Eplerenone

Approved Indications:

• Heart Failure Post-Myocardial Infarction (Post-MI):
  To reduce the risk of cardiovascular mortality and hospitalization in stable patients with left ventricular systolic dysfunction (LVEF ≤40%) and clinical evidence of heart failure following an acute myocardial infarction.
• Hypertension (Essential):
  For the treatment of high blood pressure to lower the risk of cardiovascular events such as stroke and myocardial infarction.

Important Off-label / Clinically Accepted Uses:

• Primary Aldosteronism (Off-label):
  Used in patients with aldosterone-producing adenomas or bilateral adrenal hyperplasia when surgery is not an option or as a diagnostic adjunct.
• Polycystic Ovary Syndrome (PCOS):
  Used off-label for hyperandrogenic symptoms, especially in women intolerant to spironolactone.
• Resistant Hypertension:
  Utilized in combination with other antihypertensive agents in cases of treatment-resistant hypertension.

Route of Administration: Oral

Adults:

• Heart Failure Post-MI:
• Start: 25 mg once daily.
• Target: Increase to 50 mg once daily within 4 weeks based on tolerability and serum potassium levels.
• Hypertension:
• Initial: 50 mg once daily.
• Maintenance: 50 mg once or twice daily based on clinical response.
• Maximum: 100 mg/day.

Pediatric Use:
Not recommended due to insufficient safety and efficacy data.

Elderly:
No specific dosage adjustment required, but careful monitoring of renal function and serum potassium is necessary.

Renal Impairment:

• Moderate (eGFR 30–50 mL/min/1.73 m²): Start at lower dose and monitor potassium closely.
• Severe (eGFR <30 mL/min/1.73 m²): Contraindicated.

Hepatic Impairment:

• Mild to moderate: No adjustment required.
• Severe impairment: Use with caution; limited data.

Dose Adjustments:

• Discontinue or reduce dose if serum potassium exceeds 5.5 mmol/L.
• Reassess potassium and renal function within the first week, and regularly thereafter.

Eplerenone is a selective aldosterone receptor antagonist. It binds to mineralocorticoid receptors in the distal nephron, blocking the effects of aldosterone, a hormone that promotes sodium retention and potassium excretion. This results in increased sodium and water excretion, decreased fluid overload, and lowered blood pressure. By preventing aldosterone-mediated myocardial fibrosis and vascular inflammation, Eplerenone provides cardioprotective benefits, particularly after myocardial infarction and in chronic heart failure patients with reduced ejection fraction.

• Absorption: Rapid and complete; bioavailability ~69%.
• Peak Plasma Time (Tmax): 1.5 to 2 hours post-dose.
• Protein Binding: ~50% (mainly to alpha-1-acid glycoprotein).
• Volume of Distribution (Vd): ~50 L.
• Metabolism: Extensively metabolized by CYP3A4 to inactive metabolites.
• Elimination Half-life: Approximately 4 to 6 hours.
• Excretion:
• Urine: ~67% (as metabolites)
• Feces: ~32%

• Pregnancy:
  FDA Pregnancy Category B. Animal studies show no harm to fetus, but controlled human data are lacking. Use only if clearly needed, especially in second and third trimesters.
• Lactation:
  Unknown if eplerenone is excreted into human breast milk. Caution advised. Consider alternatives or discontinue nursing based on benefit-risk assessment.

• Primary Class:
  Mineralocorticoid Receptor Antagonist
• Subclass:
  Selective Aldosterone Blocker (Second-generation, more selective than spironolactone)

• Known hypersensitivity to eplerenone or any excipient
• Serum potassium >5.5 mmol/L at initiation
• Severe renal impairment (eGFR <30 mL/min/1.73 m²)
• Concomitant use with strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin)
• Type 2 diabetes with microalbuminuria (for hypertension indication)
• Hyperkalemia or potassium-sparing diuretic use without monitoring

• Hyperkalemia Risk:
  Monitor potassium frequently, especially in elderly, diabetics, or those with renal impairment.
• Renal Function:
  Adjust dose or discontinue in worsening renal function. Risk of accumulation and toxicity.
• Drug Interactions:
  CYP3A4 inhibitors can elevate plasma levels significantly. Avoid strong inhibitors.
• Volume Depletion:
  May cause hypotension in patients with salt depletion.
• Electrolyte Monitoring:
  Monitor serum potassium and creatinine at baseline, during initiation, and regularly thereafter.
• Use in Heart Failure:
  Benefits only established in patients with LVEF ≤40%. Do not use in HF with preserved ejection fraction.

Common (≥1%):

• Electrolyte Disorders: Hyperkalemia, hyponatremia
• Renal: Increased serum creatinine
• Cardiovascular: Hypotension, dizziness
• Endocrine/Metabolic: Gynecomastia (less common than with spironolactone)
• Gastrointestinal: Diarrhea, abdominal discomfort

Serious Adverse Effects:

• Severe hyperkalemia
• Acute kidney injury
• Arrhythmias due to electrolyte imbalance

Rare:

• Allergic reactions
• Hepatic enzyme elevations
• Skin rash

• CYP3A4 Inhibitors (e.g., ketoconazole, itraconazole, clarithromycin):
  Increase eplerenone plasma levels — Contraindicated.
• Potassium-Sparing Diuretics or Potassium Supplements:
  Increases risk of hyperkalemia — avoid concurrent use.
• ACE Inhibitors / ARBs:
  Additive hyperkalemic effects — monitor serum potassium closely.
• NSAIDs:
  May impair renal function and blunt antihypertensive effects.
• Lithium:
  Risk of lithium toxicity due to reduced clearance.
• Grapefruit Juice:
  Possible CYP3A4 inhibition — use with caution.

• Heart Failure Guidelines (AHA/ACC/ESC):
  Reinforce the use of eplerenone for patients with LVEF ≤40% post-MI, particularly with signs of heart failure or diabetes.
• Hypertension Guidelines:
  Recognized as an alternative mineralocorticoid antagonist in resistant hypertension.
• Drug Safety Communications:
  Continued emphasis on hyperkalemia risk, especially with concomitant ACEIs, ARBs, and NSAIDs.

• Storage Temperature: Store below 30°C (86°F).
• Humidity/Light: Protect from excessive moisture. Keep in original packaging.
• Handling: No special handling precautions required.
• Shelf Life: Follow manufacturer’s expiry date on the packaging.