Brands, Medical Use, Clinical Data
- Tablet (film-coated - 25, 50 mg)
Brands / Synonyms
Eplerenone [Usan]; Epoxymexrenone; Inspra; INSPRA
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.
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.
Mechanism of Action
Eplerenone binds to the mineralocorticoid receptor and thereby blocks the binding of aldosterone (component of the renin-angiotensin-aldosterone-system, or RAAS). Aldosterone synthesis, which occurs primarily in the adrenal gland, is modulated by multiple factors, including angiotensin II and non-RAAS mediators such as adrenocorticotropic hormone (ACTH) and potassium. Aldosterone binds to mineralocorticoid receptors in both epithelial (e.g., kidney) and nonepithelial (e.g., heart, blood vessels, and brain) tissues and increases blood pressure through induction of sodium reabsorption and possibly other mechanisms.
The absolute bioavailability of eplerenone is unknown.
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.
Biotrnasformation / Drug Metabolism
Eplerenone is metabolized primarily by CYP3A4, however, no active metabolites have been identified in human plasma.
Eplerenone is contraindicated in all patients with the following: - serum potassium >5.5 mEq/L at initiation- creatinine clearance £30 mL/min- concomitant use with the following potent CYP3A4 inhibitors: ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, and nelfinavir.- Hypertension: Eplerenone is also contraindicated for the treatment of hypertension in patients with the following: 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, 4) concomitant use of potassium supplements or potassium-sparing diuretics (amiloride, spironolactone, or triamterene).
Inhibitors of CYP3A4-Eplerenone metabolism is predominantly mediated via CYP3A4. A
pharmacokinetic study evaluating the administration of a single dose of INSPRA 100 mg with ketoconazole 200 mg BID, a
potent inhibitor of the CYP3A4 pathway, showed a 1.7-fold increase in Cmax of eplerenone and a 5.4-fold
increase in AUC of eplerenone. INSPRA should not be used with drugs described as strong inhibitors of CYP3A4 in their
Administration of eplerenone with other CYP3A4 inhibitors (e.g., erythromycin 500 mg BID, verapamil
240 mg QD, saquinavir 1200 mg TID, fluconazole 200 mg QD) resulted in increases in Cmax of eplerenone
ranging from 1.4- to 1.6- fold and AUC from 2.0- to 2.9- fold.
ACE Inhibitors and Angiotensin II Receptor Antagonists (Congestive Heart Failure Post-Myocardial
Infarction)- In EPHESUS, 3020 (91%) patients receiving INSPRA 25 to 50 mg also received ACE inhibitors or
angiotensin II receptor antagonists (ACEI/ARB). Rates of patients with maximum potassium levels >5.5 mEq/L were
similar regardless of the use of ACEI/ARB.
ACE Inhibitors and Angiotensin II Receptor Antagonists (Hypertension)- In clinical studies of
patients with hypertension, the addition of INSPRA 50 to 100 mg to ACE inhibitors and angiotensin II receptor
antagonists increased mean serum potassium slightly (about 0.09-0.13 mEq/L). In a study in diabetics with
microalbuminuria INSPRA 200 mg combined with the ACE inhibitor enalapril 10 mg increased the frequency of
hyperkalemia (serum potassium >5.5 mEq/L) from 17% on enalapril alone to 38%.
Lithium-A drug interaction study of eplerenone with lithium has not been conducted. Lithium
toxicity has been reported in patients receiving lithium concomitantly with diuretics and ACE inhibitors. Serum
lithium levels should be monitored frequently if INSPRA is administered concomitantly with lithium.
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)-A drug interaction study of eplerenone with an
NSAID has not been conducted. The administration of other potassium-sparing antihypertensives with NSAIDs has been
shown to reduce the antihypertensive effect in some patients and result in severe hyperkalemia in patients with
impaired renal function. Therefore, when INSPRA and NSAIDs are used concomitantly, patients should be observed to
determine whether the desired effect on blood pressure is obtained.