Dosing

Dosing: Adult
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 associated with increased risk of hyperkalemia and no greater therapeutic effect.
Dose modification during concurrent use with moderate CYP3A4 inhibitors: Initial: 25 mg once daily
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):
<5.0 mEq/L:
Increase dose from 25 mg every other day to 25 mg daily or
Increase dose from 25 mg daily to 50 mg daily
5.0-5.4 mEq/L: No adjustment needed
5.5-5.9 mEq/L:
Decrease dose from 50 mg daily to 25 mg daily or
Decrease dose from 25 mg daily to 25 mg every other day or
Decrease dose from 25 mg every other day to withhold medication
≥6.0 mEq/L: Withhold medication until potassium <5.5 mEq/L, then restart at 25 mg every other day

Dosing: Geriatric
Refer to adult dosing.

Dosing: Renal Impairment
Hypertension: Clcr <50 mL/minute or serum creatinine >2.0 mg/dL in males or >1.8 mg/dL in females: Use is contraindicated; risk of hyperkalemia increases with declining renal function
All other indications: Clcr ≤30 mL/minute: Use is contraindicated.

Dosing: Hepatic Impairment
No dosage adjustment needed for mild-to-moderate impairment. Safety and efficacy not established for severe impairment.

Use

Treatment of hypertension (may be used alone or in combination with other antihypertensive agents); treatment of heart failure (HF) following acute MI

Adverse Reactions

>10%: Endocrine & metabolic: Hyperkalemia ([HF post-MI: K >5.5 mEq/L: 16%; K ≥6 mEq/L: 6%] [HTN: K >5.5 mEq/L at doses ≤100 mg: ≤1%; doses >100 mg: 9%]), hypertriglyceridemia (1% to 15%, dose related)
1% to 10%:
Central nervous system: Dizziness (3%), fatigue (2%)
Endocrine & metabolic: Hyponatremia (2%, dose related), breast pain (males <1% to 1%), gynecomastia (males <1% to 1%), hypercholesterolemia (<1% to 1%)
Gastrointestinal: Diarrhea (2%), abdominal pain (1%)
Genitourinary: Abnormal vaginal bleeding (<1% to 2%)
Renal: Creatinine increased (HF post-MI: 6%), albuminuria (1%)
Respiratory: Cough (2%)
Miscellaneous: Flu-like syndrome (2%)
<1%, postmarketing, and/or case reports: Angioneurotic edema, BUN increased, liver function tests increased, rash, uric acid increased

Contraindications

Serum potassium >5.5 mEq/L at initiation; Clcr ≤30 mL/minute; concomitant use of strong CYP3A4 inhibitors (see Drug Interactions for details)
The following additional Contraindications apply to patients with hypertension: Type 2 diabetes mellitus (noninsulin dependent, NIDDM) with microalbuminuria; serum creatinine >2.0 mg/dL in males or >1.8 mg/dL in females; Clcr <50 mL/minute; concomitant use with potassium supplements or potassium-sparing diuretics

Warnings / Precautions Drug

Concerns related to adverse effects:
• Hyperkalemia: Monitor closely for hyperkalemia; increases in serum potassium were dose related during clinical trials and rates of hyperkalemia also increased with declining renal function.
Disease-related concerns:
• Diabetes: Use with caution in heart failure patients post-MI with diabetes (especially if patient has proteinuria); risk of hyperkalemia is increased.
• Hepatic impairment: Use with caution in patients with severe hepatic impairment; safety and efficacy have not been established.
• Renal impairment: Risk of hyperkalemia is increased with declining renal function. Use with caution in patients with mild renal impairment; contraindicated with moderate-severe impairment (HTN: Clcr <50 mL/minute; other indications: Clcr ≤30 mL/minute).
Concurrent drug therapy issues:
• High potential for interactions: Dosage adjustment needed for patients on moderate CYP3A4 inhibitors.
Metabolism/Transport Effects
Substrate of CYP3A4 (major)

Interactions

ACE Inhibitors: Eplerenone may enhance the hyperkalemic effect of ACE Inhibitors. Risk C: Monitor therapy
Angiotensin II Receptor Blockers: Eplerenone may enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy
Antihypertensives: May enhance the hypotensive effect of other Antihypertensives. Risk C: Monitor therapy
Calcium Channel Blockers (Nondihydropyridine): May decrease the metabolism of Eplerenone. Exceptions: Bepridil [Off Market]. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Eplerenone. Management: A lower starting dose of eplerenone (25 mg once daily for adults) is recommended in patients with hypertension who are also taking drugs that are moderate inhibitors of CYP3A4. Risk D: Consider therapy modification
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Eplerenone. Risk X: Avoid combination
Fluconazole: May increase the serum concentration of Eplerenone. Management: Reduce the starting dose of eplerenone to 25 mg/day; monitor patients closely for increased eplerenone effects. Risk D: Consider therapy modification
Ketoconazole: May increase the serum concentration of Eplerenone. Risk X: Avoid combination
Ketoconazole (Systemic): May increase the serum concentration of Eplerenone. Risk X: Avoid combination
Macrolide Antibiotics: May decrease the metabolism of Eplerenone. Exceptions: Azithromycin; Azithromycin (Systemic); Fidaxomicin (Systemic); Spiramycin. Risk C: Monitor therapy
MAO Inhibitors: May enhance the hypotensive effect of Antihypertensives. MAO Inhibitors may enhance the orthostatic hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: May diminish the antihypertensive effect of Eplerenone. Nonsteroidal Anti-Inflammatory Agents may enhance the hyperkalemic effect of Eplerenone. Risk C: Monitor therapy

Pregnancy

B
Pregnancy Implications
No teratogenic effects were seen in animal studies, however, there are no adequate and well-controlled studies in pregnant women. Use during pregnancy only if the potential benefit to the mother outweighs the possible risk to the fetus.

Lactation

Excretion in breast milk unknown/not recommended
Dietary Considerations
May be taken with or without food. Do not use salt substitutes containing potassium.

Mechanism of Action

Aldosterone, a mineralocorticoid, increases blood pressure primarily by inducing sodium and water retention. Overexpression of aldosterone is thought to contribute to myocardial fibrosis (especially following myocardial infarction) and vascular fibrosis. Mineralocorticoid receptors are located in the kidney, heart, blood vessels, and brain. Eplerenone selectively blocks mineralocorticoid receptors reducing blood pressure in a dose-dependent manner and appears to prevent myocardial and vascular fibrosis.

Pharmacodynamics / Kinetics

Distribution: Vd: 43-90 L
Protein binding: ~50%; primarily to alpha1-acid glycoproteins
Metabolism: Primarily hepatic via CYP3A4; metabolites inactive
Bioavailability: 69%
Half-life elimination: 4-6 hours
Time to peak, plasma: ~1.5 hours; may take up to 4 weeks for full antihypertensive effect
Excretion: Urine (~67%); feces (32%); <5% as unchanged drug in urine and feces