(+)-Eplerenone

414.49

414.49

1308068-626-2

DTXSID2046094

White to off-white crystalline powder

C - Cardiovascular system

29322090

82.20000

1.05

white to beige

1.31±0.1 g/cm3(Predicted)

242-244 °C

597.9±50.0 °C(Predicted)

259.5±30.2 °C

1.587

DMSO: soluble2mg/mL, clear (warmed)

Store at RT

1.5X10-10 mm Hg at 25 °C (est)

D +5° (c = 0.437 in chloroform)

Odorless

Henry's Law constant = 4.9X10-14 atm-cu m/mol at 25 °C (est)

Hydroxyl radical reaction rate constant = 9.4X10-11 cu cm/molec-sec at 25 °C (est)|Ozone radical reaction rate constant = 1.13X10-17 cu cm/molec-sec at 25 °C (est)

3077

3

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl eplerenone, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

|Warning|H302 (50%): Harmful if swallowed [Warning Acute toxicity, oral]|P201, P202, P260, P261, P264, P270, P271, P272, P273, P280, P281, P301+P312, P302+P352, P304+P312, P304+P340, P308+P313, P312, P314, P321, P322, P330, P333+P313, P363, P405, and P501|Aggregated GHS information provided by 3 companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Eplerenone therapy has been associated with a low rate of serum aminotransferase elevations which are typically mild and transient. ALT elevations of greater than 3 times the ULN occurred in 0.7% and greater than 5 times in 0.2% of eplerenone treated compared to 0.3% and 0.3% of placebo treated subjects. Idiosyncratic, clinically apparent liver injury from eplerenone has yet to be reported. The similarity in structure to spironolactone suggests that it may share susceptibility to the acute liver injury reported rarely with that agent.

Lithium toxicity has been reported in patients receiving lithium concomitantly with diuretics and ACE inhibitors; serum lithium concentrations should be monitored if eplerenone is administered concomitantly with lithium.|Antihypertensive and/or diuretic effects may be potentiated when these medications /other hypotension-producing medications/ are used concurrently with eplerenone; although some antihypertensive and/or diuretic combinations are frequently used for therapeutic advantage, dosage adjustments may be necessary during concurrent use.|/Use of grapefruit juice with eplerenone/ may cause a small increase in exposure.|Concomitant use of potent inhibitors of CYP450 3A4 /including eltraconazole or ketoconazole/ with eplerenone is contraindicated.|For more Interactions (Complete) data for EPLERENONE (12 total), please visit the HSDB record page.

Patients with renal impairment are at an increased risk for developing hyperkalemia.|... When used for hypertension, the drug is contraindicated in patients with type 2 diabetes mellitus with microalbuminuria, serum creatinine concentrations exceeding 2 or 1.8 mg/dL in males or females, respectively, creatinine clearance less than 50 mL/minute, ... .

While data specific to eplerenone were not located(SRC, 2007), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2).

... Preclinical data show that eplerenone and/or metabolites are present in rat breast milk (0.85:1 [milk:plasma] AUC ratio) obtained after a single oral dose. Peak concentrations in plasma and milk were obtained from 0.5 to 1 hour after dosing.

Eplerenone is an aldosterone receptor antagonist and potassium-sparing diuretic used in the therapy of hypertension. Eplerenone therapy has been associated with transient elevations in serum aminotransferase levels, but has yet to be linked to cases of clinically apparent drug induced liver disease.

Diuretics

Eplerenone is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive drugs. /Included in US product labeling/|Inspra is indicated to improve survival of stable patients with left ventricular systolic dysfunction (ejection fraction less than or equal to 40%) and clinical evidence of congestive heart failure after an acute myocardial infarction.|... Eplerenone should replace spironolactone as a natriuretic and antikaliuretic in heart failure and as add-on treatment in severe systolic cardiac insufficiency, and it is indicated after an acute myocardial infarction complicated by left ventricular dysfunction and heart failure. The finding that hypertension control with diuretic-based pharmacotherapy results in better prevention of heart failure than pressure reduction with other drugs makes it pertinent to investigate whether diuretics in general, and eplerenone in particular, should constitute part of the initial pharmacotherapy for heart failure when there is no overt fluid retention and independent of the etiology. ...

FDA Pregnancy Risk Category: B /NO EVIDENCE OF RISK IN HUMANS. Adequate, well controlled studies in pregnant women have not shown increased risk of fetal abnormalities despite adverse findings in animals, or, in the absence of adequate human studies, animal studies show no fetal risk. The chance of fetal harm is remote but remains a possibility./|... When used for hypertension, the drug is contraindicated in patients with type 2 diabetes mellitus with microalbuminuria, serum creatinine concentrations exceeding 2 or 1.8 mg/dL in males or females, respectively, creatinine clearance less than 50 mL/minute, ... .|The most serious risk associated with eplerenone therapy is hyperkalemia (serum potassium greater than 5.5 mEq/L), which may cause serious, sometimes fatal, cardiac arrhythmias. Patients with impaired renal function or diabetes mellitus and patients receiving concurrent agents affecting the renin-angiotensin-aldosterone system (e.g., angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists) are at an increased risk for developing hyperkalemia. Eplerenone should be used with caution in patients with congestive heart failure following an acute myocardial infarction, who have renal impairment (i.e., serum creatinine concentrations exceeding 2 or 1.8 mg/dL in males or females, respectively, or creatinine clearance of 50 mL/minute or less) or those with diabetes mellitus (including those with proteinuria). Serum potassium concentrations should be monitored periodically in patients receiving eplerenone. Dosage reduction has been shown to decrease serum potassium concentrations.|Adverse effects reported in 1% or more of patients receiving eplerenone for the management of hypertension are dizziness, fatigue, flu-like symptoms, cough, diarrhea, abdominal pain, hyperkalemia, decreased serum sodium concentrations, abnormal vaginal bleeding, gynecomastia, hypercholesterolemia, hypertriglyceridemia, mastodynia, or albuminuria.|For more Drug Warnings (Complete) data for EPLERENONE (12 total), please visit the HSDB record page.

Apparent plasma clearance: approximately 10 L/hr. Less than 5% is recovered as unchanged drug in the urine and feces. Renal: 67%. Fecal: 32%.|Mean peak plasma concentrations of eplerenone are reached approximately 1.5 hours following oral administration. The absolute bioavailability of eplerenone is unknown. Both peak plasma levels (Cmax) and area under the curve (AUC) are dose proportional for doses of 25 to 100 mg and less than proportional at doses above 100 mg. The plasma protein binding of eplerenone is about 50% and it is primarily bound to alpha 1-acid glycoproteins. The apparent volume of distribution at steady state ranged from 43 to 90 L. Eplerenone does not preferentially bind to red blood cells.|Eplerenone is distributed into milk in rats; ... .|... Preclinical data show that eplerenone and/or metabolites are present in rat breast milk (0.85:1 [milk:plasma] AUC ratio) obtained after a single oral dose. Peak concentrations in plasma and milk were obtained from 0.5 to 1 hour after dosing.

Eplerenone metabolism is primarily mediated via CYP3A4. No active metabolites have been identified in human plasma.

Elimination: 4 to 6 hours.

Eplerenone has relative selectivity in binding to recombinant human mineralocorticoid receptors compared to its binding to recombinant human glucocorticoid, progesterone, and androgen receptors.|Eplerenone has been shown to produce sustained increases in plasma renin and serum aldosterone, consistent with the inhibition of the negative regulatory feedback of aldosterone on renin secretion. The resulting increased plasma renin activity and aldosterone circulation levels do not overcome the effect of eplerenone on blood pressure.|Eplerenone binds to the mineralocorticoid receptor and blocks the binding of aldosterone, a component of the renin-angiotensin-aldosterone-system (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, brain) tissues and increases blood pressure through induction of sodium resorption and possibly other mechanisms.

To decrease absorption: Eplerenone has been shown to bind extensively to charcoal. To enhance elimination: Eplerenone cannot be removed by hemodialysis. Monitoring: Monitor blood pressure, weight, and electrocardiogram. Patients should be monitored for fluid status and serum electrolytes (particularly sodium and potassium). Supportive care: Treatment should be symptomatic and supportive.|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/SIGNS AND SYMPTOMS/ The most likely manifestations of human overdosage would be hypotension or hyperkalemia.

CGP 30083

Oral: Tablets, film-coated: 25 mg Inspra, (Pfizer), 50 mg Inspra, (Pfizer).|Epoxymexrenone