Eplerenone

1-10%

Hyperkalemia (2-10%)

Increased risk of hyperkalemia with presence of renal dysfunction

1-3%

• Dizziness
• Fatigue/malaise
• Abdominal pain
• Diarrhea
• Albuminuria
• Hypercholesterolemia
• Hypertriglyceridemia
• Cough

<1%

Abnormal vaginal bleeding

Gynecomastia

Mastodynia

Contraindications

Hypersensitivity

For all patients: Serum potassium >5.5 mEq/L at initiation Creatinine clearance ≤30 mL/min Concomitant use with strong CYP3A inhibitors For the treatment of hypertension: Type 2 diabetes with microalbuminuria Serum creatinine >2.0 mg/dL in males, >1.8 mg/dL in females Creatinine clearance <50 mL/min Concomitant use of potassium supplements or potassium-sparing diuretics

For all patients

• Serum potassium >5.5 mEq/L at initiation
• Creatinine clearance ≤30 mL/min
• Concomitant use with strong CYP3A inhibitors

For the treatment of hypertension

• Type 2 diabetes with microalbuminuria
• Serum creatinine >2.0 mg/dL in males, >1.8 mg/dL in females
• Creatinine clearance <50 mL/min
• Concomitant use of potassium supplements or potassium-sparing diuretics

Cautions

Hyperkalemia, liver dysfunction, metabolic or respiratory acidosis, renal impairment, hypersensitivity to spironolactone

The risk of hyperkalemia is higher in patients with impaired renal function, proteinuria , diabetes and those concomitantly treated with ACEs, ARBs, NSAIDs and moderate CYP3A inhibitors

Patients taking moderate CYP3A inhibitors that cannot be avoided should have their dose of eplerenone reduced

Pregnancy Category: B

Lactation: unknown if excreted into breast milk, discontinue drug or nursing

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

Tell your doctor about all prescription, nonprescription, illegal, recreational, herbal, nutritional, or dietary drugs you're taking, especially those listed in the Eplerenone Warnings section above, and the following:

• Angiotensin converting enzyme (ACE) inhibitors, such as Lotensin or Lotrel (benazepril); Capoten (captopril); Vasotec or Vaseretic (enalapril); fosinopril; Prinzide or Zestoretic (lisinopril); and Accupril, Accuretic, or Quinaretic (quinapril)
• Angiotensin II receptor antagonists, such as Edarbi or Edarbyclor (azilsartan); Atacand or Atacand HCT (candesartan); Teveten (eprosartan); Avapro or Avalide (irbesartan); Cozaar or Hyzaar (losartan); Benicar, Azor, or Benicar HCT (olmesartan); Micardis, Micardis HCT, or Twynsta (telmisartan); and Diovan, Diovan HCT, or Exforge (valsartan)
• Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), such as Advil or Motrin (ibuprofen) and Aleve or Naprosyn (naproxen)
• Tagamet (cimetidine)
• Biaxin (clarithromycin)
• Danazol
• Rescriptor (delavirdine)
• Cardizem, Cartia, Dilacor, or Tiazac (diltiazem)
• E.E.S., E-Mycin, or Erythrocin (erythromycin)
• Diflucan (fluconazole)
• Prozac, Sarafem, or Selfemra (fluoxetine)
• Luvox (fluvoxamine)
• HIV protease inhibitors, such as Crixivan (indinavir), Norvir (ritonavir), Kaletra (lopinavir and ritonavir), and Invirase (saquinavir)
• Laniazid, Rifamate, or Rifater (isoniazid)
• Lithobid (lithium)
• Flagyl (metronidazole)
• Nefazodone
• Calan, Covera, Verelan, or Tarka (verapamil)
• Accolate (zafirlukast)
• St. John's wort

Eplerenone and Other Interactions

Eplerenone may cause dizziness.

Don't drive or perform other activities that require alertness until you know how this medicine affects you.

Eplerenone and Alcohol

Alcohol may worsen certain side effects of eplerenone.

Talk to your doctor before drinking alcoholic beverages while using this drug.

Eplerenone and Grapefruit

Grapefruit or grapefruit juice may interact with how eplerenone works in the body.

Talk to your doctor about consuming grapefruit while taking this medicine.

No cases of human overdosage with eplerenone have been reported. Lethality was not observed in mice, rats, or dogs after single oral doses that provided Cmax exposures at least 25 times higher than in humans receiving eplerenone 100 mg/day. Dogs showed emesis, salivation, and tremors at a Cmax 41 times the human therapeutic Cmax, progressing to sedation and convulsions at higher exposures.

The most likely manifestation of human overdosage would be anticipated to be hypotension or hyperkalemia. Eplerenone cannot be removed by hemodialysis. Eplerenone has been shown to bind extensively to charcoal. If symptomatic hypotension should occur, supportive treatment should be instituted. If hyperkalemia develops, standard treatment should be initiated.

Eplerenone may be found in some form under the following brand names:

• Inspra

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X - are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Eplerenone falls into category B. There are no well-done studies that have been done in humans with eplerenone. In animal studies, pregnant animals were given this medication, and the babies did not show any medical issues related to this medication.

Tell your doctor if you are breastfeeding or plan to breastfeed.

It is not known if eplerenone crosses into human milk. Because many medications can cross into human milk and because of the possibility for serious adverse reactions in nursing infants with use of this medication, a choice should be made whether to stop nursing or stop the use of this medication. Your doctor and you will decide if the benefits outweigh the risk of using eplerenone.

Do not use salt substitutes or potassium supplements while taking eplerenone, unless your doctor has told you to.

Eplerenone blocks the actions of the hormone aldosterone in the body. Aldosterone is important for the regulation of blood pressure.

Eplerenone is used to treat congestive heart failure after a heart attack. Eplerenone is also used to treat high blood pressure (hypertension).

Eplerenone may also be used for purposes not listed in this medication guide.

You may not be able to take this medicine if you have severe kidney disease, high potassium levels in your blood, or type 2 diabetes with increased levels of albumin (a protein) in your urine.

Serious drug interactions can occur when certain medicines are used together with eplerenone. Tell each of your healthcare providers about all medicines you use now, and any medicine you start or stop using.

Many drugs can interact with eplerenone, and some drugs should not be used together. Not all possible interactions are listed here. Tell your doctor about all your current medicines and any you start or stop using, especially:

• aprepitant;

• cimetidine;

• cyclosporine;

• haloperidol;

• imatinib;

• an antibiotic--ciprofloxacin, doxycycline, erythromycin, metronidazole, norfloxacin, tetracycline;

• antifungal medicine--clotrimazole, fluconazole, voriconazole;

• an antidepressant--desipramine, sertraline;

• heart or blood pressure medicine--amiodarone, benazepril, diltiazem, dronedarone, enalapril, lidocaine, lisinopril, olmesartan, valsartan, verapamil, and others;

• HIV/AIDS medicine--atazanavir, fosamprenavir, efavirenz, darunavir when given with ritonavir, saquinavir; or

• NSAIDs (nonsteroidal anti-inflammatory drugs)--aspirin, ibuprofen (Advil, Motrin), naproxen (Aleve), celecoxib, diclofenac, indomethacin, meloxicam, and others.

This list is not complete and many other drugs can interact with eplerenone. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Give a list of all your medicines to any healthcare provider who treats you.

Relatively selective mineralocorticoid (aldosterone) receptor antagonist.1 2 3 10 11

Use eplerenone as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take with or without food.
• To gain the most benefit, do not miss doses.
• Keep taking this medicine as you have been told by your doctor or other health care provider, even if you feel well.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Hyperkalemia [see Warnings and Precautions (5.1)]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice.

Congestive Heart Failure Post-Myocardial Infarction

In EPHESUS, safety was evaluated in 3307 patients treated with Eplerenone and 3301 placebo-treated patients. The overall incidence of adverse events reported with Eplerenone (78.9%) was similar to placebo (79.5%). Adverse events occurred at a similar rate regardless of age, gender, or race. Patients discontinued treatment due to an adverse event at similar rates in either treatment group (4.4% Eplerenone vs. 4.3% placebo), with the most common reasons for discontinuation being hyperkalemia, MI, and abnormal renal function.

Adverse reactions that occurred more frequently in patients treated with Eplerenone than placebo were hyperkalemia (3.4% vs. 2.0%) and increased creatinine (2.4% vs. 1.5%). Discontinuations due to hyperkalemia or abnormal renal function were less than 1.0% in both groups.

Hypertension

Eplerenone has been evaluated for safety in 3091 patients treated for hypertension. A total of 690 patients were treated for over 6 months and 106 patients were treated for over 1 year.

In placebo-controlled studies, the overall rates of adverse events were 47% with Eplerenone and 45% with placebo. Adverse events occurred at a similar rate regardless of age, gender, or race. Therapy was discontinued due to an adverse event in 3% of patients treated with Eplerenone and 3% of patients given placebo. The most common reasons for discontinuation of Eplerenone were headache, dizziness, angina pectoris/MI, and increased GGT.

Gynecomastia and abnormal vaginal bleeding were reported with Eplerenone but not with placebo. The rates increased with increasing duration of therapy.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Eplerenone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Skin: angioneurotic edema, rash

Clinical Laboratory Test Findings

Congestive Heart Failure Post-Myocardial Infarction

Creatinine: Increases of more than 0.5 mg/dL were reported for 6.5% of patients administered Eplerenone and for 4.9% of placebo-treated patients.

Potassium: In EPHESUS [see Clinical Studies (14.1)], the frequencies of patients with changes in potassium (<3.5 mEq/L or >5.5 mEq/L or ≥6.0 mEq/L) receiving Eplerenone compared with placebo are displayed in Table 2.

Rates of hyperkalemia increased with decreasing renal function.

The rates of hyperkalemia in EPHESUS in the Eplerenone treated group vs. placebo were increased in patients with proteinuria (16% vs 11%), diabetes (18% vs. 13%) or both (26% vs. 16%).

Hypertension

Potassium: In placebo-controlled fixed-dose studies, the mean increases in serum potassium were dose-related and are shown in Table 4 along with the frequencies of values >5.5 mEq/L.

CYP3A Inhibitors

Eplerenone metabolism is predominantly mediated via CYP3A. Do not use Eplerenone with drugs that are strong inhibitors of CYP3A [see Contraindications (4) and Clinical Pharmacology (12.3)].

In post-MI CHF patients taking a moderate CYP3A inhibitor, do not exceed 25 mg once daily. In patients with hypertension taking a moderate CYP3A inhibitor, initiate at 25 mg once daily. For inadequate blood pressure response, dosing may be increased to a maximum of 25 mg twice daily [see Dosage and Administration (2.3, 2.4) and Clinical Pharmacology (12.3)].

ACE Inhibitors and Angiotensin II Receptor Antagonists

The risk of hyperkalaemia increase when Eplerenone is used in combination with an ACE inhibitor and/or an ARB. A close monitoring of serum potassium and renal function is recommended, especially in patients at risk for impaired renal function, e.g., the elderly [see Warnings and Precautions(5.1)].

Lithium

A drug interaction study of Eplerenone with lithium has not been conducted. Lithium toxicity has been reported in patients receiving lithium concomitantly with diuretics and ACE inhibitors. Serum lithium levels should be monitored frequently if Eplerenone is administered concomitantly with lithium.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

A drug interaction study of Eplerenone with an NSAID has not been conducted. The administration 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. Therefore, when Eplerenone and NSAIDs are used concomitantly, monitor blood pressure and serum potassium levels.

Congestive Heart Failure Post-Myocardial Infarction

The Eplerenone post-acute myocardial infarction heart failure efficacy and survival study (EPHESUS) was a multinational, multicenter, double-blind, randomized, placebo-controlled study in patients clinically stable 3 to 14 days after an acute MI with LV dysfunction (as measured by left ventricular ejection fraction [LVEF] ≤40%) and either diabetes or clinical evidence of CHF (pulmonary congestion by exam or chest x-ray or S3). Patients with CHF of valvular or congenital etiology, patients with unstable post-infarct angina, and patients with serum potassium >5.0 mEq/L or serum creatinine >2.5 mg/dL were to be excluded. Patients were allowed to receive standard post-MI drug therapy and to undergo revascularization by angioplasty or coronary artery bypass graft surgery.

Patients randomized to Eplerenone were given an initial dose of 25 mg once daily and titrated to the target dose of 50 mg once daily after 4 weeks if serum potassium was < 5.0 mEq/L. Dosage was reduced or suspended anytime during the study if serum potassium levels were ≥ 5.5 mEq/L [see Dosage and Administration (2.1)].

EPHESUS randomized 6,632 patients (9.3% U.S.) at 671 centers in 27 countries. The study population was primarily white (90%, with 1% Black, 1% Asian, 6% Hispanic, 2% other) and male (71%). The mean age was 64 years (range, 22 to 94 years). The majority of patients had pulmonary congestion (75%) by exam or x-ray and were Killip Class II (64%). The mean ejection fraction was 33%. The average time to enrollment was 7 days post-MI. Medical histories prior to the index MI included hypertension (60%), coronary artery disease (62%), dyslipidemia (48%), angina (41%), type 2 diabetes (30%), previous MI (27%), and CHF (15%).

The mean dose of Eplerenone was 43 mg/day. Patients also received standard care including aspirin (92%), ACE inhibitors (90%), beta-blockers (83%), nitrates (72%), loop diuretics (66%), or HMG-CoA reductase inhibitors (60%).

Patients were followed for an average of 16 months (range, 0 to 33 months). The ascertainment rate for vital status was 99.7%.

The co-primary endpoints for EPHESUS were (1) the time to death from any cause, and (2) the time to first occurrence of either cardiovascular mortality [defined as sudden cardiac death or death due to progression of CHF, stroke, or other CV causes] or CV hospitalization (defined as hospitalization for progression of CHF, ventricular arrhythmias, acute MI, or stroke).

For the co-primary endpoint for death from any cause, there were 478 deaths in the Eplerenone group (14.4%) and 554 deaths in the placebo group (16.7%). The risk of death with Eplerenone was reduced by 15% [hazard ratio equal to 0.85 (95% confidence interval 0.75 to 0.96; p = 0.008 by log rank test)]. Kaplan-Meier estimates of all-cause mortality are shown in Figure 1 and the components of mortality are provided in Table 5.

Most CV deaths were attributed to sudden death, acute MI, and CHF.

The time to first event for the co-primary endpoint of CV death or hospitalization, as defined above, was longer in the Eplerenone group (hazard ratio 0.87, 95% confidence interval 0.79 to 0.95, p = 0.002). An analysis that included the time to first occurrence of CV mortality and all CV hospitalizations (atrial arrhythmia, angina, CV procedures, progression of CHF, MI, stroke, ventricular arrhythmia, or other CV causes) showed a smaller effect with a hazard ratio of 0.92 (95% confidence interval 0.86 to 0.99; p = 0.028). The combined endpoints, including combined all-cause hospitalization and mortality were driven primarily by CV mortality. The combined endpoints in EPHESUS, including all-cause hospitalization and all-cause mortality, are presented in Table 6.

Mortality hazard ratios varied for some subgroups as shown in Figure 2. Mortality hazard ratios appeared favorable for Eplerenone for both genders and for all races or ethnic groups, although the numbers of non-Caucasians were low (648, 10%). Patients with diabetes without clinical evidence of CHF and patients greater than 75 years did not appear to benefit from the use of Eplerenone. Such subgroup analyses must be interpreted cautiously.

Analyses conducted for a variety of CV biomarkers did not confirm a mechanism of action by which mortality was reduced.

Hypertension

The safety and efficacy of Eplerenone have been evaluated alone and in combination with other antihypertensive agents in clinical studies of 3091 hypertensive patients. The studies included 46% women, 14% Blacks, and 22% elderly (age ≥65). The studies excluded patients with elevated baseline serum potassium (>5.0 mEq/L) and elevated baseline serum creatinine (generally >1.5 mg/dL in males and >1.3 mg/dL in females).

Two fixed-dose, placebo-controlled, 8- to 12-week monotherapy studies in patients with baseline diastolic blood pressures of 95 to 114 mm Hg were conducted to assess the antihypertensive effect of Eplerenone. In these two studies, 611 patients were randomized to Eplerenone and 140 patients to placebo. Patients received Eplerenone in doses of 25 mg to 400 mg daily as either a single daily dose or divided into two daily doses. The mean placebo-subtracted reductions in trough cuff blood pressure achieved by Eplerenone in these studies at doses up to 200 mg are shown in Figures 3 and 4.

Patients treated with Eplerenone 50 mg to 200 mg daily experienced significant decreases in sitting systolic and diastolic blood pressure at trough with differences from placebo of 6–13 mm Hg (systolic) and 3–7 mm Hg (diastolic). These effects were confirmed by assessments with 24-hour ambulatory blood pressure monitoring (ABPM). In these studies, assessments of 24-hour ABPM data demonstrated that Eplerenone, administered once or twice daily, maintained antihypertensive efficacy over the entire dosing interval. However, at a total daily dose of 100 mg, Eplerenone administered as 50 mg twice per day produced greater trough cuff (4/3 mm Hg) and ABPM (2/1 mm Hg) blood pressure reductions than 100 mg given once daily.

Blood pressure lowering was apparent within 2 weeks from the start of therapy with Eplerenone, with maximal antihypertensive effects achieved within 4 weeks. Stopping Eplerenone following treatment for 8 to 24 weeks in six studies did not lead to adverse event rates in the week following withdrawal of Eplerenone greater than following placebo or active control withdrawal. Blood pressures in patients not taking other antihypertensives rose 1 week after withdrawal of Eplerenone by about 6/3 mm Hg, suggesting that the antihypertensive effect of Eplerenone was maintained through 8 to 24 weeks.

Blood pressure reductions with Eplerenone in the two fixed-dose monotherapy studies and other studies using titrated doses, as well as concomitant treatments, were not significantly different when analyzed by age, gender, or race with one exception. In a study in patients with low renin hypertension, blood pressure reductions in Blacks were smaller than those in whites during the initial titration period with Eplerenone.

Eplerenone has been studied concomitantly with treatment with ACE inhibitors, ARB, calcium channel blockers, beta-blockers, and hydrochlorothiazide. When administered concomitantly with one of these drugs Eplerenone usually produced its expected antihypertensive effects.

There was no significant change in average heart rate among patients treated with Eplerenone in the combined clinical studies. No consistent effects of Eplerenone on heart rate, QRS duration, or PR or QT interval were observed in 147 normal subjects evaluated for electrocardiographic changes during pharmacokinetic studies.

(e PLER en one)

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

Based on the American College of Cardiology Foundation/American Heart Association guidelines for the management of heart failure, eplerenone (along with other guideline directed medical therapies) is effective and recommended to reduce morbidity and mortality in patients with heart failure (NYHA class II-IV) with a left ventricular ejection fraction ≤35%.

Primary aldosteronism, treatment

Based on the Endocrine Society guidelines for the management of primary aldosteronism, eplerenone is an effective and recommended alternative agent for the treatment of bilateral adrenal hypersectrion; also an alternative agent for the treatment of unilateral hypersecretion in patients unwilling or unable to undergo surgery.

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

Blood pressure; serum potassium (prior to therapy, within the first week, 1 month after start of treatment or dose adjustment, then periodically as clinically indicated); additionally, check serum potassium and serum creatinine within 3 to 7 days after initiating concurrent therapy with moderate CYP3A4 inhibitor, ACE inhibitor, angiotensin-II blockers or NSAID.

ACCF/AHA heart failure guideline recommendations (ACCF/AHA [Yancy, 2013]): Serum potassium and renal function should be checked in 3 days after initiation, at 1 week after initiation, at least monthly for the first 3 months of therapy, and every 3 months thereafter. If adding or increasing the dose of concomitant ACE inhibitors or ARBs, a new cycle of monitoring should be done. If serum potassium increases to >5.5 mEq/L or renal function worsens, hold doses until potassium is <5 mEq/L and consider restarting with a reduced dose after confirming resolution of hyperkalemia/renal insufficiency for at least 72 hours.

Animal studies have failed to reveal evidence of teratogenicity. There are no controlled data in human pregnancy. FDA pregnancy category B: Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women.

FDA pregnancy category: B Use eplerenone only if clearly needed and benefit outweighs potential risk.