after 4 weeks.¹

Duration

In patients not receiving other antihypertensive drugs, BP may return to pretreatment levels within 1 week following discontinuance.^{1 21}

Food

Food does not appear to affect absorption.¹

Special Populations

In geriatric patients ≥65 years of age at steady state, peak plasma concentrations and AUC increased by 22 and 45%, respectively, compared with younger adults (18–45 years old).¹

In geriatric black patients at steady state, peak plasma concentrations and AUC were 19 and 26% lower, respectively, than in geriatric white patients.^{1 25}

In patients with severe renal impairment at steady state, peak plasma concentration and AUC were increased by 24 and 38%, respectively,¹ while in those undergoing hemodialysis, peak plasma concentrations and AUC were decreased by 3 and 26%, respectively.¹

In patients with moderate (Child-Pugh class B) hepatic impairment at steady state, peak plasma concentrations and AUC were increased by 3.6 and 42%, respectively, compared with healthy individuals.¹

In patients with heart failure (NYHA class II–IV) at steady state, peak plasma concentrations and AUC increased by 30 and 38%, respectively, compared with healthy individuals.¹

Distribution

Extent

Apparent volume of distribution at steady state is 42–90 L.¹

Plasma Protein Binding

50% (mainly α₁-acid glycoproteins).¹ Does not bind preferentially to RBCs.¹

Distributed into milk in rats; not known whether distributed into human milk.¹

Elimination

Metabolism

Metabolized to inactive metabolites principally by CYP3A4 isoenzyme.^{1 2}

Elimination Route

Approximately 67 and 32% of a dose is excreted in urine and feces, respectively, principally as metabolites.^{1 2}

Half-life

3–6 hours.¹

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).¹

Actions

• Inhibits physiologic effects of aldosterone.^{1 2 3 4 10}

• Produces sustained increases in plasma renin and serum aldosterone concentrations, reflecting the inhibition of the negative feedback of aldosterone on renin secretion.^{1 2 3 10 11}

• Some of the antihypertensive effects may be related to restoration of endothelial function by increasing the release of nitric oxide, which results in vasodilation.^{2 9 12}

• Reduces coronary vascular inflammation,^{17 18} the risk of subsequent development of interstitial myocardial and coronary perivascular fibrosis,^{2 17 18 19 20} cardiac hypertrophy,^{2 20} and/or ventricular remodeling.^{2 17 20}

Advice to Patients

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.¹

• Importance of not using concomitant potassium supplements, salt substitutes containing potassium, potassium-sparing diuretics (amiloride, triamterene, spironolactone), or potent inhibitors of liver enzymes without consulting a clinician.¹

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹

• Importance of informing patients of other important precautionary information.¹ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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