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  • CLASSES

    Steroidal Mineralocorticoid Receptor Antagonists

    DEA CLASS

    Rx

    DESCRIPTION

    Selective aldosterone receptor antagonist (SARA)
    Used to treat hypertension; also used to treat heart failure in post-myocardial infarction patients
    Metabolized by CYP3A4; associated with a risk of hyperkalemia

    COMMON BRAND NAMES

    Inspra

    HOW SUPPLIED

    Eplerenone/Inspra Oral Tab: 25mg, 50mg

    DOSAGE & INDICATIONS

    For the treatment of hypertension, either as monotherapy or in combination with other antihypertensive agents.
    Oral dosage
    Adults

    50 mg PO once daily. For inadequate blood pressure response after 4 weeks of treatment, may increase dosage to 50 mg PO twice daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Doses greater than 100 mg/day do not provide additional blood-pressure lowering benefit and present an increased risk of hyperkalemia.

    For the reduction of cardiovascular mortality in stable patients with left ventricular systolic dysfunction (ejection fraction of 40% or less) and congestive heart failure after an acute myocardial infarction.
    Oral dosage
    Adults

    Initially, 25 mg PO once daily. Increase dosage to 50 mg PO once daily as tolerated within 4 weeks. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Monitor serum potassium concentrations at baseline, within the first week of eplerenone therapy, and at 1 month after dosage initiation or adjustments; monitor more frequently in at-risk patients. If the serum potassium concentration is 5.5 mEq/L or more, decrease the dosage. Hold eplerenone if the serum potassium concentration is 6 mEq/L or more; may restart at 25 mg PO every other day once the serum potassium concentration is less than 5.5 mEq/L. Guidelines recommend an aldosterone antagonist, in select patients, in combination with an angiotensin-converting enzyme (ACE) inhibitor, angiotensin receptor blocker (ARB), or  angiotensin receptor-neprilysin inhibitor (ARNI) and evidence-based beta blocker for patients with chronic reduced ejection fraction heart failure (HFrEF) to reduce morbidity and mortality. An aldosterone receptor antagonist is recommended in patients with HFrEF NYHA class II to IV with a GFR of more than 30 mL/minute and potassium less than 5 mEq/L. An aldosterone receptor antagonist may be considered to decrease hospitalizations in patients with preserved ejection fraction heart failure (HFpEF) with EF of 45% or more, elevated B-type natriuretic peptide (BNP) concentrations, or HF admission within 1 year, and estimated GFR of more than 30 mL/minute, creatinine less than 2.5 mg/dL, and potassium less than 5 mEq/L.

    MAXIMUM DOSAGE

    Adults

    100 mg/day PO for hypertension; 50 mg/day PO for heart failure.

    Elderly

    100 mg/day PO for hypertension; 50 mg/day PO for heart failure.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No initial dosage adjustments are necessary for patients with mild to moderate hepatic impairment; eplerenone has not been studied in severe hepatic impairment.

    Renal Impairment

    CrCl 50 mL/minute or more: No dosage adjustment recommended.
    CrCl less than 50 mL/minute: Use contraindicated in patients treated for hypertension. Use with cautious electrolyte monitoring in patients with heart failure. For patients with CrCl 30 to 49 mL/minute treated for heart failure, clinical practice guidelines recommend 25 mg PO every other day during the first 4 weeks followed by 25 mg PO once daily.
    CrCl 30 mL/minute or less: Use contraindicated.
     
    Intermittent hemodialysis
    See dosage for patients with renal impairment. Eplerenone is not removed by hemodialysis.

    ADMINISTRATION

    Oral Administration

    May administer eplerenone without regard to food.
    Advise patients not to use dietary salt substitutes that contain potassium while taking eplerenone.

    STORAGE

    Inspra:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Adrenal insufficiency, diabetes mellitus, hyperkalemia, proteinuria, renal disease, renal failure, renal impairment

    Eplerenone is contraindicated in any patient with hyperkalemia (serum potassium greater than 5.5 mEq/L), a creatinine clearance 30 mL/minute or less, or receiving concomitant therapy with strong CYP3A4 inhibitors. Additional contraindications for patients with hypertension include type 2 diabetes mellitus with microalbuminuria, a serum creatinine greater than 2 mg/dL in males or greater than 1.8 mg/dL in females, a creatinine clearance less than 50 mL/minute, and concomitant potassium sparing diuretics or potassium supplements. The Endocrine Society guidelines on the diagnosis and treatment of primary adrenal insufficiency state that use of aldosterone antagonists, such as eplerenone, are contraindicated in patients with adrenal insufficiency (Addison's disease). Hyperkalemia stimulates aldosterone production and aldosterone, in turn, enhances sodium and water reabsorption in exchange for potassium excretion in the distal tubule and collecting duct of the kidney. In Addison's disease, aldosterone deficiency results in hyponatremia, hypovolemia, hypotension and hyperkalemia. Thus, eplerenone therapy will exacerbate the hyponatremia, hypovolemia, hypotension and hyperkalemia seen in adrenal insufficiency and worsen the signs and symptoms of the disease.   Eplerenone-induced hyperkalemia can cause life-threatening cardiac arrhythmias, and it is more likely to occur in patients with renal impairment or renal failure, renal disease, proteinuria, diabetes mellitus, those who are receiving angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), nonsteroidal anti-inflammatory drugs (NSAIDs), moderate CYP3A4 inhibitors, or in elderly patients. Eplerenone dose reduction is required for patients receiving moderate CYP3A4 inhibitors that cannot be avoided. Measure serum potassium before initiating eplerenone therapy, within the first week of therapy, and 1 month after the start of treatment or any dose adjustment. Monitor periodically thereafter. Measure serum potassium and serum creatinine within 3 to 7 days of initiating a moderate CYP3A4 inhibitor, ACE inhibitor, ARB, or NSAID. Patients receiving eplerenone should be informed not to use dietary salt substitutes containing potassium without consulting their prescribing health care professional.

    Hepatic disease

    Although eplerenone was not found to have any associated adverse effects in patients with mild to moderate hepatic impairment, it should be used cautiously in patients with severe hepatic disease; the use of eplerenone has not been evaluated in patients with severe hepatic impairment.

    Driving or operating machinery

    Because eplerenone may cause dizziness, patients should use caution in driving or operating machinery until the effects of the drug are known.

    Children, infants, neonates

    Safety and efficacy of eplerenone in neonates, infants, children, and adolescents have not been established. In a 10-week study of hypertensive pediatric patients (n = 304; age range: 4 to 16 years), doses up to 100 mg/day did not effectively lower blood pressure even though drug exposure was similar to that in adults. In this study and a 1-year pediatric safety study (n = 149; age range: 5 to 17 years), the incidence of adverse events was similar to that of adults. Eplerenone has not been studied in pediatric heart failure patients or in those younger than 4 years.

    Pregnancy

    Data are insufficient with eplerenone use during pregnancy to establish a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. No adverse developmental effects were observed when eplerenone was administered to pregnant rats and rabbits during organogenesis at exposures 32 and 31 times, respectively, the human exposure at the 100 mg/day therapeutic dose.

    Breast-feeding

    There are no human data available on whether eplerenone is present in human milk, or has effects on milk production or the breast-fed infant. Eplerenone is present in the milk of lactating rats. When a drug is present in animal milk, it is likely the drug will be present in human milk. Previous American Academy of Pediatrics (AAP) recommendations classified spironolactone as compatible with breast-feeding, and it may serve as a possible alternative.

    Infertility, reproductive risk

    Based on animal data, eplerenone may be associated with reproductive risk and male infertility. In mature rats, male fertility was decreased with eplerenone exposure at 17 times the 100 mg/day human therapeutic dose. Reversibility of effects was not evaluated.

    Geriatric

    Eplerenone-induced hyperkalemia can cause life-threatening cardiac arrhythmias; hyperkalemia is more likely to occur in certain patient populations such as the elderly. A subgroup analysis of the EPHESUS trial demonstrated that geriatric patients older than 75 years did not appear to benefit from the use of eplerenone for the treatment of heart failure post-MI and are at increased risk of hyperkalemia due to age-related decreases in creatinine clearance. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, antihypertensive regimens should be individualized to achieve the desired outcome while minimizing adverse effects. Antihypertensives may cause dizziness, postural hypotension, fatigue, and there is an increased risk for falls. There are many drug interactions that can potentiate the effects of antihypertensives. Some agents require a gradual taper to avoid adverse consequences caused by abrupt discontinuation.

    ADVERSE REACTIONS

    Severe

    hyperkalemia / Delayed / 3.4-3.4
    bradycardia / Rapid / Incidence not known
    muscle paralysis / Delayed / Incidence not known
    myocardial infarction / Delayed / Incidence not known

    Moderate

    hypertriglyceridemia / Delayed / 0-15.0
    hyponatremia / Delayed / 2.3-2.3
    vaginal bleeding / Delayed / 0.6-2.1
    hypercholesterolemia / Delayed / 0-1.0
    elevated hepatic enzymes / Delayed / 0-0.7
    hyperuricemia / Delayed / 0.3-0.3
    postmenopausal bleeding / Delayed / Incidence not known
    infertility / Delayed / Incidence not known
    angina / Early / Incidence not known
    edema / Delayed / Incidence not known

    Mild

    dizziness / Early / 3.0-3.0
    cough / Delayed / 2.0-2.0
    diarrhea / Early / 2.0-2.0
    fatigue / Early / 2.0-2.0
    mastalgia / Delayed / 0.3-1.3
    gynecomastia / Delayed / 0.5-1.0
    abdominal pain / Early / 1.0-1.0
    paresthesias / Delayed / Incidence not known
    weakness / Early / Incidence not known
    menstrual irregularity / Delayed / Incidence not known
    amenorrhea / Delayed / Incidence not known
    hirsutism / Delayed / Incidence not known
    headache / Early / Incidence not known
    rash / Early / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Dichloralphenazone; Isometheptene: (Major) Sympathomimetics can antagonize the antihypertensive effects of adrenergic agonists when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Aldesleukin, IL-2: (Moderate) Eplerenone may potentiate the hypotension seen with aldesleukin, IL 2.
    Alemtuzumab: (Moderate) Alemtuzumab may cause hypotension. Careful monitoring of blood pressure and hypotensive symptoms is recommended especially in patients with ischemic heart disease and in patients on antihypertensive agents.
    Alfentanil: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when eplerenone is administered with alfentanil. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
    Aliskiren; Amlodipine: (Moderate) Amlodipine can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Amlodipine can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
    Aliskiren; Valsartan: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin II receptor antagonists (ARBs). Hyperkalemia risk is increased when eplerenone is used with ARBs. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Alprostadil: (Minor) The concomitant use of systemic alprostadil injection and antihypertensive agents, such as eplerenone, may cause additive hypotension. Caution is advised with this combination. Systemic drug interactions with the urethral suppository (MUSE) or alprostadil intracavernous injection are unlikely in most patients because low or undetectable amounts of the drug are found in the peripheral venous circulation following administration. In those men with significant corpora cavernosa venous leakage, hypotension might be more likely. Use caution with in-clinic dosing for erectile dysfunction (ED) and monitor for the effects on blood pressure. In addition, the presence of medications in the circulation that attenuate erectile function may influence the response to alprostadil. However, in clinical trials with alprostadil intracavernous injection, anti-hypertensive agents had no apparent effect on the safety and efficacy of alprostadil.
    Ambrisentan: (Moderate) Although no specific interactions have been documented, ambrisentan has vasodilatory effects and may contribute additive hypotensive effects when given with other antihypertensive agents. Patients receiving ambrisentan in combination with other antihypertensive agents should be monitored for decreases in blood pressure.
    Amifostine: (Major) Patients receiving antihypertensive agents should be closely monitored during amifostine infusions due to additive effects. If possible, patients should not take their antihypertensive medication 24 hours before receiving amifostine. Patients who can not stop their antihypertensive agents should not receive amifostine or be closely monitored during the infusion and, possibly, given lower doses.
    Amiloride: (Contraindicated) Eplerenone should not be used concomitantly with potassium-sparing diuretics (e.g., amiloride, spironolactone, triamterene) because of the increased risk of developing hyperkalemia. The combine use of these medications in patients with hypertension or renal impairment contraindicated.
    Amiloride; Hydrochlorothiazide, HCTZ: (Contraindicated) Eplerenone should not be used concomitantly with potassium-sparing diuretics (e.g., amiloride, spironolactone, triamterene) because of the increased risk of developing hyperkalemia. The combine use of these medications in patients with hypertension or renal impairment contraindicated.
    Amiodarone: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with a CYP3A4 inhibitor in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving a concurrent CYP3A4 inhibitor, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. In addition, measure serum creatinine and serum potassium within 3 to 7 days of initiating a CYP3A4 inhibitor and periodically thereafter. Eplerenone is a CYP3A4 substrate. Amiodarone is a CYP3A4 inhibitor. Coadministration with moderate CYP3A4 inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Amlodipine: (Moderate) Amlodipine can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
    Amlodipine; Atorvastatin: (Moderate) Amlodipine can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
    Amlodipine; Benazepril: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin-converting enzyme (ACE) inhibitors. Hyperkalemia risk is increased when eplerenone is used with ACE inhibitors. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations. (Moderate) Amlodipine can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
    Amlodipine; Celecoxib: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and nonsteroidal antiinflammatory drugs (NSAIDs), and monitor blood pressure. The concomitant use 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. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations. (Moderate) Amlodipine can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
    Amlodipine; Olmesartan: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin II receptor antagonists (ARBs). Hyperkalemia risk is increased when eplerenone is used with ARBs. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations. (Moderate) Amlodipine can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
    Amlodipine; Valsartan: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin II receptor antagonists (ARBs). Hyperkalemia risk is increased when eplerenone is used with ARBs. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations. (Moderate) Amlodipine can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
    Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin II receptor antagonists (ARBs). Hyperkalemia risk is increased when eplerenone is used with ARBs. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations. (Moderate) Amlodipine can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
    Amobarbital: (Moderate) Concurrent use of amobarbital with antihypertensive agents may lead to hypotension. Monitor for decreases in blood pressure during times of coadministration.
    Amoxicillin; Clarithromycin; Omeprazole: (Contraindicated) Coadministration of clarithromycin and eplerenone is contraindicated. Clarithromycin potently inhibits the hepatic CYP3A4 isoenzyme and can increase the serum concentrations of eplerenone. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Amphetamine; Dextroamphetamine Salts: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents may be needed in patients receiving eplerenone and amphetamines. Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents.
    Amyl Nitrite: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Angiotensin II receptor antagonists: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin II receptor antagonists (ARBs). Hyperkalemia risk is increased when eplerenone is used with ARBs. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Angiotensin-converting enzyme inhibitors: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin-converting enzyme (ACE) inhibitors. Hyperkalemia risk is increased when eplerenone is used with ACE inhibitors. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Apomorphine: (Moderate) Use of eplerenone and apomorphine together can increase the hypotensive effects of apomorphine. Monitor blood pressure regularly during use of this combination.
    Apraclonidine: (Minor) Alpha blockers as a class may reduce heart rate and blood pressure. While no specific drug interactions have been identified with systemic agents and apraclonidine during clinical trials, it is theoretically possible that additive blood pressure reductions could occur when apraclonidine is combined with the use of antihypertensive agents. Patients using cardiovascular drugs concomitantly with apraclonidine should have their pulse and blood pressure monitored periodically.
    Aprepitant, Fosaprepitant: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with a CYP3A4 inhibitor in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving a concurrent CYP3A4 inhibitor, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. In addition, measure serum creatinine and serum potassium within 3 to 7 days of initiating a CYP3A4 inhibitor and periodically thereafter. Eplerenone is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days. Coadministration with moderate CYP3A4 inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Aripiprazole: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents.
    Articaine; Epinephrine: (Moderate) Antihypertensives, including eplerenone, antagonize the vasopressor effects of parenteral epinephrine.
    Asenapine: (Moderate) Secondary to alpha-blockade, asenapine can produce vasodilation that may result in additive effects during concurrent use of antihypertensive agents. The potential reduction in blood pressure can precipitate orthostatic hypotension and associated dizziness, tachycardia, and syncope. If concurrent use of asenapine and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
    Atazanavir: (Contraindicated) Coadministration of atazanavir and eplerenone is contraindicated. Atazanavir potently inhibits the hepatic CYP3A4 isoenzyme and can increase the serum concentrations of eplerenone. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Atazanavir; Cobicistat: (Contraindicated) Coadministration of atazanavir and eplerenone is contraindicated. Atazanavir potently inhibits the hepatic CYP3A4 isoenzyme and can increase the serum concentrations of eplerenone. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension. (Contraindicated) Eplerenone is contraindicated for use with cobicistat due to increased eplerenone exposure which increases the risk of developing hyperkalemia and hypotension. Cobicitat is a strong CYP3A4 inhibitor; eplerenone is a sensitive CYP3A4 substrate. Another strong CYP3A4 inhibitor increased serum eplerenone concentrations by roughly 5-fold.
    Azilsartan: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin II receptor antagonists (ARBs). Hyperkalemia risk is increased when eplerenone is used with ARBs. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Azilsartan; Chlorthalidone: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin II receptor antagonists (ARBs). Hyperkalemia risk is increased when eplerenone is used with ARBs. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Baclofen: (Moderate) Baclofen has been associated with hypotension. Concurrent use with baclofen and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
    Benazepril: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin-converting enzyme (ACE) inhibitors. Hyperkalemia risk is increased when eplerenone is used with ACE inhibitors. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Benazepril; Hydrochlorothiazide, HCTZ: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin-converting enzyme (ACE) inhibitors. Hyperkalemia risk is increased when eplerenone is used with ACE inhibitors. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Benzphetamine: (Major) Benzphetamine can increase both systolic and diastolic blood pressure and may counteract the activity of eplerenone. This represents a pharmacodynamic, and not a pharmacokinetic, interaction. Close monitoring of blood pressure, especially in patients who are taking antihypertensive agents, may be needed.
    Berotralstat: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with berotralstat in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving berotralstat, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. Measure serum creatinine and serum potassium within 3 to 7 days of initiating berotralstat and periodically thereafter. Eplerenone is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor. Coadministration with moderate CYP3A4 inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Boceprevir: (Contraindicated) Coadministration of boceprevir and eplerenone is contraindicated. Boceprevir potently inhibits the hepatic CYP3A4 isoenzyme and can increase the serum concentrations of eplerenone. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Bortezomib: (Moderate) Patients on antihypertensive agents receiving bortezomib treatment may require close monitoring of their blood pressure and dosage adjustment of their medication. During clinical trials of bortezomib, hypotension was reported in roughly 12 percent of patients.
    Bosentan: (Moderate) Although no specific interactions have been documented, bosentan has vasodilatory effects and may contribute additive hypotensive effects when given with eplerenone.
    Bupivacaine; Epinephrine: (Moderate) Antihypertensives, including eplerenone, antagonize the vasopressor effects of parenteral epinephrine.
    Bupivacaine; Meloxicam: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and nonsteroidal antiinflammatory drugs (NSAIDs), and monitor blood pressure. The concomitant use 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. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Candesartan: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin II receptor antagonists (ARBs). Hyperkalemia risk is increased when eplerenone is used with ARBs. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Candesartan; Hydrochlorothiazide, HCTZ: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin II receptor antagonists (ARBs). Hyperkalemia risk is increased when eplerenone is used with ARBs. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Captopril: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin-converting enzyme (ACE) inhibitors. Hyperkalemia risk is increased when eplerenone is used with ACE inhibitors. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Captopril; Hydrochlorothiazide, HCTZ: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin-converting enzyme (ACE) inhibitors. Hyperkalemia risk is increased when eplerenone is used with ACE inhibitors. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Carbidopa; Levodopa: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Carbidopa; Levodopa; Entacapone: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Cariprazine: (Moderate) Orthostatic vital signs should be monitored in patients who are at risk for hypotension, such as those receiving cariprazine in combination with antihypertensive agents. Atypical antipsychotics may cause orthostatic hypotension and syncope, most commonly during treatment initiation and dosage increases. Patients should be informed about measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning, or rising slowly from a seated position. Consider a cariprazine dose reduction if hypotension occurs.
    Celecoxib: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and nonsteroidal antiinflammatory drugs (NSAIDs), and monitor blood pressure. The concomitant use 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. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Celecoxib; Tramadol: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and nonsteroidal antiinflammatory drugs (NSAIDs), and monitor blood pressure. The concomitant use 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. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Ceritinib: (Contraindicated) Eplerenone is contraindicated for use with ceritinib due to increased eplerenone exposure which increases the risk of developing hyperkalemia and hypotension. Ceritinib is a strong CYP3A4 inhibitor; eplerenone is a sensitive CYP3A4 substrate. Another strong CYP3A4 inhibitor increased serum eplerenone concentrations by roughly 5-fold.
    Chloramphenicol: (Contraindicated) Coadministration of chloramphenicol and eplerenone is contraindicated. Chloramphenicol potently inhibits the hepatic CYP3A4 isoenzyme and can increase the serum concentrations of eplerenone. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Chloroprocaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and nonsteroidal antiinflammatory drugs (NSAIDs), and monitor blood pressure. The concomitant use 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. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Ciprofloxacin: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with a CYP3A4 inhibitor in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving a concurrent CYP3A4 inhibitor, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. In addition, measure serum creatinine and serum potassium within 3 to 7 days of initiating a CYP3A4 inhibitor and periodically thereafter. Eplerenone is a CYP3A4 substrate. Ciprofloxacin is a CYP3A4 inhibitor. Coadministration with moderate CYP3A4 inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Citric Acid; Potassium Citrate; Sodium Citrate: (Contraindicated) The use of potassium supplements in patients receiving eplerenone for the treatment of hypertension is contraindicated. Concomitant use may increase the risk of hyperkalemia. Minimize the risk of hyperkalemia with proper patient selection and monitoring.
    Clarithromycin: (Contraindicated) Coadministration of clarithromycin and eplerenone is contraindicated. Clarithromycin potently inhibits the hepatic CYP3A4 isoenzyme and can increase the serum concentrations of eplerenone. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Clozapine: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Cobicistat: (Contraindicated) Eplerenone is contraindicated for use with cobicistat due to increased eplerenone exposure which increases the risk of developing hyperkalemia and hypotension. Cobicitat is a strong CYP3A4 inhibitor; eplerenone is a sensitive CYP3A4 substrate. Another strong CYP3A4 inhibitor increased serum eplerenone concentrations by roughly 5-fold.
    Cocaine: (Major) Use of cocaine with antihypertensive agents may increase the antihypertensive effects of the antihypertensive medications or may potentiate cocaine-induced sympathetic stimulation.
    Co-Enzyme Q10, Ubiquinone: (Moderate) Co-enzyme Q10, ubiquinone (CoQ10) may lower blood pressure. CoQ10 use in combination with antihypertensive agents may lead to additional reductions in blood pressure in some individuals. Patients who choose to take CoQ10 concurrently with antihypertensive medications should receive periodic blood pressure monitoring. Patients should be advised to inform their prescriber of their use of CoQ10.
    Conivaptan: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with conivaptan in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving conivaptan, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. Measure serum creatinine and serum potassium within 3 to 7 days of initiating conivaptan and periodically thereafter. Eplerenone is a CYP3A substrate; conivaptan is a moderate CYP3A inhibitor. Coadministration with moderate CYP3A inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Crizotinib: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with crizotinib in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving concurrent crizotinib, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. Measure serum creatinine and serum potassium within 3 to 7 days of initiating crizotinib and periodically thereafter. Eplerenone is a CYP3A4 substrate. Crizotinib is a moderate CYP3A inhibitor. Coadministration with moderate CYP3A4 inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Cyclosporine: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with a CYP3A4 inhibitor in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving a concurrent CYP3A4 inhibitor, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. In addition, measure serum creatinine and serum potassium within 3 to 7 days of initiating a CYP3A4 inhibitor and periodically thereafter. Eplerenone is a CYP3A4 substrate. Cyclosporine is a CYP3A4 inhibitor. Coadministration with moderate CYP3A4 inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Dabrafenib: (Major) The concomitant use of dabrafenib and eplerenone may lead to decreased eplerenone concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of eplerenone efficacy. Dabrafenib is a moderate CYP3A4 inducer and eplerenone is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 65%.
    Danazol: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with a CYP3A4 inhibitor in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving a concurrent CYP3A4 inhibitor, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. In addition, measure serum creatinine and serum potassium within 3 to 7 days of initiating a CYP3A4 inhibitor and periodically thereafter. Eplerenone is a CYP3A4 substrate. Danazol is a CYP3A4 inhibitor. Coadministration with moderate CYP3A4 inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Darunavir: (Contraindicated) Coadministration of darunavir and eplerenone is contraindicated. Darunavir potently inhibits the hepatic CYP3A4 isoenzyme and can increase the serum concentrations of eplerenone. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Darunavir; Cobicistat: (Contraindicated) Coadministration of darunavir and eplerenone is contraindicated. Darunavir potently inhibits the hepatic CYP3A4 isoenzyme and can increase the serum concentrations of eplerenone. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension. (Contraindicated) Eplerenone is contraindicated for use with cobicistat due to increased eplerenone exposure which increases the risk of developing hyperkalemia and hypotension. Cobicitat is a strong CYP3A4 inhibitor; eplerenone is a sensitive CYP3A4 substrate. Another strong CYP3A4 inhibitor increased serum eplerenone concentrations by roughly 5-fold.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Contraindicated) Coadministration of darunavir and eplerenone is contraindicated. Darunavir potently inhibits the hepatic CYP3A4 isoenzyme and can increase the serum concentrations of eplerenone. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension. (Contraindicated) Eplerenone is contraindicated for use with cobicistat due to increased eplerenone exposure which increases the risk of developing hyperkalemia and hypotension. Cobicitat is a strong CYP3A4 inhibitor; eplerenone is a sensitive CYP3A4 substrate. Another strong CYP3A4 inhibitor increased serum eplerenone concentrations by roughly 5-fold.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Contraindicated) Coadministration of ritonavir and eplerenone is contraindicated. Ritonavir potently inhibits the hepatic CYP3A4 isoenzyme and can increase the serum concentrations of eplerenone. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Delavirdine: (Contraindicated) Coadministration of delavirdine and eplerenone is contraindicated. Delavirdine potently inhibits the hepatic CYP3A4 isoenzyme and can increase the serum concentrations of eplerenone. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Contraindicated) The use of potassium supplements in patients receiving eplerenone for the treatment of hypertension is contraindicated. Concomitant use may increase the risk of hyperkalemia. Minimize the risk of hyperkalemia with proper patient selection and monitoring.
    Dextromethorphan; Quinidine: (Moderate) Quinidine can decrease blood pressure and should be used cautiously in patients receiving antihypertensive agents due to the potential for additive hypotension.
    Diazoxide: (Moderate) Additive hypotensive effects can occur with the concomitant administration of diazoxide with other antihypertensive agents. This interaction can be therapeutically advantageous, but dosages must be adjusted accordingly. The manufacturer advises that IV diazoxide should not be administered to patients within 6 hours of receiving other antihypertensive agents.
    Diclofenac: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and nonsteroidal antiinflammatory drugs (NSAIDs), and monitor blood pressure. The concomitant use 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. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Diclofenac; Misoprostol: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and nonsteroidal antiinflammatory drugs (NSAIDs), and monitor blood pressure. The concomitant use 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. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Diethylpropion: (Major) Diethylpropion has vasopressor effects and may limit the benefit of eplerenone. Although leading drug interaction texts differ in the potential for an interaction between diethylpropion and eplerenone, these effects are likely to be clinically significant and have been described in hypertensive patients taking eplerenone.
    Diflunisal: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and nonsteroidal antiinflammatory drugs (NSAIDs), and monitor blood pressure. The concomitant use 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. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Diltiazem: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with a CYP3A4 inhibitor in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving a concurrent CYP3A4 inhibitor, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. In addition, measure serum creatinine and serum potassium within 3 to 7 days of initiating a CYP3A4 inhibitor and periodically thereafter. Eplerenone is a CYP3A4 substrate. Diltiazem is a CYP3A4 inhibitor. Coadministration with moderate CYP3A4 inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Diphenhydramine; Ibuprofen: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and nonsteroidal antiinflammatory drugs (NSAIDs), and monitor blood pressure. The concomitant use 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. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Diphenhydramine; Naproxen: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and nonsteroidal antiinflammatory drugs (NSAIDs), and monitor blood pressure. The concomitant use 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. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Dronedarone: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with a CYP3A4 inhibitor in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving a concurrent CYP3A4 inhibitor, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. In addition, measure serum creatinine and serum potassium within 3 to 7 days of initiating a CYP3A4 inhibitor and periodically thereafter. Eplerenone is a CYP3A4 substrate. Dronedarone is a CYP3A4 inhibitor. Coadministration with moderate CYP3A4 inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Drospirenone: (Moderate) Drospirenone has antimineralocorticoid effects and may increase serum potassium, therefore concurrent use of eplerenone may increase the risk of hyperkalemia, especially in the presence of renal impairment. Monitor serum potassium during the 1st month of drospirenone treatment if eplerenone is used concurrently and thereafter as clinically indicated. Also monitor for any changes in blood pressure, fluid retention, or renal function.
    Drospirenone; Estetrol: (Moderate) Drospirenone has antimineralocorticoid effects and may increase serum potassium, therefore concurrent use of eplerenone may increase the risk of hyperkalemia, especially in the presence of renal impairment. Monitor serum potassium during the 1st month of drospirenone treatment if eplerenone is used concurrently and thereafter as clinically indicated. Also monitor for any changes in blood pressure, fluid retention, or renal function.
    Drospirenone; Estradiol: (Moderate) Drospirenone has antimineralocorticoid effects and may increase serum potassium, therefore concurrent use of eplerenone may increase the risk of hyperkalemia, especially in the presence of renal impairment. Monitor serum potassium during the 1st month of drospirenone treatment if eplerenone is used concurrently and thereafter as clinically indicated. Also monitor for any changes in blood pressure, fluid retention, or renal function.
    Drospirenone; Ethinyl Estradiol: (Moderate) Drospirenone has antimineralocorticoid effects and may increase serum potassium, therefore concurrent use of eplerenone may increase the risk of hyperkalemia, especially in the presence of renal impairment. Monitor serum potassium during the 1st month of drospirenone treatment if eplerenone is used concurrently and thereafter as clinically indicated. Also monitor for any changes in blood pressure, fluid retention, or renal function.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Drospirenone has antimineralocorticoid effects and may increase serum potassium, therefore concurrent use of eplerenone may increase the risk of hyperkalemia, especially in the presence of renal impairment. Monitor serum potassium during the 1st month of drospirenone treatment if eplerenone is used concurrently and thereafter as clinically indicated. Also monitor for any changes in blood pressure, fluid retention, or renal function.
    Duloxetine: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
    Duvelisib: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with duvelisib in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving duvelisib, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. Measure serum creatinine and serum potassium within 3 to 7 days of initiating duvelisib and periodically thereafter. Eplerenone is a CYP3A4 substrate. duvelisib is a moderate CYP3A4 inhibitor. Coadministration with moderate CYP3A4 inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Efavirenz: (Moderate) Efavirenz is a CYP3A4 inducer and may causes a decrease in eplerenone serum concentration. It is not known if the interaction is clinically significant.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Efavirenz is a CYP3A4 inducer and may causes a decrease in eplerenone serum concentration. It is not known if the interaction is clinically significant.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Efavirenz is a CYP3A4 inducer and may causes a decrease in eplerenone serum concentration. It is not known if the interaction is clinically significant.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Contraindicated) Eplerenone is contraindicated for use with cobicistat due to increased eplerenone exposure which increases the risk of developing hyperkalemia and hypotension. Cobicitat is a strong CYP3A4 inhibitor; eplerenone is a sensitive CYP3A4 substrate. Another strong CYP3A4 inhibitor increased serum eplerenone concentrations by roughly 5-fold.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Contraindicated) Eplerenone is contraindicated for use with cobicistat due to increased eplerenone exposure which increases the risk of developing hyperkalemia and hypotension. Cobicitat is a strong CYP3A4 inhibitor; eplerenone is a sensitive CYP3A4 substrate. Another strong CYP3A4 inhibitor increased serum eplerenone concentrations by roughly 5-fold.
    Enalapril, Enalaprilat: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin-converting enzyme (ACE) inhibitors. Hyperkalemia risk is increased when eplerenone is used with ACE inhibitors. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Enalapril; Felodipine: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin-converting enzyme (ACE) inhibitors. Hyperkalemia risk is increased when eplerenone is used with ACE inhibitors. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations. (Moderate) Felodipine can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
    Enalapril; Hydrochlorothiazide, HCTZ: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin-converting enzyme (ACE) inhibitors. Hyperkalemia risk is increased when eplerenone is used with ACE inhibitors. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Encorafenib: (Moderate) Coadministration of encorafenib with eplerenone may result in increased toxicity or decreased efficacy of eplerenone. Eplerenone is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Enflurane: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Ephedrine: (Major) The cardiovascular effects of sympathomimetics, such as ephedrine, may reduce the antihypertensive effects produced by eplerenone. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Ephedrine; Guaifenesin: (Major) The cardiovascular effects of sympathomimetics, such as ephedrine, may reduce the antihypertensive effects produced by eplerenone. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Epinephrine: (Moderate) Antihypertensives, including eplerenone, antagonize the vasopressor effects of parenteral epinephrine.
    Epoprostenol: (Moderate) Epoprostenol can have additive effects when administered with other antihypertensive agents. These effects can be used to therapeutic advantage, but dosage adjustments may be necessary.
    Eprosartan: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin II receptor antagonists (ARBs). Hyperkalemia risk is increased when eplerenone is used with ARBs. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin II receptor antagonists (ARBs). Hyperkalemia risk is increased when eplerenone is used with ARBs. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Erythromycin: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with a CYP3A4 inhibitor in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving a concurrent CYP3A4 inhibitor, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. In addition, measure serum creatinine and serum potassium within 3 to 7 days of initiating a CYP3A4 inhibitor and periodically thereafter. Eplerenone is a CYP3A4 substrate. Erythromycin is a CYP3A4 inhibitor. Coadministration with moderate CYP3A4 inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Erythromycin; Sulfisoxazole: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with a CYP3A4 inhibitor in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving a concurrent CYP3A4 inhibitor, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. In addition, measure serum creatinine and serum potassium within 3 to 7 days of initiating a CYP3A4 inhibitor and periodically thereafter. Eplerenone is a CYP3A4 substrate. Erythromycin is a CYP3A4 inhibitor. Coadministration with moderate CYP3A4 inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Etodolac: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and nonsteroidal antiinflammatory drugs (NSAIDs), and monitor blood pressure. The concomitant use 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. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Etomidate: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Famotidine; Ibuprofen: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and nonsteroidal antiinflammatory drugs (NSAIDs), and monitor blood pressure. The concomitant use 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. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Fedratinib: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with fedratinib in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving fedratinib, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. Measure serum creatinine and serum potassium within 3 to 7 days of initiating fedratinib and periodically thereafter. Eplerenone is a CYP3A4 substrate. fedratinib is a moderate CYP3A4 inhibitor. Coadministration with moderate CYP3A4 inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Felodipine: (Moderate) Felodipine can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
    Fenoprofen: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and nonsteroidal antiinflammatory drugs (NSAIDs), and monitor blood pressure. The concomitant use 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. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Finerenone: (Moderate) Monitor serum potassium concentrations closely if finerenone and eplerenone are used together. Concomitant use may increase the risk of hyperkalemia.
    Fish Oil, Omega-3 Fatty Acids (Dietary Supplements): (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Fluconazole: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with a CYP3A4 inhibitor in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving a concurrent CYP3A4 inhibitor, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. In addition, measure serum creatinine and serum potassium within 3 to 7 days of initiating a CYP3A4 inhibitor and periodically thereafter. Eplerenone is a CYP3A4 substrate. Fluconazole is a CYP3A4 inhibitor. Coadministration with moderate CYP3A4 inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Flurbiprofen: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and nonsteroidal antiinflammatory drugs (NSAIDs), and monitor blood pressure. The concomitant use 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. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Fluvoxamine: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with a CYP3A4 inhibitor in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving a concurrent CYP3A4 inhibitor, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. In addition, measure serum creatinine and serum potassium within 3 to 7 days of initiating a CYP3A4 inhibitor and periodically thereafter. Eplerenone is a CYP3A4 substrate. Fluvoxamine is a CYP3A4 inhibitor. Coadministration with moderate CYP3A4 inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Fosamprenavir: (Contraindicated) Coadministration of fosamprenavir and eplerenone is contraindicated. Fosamprenavir potently inhibits the hepatic CYP3A4 isoenzyme and can increase the serum concentrations of eplerenone. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Fosinopril: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin-converting enzyme (ACE) inhibitors. Hyperkalemia risk is increased when eplerenone is used with ACE inhibitors. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin-converting enzyme (ACE) inhibitors. Hyperkalemia risk is increased when eplerenone is used with ACE inhibitors. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Fospropofol: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    General anesthetics: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Grapefruit juice: (Contraindicated) Concomitant use of grapefruit or grapefruit juice and eplerenone is contraindicated. Grapefruit potently inhibits the hepatic CYP3A4 isoenzyme and may increase serum eplerenone concentrations by about 25% and, hence, can increase the risk of developing eplerenone-induced hyperkalemia and hypotension.
    Guaifenesin; Potassium Guaiacolsulfonate: (Contraindicated) The use of potassium supplements in patients receiving eplerenone for the treatment of hypertension is contraindicated. Concomitant use may increase the risk of hyperkalemia. Minimize the risk of hyperkalemia with proper patient selection and monitoring.
    Haloperidol: (Moderate) In general, haloperidol should be used cautiously with antihypertensive agents due to the possibility of additive hypotension.
    Halothane: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Hetastarch; Dextrose; Electrolytes: (Contraindicated) The use of potassium supplements in patients receiving eplerenone for the treatment of hypertension is contraindicated. Concomitant use may increase the risk of hyperkalemia. Minimize the risk of hyperkalemia with proper patient selection and monitoring.
    Hydralazine; Isosorbide Dinitrate, ISDN: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Hydrochlorothiazide, HCTZ; Moexipril: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin-converting enzyme (ACE) inhibitors. Hyperkalemia risk is increased when eplerenone is used with ACE inhibitors. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Hydrocodone; Ibuprofen: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and nonsteroidal antiinflammatory drugs (NSAIDs), and monitor blood pressure. The concomitant use 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. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Hydrocodone; Potassium Guaiacolsulfonate: (Contraindicated) The use of potassium supplements in patients receiving eplerenone for the treatment of hypertension is contraindicated. Concomitant use may increase the risk of hyperkalemia. Minimize the risk of hyperkalemia with proper patient selection and monitoring.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Contraindicated) The use of potassium supplements in patients receiving eplerenone for the treatment of hypertension is contraindicated. Concomitant use may increase the risk of hyperkalemia. Minimize the risk of hyperkalemia with proper patient selection and monitoring.
    Ibritumomab Tiuxetan: (Contraindicated) Eplerenone should not be used concomitantly with potassium supplements (including dietary salt substitutes containing potassium) because of the increased risk of developing hyperkalemia. The use of eplerenone in hypertensive patients treated with these medications is contraindicated. When medically necessary to replace losses, use potassium phosphates cautiously with eplerenone, as both drugs increase serum potassium concentrations. Those at risk for hyperkalemia include elderly patients or patients with impaired renal function. Patients at risk for hyperkalemia include elderly patients or patients with impaired renal function. Patients should have serum potassium and other electrolyte concentration determinations at periodic intervals. (Contraindicated) The use of potassium supplements in patients receiving eplerenone for the treatment of hypertension is contraindicated. Concomitant use may increase the risk of hyperkalemia. Minimize the risk of hyperkalemia with proper patient selection and monitoring.
    Ibuprofen: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and nonsteroidal antiinflammatory drugs (NSAIDs), and monitor blood pressure. The concomitant use 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. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Ibuprofen; Oxycodone: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and nonsteroidal antiinflammatory drugs (NSAIDs), and monitor blood pressure. The concomitant use 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. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Ibuprofen; Pseudoephedrine: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and nonsteroidal antiinflammatory drugs (NSAIDs), and monitor blood pressure. The concomitant use 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. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Idelalisib: (Contraindicated) Coadministration of idelalisib and eplerenone is contraindicated. Idelalisib potently inhibits the hepatic CYP3A4 isoenzyme and can increase the serum concentrations of eplerenone. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Iloperidone: (Moderate) Secondary to alpha-blockade, iloperidone can produce vasodilation that may result in additive effects during concurrent use with antihypertensive agents. The potential reduction in blood pressure can precipitate orthostatic hypotension and associated dizziness, tachycardia, and syncope. If concurrent use of iloperidone and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
    Iloprost: (Moderate) Further reductions in blood pressure may occur when inhaled iloprost is administered to patients receiving other antihypertensive agents.
    Imatinib: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with a CYP3A4 inhibitor in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving a concurrent CYP3A4 inhibitor, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. In addition, measure serum creatinine and serum potassium within 3 to 7 days of initiating a CYP3A4 inhibitor and periodically thereafter. Eplerenone is a CYP3A4 substrate. Imatinib is a CYP3A4 inhibitor. Coadministration with moderate CYP3A4 inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Indinavir: (Contraindicated) Coadministration of indinavir and eplerenone is contraindicated. Indinavir potently inhibits the hepatic CYP3A4 isoenzyme and can increase the serum concentrations of eplerenone. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Indomethacin: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and nonsteroidal antiinflammatory drugs (NSAIDs), and monitor blood pressure. The concomitant use 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. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Intravenous Lipid Emulsions: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Iodine; Potassium Iodide, KI: (Contraindicated) The use of potassium supplements in patients receiving eplerenone for the treatment of hypertension is contraindicated. Concomitant use may increase the risk of hyperkalemia. Minimize the risk of hyperkalemia with proper patient selection and monitoring.
    Irbesartan: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin II receptor antagonists (ARBs). Hyperkalemia risk is increased when eplerenone is used with ARBs. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Irbesartan; Hydrochlorothiazide, HCTZ: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin II receptor antagonists (ARBs). Hyperkalemia risk is increased when eplerenone is used with ARBs. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Isavuconazonium: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with a CYP3A4 inhibitor in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving a concurrent CYP3A4 inhibitor, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. In addition, measure serum creatinine and serum potassium within 3 to 7 days of initiating a CYP3A4 inhibitor and periodically thereafter. Eplerenone is a CYP3A4 substrate. Isavuconazonium is a CYP3A4 inhibitor. Coadministration with moderate CYP3A4 inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Isoflurane: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Isoproterenol: (Moderate) The pharmacologic effects of isoproterenol may cause an increase in blood pressure. If isoproterenol is used concomitantly with antihypertensives, the blood pressure should be monitored as the administration of isoproterenol can compromise the effectiveness of antihypertensive agents.
    Isosorbide Dinitrate, ISDN: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Isosorbide Mononitrate: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Isradipine: (Moderate) Isradipine can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
    Itraconazole: (Contraindicated) Eplerenone is contraindicated for use during and for 2 weeks after itraconazole therapy due to increased eplerenone exposure which increases the risk of developing hyperkalemia and hypotension. Itraconazole is a strong CYP3A4 inhibitor; eplerenone is a sensitive CYP3A4 substrate. Another strong CYP3A4 inhibitor increased serum eplerenone concentrations by roughly 5-fold.
    Ketamine: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Ketoconazole: (Contraindicated) Concomitant use of ketoconazole and eplerenone is contraindicated. Ketoconazole, due to the inhibition of hepatic CYP3A4 isoenzymes, increases serum eplerenone concentrations by roughly 5-fold and, hence, increases the risk of developing hyperkalemia and hypotension.
    Ketoprofen: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and nonsteroidal antiinflammatory drugs (NSAIDs), and monitor blood pressure. The concomitant use 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. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Ketorolac: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and nonsteroidal antiinflammatory drugs (NSAIDs), and monitor blood pressure. The concomitant use 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. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Lansoprazole; Amoxicillin; Clarithromycin: (Contraindicated) Coadministration of clarithromycin and eplerenone is contraindicated. Clarithromycin potently inhibits the hepatic CYP3A4 isoenzyme and can increase the serum concentrations of eplerenone. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Lansoprazole; Naproxen: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and nonsteroidal antiinflammatory drugs (NSAIDs), and monitor blood pressure. The concomitant use 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. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Lefamulin: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with oral lefamulin in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving oral lefamulin, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. Measure serum creatinine and serum potassium within 3 to 7 days of initiating oral lefamulin and periodically thereafter. Eplerenone is a CYP3A4 substrate. Oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Coadministration with moderate CYP3A4 inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Lesinurad: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of eplerenone; monitor for potential reduction in efficacy. Eplerenone is a sensitive CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Lesinurad; Allopurinol: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of eplerenone; monitor for potential reduction in efficacy. Eplerenone is a sensitive CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Letermovir: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with a CYP3A4 inhibitor in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving a concurrent CYP3A4 inhibitor, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. In addition, measure serum creatinine and serum potassium within 3 to 7 days of initiating a CYP3A4 inhibitor and periodically thereafter. Eplerenone is a CYP3A4 substrate. Coadministration is contraindicated in patients also receiving cyclosporine, because the magnitude of the interaction may be amplified. Eplerenone is predominately metabolized by CYP3A. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor. Concurrent administration with a strong CYP3A inhibitor increased the maximum plasma concentration (Cmax) and exposure (AUC) of eplerenone by 1.7- and 5.4-fold, respectively. When given with a moderate CYP3A inhibitor, the Cmax and AUC of eplerenone increased by 40% to 60% and 100% to 190%, respectively.
    Levamlodipine: (Moderate) Amlodipine can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
    Levodopa: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Levoketoconazole: (Contraindicated) Concomitant use of ketoconazole and eplerenone is contraindicated. Ketoconazole, due to the inhibition of hepatic CYP3A4 isoenzymes, increases serum eplerenone concentrations by roughly 5-fold and, hence, increases the risk of developing hyperkalemia and hypotension.
    Lidocaine; Epinephrine: (Moderate) Antihypertensives, including eplerenone, antagonize the vasopressor effects of parenteral epinephrine.
    Lisdexamfetamine: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents may be needed in patients receiving eplerenone and lisdexamfetamine. Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents.
    Lisinopril: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin-converting enzyme (ACE) inhibitors. Hyperkalemia risk is increased when eplerenone is used with ACE inhibitors. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Lisinopril; Hydrochlorothiazide, HCTZ: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin-converting enzyme (ACE) inhibitors. Hyperkalemia risk is increased when eplerenone is used with ACE inhibitors. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Lithium: (Major) Although no drug interaction studies are known to have been conducted with eplerenone and lithium to date, lithium toxicity has been reported in patients receiving lithium concomitantly with diuretics (e.g., thiazides, spironolactone, triamterene) and ACE inhibitors. Through its effects on aldosterone, eplerenone promotes natruresis and therefore may stimulate a reflex increase in lithium and sodium reabsorption in the kidney. Therefore, if eplerenone is administered concomitantly with lithium, serum lithium levels should be monitored frequently.
    Lonafarnib: (Contraindicated) Eplerenone is contraindicated for use with lonafarnib due to increased eplerenone exposure which increases the risk of developing hyperkalemia and hypotension. Eplerenone is a sensitive CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Another strong CYP3A4 inhibitor increased serum eplerenone concentrations by roughly 5-fold.
    Lopinavir; Ritonavir: (Contraindicated) Coadministration of ritonavir and eplerenone is contraindicated. Ritonavir potently inhibits the hepatic CYP3A4 isoenzyme and can increase the serum concentrations of eplerenone. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Losartan: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin II receptor antagonists (ARBs). Hyperkalemia risk is increased when eplerenone is used with ARBs. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Losartan; Hydrochlorothiazide, HCTZ: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin II receptor antagonists (ARBs). Hyperkalemia risk is increased when eplerenone is used with ARBs. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Lovastatin; Niacin: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
    Lumacaftor; Ivacaftor: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of eplerenone by decreasing its systemic exposure. If used together, monitor blood pressure closely. Eplerenone is a CYP3A4 substrate. Lumacaftor is a strong CYP3A inducer.
    Lumacaftor; Ivacaftor: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of eplerenone by decreasing its systemic exposure. If used together, monitor blood pressure closely. Eplerenone is a CYP3A4 substrate. Lumacaftor is a strong CYP3A inducer.
    Lurasidone: (Moderate) Due to the antagonism of lurasidone at alpha-1 adrenergic receptors, the drug may enhance the hypotensive effects of alpha-blockers and other antihypertensive agents. If concurrent use of lurasidone and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
    Meclofenamate Sodium: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and nonsteroidal antiinflammatory drugs (NSAIDs), and monitor blood pressure. The concomitant use 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. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Mefenamic Acid: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and nonsteroidal antiinflammatory drugs (NSAIDs), and monitor blood pressure. The concomitant use 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. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Meloxicam: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and nonsteroidal antiinflammatory drugs (NSAIDs), and monitor blood pressure. The concomitant use 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. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Methamphetamine: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like eplerenone. Close monitoring of blood pressure is advised.
    Methohexital: (Moderate) Concurrent use of methohexital and antihypertensive agents increases the risk of developing hypotension.
    Methylphenidate Derivatives: (Moderate) Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidate derivatives and antihypertensive agents, particularly during initial coadministration and after dosage increases of methylphenidate derivatives. Methylphenidate derivatives can reduce the hypotensive effect of antihypertensive agents such as eplerenone.
    Mifepristone: (Contraindicated) Coadministration of mifepristone and eplerenone is contraindicated. Mifepristone potently inhibits the hepatic CYP3A4 isoenzyme and can increase the serum concentrations of eplerenone. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Milrinone: (Moderate) Concurrent administration of antihypertensive agents could lead to additive hypotension when administered with milrinone. Titrate milrinone dosage according to hemodynamic response.
    Mitotane: (Moderate) Use caution if mitotane and eplerenone are used concomitantly, and monitor for decreased efficacy of eplerenone and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and eplerenone is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of eplerenone. Coadministration with another strong CYP3A inducer, St. John's Wort, resulted in a small (30%) decrease in the AUC of eplerenone.
    Moexipril: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin-converting enzyme (ACE) inhibitors. Hyperkalemia risk is increased when eplerenone is used with ACE inhibitors. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Monoamine oxidase inhibitors: (Moderate) Additive hypotensive effects may be seen when MAOIs are combined with antihypertensives or medications with hypotensive properties. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with eplerenone.
    Nabumetone: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and nonsteroidal antiinflammatory drugs (NSAIDs), and monitor blood pressure. The concomitant use 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. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Naproxen: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and nonsteroidal antiinflammatory drugs (NSAIDs), and monitor blood pressure. The concomitant use 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. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Naproxen; Esomeprazole: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and nonsteroidal antiinflammatory drugs (NSAIDs), and monitor blood pressure. The concomitant use 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. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Naproxen; Pseudoephedrine: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and nonsteroidal antiinflammatory drugs (NSAIDs), and monitor blood pressure. The concomitant use 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. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Nebivolol; Valsartan: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin II receptor antagonists (ARBs). Hyperkalemia risk is increased when eplerenone is used with ARBs. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Nefazodone: (Contraindicated) Coadministration of nefazodone and eplerenone is contraindicated. Nefazodone potently inhibits the hepatic CYP3A4 isoenzyme and can increase the serum concentrations of eplerenone. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Nelfinavir: (Contraindicated) Coadministration of nelfinavir and eplerenone is contraindicated. Nelfinavir potently inhibits the hepatic CYP3A4 isoenzyme and can increase the serum concentrations of eplerenone. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Nesiritide, BNP: (Major) The potential for hypotension may be increased when coadministering nesiritide with antihypertensive agents.
    Netupitant, Fosnetupitant; Palonosetron: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with a CYP3A4 inhibitor in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving a concurrent CYP3A4 inhibitor, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. In addition, measure serum creatinine and serum potassium within 3 to 7 days of initiating a CYP3A4 inhibitor and periodically thereafter. Eplerenone is a CYP3A4 substrate. Netupitant is a CYP3A4 inhibitor. Coadministration with moderate CYP3A4 inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Niacin, Niacinamide: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
    Niacin; Simvastatin: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
    Nicardipine: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with a CYP3A4 inhibitor in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving a concurrent CYP3A4 inhibitor, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. In addition, measure serum creatinine and serum potassium within 3 to 7 days of initiating a CYP3A4 inhibitor and periodically thereafter. Eplerenone is a CYP3A4 substrate. Nicardipine is a CYP3A4 inhibitor. Coadministration with moderate CYP3A4 inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Nifedipine: (Moderate) Nifedipine can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
    Nilotinib: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with a CYP3A4 inhibitor in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving a concurrent CYP3A4 inhibitor, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. In addition, measure serum creatinine and serum potassium within 3 to 7 days of initiating a CYP3A4 inhibitor and periodically thereafter. Eplerenone is a CYP3A4 substrate. Nilotinib is a CYP3A4 inhibitor. Coadministration with moderate CYP3A4 inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Nimodipine: (Moderate) Nimodipine can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
    Nirmatrelvir; Ritonavir: (Contraindicated) Coadministration of ritonavir and eplerenone is contraindicated. Ritonavir potently inhibits the hepatic CYP3A4 isoenzyme and can increase the serum concentrations of eplerenone. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension. (Major) Avoid concomitant use of ritonavir-boosted nirmatrelvir and eplerenone and consider an alternative COVID-19 therapy. Coadministration may increase eplerenone exposure resulting in increased toxicity. Eplerenone is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor.
    Nisoldipine: (Moderate) Nisoldipine can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
    Nitrates: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Nitroglycerin: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Nitroprusside: (Moderate) Additive hypotensive effects may occur when nitroprusside is used concomitantly with other antihypertensive agents. Dosages should be adjusted carefully, according to blood pressure.
    Nonsteroidal antiinflammatory drugs: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and nonsteroidal antiinflammatory drugs (NSAIDs), and monitor blood pressure. The concomitant use 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. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Olanzapine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Olanzapine; Fluoxetine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Olanzapine; Samidorphan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Olmesartan: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin II receptor antagonists (ARBs). Hyperkalemia risk is increased when eplerenone is used with ARBs. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin II receptor antagonists (ARBs). Hyperkalemia risk is increased when eplerenone is used with ARBs. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations. (Moderate) Amlodipine can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
    Olmesartan; Hydrochlorothiazide, HCTZ: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin II receptor antagonists (ARBs). Hyperkalemia risk is increased when eplerenone is used with ARBs. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Ombitasvir; Paritaprevir; Ritonavir: (Contraindicated) Coadministration of ritonavir and eplerenone is contraindicated. Ritonavir potently inhibits the hepatic CYP3A4 isoenzyme and can increase the serum concentrations of eplerenone. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Oritavancin: (Moderate) Eplerenone is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of eplerenone may be reduced if these drugs are administered concurrently.
    Oxaprozin: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and nonsteroidal antiinflammatory drugs (NSAIDs), and monitor blood pressure. The concomitant use 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. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Oxymetazoline: (Major) The vasoconstricting actions of oxymetazoline, an alpha adrenergic agonist, may reduce the antihypertensive effects produced by eplerenone. If these drugs are used together, closely monitor for changes in blood pressure.
    Paliperidone: (Moderate) Paliperidone may cause orthostatic hypotension, thereby enhancing the hypotensive effects of antihypertensive agents. Orthostatic vital signs should be monitored in patients receiving paliperidone and eplerenone who are susceptible to hypotension.
    Penicillin G: (Minor) Potassium-containing medications, such as penicillin G potassium, may potentially increase the risk of hyperkalemia in patients receiving eplerenone. Monitor serum potassium if eplerenone is used concurrently with drugs with potential to induce hyperkalemia.
    Pentoxifylline: (Moderate) Pentoxifylline has been used concurrently with antihypertensive drugs (beta blockers, diuretics) without observed problems. Small decreases in blood pressure have been observed in some patients treated with pentoxifylline; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensives. If indicated, dosage of the antihypertensive agents should be reduced.
    Perindopril: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin-converting enzyme (ACE) inhibitors. Hyperkalemia risk is increased when eplerenone is used with ACE inhibitors. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Perindopril; Amlodipine: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin-converting enzyme (ACE) inhibitors. Hyperkalemia risk is increased when eplerenone is used with ACE inhibitors. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations. (Moderate) Amlodipine can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
    Piroxicam: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and nonsteroidal antiinflammatory drugs (NSAIDs), and monitor blood pressure. The concomitant use 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. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Posaconazole: (Contraindicated) Coadministration of posaconazole and eplerenone is contraindicated. Posaconazole potently inhibits the hepatic CYP3A4 isoenzyme and can increase the serum concentrations of eplerenone. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Potassium Acetate: (Contraindicated) The use of potassium supplements in patients receiving eplerenone for the treatment of hypertension is contraindicated. Concomitant use may increase the risk of hyperkalemia. Minimize the risk of hyperkalemia with proper patient selection and monitoring.
    Potassium Bicarbonate: (Contraindicated) The use of potassium supplements in patients receiving eplerenone for the treatment of hypertension is contraindicated. Concomitant use may increase the risk of hyperkalemia. Minimize the risk of hyperkalemia with proper patient selection and monitoring.
    Potassium Chloride: (Contraindicated) The use of potassium supplements in patients receiving eplerenone for the treatment of hypertension is contraindicated. Concomitant use may increase the risk of hyperkalemia. Minimize the risk of hyperkalemia with proper patient selection and monitoring.
    Potassium Citrate: (Contraindicated) The use of potassium supplements in patients receiving eplerenone for the treatment of hypertension is contraindicated. Concomitant use may increase the risk of hyperkalemia. Minimize the risk of hyperkalemia with proper patient selection and monitoring.
    Potassium Citrate; Citric Acid: (Contraindicated) The use of potassium supplements in patients receiving eplerenone for the treatment of hypertension is contraindicated. Concomitant use may increase the risk of hyperkalemia. Minimize the risk of hyperkalemia with proper patient selection and monitoring.
    Potassium Gluconate: (Contraindicated) The use of potassium supplements in patients receiving eplerenone for the treatment of hypertension is contraindicated. Concomitant use may increase the risk of hyperkalemia. Minimize the risk of hyperkalemia with proper patient selection and monitoring.
    Potassium Iodide, KI: (Contraindicated) The use of potassium supplements in patients receiving eplerenone for the treatment of hypertension is contraindicated. Concomitant use may increase the risk of hyperkalemia. Minimize the risk of hyperkalemia with proper patient selection and monitoring.
    Potassium Phosphate: (Contraindicated) Eplerenone should not be used concomitantly with potassium supplements (including dietary salt substitutes containing potassium) because of the increased risk of developing hyperkalemia. The use of eplerenone in hypertensive patients treated with these medications is contraindicated. When medically necessary to replace losses, use potassium phosphates cautiously with eplerenone, as both drugs increase serum potassium concentrations. Those at risk for hyperkalemia include elderly patients or patients with impaired renal function. Patients at risk for hyperkalemia include elderly patients or patients with impaired renal function. Patients should have serum potassium and other electrolyte concentration determinations at periodic intervals.
    Potassium Phosphate; Sodium Phosphate: (Contraindicated) Eplerenone should not be used concomitantly with potassium supplements (including dietary salt substitutes containing potassium) because of the increased risk of developing hyperkalemia. The use of eplerenone in hypertensive patients treated with these medications is contraindicated. When medically necessary to replace losses, use potassium phosphates cautiously with eplerenone, as both drugs increase serum potassium concentrations. Those at risk for hyperkalemia include elderly patients or patients with impaired renal function. Patients at risk for hyperkalemia include elderly patients or patients with impaired renal function. Patients should have serum potassium and other electrolyte concentration determinations at periodic intervals.
    Potassium: (Contraindicated) The use of potassium supplements in patients receiving eplerenone for the treatment of hypertension is contraindicated. Concomitant use may increase the risk of hyperkalemia. Minimize the risk of hyperkalemia with proper patient selection and monitoring.
    Potassium-sparing diuretics: (Contraindicated) Eplerenone should not be used concomitantly with potassium-sparing diuretics (e.g., amiloride, spironolactone, triamterene) because of the increased risk of developing hyperkalemia. The combine use of these medications in patients with hypertension or renal impairment contraindicated.
    Prazosin: (Moderate) Prazosin is well-known to produce a 'first-dose' phenomenon. Some patients develop significant hypotension shortly after administration of the first dose. The first dose response (acute postural hypotension) of prazosin may be exaggerated in patients who are receiving beta-adrenergic blockers, diuretics, or other antihypertensive agents. Concomitant administration of prazosin with other antihypertensive agents is not prohibited, however. This can be therapeutically advantageous, but lower dosages of each agent should be used.
    Prilocaine; Epinephrine: (Moderate) Antihypertensives, including eplerenone, antagonize the vasopressor effects of parenteral epinephrine.
    Procainamide: (Moderate) Procainamide can decrease blood pressure and should be used cautiously in patients receiving antihypertensive agents. Intravenous administration of procainamide is more likely to cause hypotensive effects.
    Procaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Propofol: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Quinapril: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin-converting enzyme (ACE) inhibitors. Hyperkalemia risk is increased when eplerenone is used with ACE inhibitors. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Quinapril; Hydrochlorothiazide, HCTZ: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin-converting enzyme (ACE) inhibitors. Hyperkalemia risk is increased when eplerenone is used with ACE inhibitors. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Quinidine: (Moderate) Quinidine can decrease blood pressure and should be used cautiously in patients receiving antihypertensive agents due to the potential for additive hypotension.
    Quinine: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with a CYP3A4 inhibitor in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving a concurrent CYP3A4 inhibitor, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. In addition, measure serum creatinine and serum potassium within 3 to 7 days of initiating a CYP3A4 inhibitor and periodically thereafter. Eplerenone is a CYP3A4 substrate. Quinine is a CYP3A4 inhibitor. Coadministration with moderate CYP3A4 inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Ramipril: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin-converting enzyme (ACE) inhibitors. Hyperkalemia risk is increased when eplerenone is used with ACE inhibitors. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Rasagiline: (Moderate) Orthostatic hypotension has been reported during administration of rasagiline. Therefore, caution is advised during concurrent use with antihypertensive agents. Rasagiline is a selective MAO-B inhibitor at manufacturer recommended doses; therefore, serious hypertensive reactions with agents affecting catecholamine release (e.g., guanabenz, reserpine, guanethidine) are unlikely. Nevertheless, patients receiving rasagiline in combination with an antihypertensive should be instructed to rise slowly from a sitting position, and to report syncope, and changes in heart rate or blood pressure to their health care provider.
    Ribociclib: (Contraindicated) Eplerenone is contraindicated for use with ribociclib due to increased eplerenone exposure which increases the risk of developing hyperkalemia and hypotension. Ribociclib is a strong CYP3A4 inhibitor; eplerenone is a sensitive CYP3A4 substrate. Another strong CYP3A4 inhibitor increased serum eplerenone concentrations by roughly 5-fold.
    Ribociclib; Letrozole: (Contraindicated) Eplerenone is contraindicated for use with ribociclib due to increased eplerenone exposure which increases the risk of developing hyperkalemia and hypotension. Ribociclib is a strong CYP3A4 inhibitor; eplerenone is a sensitive CYP3A4 substrate. Another strong CYP3A4 inhibitor increased serum eplerenone concentrations by roughly 5-fold.
    Risperidone: (Moderate) Risperidone may induce orthostatic hypotension and thus enhance the hypotensive effects of antihypertensive agents. Lower initial doses or slower dose titration of risperidone may be necessary in patients receiving antihypertensive agents concomitantly.
    Ritonavir: (Contraindicated) Coadministration of ritonavir and eplerenone is contraindicated. Ritonavir potently inhibits the hepatic CYP3A4 isoenzyme and can increase the serum concentrations of eplerenone. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Rofecoxib: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and nonsteroidal antiinflammatory drugs (NSAIDs), and monitor blood pressure. The concomitant use 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. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Sacubitril; Valsartan: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin II receptor antagonists (ARBs). Hyperkalemia risk is increased when eplerenone is used with ARBs. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Saquinavir: (Contraindicated) Coadministration of saquinavir boosted with ritonavir and eplerenone is contraindicated. Saquinavir boosted with ritonavir potently inhibits the hepatic CYP3A4 isoenzyme and can increase the serum concentrations of eplerenone. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Sevoflurane: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
    Silodosin: (Moderate) During clinical trials with silodosin, the incidence of dizziness and orthostatic hypotension was higher in patients receiving concomitant antihypertensive treatment. Thus, caution is advisable when silodosin is administered with antihypertensive agents.
    Simeprevir: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with a CYP3A4 inhibitor in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving a concurrent CYP3A4 inhibitor, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. In addition, measure serum creatinine and serum potassium within 3 to 7 days of initiating a CYP3A4 inhibitor and periodically thereafter. Eplerenone is a CYP3A4 substrate. Simeprevir is a CYP3A4 inhibitor. Coadministration with moderate CYP3A4 inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Sodium Sulfate; Magnesium Sulfate; Potassium Chloride: (Contraindicated) The use of potassium supplements in patients receiving eplerenone for the treatment of hypertension is contraindicated. Concomitant use may increase the risk of hyperkalemia. Minimize the risk of hyperkalemia with proper patient selection and monitoring.
    Spironolactone: (Contraindicated) Eplerenone should not be used concomitantly with potassium-sparing diuretics (e.g., amiloride, spironolactone, triamterene) because of the increased risk of developing hyperkalemia. The combine use of these medications in patients with hypertension or renal impairment contraindicated.
    Spironolactone; Hydrochlorothiazide, HCTZ: (Contraindicated) Eplerenone should not be used concomitantly with potassium-sparing diuretics (e.g., amiloride, spironolactone, triamterene) because of the increased risk of developing hyperkalemia. The combine use of these medications in patients with hypertension or renal impairment contraindicated.
    St. John's Wort, Hypericum perforatum: (Minor) St. John's Wort is a CYP3A4 inducer and causes a small (30%) decrease in eplerenone AUC. It is not known if the interaction is clinically significant. Advise patients to avoid this herbal dietary supplement. If a patient is using St. John's Wort with eplerenone, monitor the patient closely for evidence of decreased efficacy.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Major) Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially with pre-existing risk factors for hyperkalemia. Trimethoprim should be used with caution with other drugs known to cause significant hyperkalemia such as eplerenone.
    Sulindac: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and nonsteroidal antiinflammatory drugs (NSAIDs), and monitor blood pressure. The concomitant use 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. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Sumatriptan; Naproxen: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and nonsteroidal antiinflammatory drugs (NSAIDs), and monitor blood pressure. The concomitant use 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. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Telithromycin: (Contraindicated) Coadministration of telithromycin and eplerenone is contraindicated. Telithromycin potently inhibits the hepatic CYP3A4 isoenzyme and can increase the serum concentrations of eplerenone. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Telmisartan: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin II receptor antagonists (ARBs). Hyperkalemia risk is increased when eplerenone is used with ARBs. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Telmisartan; Amlodipine: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin II receptor antagonists (ARBs). Hyperkalemia risk is increased when eplerenone is used with ARBs. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations. (Moderate) Amlodipine can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
    Telmisartan; Hydrochlorothiazide, HCTZ: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin II receptor antagonists (ARBs). Hyperkalemia risk is increased when eplerenone is used with ARBs. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Tetrabenazine: (Moderate) Tetrabenazine may induce orthostatic hypotension and thus enhance the hypotensive effects of antihypertensive agents. Lower initial doses or slower dose titration of tetrabenazine may be necessary in patients receiving antihypertensive agents concomitantly.
    Tetracaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of tetracaine and antihypertensive agents.
    Thiopental: (Moderate) Concurrent use of thiopental and alpha-blockers or antihypertensive agents increases the risk of developing hypotension.
    Thiothixene: (Moderate) Thiothixene should be used cautiously in patients receiving antihypertensive agents. Additive hypotensive effects are possible.
    Tipranavir: (Contraindicated) Coadministration of tipranavir and eplerenone is contraindicated. Tipranavir potently inhibits the hepatic CYP3A4 isoenzyme and can increase the serum concentrations of eplerenone. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Tizanidine: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Tolmetin: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and nonsteroidal antiinflammatory drugs (NSAIDs), and monitor blood pressure. The concomitant use 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. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Trandolapril: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin-converting enzyme (ACE) inhibitors. Hyperkalemia risk is increased when eplerenone is used with ACE inhibitors. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Trandolapril; Verapamil: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with a CYP3A4 inhibitor in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving a concurrent CYP3A4 inhibitor, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. In addition, measure serum creatinine and serum potassium within 3 to 7 days of initiating a CYP3A4 inhibitor and periodically thereafter. Eplerenone is a CYP3A4 substrate. Verapamil is a CYP3A4 inhibitor. Coadministration with moderate CYP3A4 inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension. (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin-converting enzyme (ACE) inhibitors. Hyperkalemia risk is increased when eplerenone is used with ACE inhibitors. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Trazodone: (Minor) Due to additive hypotensive effects, patients receiving antihypertensive agents concurrently with trazodone may have excessive hypotension. Decreased dosage of the antihypertensive agent may be required when given with trazodone.
    Triamterene: (Contraindicated) Eplerenone should not be used concomitantly with potassium-sparing diuretics (e.g., amiloride, spironolactone, triamterene) because of the increased risk of developing hyperkalemia. The combine use of these medications in patients with hypertension or renal impairment contraindicated.
    Triamterene; Hydrochlorothiazide, HCTZ: (Contraindicated) Eplerenone should not be used concomitantly with potassium-sparing diuretics (e.g., amiloride, spironolactone, triamterene) because of the increased risk of developing hyperkalemia. The combine use of these medications in patients with hypertension or renal impairment contraindicated.
    Trimethoprim: (Major) Trimethoprim has a potassium-sparing effect on the distal nephron and may induce hyperkalemia, especially with pre-existing risk factors for hyperkalemia. Trimethoprim should be used with caution with other drugs known to cause significant hyperkalemia such as eplerenone.
    Tucatinib: (Contraindicated) Eplerenone is contraindicated for use with tucatinib due to increased eplerenone exposure which increases the risk of developing hyperkalemia and hypotension. tucatinib is a strong CYP3A4 inhibitor; eplerenone is a sensitive CYP3A4 substrate. Another strong CYP3A4 inhibitor increased serum eplerenone concentrations by roughly 5-fold.
    Valdecoxib: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and nonsteroidal antiinflammatory drugs (NSAIDs), and monitor blood pressure. The concomitant use 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. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Valsartan: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin II receptor antagonists (ARBs). Hyperkalemia risk is increased when eplerenone is used with ARBs. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Valsartan; Hydrochlorothiazide, HCTZ: (Major) Monitor serum potassium and serum creatinine concentrations within 3 to 7 days of initiating coadministration of eplerenone and angiotensin II receptor antagonists (ARBs). Hyperkalemia risk is increased when eplerenone is used with ARBs. Patients who develop hyperkalemia may continue eplerenone with proper dose adjustment; eplerenone dose reduction decreases potassium concentrations.
    Vemurafenib: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as eplerenone, could be expected with concurrent use. Use caution, and monitor therapeutic effects of eplerenone when coadministered with vemurafenib.
    Verapamil: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with a CYP3A4 inhibitor in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving a concurrent CYP3A4 inhibitor, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. In addition, measure serum creatinine and serum potassium within 3 to 7 days of initiating a CYP3A4 inhibitor and periodically thereafter. Eplerenone is a CYP3A4 substrate. Verapamil is a CYP3A4 inhibitor. Coadministration with moderate CYP3A4 inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Voriconazole: (Contraindicated) Coadministration of voriconazole and eplerenone is contraindicated. Voriconazole potently inhibits the hepatic CYP3A4 isoenzyme and can increase the serum concentrations of eplerenone. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Voxelotor: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with voxelotor in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving voxelotor, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. Measure serum creatinine and serum potassium within 3 to 7 days of initiating voxelotor and periodically thereafter. Eplerenone is a CYP3A substrate. Voxelotor is a moderate CYP3A inhibitor. Coadministration with moderate CYP3A inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Yohimbine: (Moderate) Yohimbine can increase blood pressure and therefore can antagonize the therapeutic action of antihypertensive agents. Use with particular caution in hypertensive patients with high or uncontrolled BP.
    Ziprasidone: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.

    PREGNANCY AND LACTATION

    Pregnancy

    Data are insufficient with eplerenone use during pregnancy to establish a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. No adverse developmental effects were observed when eplerenone was administered to pregnant rats and rabbits during organogenesis at exposures 32 and 31 times, respectively, the human exposure at the 100 mg/day therapeutic dose.

    There are no human data available on whether eplerenone is present in human milk, or has effects on milk production or the breast-fed infant. Eplerenone is present in the milk of lactating rats. When a drug is present in animal milk, it is likely the drug will be present in human milk. Previous American Academy of Pediatrics (AAP) recommendations classified spironolactone as compatible with breast-feeding, and it may serve as a possible alternative.

    MECHANISM OF ACTION

    Eplerenone is a competitive antagonist of aldosterone at mineralocorticoid receptors. The drug has been shown to antagonize both epithelial and nonepithelial aldosterone effects within the kidney, blood vessels, and heart. Eplerenone produces sustained increases in plasma renin and serum aldosterone, consistent with inhibition of the negative regulatory feedback of aldosterone on renin secretion. Eplerenone also appears to increase urinary excretion of serum aldosterone, plasma renin, and sodium. These effects contribute to eplerenone's blood pressure reduction properties and may prove to be effective in other disease states where the renin-angiotensin-aldosterone system is involved such as stroke, heart failure, ventricular hypertrophy, myocardial necrosis, cardiac fibrosis, and malignant nephrosclerosis. Eplerenone may also possess some degree of anti-fibrotic action. Clinically in the treatment of hypertension, the blood pressure lowering effect of eplerenone is typically apparent within 2 weeks from the start of therapy, with maximal antihypertensive effects achieved within 4 weeks.
     
    In animal studies eplerenone has been found to: prevent proteinuria and renal vascular lesions associated with hypertension; restore nitric oxide-mediated endothelial function associated with hypertension; attenuate development of cardiac fibrosis and heart failure following myocardial infarction by reducing reactive left-ventricular remodeling; and decrease subsequent constrictive coronary artery remodeling via a reduction on collagen accumulation following angioplasty. These findings indicate that treatment with eplerenone may reduce end-organ damage associated with hypertension, myocardial infarction, and heart failure through mechanisms beyond a reduction in blood pressure.

    PHARMACOKINETICS

    Eplerenone is administered orally. The plasma protein binding is about 50% and is primarily to alpha 1-acid glycoproteins. Metabolism is mediated primarily by hepatic cytochrome P450 isoenzyme CYP3A4 to inactive metabolites. Although a substrate of CYP3A4, it does not appear to significantly inhibit or induce the CYP450 system and does not affect P-glycoprotein. Strong inhibitors of CYP3A4 unpredictably increase blood concentrations and should not be used concomitantly; dosage adjustments are required when used concurrently with less potent CYP3A4 inhibitors. Less than 5% of a dose is recovered as unchanged drug in the urine or feces. The drug is mainly excreted by the kidneys, with 66% of the total dose recovered in the urine and 32% recovered in the feces. The elimination half-life is roughly 4—6 hours.
     
    Affected cytochrome P450 isoenzymes: CYP3A4

    Oral Route

    Eplerenone exhibits good bioavailability. Oral absorption is not affected by food. Both peak plasma levels (Cmax) and area under the curve (AUC) are dose proportional over doses of 25—100 mg and less than proportional at doses above 100 mg. Time to maximum concentration (Tmax) is achieved in 1.3 hours. Blood pressure lowering is typically apparent within 2 weeks from the start of therapy with eplerenone, with maximal antihypertensive effects achieved within 4 weeks.