Schedule H

Oral

Tablets:

• Eplerenone 25 mg (film-coated)

• Eplerenone 50 mg (film-coated)

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indications (Approved / Standard in India)

1. Heart Failure with Reduced Ejection Fraction (HFrEF)

Post-acute myocardial infarction with left ventricular dysfunction (LVEF ≤40%) and clinical evidence of heart failure

Parameter Dosing Details

Starting dose 25 mg orally once daily

Titration Increase to 50 mg once daily after 4 weeks if serum potassium ≤5.0 mmol/L and eGFR stable

Usual maintenance dose 50 mg once daily

Maximum dose 50 mg once daily

Initiation Criteria:

• Serum potassium ≤5.0 mmol/L before initiation

• eGFR ≥30 mL/min/1.73m²

• Ideally initiate 3–14 days post-MI

Dose Adjustment During Therapy:

Serum Potassium (mmol/L) Action

<5.0 Continue current dose; consider uptitration if on 25 mg

5.0–5.4 Maintain current dose; monitor closely

5.5–5.9 Reduce dose from 50 mg to 25 mg OR from 25 mg to 25 mg alternate days

≥6.0 Withhold eplerenone; recheck potassium; resume at lower dose when K+ <5.5

Key Clinical Notes:

• Use as adjunct to standard HFrEF therapy (ACEI/ARB/ARNI, beta-blocker, loop diuretics)

• EPHESUS trial demonstrated mortality reduction post-MI with LV dysfunction

• Provides mortality benefit independent of its effect on blood pressure

1. Chronic Heart Failure (NYHA Class II–IV) with LVEF ≤35%

As adjunct to standard therapy in symptomatic chronic HFrEF

Parameter Dosing Details

Starting dose 25 mg orally once daily

Titration Increase to 50 mg once daily after 4 weeks based on potassium and renal function

Usual maintenance dose 50 mg once daily

Maximum dose 50 mg once daily

Key Clinical Notes:

• EMPHASIS-HF trial showed mortality and hospitalization benefit in NYHA II–IV HFrEF

• Part of guideline-directed medical therapy (GDMT) for HFrEF

• Preferred over spironolactone in patients experiencing gynecomastia or breast tenderness

1. Hypertension (Resistant Hypertension — Add-on Therapy)

As add-on therapy when blood pressure not controlled with first-line agents

Parameter Dosing Details

Starting dose 50 mg orally once daily

Titration May reduce to 25 mg once daily if hypotension or hyperkalaemia occurs

Usual maintenance dose 50 mg once daily

Maximum dose 50 mg once daily (as monotherapy); may be given with other antihypertensives

Key Clinical Notes:

• Particularly effective in resistant hypertension with suspected primary aldosteronism

• May be used when spironolactone not tolerated (anti-androgenic effects)

• Less antihypertensive potency than spironolactone at equivalent doses

Secondary Indications — Adults Only (Off-label)

Indication Dose Duration Notes

Primary Aldosteronism (when surgery not feasible) (OFF-LABEL) 25–50 mg once daily; titrate to blood pressure and potassium Long-term Endocrinology specialist only. Alternative when spironolactone causes anti-androgenic effects. Evidence: Case series, international guidelines.

Heart Failure with Preserved Ejection Fraction (HFpEF) (OFF-LABEL) 25–50 mg once daily Long-term Cardiology specialist only. Limited benefit in trials; may be considered in selected patients. Evidence: TOPCAT trial (subgroup analysis).

PAEDIATRIC DOSING (Specialist Only)

Primary Indications

NOT APPROVED for paediatric use in India.

Limited safety and efficacy data in children. Use only under paediatric cardiologist supervision.

Secondary Indications — Paediatric (Off-label)

Indication Dose Duration Notes

Heart Failure in Children (OFF-LABEL) 0.5–1 mg/kg/day once daily (max 25–50 mg/day) Based on clinical response Paediatric cardiologist only. Very limited data. Evidence: Small case series, extrapolated from adult data.

Clear Statement: NOT recommended below 1 year of age. Use in any paediatric age group requires paediatric cardiology specialist supervision with close monitoring of serum potassium and renal function.

Safety Monitoring in Children:

• Serum potassium and creatinine at baseline and weekly initially

• ECG monitoring for hyperkalaemia signs

• Blood pressure monitoring

• Growth and development assessment

Critical: Eplerenone is CONTRAINDICATED in severe renal impairment due to hyperkalaemia risk.

≥50 Standard dosing (25–50 mg/day) Standard dosing (50 mg/day)

30–49 Start 25 mg alternate days; maximum 25 mg/day Start 25 mg once daily; use with caution

<30 CONTRAINDICATED CONTRAINDICATED

Haemodialysis CONTRAINDICATED CONTRAINDICATED

Peritoneal Dialysis CONTRAINDICATED CONTRAINDICATED

• Serum potassium >5.0 mmol/L at initiation

• eGFR <30 mL/min/1.73m² or creatinine clearance <30 mL/min

• Severe hepatic impairment (Child-Pugh C)

• Known hypersensitivity to eplerenone or any formulation excipient

• Concomitant use with strong CYP3A4 inhibitors (ketoconazole, itraconazole, nefazodone, clarithromycin, ritonavir, nelfinavir)

• Concomitant use with potassium-sparing diuretics (spironolactone, amiloride, triamterene)

• Type 2 diabetes mellitus with microalbuminuria AND concurrent ACEI or ARB therapy (significantly increased hyperkalaemia risk)

• Addison's disease

• Elderly patients — higher risk of hyperkalaemia due to age-related decline in renal function

• Concurrent ACEI or ARB therapy — additive potassium retention; requires close monitoring

• Diabetes mellitus — increased risk of hyperkalaemia even without renal impairment

• Mild-moderate renal impairment (eGFR 30–49) — use lower doses with frequent monitoring

• Dehydration or hypovolaemia — correct before initiating

• Concurrent potassium supplements — avoid or use with extreme caution

• Concurrent NSAIDs — may reduce eplerenone efficacy and worsen renal function

• Moderate CYP3A4 inhibitors (verapamil, diltiazem, erythromycin) — may increase eplerenone levels

• Acute illness with risk of dehydration (diarrhoea, vomiting) — consider temporary discontinuation

Parameter Details

Risk Category Not formally classified in India; animal studies suggest risk at high doses. Limited human data.

Preferred alternatives If MRA essential during pregnancy: hydralazine, methyldopa, labetalol for hypertension. Avoid MRAs if possible.

When may be used Only if potential benefit clearly outweighs risk; cardiologist and obstetrician input mandatory

Monitoring Maternal serum potassium, renal function, blood pressure; fetal growth monitoring

Parameter Details

Compatibility Unknown; not recommended due to lack of safety data

Preferred alternatives If MRA essential, spironolactone has more data (though also limited). Consider avoiding MRAs if possible during lactation.

Drug levels in milk Unknown; high protein binding (~50%) may limit transfer

Infant monitoring If inadvertently exposed: monitor for poor feeding, hypotonia, electrolyte disturbances

Parameter Recommendation

Starting dose 25 mg once daily (or 25 mg alternate days if eGFR 30–49)

Titration Slower titration; increase after 4–8 weeks if tolerated and potassium stable

Special risks Higher risk of hyperkalaemia (age-related renal decline often underestimated by serum creatinine); hypotension risk; postural symptoms; falls risk if over-diuresed

Monitoring More frequent potassium and renal function monitoring (weekly for first month, then every 2–4 weeks)

Interacting Drug Mechanism & Effect Management

Strong CYP3A4 Inhibitors (ketoconazole, itraconazole, clarithromycin, ritonavir, nelfinavir) Markedly increased eplerenone levels (up to 5-fold) CONTRAINDICATED — Do not combine

Potassium-Sparing Diuretics (spironolactone, amiloride, triamterene) Additive hyperkalaemia CONTRAINDICATED — Do not combine

Potassium Supplements Additive hyperkalaemia Avoid concurrent use unless treating documented hypokalaemia under close monitoring

Lithium Reduced lithium excretion; increased lithium toxicity risk Avoid combination; if essential, monitor lithium levels frequently

Ciclosporin, Tacrolimus Both cause hyperkalaemia; additive with eplerenone Avoid if possible; if used, monitor potassium very closely

Trimethoprim / Co-trimoxazole Trimethoprim blocks ENaC; additive hyperkalaemia with eplerenone Avoid combination; significant hyperkalaemia risk

Interacting Drug Effect Management

ACE Inhibitors / ARBs / ARNI Additive potassium retention; hyperkalaemia risk Expected combination in HFrEF therapy. Monitor potassium closely (baseline, 1 week, then monthly). Dose-reduce eplerenone if K+ rises.

Moderate CYP3A4 Inhibitors (verapamil, diltiazem, erythromycin, fluconazole) Moderate increase in eplerenone levels (~2-fold) Use with caution; do not exceed eplerenone 25 mg/day if concurrent use

NSAIDs (diclofenac, ibuprofen, naproxen) Reduced antihypertensive effect; worsened renal function; increased hyperkalaemia risk Avoid if possible; if essential, monitor BP, renal function, potassium

CYP3A4 Inducers (rifampicin, phenytoin, carbamazepine, St. John's Wort) Reduced eplerenone levels; decreased efficacy May need higher eplerenone dose or alternative MRA

Digoxin No direct interaction, but both used in HF; hyperkalaemia can affect digoxin toxicity threshold Monitor potassium and digoxin levels

Alpha-blockers (prazosin, terazosin) Additive hypotension Monitor blood pressure; adjust doses as needed

• Hyperkalaemia (dose-related; most common serious effect)

• Dizziness

• Hypotension

• Headache

• Fatigue

• Diarrhoea

• Nausea

• Increased serum creatinine (usually mild, reversible)

• Cough

Note: Unlike spironolactone, eplerenone has minimal anti-androgenic effects — gynecomastia, breast tenderness, and menstrual irregularities are uncommon.

Adverse Effect Clinical Notes

Severe Hyperkalaemia (K+ ≥6.0 mmol/L) Risk of fatal arrhythmias (bradycardia, heart block, VF). Risk factors: renal impairment, concurrent ACEI/ARB, diabetes. Withhold drug; treat hyperkalaemia emergently.

Acute Kidney Injury Especially with concurrent ACEI/ARB/NSAIDs, dehydration, or in elderly. Monitor creatinine.

Angioedema Rare; especially when combined with ACEI. Discontinue immediately.

Hypotension / Syncope May cause falls, especially in elderly or over-diuresed patients

Hepatotoxicity Rare; elevated transaminases reported. Monitor if symptoms develop.

Hyponatraemia Uncommon; usually with concurrent diuretics

After initiation (1 week) Serum potassium and creatinine

After dose change Serum potassium and creatinine within 1 week

First 3 months Serum potassium and creatinine monthly

Long-term (stable patients) Serum potassium and creatinine every 3–6 months

Additional monitoring triggers During intercurrent illness (dehydration risk); when adding ACEI/ARB/NSAID; acute kidney injury; worsening heart failure

Action for Potassium Monitoring:

• K+ <5.0: Continue therapy; consider uptitration

• K+ 5.0–5.4: Maintain dose; recheck in 1 week

• K+ 5.5–5.9: Reduce dose or change to alternate day; recheck in 1 week

• K+ ≥6.0: Withhold eplerenone; treat hyperkalaemia; restart at lower dose when K+ <5.0

• Eptus® (Glenmark)

• Inspra® (Pfizer)

• Epleret® (Eris Lifesciences)

• Epnone® (Lupin)

• Eplecor® (Torrent)

• Aldactone-E® (RPG — limited availability)

• Various generic brands

Note: Eplerenone is NOT listed in NLEM 2022. Not under NPPA price control. Prices vary between brands. Spironolactone is more cost-effective but has different side-effect profile.

1. Choose eplerenone over spironolactone for anti-androgenic side effects — Eplerenone is highly selective for mineralocorticoid receptors with minimal binding to androgen/progesterone receptors. Preferred in males who develop gynecomastia or breast tenderness on spironolactone.

1. Check potassium and creatinine BEFORE starting — Never initiate eplerenone if baseline K+ >5.0 mmol/L or eGFR <30 mL/min/1.73m². These are absolute contraindications.

1. Triple RAAS blockade is dangerous — Avoid combining eplerenone with ACEI + ARB simultaneously. While ACEI/ARB + eplerenone is standard in HFrEF, adding all three creates unacceptable hyperkalaemia risk.

1. Mortality benefit in HFrEF is proven — EPHESUS and EMPHASIS-HF trials demonstrated clear mortality reduction. Eplerenone is part of guideline-directed medical therapy for HFrEF — ensure eligible patients receive it.

1. Watch potassium during intercurrent illness — Advise patients (or caregivers) to hold eplerenone during episodes of dehydration (vomiting, diarrhoea, reduced oral intake). Resume when rehydrated and potassium rechecked.

1. CYP3A4 inhibitors are a major concern — Strong inhibitors are contraindicated. When prescribing new medications, always check for CYP3A4 interactions. Common culprits: azole antifungals, macrolides, protease inhibitors.

eplerenone; aldosterone-antagonist; MRA; heart-failure; HFrEF; post-MI; resistant-hypertension; hyperkalaemia-risk; potassium-monitoring; spironolactone-alternative; Schedule-H

RxIndia v1.0 — 06 Jun 2025

• CDSCO Approved Drug Formulations List

• Indian Pharmacopoeia 2022

• National Formulary of India (NFI) 2021

• API Textbook of Medicine (11th Edition)

• ICMR Guidelines on Hypertension Management

• AIIMS Standard Treatment Guidelines — Cardiovascular Section

• Cardiological Society of India (CSI) Heart Failure Guidelines

• Harrison's Principles of Internal Medicine (21st Edition)

• Goodman & Gilman's The Pharmacological Basis of Therapeutics (14th Edition)

• EPHESUS Trial (N Engl J Med 2003)

• EMPHASIS-HF Trial (N Engl J Med 2011)

• Product package inserts (Inspra®, Eptus®)