Description

Inspra (eplerenone tablets; Pfizer, Inc., New York, NY) is an aldosterone blocker that works by binding at the mineralocorticoid receptor. It has some similarities to the potassium-sparing diuretic spironolactone, but rarely causes gynecomastia. It had been approved for hypertension. The new FDA labeling provides "for improving survival of stable patients with left ventricular systolic dysfunction (ejection fraction 40%) and clinical evidence of congestive heart failure after an acute myocardial infarction" (based on a letter from the FDA). This labeling relates to the results of the large, multicenter Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) that showed that eplerenone reduced mortality by 15% in heart failure patients post-myocardial infarction. Eplerenone also decreased the risk of cardiovascular death and hospitalizations in this study.
Pharmacology

Eplerenone binds to the mineralocorticoid receptor, thereby blocking the ability of aldosterone to bind. Aldosterone is known to bind to these receptors in the kidney and cardiovascular system, increasing blood pressure through increasing sodium reabsorption and probably other mechanisms. The drug is cleared by cytochrome P450 (CYP)3A4 metabolism. Peak plasma concentrations are achieved about 1.5 hours after oral administration. Its absorption is not affected by food. Eplerenone has an elimination half-life of 4 6 hours. Blood levels of eplerenone are increased by inhibitors of CYP3A4, such as ketoconazole and saquinavir. About 50% is bound by plasma protein. Steady state of eplerenone is achieved within 2 days.
Indications

Eplerenone is indicated for the treatment of hypertension. It can be used alone or in combination with other antihypertensive therapies. Eplerenone "is indicated to improve survival of stable patients with left ventricular systolic dysfunction (ejection fraction 40%) and clinical evidence of congestive heart failure after an acute myocardial infarction."
Contraindications

Eplerenone is contraindicated in: 1) all patients with a serum potassium concentration greater than 5.5 mEq/L; 2) creatinine clearance 30 mL/min; or 3) in patients on potent CYP3A4 inhibitors: ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir, or other potent CYP3A4 inhibitors. Eplerenone is contraindicated for the treatment of hypertension patients with: 1) type 2 diabetes with microalbuminuria; 2) serum creatinine >2.0 mg/dL in males or >1.8 mg/dL in females; 3) creatinine clearance <50 mL/min; or 4) concomitant use of either potassium supplements or potassium-sparing diuretics (amiloride, spironolactone, triamterene).
Warnings: Hyperkalemia in Patients Treated for Hypertension

The primary risk of eplerenone is hyperkalemia (which can cause serious arrhythmias). Periodic monitoring of potassium levels is recommended for patients at risk of developing hyperkalemia. This includes patients who are receiving concomitant angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. Dose reduction of eplerenone may decrease potassium levels.
Precautions

Hyperkalemia (>5.5 mEq/L) in patients treated for congestive heart failure postmyocardial infarction is one precaution. Proper dose adjustment and patient selection may help minimize this issue. Dose reduction has been shown to decrease the potassium level.

Congestive heart failure patients post infarction with serum creatinine levels >2.0 mg/dL (males) or >1.8 mg/dL (females) or creatinine clearance 50 mL/min should be treated with caution, as should diabetic patients with congestive heart failure post-myocardial infarction, including those with proteinuria. Patients with congestive heart failure post-myocardial infarction plus hypertension with impaired renal function should be treated with caution. There are no well controlled studies of eplerenone in pregnant females or pediatric patients. In the congestive heart failure post-myocardial infarction studies, patients over 75 years did not benefit from eplerenone. Incidence of hyperkalemia was increased in patients 65 and older. In hypertensive studies there was no overall difference in safety or effectiveness between young and old patients.
Adverse Events

In the congestive heart failure post-myocardial infarc tion trial, the adverse events occurring more frequently in eplerenone patients than placebo patients were hyperkalemia (3.4% vs. 2.0%) and increased creatinine (2.4% vs. 1.5%). Discontinuation due to adverse events was similar between eplerenone vs. placebo (4.4% vs. 4.3%). Discontinuation secondary to hyperkalemia or abnormal renal function was <1.0%. In hypertension trials, therapy was discontinued due to adverse events in 3% of eplerenone and placebo patients. The most common reasons for discontinuing drug were headache, dizziness, angina/myocardial infarction, and increased gammaglutamyl tranpeptidase. In controlled studies, the rates of gynecomastia were 0.5%, and for abnormal vaginal bleeding the rate was 0.6%.
Dosage

For congestive heart failure post-myocardial infarction, treatment is initiated at 25 mg once daily and titrated to a target of 50 mg once daily within 4 weeks. Serum potassium should be monitored at pretreatment baseline within the first week and at one month after start of therapy or dose adjustment, with periodic measures thereafter. The dose should be adjusted if needed as per the instructions in the package insert/ Physicians' Desk Reference. For hypertension, the recommended starting dose of eplerenone is 50 mg once daily and full therapeutic effect occurs in four weeks. The dose can be titrated to 50 mg twice daily, if needed. The starting dose should be reduced to 25 mg once daily in patients receiving weak CYP3A4 inhibitors (such as erythromycin, saquinavir, verapamil, and fluconazole).
Summary

Inspra (eplerenone tablets) is an aldosterone antagonist that is now indicated for improving survival in patients who develop congestive heart failure after myocardial infarction. In a major trial it reduced mortality rate by 15% in patients who were already on standard therapy. The drug is also approved for the treatment of hypertension either alone or in combination with other antihypertensive agents. Eplerenone is contraindicated if the serum potassium is greater than 5.5 mEq/L at initiation, creatinine clearance is 30 mL/min, and with concomi tant use of potent CYP3A4 inhibitors.