PHARMACOLOGY NOTES
`
`Eplerenone (Inspra), a new aldosterone antagonist for
`the treatment of systemic hypertension and heart failure
`
`JENNIFER CRAFT, PHARMD, BCPS
`
`Eplerenone is the second oral aldosterone antagonist available in the
`USA for the treatment of essential hypertension and heart failure.
`Treatment has been associated with reductions in blood pressure and
`improved survival (15% reduction in total mortality) for patients with
`heart failure who are in stable condition after a myocardial infarction.
`Due to the selectivity of eplerenone for the aldosterone receptor, adverse
`effects such as gynecomastia and vaginal bleeding seem to be less likely
`in patients who take eplerenone than in those who take spironolactone.
`The most severe side effect of spironolactone, hyperkalemia, was also
`observed with eplerenone. While eplerenone is more selective, with the
`potential for fewer side effects, its overall efficacy has not been proven
`to be superior to that of spironolactone in clinical trials. The American
`College of Cardiology recommends trying spironolactone first and then
`switching to eplerenone if patients develop gynecomastia, menstrual
`irregularities, or impotence.
`
`Eplerenone (Inspra) is the second aldosterone antagonist
`
`available in the USA. It received Food and Drug Admin-
`istration approval on September 27, 2002, and October
`7, 2003, for the treatment of hypertension and heart failure,
`respectively. Aldosterone, a hormone of the renin-angiotensin-
`aldosterone system, has been linked to hypertension, cardiac hy-
`pertrophy, and cardiac and vascular fibrosis. Despite treatment
`with an angiotensin-converting enzyme inhibitor or angiotensin
`II receptor blocker, suppression of aldosterone is incomplete due
`to non–angiotensin II regulators of aldosterone production, such
`as serum potassium. Until recently, the only approved aldosterone
`antagonist for the treatment of hypertension and heart failure
`was spironolactone. Spironolactone, although effective for these
`conditions, has progestational and antiandrogenic adverse effects
`due to its nonspecific binding to various steroid receptors.
`Hypertension affects approximately 50 million people in the
`USA and 1 billion people worldwide (1). Achieving goal blood
`pressures (BP) with antihypertensive medications has been as-
`sociated with a 35% to 40% reduction in stroke incidence, a
`20% to 25% reduction in myocardial infarction incidence, and a
`>50% reduction in heart failure incidence (1). It is estimated that
`current control rates are still far below the Healthy People 2010
`goal of 50% (1). Most patients require 2 or more antihypertensive
`medications with different mechanisms of action to reach the goal
`BP values of the Joint National Committee VII.
`Nearly 5 million patients in the USA have heart failure, and
`500,000 new cases are diagnosed each year. Five hundred mil-
`lion dollars is spent annually on the treatment of heart failure
`
`(2). According to the American College of Cardiology/American
`Heart Association Guidelines for the Evaluation and Management
`of Chronic Heart Failure in the Adult, the addition of aldosterone
`antagonists should be considered for patients with recent or cur-
`rent symptoms at rest despite the use of angiotensin-converting
`enzyme inhibitors, diuretics, beta-blockers, and/or digoxin. It has
`been proposed that aldosterone adversely affects the function and
`structure of the heart; utilizing aldosterone antagonists in addition
`to standard drug therapy for heart failure in clinical trials reduced
`mortality and hospitalization rates (2).
`
`INDICATION(S)
`Eplerenone is currently indicated in the USA for the treat-
`ment of hypertension, either alone or in combination with other
`agents, and for the first-line treatment of heart failure secondary
`to myocardial infarction (3).
`
`PHARMACOLOGY/PHARMACOKINETICS
`Eplerenone selectively binds to the mineralocorticoid re-
`ceptor, thereby blocking the binding of aldosterone and thus
`inhibiting sodium reabsorption and other deleterious aldosterone-
`mediated mechanisms (3).
`Eplerenone is metabolized via the cytochrome P450 (CYP)
`3A4 pathway. No active metabolites are known to exist. The
`elimination half-life is 4 to 6 hours. Steady state is achieved
`within 2 days. Blood levels are potentiated and increased with
`concomitant use of inhibitors of the CYP3A4 pathway (e.g., ke-
`toconazole, saquinavir, erythromycin). The pharmacokinetics of
`eplerenone did not differ between men and women or between
`whites and blacks. Steady-state area under the curve and maxi-
`mum concentration are increased with renal and hepatic insuf-
`ficiency. Hemodialysis does not remove eplerenone.
`
`CLINICAL TRIALS
`Most published clinical trials evaluated the efficacy of eplere-
`none for the treatment of hypertension. One group of researchers,
`utilizing the same patient population, conducted many of the tri-
`als (referenced below). The data were manipulated to reach the
`
`From the Department of Pharmacy Services, Baylor University Medical Center,
`Dallas, Texas.
`Corresponding author: Jennifer Craft, PharmD, BCPS, Department of Pharmacy
`Services, Baylor University Medical Center, 3500 Gaston Avenue, Dallas, Texas 75246
`
`
`BUMC PROCEEDINGS 2004;17:217–220
`
`217
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`
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`JANSSEN EXHIBIT 2062
`Mylan v. Janssen IPR2016-01332
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`desired outcomes for each clinical trial. No clinical trials directly
`compared eplerenone and spironolactone for either indication.
`Even though a few trials did have a spironolactone arm, this arm
`was compared only with placebo.
`
`Hypertension trials
`A multicenter, double-blind, randomized, active-controlled,
`titration-to-effect trial comparing eplerenone to amlodipine
`showed noninferiority to amlodipine by assessing mean change
`in seated systolic BP. Patients ≥50 years of age with hypertension
`(systolic BP 150–165 mm Hg/diastolic BP ≤95 mm Hg) received
`either eplerenone (n = 134) or amlodipine (n = 135) as follows:
`The initial doses were eplerenone 50 mg daily or amlodipine 2.5
`mg daily. If systolic BP was >140 mm Hg at 2 weeks, doses were
`increased to eplerenone 100 mg daily or amlodipine 5 mg daily.
`If systolic BP was >140 mm Hg at 6 weeks, doses were increased
`to eplerenone 200 mg daily or amlodipine 10 mg daily. Patients
`were excluded if they had any of the following: serum potassium
`≥5 mEq/L, serum creatinine >1.7 mg/dL (men) or >1.5 mg/dL
`(women), or diagnosis of significant heart, liver, or kidney dis-
`ease. After 24 weeks, mean doses of eplerenone and amlodipine
`were 155 mg and 7.4 mg, respectively. No statistically significant
`difference in reduction of systolic BP (95% confidence interval,
`–2.8 to 3.5) or reduction of pulse pressure (16 mm Hg for eplere-
`none vs 13 mm Hg for amlodipine, P = 0.07) was observed. A
`significantly larger decrease in diastolic BP was observed with
`amlodipine (95% confidence interval, –4.4 to –0.5, P = 0.014).
`Patients taking amlodipine had slightly more side effects (70%
`incidence vs 64% for eplerenone); the difference was due mainly
`to peripheral edema in some patients taking amlodipine (P <
`0.05). The most commonly reported adverse event for eplere-
`none was headache (16.4%). Severe hyperkalemia was noted in
`3% of the eplerenone-treated group and 1.5% of the amlodipine
`group. Neither group reported gynecomastia, breast tenderness,
`or menstrual irregularities (4).
`The trial was well designed, the target sample size for each
`group was met, and appropriate methods were used to measure
`systolic BP. This trial would have revealed more beneficial results
`if it had been designed to compare spironolactone to eplerenone,
`was not limited to prove noninferiority only, and included mor-
`bidity and mortality information.
`An 8-week multicenter, double-blind, placebo lead-in,
`parallel-group, dose-ranging study, conducted in adults (aged
`21–80 years) with diastolic BP between 95 and 114 mm Hg,
`evaluated adjusted mean changes in diastolic BP from baseline.
`Patients received eplerenone 50 mg daily (n = 54), 100 mg daily
`(n = 49), 400 mg daily (n = 56), 25 mg twice daily (n = 55), 50
`mg twice daily (n = 54), or 200 mg twice daily (n = 48); placebo
`(n = 53); or spironolactone 50 mg twice daily (n = 48). Patient
`exclusion criteria included the following: malignant hyperten-
`sion; current use of other medications that influenced BP; current
`use of nonsteroidal antiinflammatory drugs; myocardial infarc-
`tion, percutaneous transluminal coronary angioplasty, coronary
`artery bypass graft, angina pectoris, or intermittent claudication
`in the past 6 months; valve disease; cardiomyopathy/heart fail-
`ure; stroke/transient ischemic attack; insulin-dependent diabetes
`mellitus; hepatic disease; serum creatinine >1.5 mg/dL; serum
`potassium >5 mEq/L; alcohol/drug abuse; sensitivity to steroids;
`
`or working a night shift. After 8 weeks, reductions in mean sys-
`tolic BP/diastolic BP from baseline were observed for all doses of
`eplerenone (P < 0.05). No significant differences in reduction
`were noted between daily and twice-daily regimens. Dose-related
`decreases in all measurements were observed for eplerenone. The
`overall incidence of adverse events was 46%, with headache being
`reported most frequently. Significant changes in serum potassium
`levels from baseline were observed in the groups that received
`eplerenone 400 mg daily or 25 mg, 50 mg, or 100 mg twice daily
`and in the spironolactone group (P < 0.05). There were no re-
`ports of menstrual abnormalities, impotence, or gynecomastia.
`One spironolactone-treated patient experienced intermenstrual
`bleeding (5). The use of a spironolactone control was beneficial
`in allowing for observation of positive and negative outcomes
`among the treatment groups; however, eplerenone was never
`directly compared with spironolactone. Both were compared
`with placebo only.
`A 12-week multicenter, double-blind, randomized, placebo-
`controlled, parallel-arm, intention-to-treat trial evaluated the
`mean changes in diastolic BP between placebo and eplerenone.
`Patients with systolic BP <180 mm Hg, diastolic BP 95 to 110
`mm Hg, or 24-hour mean diastolic BP ≥85 mm Hg received
`eplerenone 25 mg, 50 mg, 100 mg, or 200 mg once daily or
`placebo (n = 90 for each dose range and placebo). Patients with
`recent myocardial infarction or unstable angina, heart failure,
`hepatic/renal disease, secondary hypertension, uncontrolled
`diabetes mellitus, serum creatinine >1.7 mg/dL for men or >1.5
`mg/dL for women, or baseline serum potassium >5 mEq/L were
`excluded. After 12 weeks, significant reductions in diastolic BP
`were observed in the 50 mg, 100 mg, and 200 mg eplerenone
`groups. Significant reductions in systolic BP were observed for
`all doses of eplerenone. The eplerenone groups had dose-related
`increases in serum potassium or elevated serum potassium levels
`compared with the placebo group. The most common reported
`adverse events in patients receiving eplerenone was headache
`(11.6%); however, the frequency was not significantly higher than
`in those receiving placebo. One patient each in the eplerenone
`100 mg and placebo group experienced impotence (6). Limita-
`tions to the study were that 3 of the 5 arms failed to reach their
`target sample size, and statistical analysis was performed by using
`one-sided tests.
`Eplerenone monotherapy in black and white adult popula-
`tions was compared with placebo and losartan in a randomized,
`double-blind, placebo- and active-controlled, placebo run-in, par-
`allel group trial. The study population was stratified at a 2:1 ratio
`of black to white patients. The primary endpoint was the mean
`change in diastolic BP from baseline to final visit. Patients were
`eligible for inclusion if their systolic BP was <180 mm Hg and
`diastolic BP was between 95 and 109 mm Hg without medication.
`Patients receiving 1 or 2 antihypertensive medications were eli-
`gible if their BP was <140/90 mm Hg. Eplerenone treatment was
`initiated at a dose of 50 mg, titrated to 100 mg/day, and increased
`if necessary to a maximum of 200 mg/day; losartan treatment were
`initiated at 50 mg and titrated to 100 mg/day if BP was ≥140/90
`mm Hg at weeks 4, 8, or 12. Eplerenone demonstrated a signifi-
`cantly greater reduction in mean BP from baseline than placebo
`or losartan for all patients combined (P < 0.001) and for black
`patients (P ≤ 0.001). Mean changes in white patients’ BP were
`
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`significantly greater for the eplerenone arm than for the placebo
`arm (P = 0.001) but were not significantly different than those
`for the losartan arm. No patients in the eplerenone arm experi-
`enced impotence, gynecomastia, or breast tenderness; however,
`2 patients reported menstrual disorders and 2 reported decreased
`libido. The observed change in serum potassium level was signifi-
`cantly greater for the eplerenone arm than for the other arms,
`with a change of +0.09 ± 0.03 mEq/L (P < 0.001 for eplerenone
`vs placebo, P = 0.003 for eplerenone vs losartan). More patients
`within the placebo and losartan arms than the eplerenone arm
`discontinued treatment because of treatment failure (P = 0.0001
`for eplerenone vs placebo, P < 0.001 for eplerenone vs losartan).
`Upper respiratory system disorders were the most frequently
`reported adverse events for both the eplerenone and losartan
`arms. Two patients in the eplerenone group reported menstrual
`disorders, and 2 reported decreased libido (7).
`Even though this trial included both black and white patients,
`most of the trial population (63%) was black, which may limit
`application of the results to all races and may also have influ-
`enced the improved efficacy seen in the “all patients” group. The
`researchers failed to list their target sample sizes for each arm.
`Patients were withdrawn if their systolic BP was >150 mm Hg
`or diastolic BP was >96 mm Hg after treatment initiation, thus
`excluding patients whose need for BP reduction was greatest.
`
`Heart failure trials
`The Eplerenone Post-AMI Heart Failure Efficacy and Sur-
`vival Study (EPHESUS), a 16-month international, multicenter,
`randomized, double-blind, placebo-controlled study, evaluated
`the efficacy of eplerenone in reducing morbidity and mortality
`among patients with acute myocardial infarction complicated by
`left ventricular dysfunction and heart failure. Primary endpoints
`were time to death from any cause, time to death from cardiovas-
`cular causes, or hospitalization for heart failure, acute myocardial
`infarction, stroke, or ventricular arrhythmia. Patients received
`eplerenone 25 mg daily or matching placebo for 4 weeks and then
`the eplerenone dose was increased if necessary to a maximum of
`50 mg daily. To be eligible, patients must have experienced an
`acute myocardial infarction within the prior 3 to 14 days, have
`left ventricular dysfunction, or have evidence of heart failure.
`Excluding potassium-sparing diuretics, standard drug therapy
`was allowed. Death from any cause occurred in 14.4% of pa-
`tients in the eplerenone arm and 16.7% of those in the placebo
`arm (relative risk, 0.85; P = 0.0008). Mortality rates at 1 year
`were 11.8% and 13.6% in the eplerenone and placebo groups,
`respectively. Death from cardiovascular causes or hospitalization
`for cardiovascular events occurred in 27% of patients receiving
`eplerenone and 30% of patients receiving placebo (relative risk,
`0.87; P = 0.002). Systolic BP and diastolic BP increased in both
`groups from baseline throughout the trial; however, the increase
`was less for the eplerenone group. Subgroup analyses, defined
`a priori, revealed a benefit from eplerenone in patients treated
`with angiotensin-converting enzyme inhibitors or beta-blockers.
`Serum concentrations of potassium and creatinine increased in
`both groups, and the increases were greater in patients who re-
`ceived eplerenone. Serious hyperkalemia was more frequent in
`the eplerenone-treated patients (5.5%) than in those treated with
`placebo (3.9%) (P = 0.002) (8).
`
`Table 1. Adverse events reported most frequently with eplerenone
`
`Adverse event
`Hyperkalemia (K+ >5.5 mEq/L)
`
`Hypertriglyceridemia
`Hyponatremia
`Mastodynia
`Abnormal vaginal bleeding
`Gynecomastia
`
`Rate (%) of adverse event
`33% (eplerenone alone)
`38% (eplerenone and enalapril)
`15%
`2.3%
`0.8% (men)
`0.6% (women)
`0.5% (men)
`
`
`
`EPHESUS was a large, well-designed outcome trial in which
`eplerenone yielded substantial improvement in mortality and
`morbidity compared with placebo. When compared with results
`of the RALES trial, however, these results are modest, and the
`improvement was only half of that observed in the RALES trial.
`Major differences between the 2 trials, such as differences in
`the patient populations (patients in RALES were sicker and
`older) and different baseline treatment regimens (more patients
`in EPHESUS were on beta-blockers, aspirin, statins, and/or
`angiotensin-converting enzyme inhibitors) may explain the dif-
`ferences in results.
`The 4E-Left Ventricular Hypertrophy Study, a 9-month
`double-blind, randomized trial, enrolled 202 patients with left
`ventricular hypertrophy and hypertension. Patients received
`eplerenone 200 mg daily, enalapril 40 mg daily, or eplerenone
`200 mg daily plus enalapril 10 mg daily. After 8 weeks, hydrochlo-
`rothiazide 12.5 to 25 mg and/or amlodipine 10 mg was added if
`diastolic BP was >90 mm Hg. The study’s purpose was to compare
`left ventricular mass regression by magnetic resonance imaging
`in patients receiving eplerenone alone, enalapril alone, or the
`combination. Eplerenone significantly reduced left ventricular
`mass from baseline (–15 ± 3 g; n = 50), like enalapril (–20 ± 3 g;
`n = 54; P = 0.258), but the combination was more effective than
`eplerenone alone (–27 ± 3 g; n = 49; P = 0.007). All treatments
`reduced both systolic and diastolic BP equally. The most common
`side effect of eplerenone was hyperkalemia (9).
`Measuring left ventricular hypertrophy with magnetic reso-
`nance imaging is investigational, and the correlation between
`quantity of regression and clinical effect is controversial. The
`target sample size of 55 patients per group to adequately power
`the study for the primary endpoint was not met for any of the
`groups. The statistical test evaluated only how well the medica-
`tion reduced left ventricular size and not the potential for left
`ventricular growth despite adequate treatment.
`
`ADVERSE EFFECTS
`The overall adverse effect rate for patients on eplerenone
`was 47%, and 3% of patients discontinued its use as a result. The
`most notable/common adverse effects observed in clinical trials
`are summarized in Table 1.
`
`DOSING AND ADMINISTRATION
`The recommended starting dose of eplerenone for the treat-
`ment of essential hypertension is 50 mg once daily titrated to a
`maximum of 50 mg twice daily. For the treatment of heart failure,
`
`APRIL 2004
`
`EPLERENONE (INSPRA) FOR THE TREATMENT OF SYSTEMIC HYPERTENSION AND HEART FAILURE
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`Table 2. Costs of eplerenone and spironolactone
`
`Drug/dose
`Eplerenone 25 mg
`Eplerenone 50 mg
`Spironolactone 25 mg
`Spironolactone 50 mg
`Spironolactone 100 mg
`
`Cost per tablet
`$2.93
`$2.93
`$0.26
`$0.48
`$0.80
`
`
`
`the recommended starting dose is 25 mg once daily, titrated over
`4 weeks if tolerated to the target dose of 50 mg once daily. No
`adjustment is necessary for patients with mild to moderate hepatic
`impairment (Child-Pugh Class B) or for the elderly. Patients tak-
`ing a CYP3A4 inhibitor should receive an initial starting dose of
`25 mg once daily. The maximum effective dose should be limited
`to 100 mg daily to avoid the increased risk of hyperkalemia with
`higher doses.
`
`PREGNANCY CATEGORY
`There are no adequate studies in pregnant women; therefore,
`a pregnancy B category has been assigned.
`
`DRUG INTERACTIONS
`Eplerenone does not inhibit any cytochrome isoenzymes.
`Inhibitors of CYP3A4 such as ketoconazole caused a fivefold
`increase in exposure, while less potent inhibitors of CYP3A4
`(erythromycin, saquinavir, verapamil, and fluconazole) yielded a
`twofold increase in exposure. St. John’s wort caused a small (30%)
`decrease in the area under the curve. Grapefruit juice caused a
`small (25%) increase in exposure.
`
`DOSAGE FORMS
`Eplerenone is available as 25- and 50-mg tablets. The 100-
`mg tablet will not be marketed and is no longer included in the
`labeling.
`
`ECONOMIC ISSUES
`The cost of eplerenone is compared with the cost of spi-
`ronolactone in Table 2. All costs are based on BUMC pharmacy
`acquisition costs.
`
`A 1-month supply of eplerenone is estimated to cost $87.90
`for treatment of congestive heart failure and $175.80 for treat-
`ment of hypertension based on current maximum dosage recom-
`mendations. For the same period, spironolactone is estimated to
`cost $14.40 for treatment of congestive heart failure and $24.00
`for treatment of hypertension based on current maximum dosage
`recommendations. Therefore, eplerenone is approximately 6 to
`7 times more expensive than spironolactone for the treatment
`of either hypertension or congestive heart failure.
`
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