Eplerenone

C03D - Potassium-sparing agents ATC C03DA04 Small molecule approved 2002 Oral Natural product

JFDA label: Epnone 50mg

Mechanism of Action

Antagonist of Mineralocorticoid receptor — Mineralocorticoid receptor antagonist

Target	Action	Gene / class
Mineralocorticoid receptor efficacy	ANTAGONIST	NR3C2

Indications

Approved

Heart failure
Heart failure post-myocardial infarction (MI)
Hypertension
STEMI/NSTE-ACS

Off-label

Heart failure (NYHA class II-IV) with left ventricular ejection fraction ≤35%
Primary aldosteronism, treatment

Contraindications

Source: Lexicomp

Additional contraindications (not in US labeling): Hypersensitivity to eplerenone or any component of the formulation Absolute
CrCl Per the Endocrine Society clinical practice guidelines, use in patients with Addison disease is contraindicated (Endocrine Society [Bornstein 2016]) Absolute
CrCl ≤30 mL/minute Absolute
Serum potassium >5.5 mEq/L at initiation Absolute
clinically significant hyperkalemia Absolute
concomitant use of strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir). The following additional contraindications apply to patients with hypertension: Type 2 diabetes mellitus (noninsulin dependent, NIDDM) with microalbuminuria Absolute
concomitant use with potassium supplements or potassium-sparing diuretics The following additional contraindications apply to patients with hypertension: Serum creatinine >1.5 mg/dL [132 micromole/L] in males or >1.3 mg/dL [115 micromole/L] in females Absolute
serum creatinine >2.0 mg/dL in males or >1.8 mg/dL in females Absolute
serum potassium >5 mEq/L at initiation Absolute
severe hepatic impairment (Child-Pugh class C) Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Nervous system disorders (2)

Common Dizziness · fatigue

Renal and urinary disorders (3)

Common Abnormal vaginal hemorrhage · Increased serum creatinine · mastalgia

Metabolism and nutrition disorders (4)

Common albuminuria · gynecomastia · hypercholesterolemia · Hyponatremia

Gastrointestinal disorders (2)

Common abdominal pain · Diarrhea

Other (2)

Very Common Endocrine & metabolic: Hyperkalemia · hypertriglyceridemia

Respiratory, thoracic and mediastinal disorders (2)

Common Cough · flu-like symptoms

Dosing

Source: Lexicomp

Hypertension: Oral: Initial: 50 mg once daily; may increase to 50 mg twice daily if response is not adequate; may take up to 4 weeks for full therapeutic response. Doses >100 mg/day are not recommended due to increased risk of hyperkalemia and no greater therapeutic effect. Dose modification during concurrent use with moderate CYP3A4 inhibitors: Initial: 25 mg once daily; may increase to 25 mg twice daily if response is not adequate (maximum: 50 mg/day). Heart failure: Heart failure (post MI): Oral: Initial: 25 mg once daily; dosage goal: Titrate to 50 mg once daily within 4 weeks, as tolerated Dosage adjustment per serum potassium concentrations for HF (post-MI): Increase dose from 25 mg every other day to 25 mg once daily or Increase dose from 25 mg once daily to 50 mg once daily 5 to 5.4 mEq/L: No adjustment needed 5.5 to 5.9 mEq/L: Decrease dose from 50 mg once daily to 25 mg once daily or Decrease dose from 25 mg once daily to 25 mg every other day or Modify dose from 25 mg every other day to withhold medication ≥6 mEq/L: Withhold medication until potassium Alternatively, the ACCF/AHA 2013 HF guidelines recommend withholding treatment if potassium >5.5 mEq/L or renal function worsens; hold doses until potassium is Dose modification during concurrent use with moderate CYP3A4 inhibitors: Initial: 25 mg once daily; maximum: 25 mg/day. Heart failure (NYHA class II-IV with LVEF ≤35%) (off-label dose): Initial: 25 mg once daily; maximum: 50 mg/daily (ACCF/AHA [Yancy, 2013]) Primary aldosteronism, treatment (off-label use): Oral: Initial: 25 mg twice daily (Funder 2016)

Refer to adult dosing.

Hypertension: CrCl ≥50 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling. CrCl 2 mg/dL (males) or >1.8 mg/dL (females): Use is contraindicated; risk of hyperkalemia increases with declining renal function. Heart failure (post-MI): CrCl >50 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling. CrCl 31 to 50 mL/minute or serum creatinine >2 mg/dL (males) or >1.8 mg/dL (females): There are no dosage adjustment provided in the manufacturer’s labeling; use with caution. CrCl ≤30 mL/minute: Use is contraindicated. Heart failure (including post-MI) (ACCF/AHA [Yancy 2013]: eGFR ≥50 mL/minute/1.73 m2: Initial dose: 25 mg once daily; Maintenance dose (after 4 weeks of treatment and potassium ≤5 mEq/L): 50 mg once daily eGFR 30 to 49 mL/minute/1.73 m2: Initial dose: 25 mg once every other day; Maintenance dose (after 4 weeks of treatment and potassium ≤5 mEq/L): 25 mg once daily eGFR 2: Not recommended. Hemodialysis: Not removed by hemodialysis.

There are no dosage adjustments provided in the manufacturer's labeling. Systemic exposure is increased in moderate hepatic impairment (Child-Pugh class B).

Warnings & Precautions

Source: Lexicomp

Hyperkalemia

Hyperkalemia may occur; risk of hyperkalemia is increased with renal impairment, proteinuria, diabetes, and patients taking concomitant ACE inhibitors, angiotensin-II blockers, NSAIDs, and/or moderate CYP3A inhibitors. Monitor closely for hyperkalemia; increases in serum potassium were dose related during clinical trials (ACCF/AHA [Yancy 2013]). Dose reduction or interruption of therapy may be necessary with development of hyperkalemia. If concomitant moderate CYP3A4 inhibitor therapy cannot be avoided, reduce dose of eplerenone. Use is contraindicated in patients with potassium >5.5 mEq/L at initiation of therapy. Disease-related concerns:

Diabetes

Use with caution in patients with heart failure post-MI with diabetes (especially if patient has proteinuria); risk of hyperkalemia is increased.

Heart failure

When evaluating a heart failure patient for eplerenone treatment, eGFR should be >30 mL/minute/1.73 m2 or creatinine should be ≤2.5 mg/dL (men) or ≤2 mg/dL (women) with no recent worsening and potassium 6 mEq/L. The ACCF/AHA recommends considering discontinuation upon the development of serum potassium >5.5 mEq/L or worsening renal function with careful evaluation of the entire medical regimen. Avoid routine triple therapy with the combined use of an ACE inhibitor, ARB, and eplerenone. Instruct patients with heart failure to discontinue use during an episode of diarrhea or dehydration or when loop diuretic therapy is interrupted (ACCF/AHA [Yancy, 2013]).

Hepatic impairment

Use with caution in patients with moderate to severe hepatic impairment.

Renal impairment

Risk of hyperkalemia is increased with declining renal function. Use with caution in patients with mild renal impairment; based on indication and degree of impairment use may be contraindicated (refer to contraindications field). Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Potassium supplements

Avoid potassium supplements, potassium-containing salt substitutes, a diet rich in potassium, or other drugs that can cause hyperkalemia (eg, other potassium-sparing diuretics, NSAIDS). Concomitant use of potassium supplements or potassium-sparing diuretics is contraindicated in the treatment of hypertension.

Pregnancy & Lactation

Pregnancy

FDA category B

Adverse events have been observed in some animal reproduction studies. Information related to eplerenone use in pregnancy is limited (Cabassi, 2012; Morton, 2011). The use of mineralocorticoid receptor antagonists is not recommended to treat chronic uncomplicated hypertension in pregnant women and should generally be avoided in women of reproductive potential (ACOG, 2013).

Lactation

It is not known if eplerenone is excreted in breast milk. Due to the potential for serious adverse reactions in the nursing infant, the manufacturer recommends a decision be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of treatment to the mother.

Monitoring

Clinical pearl	Blood pressure; serum potassium (prior to therapy, within the first week, 1 month after start of treatment or dose adjustment, then periodically as clinically indicated); additionally, check serum potassium and serum creatinine within 3 to 7 days after initiating concurrent therapy with moderate a CYP3A4 inhibitor, ACE inhibitor, ARB or NSAID. ACCF/AHA heart failure guideline recommendations (ACCF/AHA [Yancy, 2013]): Serum potassium and renal function should be checked in 3 days after initiation, at 1 week after initiation, at least monthly for the first 3 months of therapy, and every 3 months thereafter. If adding or increasing the dose of concomitant ACE inhibitors or ARBs, a new cycle of monitoring should be done. If serum potassium increases to >5.5 mEq/L or renal function worsens, hold doses until potassium is

Clinical pearl

Blood pressure; serum potassium (prior to therapy, within the first week, 1 month after start of treatment or dose adjustment, then periodically as clinically indicated); additionally, check serum potassium and serum creatinine within 3 to 7 days after initiating concurrent therapy with moderate a CYP3A4 inhibitor, ACE inhibitor, ARB or NSAID. ACCF/AHA heart failure guideline recommendations (ACCF/AHA [Yancy, 2013]): Serum potassium and renal function should be checked in 3 days after initiation, at 1 week after initiation, at least monthly for the first 3 months of therapy, and every 3 months thereafter. If adding or increasing the dose of concomitant ACE inhibitors or ARBs, a new cycle of monitoring should be done. If serum potassium increases to >5.5 mEq/L or renal function worsens, hold doses until potassium is

Chemistry & Properties

Formula	C24H30O6
Molecular weight	414.5 g/mol
IUPAC name	methyl (1R,2S,9R,10R,11S,14R,15S,17R)-2,15-dimethyl-5,5'-dioxospiro[18-oxapentacyclo[8.8.0.01,17.02,7.011,15]octadec-6-ene-14,2'-oxolane]-9-carboxylate
CAS	107724-20-9
PubChem CID	443872
InChIKey	`JUKPWJGBANNWMW-VWBFHTRKSA-N`
logP	3.12 (XLogP 1.4)
Polar surface area	82.2 Å²
H-bond acceptors / donors	6 / 0
Drug-likeness (QED)	0.48
Lipinski violations	0

SMILES

COC(=O)[C@@H]1CC2=CC(=O)CC[C@]2(C)[C@@]23O[C@@H]2C[C@@]2(C)[C@@H](CC[C@@]24CCC(=O)O4)[C@H]13

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	70.0%
Half-life	1.038 h
Volume of distribution	1.366 L/kg
Protein binding	74.1%
BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP1A2	Substrate	—
CYP2C8	Inhibitor	—
CYP3A4	Substrate	—

Receptor binding (top 2)

Target	Action	Affinity
Mineralocorticoid receptor (NR3C2)	Antagonist	pKi 6.9
Mineralocorticoid receptor (NR3C2)	Antagonist	pIC50 6.4

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)MDR1 (Substrate)P-gp (Substrate)

Drug–drug interactions (85, DDInter)

Interacting drug	Severity	Management
Aminobenzoic acid	major
Aprepitant	major
Ceritinib	major
Clarithromycin	major
Clotrimazole	major
Cobicistat	major
Crizotinib	major
Erythromycin	major
Fedratinib	major
Fluconazole	major
Idelalisib	major
Imatinib	major
Ketoconazole	major
Potassium Iodide	major
Potassium acetate	major
Potassium bicarbonate	major
Potassium chloride	major
Potassium citrate	major
Potassium gluconate	major
Potassium perchlorate	major
Ribociclib	major
Acetylsalicylic acid	moderate
Alimemazine	moderate
Amifostine	moderate
Betamethasone	moderate
Brigatinib	moderate
Brimonidine (ophthalmic)	moderate
Brimonidine (topical)	moderate
Budesonide	moderate
Bupropion	moderate
Canagliflozin	moderate
Celecoxib	moderate
Chlorphenesin	moderate
Corticotropin	moderate
Cyclosporine	moderate
Dabrafenib	moderate
Dapagliflozin	moderate
Deferasirox	moderate
Deflazacort	moderate
Dexamethasone	moderate

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Registered Products (4)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Epnone	Tablet 25 mg	30 tab	Manar Drug Store	7.470
Epnone	Tablet 50 mg	30 tab	Manar Drug Store	13.070
Elerax	Tablet 25 mg	30 tab	UNITED PHARM.MFG.CO.LTD(UPM)/JORDAN	17.970
Elerax 50mg F.C.T	Tablet 50 mg	30 tab	UNITED PHARM.MFG.CO.LTD(UPM)/JORDAN	17.970