An inhibitor of the mineralocorticoid receptor is eplerenone (Inspra) (like spironolactone). When the left ventricular ejection fraction is less than 40%, it is utilised to treat heart failure and hypertension in patients who have recently suffered a myocardial infarction. It stops fibrosis and cardiac and vascular remodelling. In patients who are at risk for hyperkalemia, it should be used with the utmost caution.

Eplerenone Uses:

• Heart failure post-MI:

  • Patients with symptomatic heart failure who are not in critical condition and have an LVEF of less than 40% after an acute MI can live longer with the help of eplerenone.
  • Guideline recommendations:
    • The American College of Cardiology and the American Heart Association (ACCF/AHA) 2013 guidelines advocate the use of aldosterone antagonists along with other standard therapies.
    • All of this is done to lower morbidity and mortality in individuals with acute CAD who have a history of diabetes mellitus and LVEF less than 40% and are experiencing symptomatic heart failure.

• Hypertension:

  • Eplerenone is not recommended as a first-line treatment for hypertension.

• Use: Off-Label: Adult

  • Acute coronary syndromes
  • Heart failure (NYHA class II-IV) with left ventricular ejection fraction ≤35%
  • In the treatment of primary aldosteronism

Eplerenone (Inspra) Dose in Adults

Eplerenone (Inspra) Dose as an alternative agent in the treatment of Hypertension:

• Oral: Initially it is given as 50 mg once daily and may be increased to 50 mg two times a day if the response is not adequate.
• The maximum allowed dose is 100 mg/day

• Dose modification during concurrent use with moderate CYP3A4 inhibitors:

  • Initial: If the reaction is insufficient, the dose may be increased to 25 mg twice daily (maximum: 50 mg/day).

Eplerenone (Inspra) Dose in the treatment of Heart failure:

• Heart failure (post-MI):

  • Oral: Initially can be given 25 mg once a day.
  • The best dosage is to increase it by 50 mg once daily over the course of 4 weeks, as tolerated.

• Dosage adjustment per serum potassium concentrations for HF (post-MI):

  • <5 mEq/L:

    • The dosage should be increased from 25 mg every other day to 25 mg once daily OR from 25 mg once daily to 50 mg once day.

  • 5 to 5.4 mEq/L:

    • No adjustment required. 

  • 5 to 5.9 mEq/L:

    • Reduce the dosage to 25 mg once day from 50 mg once daily, or 25 mg once daily from 25 mg every other day, or
    • Change the dosage from 25 mg every other day to stop taking the drug.

  • ≥6 mEq/L:

    • Restart medicine at 25 mg every other day after waiting until potassium levels are below 5.5 mEq/L.
  • Alternatively, if potassium levels are higher than 5.5 mEq/L or if there is a progressive deterioration in renal function, the ACCF/AHA 2013 HF recommendations advise delaying medication.
  • Treatment might be postponed until the potassium level is below 5 mEq/L.
    After establishing remission of hyperkalemia/renal insufficiency for at least 72 hours, think about restarting with a lower dose.

  • Dose modification during concurrent use with moderate CYP3A4 inhibitors:

    • 25 mg once daily at first; 25 mg daily at most.

Eplerenone (Inspra) Dose in the treatment of Heart failure (NYHA class II-IV with LVEF ≤35%) (off-label dose):

• Initial: 25 mg once a day;
• The maximum dose: 50 mg/daily.

Eplerenone (Inspra) Dose in the treatment of primary aldosteronism (off-label):

• Oral: Initial: 25 mg two times a day.

Use in Children:

Not indicated.

Eplerenone Pregnancy Category: B

• The case reports pertaining to the use of eplerenone in pregnancy are the only source of information.
• Both untreated hypertension, and heart failure can lead to adverse pregnancy outcomes.
• Mineralocorticoid receptor inhibitors should not be used to treat uncomplicated chronic hypertension in pregnant women.
• They should also be avoided in women with reproductive potential.

Use during breastfeeding:

• This drug secreted in breastmilk is yet to be studied.

Eplerenone (Inspra) Dose in Kidney Disease:

• Hypertension:

  • CrCl ≥50 mL/minute:
    • No dose adjustment required
  • CrCl <50 mL/minute or serum creatinine >2 mg/dL (males) or >1.8 mg/dL (females):
    • Absolute contraindication due to the risk of hyperkalemia increases with declining renal function.

• Heart failure (post-MI):

  • CrCl >50 mL/minute:
    • No dose adjustment is required
  • CrCl 31 to 50 mL/minute or serum creatinine >2 mg/dL (males) or >1.8 mg/dL (females):
    • Use with caution is advised and no dose adjustment is required according to the manufacturer
  • CrCl ≤30 mL/minute:
    • Absolutely contraindicated

• Heart failure (including post-MI):

  • eGFR ≥50 mL/minute/1.73 m²:
    • Initial dose: 25 mg once daily per orally.
    • If potassium levels are still below 5 mEq/L after 4 weeks of treatment, increase the dose up to 50 mg once a day.
  • eGFR 30 to 49 mL/minute/1.73 m²:
    • Initial dose: 25 mg once every other day.
    • if potassium levels remain below 5 mEq/L and after 4 weeks of treatment, provide the maintenance dose.:
      • The dose can be titrated up to 25 mg once daily
  • eGFR <30 mL/minute/1.73 m²:
    • Not recommended.
  • Hemodialysis:
    • Not effective

Dose in Liver disease:

• There are no dosage adjustments required in liver disease as per the manufacturer's labeling.
• Systemic bioavailability is increased in moderate hepatic impairment (Child-Pugh class B).

Common Side Effects of Eplerenone (Inspra):

• Endocrine & metabolic:

  • Hyperkalemia
  • Hypertriglyceridemia

Less Common Side Effects of Eplerenone (Inspra):

• Central Nervous System:

  • Dizziness
  • Fatigue

• Endocrine & Metabolic:

  • Hyponatremia
  • Albuminuria
  • Gynecomastia
  • Hypercholesterolemia

• Gastrointestinal:

  • Diarrhea
  • Abdominal Pain

• Genitourinary:

  • Abnormal Vaginal Hemorrhage
  • Mastalgia

• Renal:

  • Increased Serum Creatinine

• Respiratory:

  • Cough
  • Flu-Like Symptoms

Contraindications to Eplerenone (Inspra):

• Serum potassium >5.5 mEq/L at initiation
• CrCl = 30 mL/minute
• Concurrent use of ritonavir, nelfinavir, troleandomycine, clarithromycine, and other potent CYP3A4 inhibitors like itraconazole or ketoconazole.
• Hypertension patients should be aware of the following contraindications:
  • It is concerning when men's serum creatinine levels surpass 2.0 mg/dL and women's serum creatinine levels exceed 1.8 mg/dL in type 2 diabetes mellitus (noninsulin-dependent, NIDDM).
  • CrCl 50mL/minute
  • Concomitant use of potassium supplements or potassium–sparing diuretics (eg amiloride, stronolactone, triamterene)
• According to the Endocrine Society clinical guidelines, Addison disease patients should not be treated.

Canadian labeling:Additional contraindications not listed in the US labeling:

• The use of any component or hypersensitivity to eplerenone could limit its effectiveness.
• Serum potassium levels at the start of therapy shouldn't be higher than 5 mEq/L.
• serious liver damage (Child Puugh class C).
• Use potassium supplements or potassium-saving diuretics simultaneously.

Hypertension patients should be aware of the following contraindications:

• Males and females with maximum blood creatinine values of 1.5 mg/dL (132 micromole/L) and 1.3 mg/dL (115 micromole/L), respectively

Warnings and precautions

• Hyperkalemia:

  • Eplerenone therapy may cause hyperkalemia. Hyperkalemia can be more common in patients with kidney impairment, protein nephropathy and diabetes mellitus who are also taking ACE inhibitors, angiotensin II blockers, NSAIDs and/or moderate CYP3A inhibits.
  • Hyperkalemia should be monitored closely. Hyperkalemia due to dosing may occur.
  • Hyperkalemia can be treated by reducing doses or interrupting treatment.
  • Reduce the dosage of eplerenone if you have to take CYP3A4 inhibitor therapy.
  • It is not advised if the serum potassium level is greater than 5.5 mEq/L.

• Diabetes:

  • Patients with diabetes and heart failure after MI (especially those with diabetic nephropathy), should exercise caution due to the possibility of hyperkalemia.

• Heart failure:

  • If a patient with heart failure is being evaluated for treatment with a mineralocorticoid-receptor inhibitor, their eGFR must not be lower than 30 mL/minute/1.73m2, and creatinine should not exceed 2.5 mg/dL (for men) or 2 mg/dL (for women). 
  • The renal function must be stable and not have experienced any severe hyperkalemia. Serum potassium should not exceed 5mEq/L.
  • Monitoring serum potassium levels is crucial, and any excessive levels should be treated.
  • The manufacturer advises delaying treatment if serum potassium levels are greater than 6 mEq/L.
  • If serum potassium levels are higher than 5.5 mEq/L or if renal function is deteriorating, ACCF/AHA advises stopping medication.
  • Combining ARB and ACE inhibitors is not recommended.
  • Patients with heart disease should be instructed to stop taking diuretic medication if they experience diarrhea, dehydration, or if loop diuretic therapy has been stopped.

• Hepatic impairment

  • For patients with severe or moderate hepatic impairment, it should be administered with caution.

• Renal impairment

  • As the renal function declines, the risk of hyperkalemia increases.
  • In patients with modest renal impairment, it should be used with caution.
  • It should not be used by those with severe renal impairment.

Eplerenone: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

• Vital signs like blood pressure.
• Blood potassium levels before therapy, during the first week, the first month, or following a dose change. then repeat as needed by a clinician.
• Additionally, for at least 3–7 days after the commencement of concurrent therapy with moderate doses of CYP3A4 or ACE inhibitors, ARBs, or NSAIDs, monitor serum potassium and serum creatinine levels.
• Heart failure:
  • Initiation should be completed within 3 days, 1 week, and 3 months. Then, the renal function and serum potassium should be tested every 3 months.
  • It is important to monitor the patient's response to any concomitant ACE inhibitors and/or ARBs by starting a new monitoring cycle.
  • Keep potassium levels at a minimum of 5.5 mEq/L. If renal function is worsening, you should hold potassium doses until potassium is below 5 mEq/L. After 72 hours, confirm that hyperkalemia/renal impairment has been resolved.

How to administer Eplerenone (Inspra)?

It can be taken orally with or without food.

Mechanism of action of Eplerenone (Inspra):

• Eplerenone (Inspra), is a mineralocorticoid-receptor inhibitor. 
• It inhibits the mineralocorticoid-receptors selectively in a dose-dependent way. 
• The inhibition of mineralocorticoid-receptors could prevent vascular or myocardial fibrillation.
• Mineralocorticoids can cause water and sodium retention. 
• Myocardial or vascular fibrosis may be caused by the overexpression of mineralocorticoid-receptors, especially after myocardial injury.
• Mineralocorticoid receptors can be found in the kidney, myocardium and blood vessels.

Protein binding:

• About 50%; primarily to alpha-1-acid glycoproteins

Metabolism:

• It is metabolized primarily in the liver via CYP3A4 to inactive metabolites.

Bioavailability:

• 69%

Half-life elimination:

• About 3 to 6 hours

Time to peak, plasma:

• About 1.5 to 2 hours;
• It may take up to 4 weeks for the full antihypertensive effect

Excretion:

• Urine (~67%);
• feces (~32%);
• Less than 5% as unchanged drug in urine and feces

International Brand Names of Eplerenone:

• Inspra
• MINT-Eplerenone
• Aldonist
• Aldospira
• Diuron
• Elecor
• Epleron
• Eplerona
• Eplerone
• Epletor
• Epnone
• Eptus
• Eraloner
• Espler
• Fliven
• Heperona
• Idirenone
• Inpler
• Inspra
• Inspra IC
• Oldren
• Renial
• Selara
• Tensopleron

Eplerenone Brand Names in Pakistan:

Correct spelling: Eplerenone, Inspra Incorrect Spelling: Eplarenone, Epleranone, Eplerenon, Enspra