エプレレノン

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals -> Diuretics

log Kow = 7.1 at pH 7.0

1.3

Slightly soluble

Very slightly soluble in water, with its solubility essentially pH dependent

9.03e-03 g/L

Breast Feeding; Lactation; Milk, Human; Antihypertensive Agents; Mineralocorticoid Receptor Antagonists

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

This chemical does not meet GHS hazard criteria for 50% (2 of 4) of reports.

Warning

H302 (50%): Harmful if swallowed [Warning Acute toxicity, oral]

P203, P261, P264, P270, P271, P272, P280, P301+P317, P302+P352, P304+P340, P317, P318, P321, P330, P333+P317, P362+P364, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 4 reports by companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

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.

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.

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.

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.

Hyperkalemia is by far the most common adverse effect of eplerenone. Clinical trial experience indicates an approximately 1.5 to 2.0 fold risk of hyperkalemia, with a number needed to harm ranging from 23 to 62. While serious hyperkalemia (greater than or equal to 6 mEq/L) was more common in both the EMPHASIS and EPHESUS trials, the adverse effect was usually manageable by reducing the dose or temporarily discontinuing the drug. In contrast, hypokalemia—which correlates with an increased risk of death from any cause among heart failure patients—was significantly reduced. Though serum creatinine may rise on eplerenone, the EMPHASIS-HF trial found no increased risk of renal failure.

... 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.

There are no known overdose reports of eplerenone, but the most likely manifestations of overdose would be hypotension or hyperkalemia. Researchers have not observed any lethality in overdose studies in mice, rats, or dogs, but dogs demonstrated emesis, salivations, and tremors at a concentration 41 times the human therapeutic concentration of eplerenone. These progressed to sedation and convulsions at higher exposures.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Eplerenone

vLess-DILI-concern

4

Adverse reactions

DOI:10.1016/j.drudis.2016.02.015

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ There was no drug-related tumor response in heterozygous p53 deficient mice when tested for 6 months at dosages up to 1000 mg/kg/day (systemic AUC exposures up to 9 times the exposure in humans receiving the 100-mg/day therapeutic dose). Statistically significant increases in benign thyroid tumors were observed after 2 years in both male and female rats when administered eplerenone 250 mg/kg/day (highest dose tested) and in male rats only at 75 mg/kg/day. These dosages provided systemic AUC exposures approximately 2 to 12 times higher than the average human therapeutic exposure at 100 mg/day. Repeat dose administration of eplerenone to rats increases the hepatic conjugation and clearance of thyroxin, which results in increased levels of TSH by a compensatory mechanism. Drugs that have produced thyroid tumors by this rodent specific mechanism have not shown a similar effect in humans.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Studies in animals have not shown that eplerenone causes teratogenic effects in the fetus. However, decreased body weight in maternal rabbits and increased rabbit fetal resorptions and post-implantation loss were observed at the highest administered dosage (up to 32 (rats) and 31 (rabbits times the human AUC for the 100 mg/day human therapeutic dose.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Dose-related prostate atrophy was observed in dogs administered 15 mg/kg of body weight per day and higher (AUC 5 times that at the 100 mg/day human therapeutic dose). The prostate atrophy was reversible after daily treatment for 1 year. There was no decline in libido, sexual performance, or semen quality in the dogs with prostrate atrophy.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Male rats treated with eplerenone at 1000 mg/kg/day for 10 weeks (17 times a human therapeutic dose) had decreased weights of seminal vesicles and epididymides and slightly decreased fertility.

/GENOTOXICITY/ Eplerenone was non-genotoxic in the following assays: in vitro bacterial mutagenesis, in vitro mammalian cell mutagenesis, in vitro chromosomal aberration, in vivo rat one marrow micronucleus formation, and in vivo/ex vivo unscheduled DNA synthesis in rat liver.

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).

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/

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.

C03DA04

C - Cardiovascular system

QC - Cardiovascular system

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.

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.

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.

4-6 hours

Elimination: 4 to 6 hours.

Eplerenone is metabolized primarily by CYP3A4, however, no active metabolites have been identified in human plasma.

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

Eplerenone has known human metabolites that include 21-hydroxyeplerenone and 6beta-hydroxyeplerenone.

6995V82D0B

EPLERENONE

Established Pharmacologic Class [EPC] - Aldosterone Antagonist

Mechanisms of Action [MoA] - Aldosterone Antagonists

Eplerenone is an Aldosterone Antagonist. The mechanism of action of eplerenone is as an Aldosterone Antagonist.

EPLERENONE

Drugs used in the treatment of acute or chronic vascular HYPERTENSION regardless of pharmacological mechanism. Among the antihypertensive agents are DIURETICS; (especially DIURETICS, THIAZIDE); ADRENERGIC BETA-ANTAGONISTS; ADRENERGIC ALPHA-ANTAGONISTS; ANGIOTENSIN-CONVERTING ENZYME INHIBITORS; CALCIUM CHANNEL BLOCKERS; GANGLIONIC BLOCKERS; and VASODILATOR AGENTS.

Drugs that bind to and block the activation of MINERALOCORTICOID RECEPTORS by MINERALOCORTICOIDS such as ALDOSTERONE.

The absolute bioavailability of eplerenone is unknown.

43 to 90 L

Apparent plasma cl=10 L/hr

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; ... .

THERAP CAT: Antihypertensive. In treatment of congestive heart failure.

Indicated to improve survival of stable patients with left ventricular systolic dysfunction ... and clinical evidence of congestive heart failure after acute myocardial infarction

MEDICATION

Use (kg; approx.) in Germany (2009): >250

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

Epoxymexrenone