EPLERON

Eplerenone, an aldosterone receptor antagonist similar to spironolactone, has been shown to produce sustained increases in plasma renin and serum aldosterone, consistent with inhibition of the negative regulatory feedback of aldosterone on renin secretion.

The resulting increased plasma renin activity and aldosterone circulating levels do not overcome the effects of eplerenone.

Eplerenone selectively binds to recombinant human mineralocorticoid receptors relative to its binding to recombinant human glucocorticoid, progesterone and androgen receptors.

For improvement of survival of stable patients with left ventricular systolic dysfunction (ejection fraction <40%) and clinical evidence of congestive heart failure after an acute myocardial infarction.

The absolute bioavailability of eplerenone is unknown.

Eplerenone is metabolized primarily by

CYP3A4, however, no active metabolites have been identified in human plasma.

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The most likely symptoms of human overdosage would be anticipated to be hypotension or hyperkalemia.

However, no cases of human overdosage with eplerenone have been reported.

• serum potassium >5.5 mEq/L at initiation,.

• creatinine clearance ≤30 mL/min, or.

• concomitant administration of strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, and nelfinavir) .

• type 2 diabetes with microalbuminuria,.

• serum creatinine >2.0 mg/dL in males or >1.8 mg/dL in females,.

• creatinine clearance <50 mL/min, or.

• concomitant administration of potassium supplements or potassium-sparing diuretics (e.g., amiloride, spironolactone, or triamterene) .

• Serum potassium >5.5 mEq/L at initiation.

• Creatinine clearance ≤30 mL/min.

• Type 2 diabetes with microalbuminuria.

• Serum creatinine >2.0 mg/dL in males, >1.8 mg/dL in females.

• Creatinine clearance <50 mL/min.

• Concomitant use of potassium supplements or potassium-sparing diuretics.

Initiate treatment with 25 mg once daily.

Titrate to maximum of 50 mg once daily within 4 weeks, as tolerated.

Dose adjustments may be required based on potassium levels.

Hypertension: 50 mg once daily, alone or combined with other antihypertensive agents.

For inadequate response, increase to 50 mg twice daily.

Higher dosages are not recommended.

For all patients

Measure serum potassium before starting INSPRA and periodically thereafter. 2.1 Heart Failure Post-Myocardial Infarction Initiate treatment at 25 mg once daily and titrate to the recommended dose of 50 mg once daily, preferably within 4 weeks as tolerated by the patient.

Once treatment with

INSPRA has begun, adjust the dose based on the serum potassium level as shown in Table 1.

Table 1.

Dose Adjustment in Heart Failure Post-MI Serum Potassium (mEq/L) Dose Adjustment <5.0 25 mg every other day to 25 mg once daily 25 mg once daily to 50 mg once daily 5.0-5.4 No adjustment 5.5-5.9 50 mg once daily to 25 mg once daily 25 mg once daily to 25 mg every other day 25 mg every other day to withhold ≥6.0 Withhold and restart at 25 mg every other day when potassium levels fall to <5.5 mEq/L 2.2 Hypertension The recommended starting dose of INSPRA is 50 mg administered once daily.

The full therapeutic effect of

INSPRA is apparent within 4 weeks.

For patients with an inadequate blood pressure response to 50 mg once daily increase the dosage of INSPRA to 50 mg twice daily.

Higher dosages of

INSPRA are not recommended because they have no greater effect on blood pressure than 100 mg and are associated with an increased risk of hyperkalemia. 2.3 Recommended Monitoring Measure serum potassium before initiating INSPRA therapy, within the first week, and at one month after the start of treatment or dose adjustment.

Assess serum potassium periodically thereafter.

Check serum potassium and serum creatinine within 3-7 days of a patient initiating a moderate CYP3A inhibitor ACE inhibitors, angiotensin II blockers or nonsteroidal anti-inflammatories. 2.4 Dose Modification for Use with Moderate CYP3A Inhibitors In post-MI HFrEF patients receiving a moderate CYP3A inhibitor (e.g., erythromycin, saquinavir, verapamil, and fluconazole), do not exceed 25 mg once daily.

In patients with hypertension receiving a moderate CYP3A inhibitor, initiate at 25 mg once daily.

For inadequate blood pressure response, dosing may be increased to a maximum of 25 mg twice daily.

Tablets are yellow, diamond biconvex, and film-coated.

They are debossed with “VLE” on one side.

They are supplied as follows

Dose Deboss Side 2 NDC 58151-xxx-xx Bottle/30 25 mg NSR 25 142-93 50 mg NSR 50 143-93 Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) .

The available data from published case reports on eplerenone use during pregnancy are insufficient to establish a drug-associated risk of major birth defects, miscarriage, adverse maternal or fetal outcomes.

In animal studies, no adverse developmental effects were observed when eplerenone was administered to pregnant rats and rabbits during organogenesis at exposures and 31 times, respectively the human exposure at the 100 mg/day therapeutic dose.

The estimated background risk of major birth defects and miscarriage for the indicated population are unknown.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Maternal and/or Embryo/Fetal Risk Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage).

Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death.

Pregnant women with hypertension should be carefully monitored and managed accordingly.

Pregnant women with heart failure are at increased risk for preterm birth.

Stroke volume and heart rate increase during pregnancy, increasing cardiac output, especially during the first trimester.

Clinical classification of heart disease may worsen with pregnancy and lead to maternal death.

Closely monitor pregnant patients for destabilization of their heart failure.

Embryo-fetal development studies were conducted with doses up to 1000 mg/kg/day in rats and 300 mg/kg/day in rabbits (exposures up to and 31 times the human AUC for the 100 mg/day therapeutic dose, respectively) administered during organogenesis.

No teratogenic effects were seen in rats or rabbits, although decreased rat fetal weights were observed, and decreased body weight in maternal rabbits and increased rabbit fetal resorptions and post-implantation loss were observed at the highest administered dosages.

In a pre.

• and postnatal development study, pregnant rats were administered eplerenone at doses up to 1000 mg/kg/day from Gestation Day 6 through Lactation Day 20.

Decreased pup weights were observed beginning at birth at 1000 mg/kg/day.

The safety and effectiveness of

INSPRA for treatment of hypertension have not been established in pediatric patients.

In a 10-week study of 304 hypertensive pediatric patients ages to 16 years treated with INSPRA up to 100 mg per day, doses that produced exposure similar to that in adults, INSPRA did not lower blood pressure effectively.

In this study and in a 1-year pediatric safety study in 149 patients (age range to 17 years), the incidence of reported adverse events was similar to that of adults.

INSPRA was not studied for treatment of hypertension in pediatric patients younger than 4 years of age because the study in older pediatric patients did not demonstrate effectiveness.

INSPRA have not been established in pediatric patients with heart failure.

Of the total number of patients in EPHESUS, 3340 (50%) were and over, while 1326 (20%) were and over.

Patients greater than 75 years did not appear to benefit from the use of INSPRA.

No differences in overall incidence of adverse events were observed between elderly and younger patients.

However, due to age-related decreases in creatinine clearance, the incidence of laboratory-documented hyperkalemia was increased in patients and older.

Of the total number of subjects in clinical hypertension studies of INSPRA, 1123 (23%) were and over, while 212 (4%) were and over.

No overall differences in safety or effectiveness were observed between elderly subjects and younger subjects, however due to age-related decreases in creatine clearance, the risk of hyperkalemia may be increased.