Label: EPLERENONE- eplerenone tablet, film coated

  • NDC Code(s): 0378-1030-05, 0378-1030-10, 0378-1030-77, 0378-1030-93, view more
    0378-1031-05, 0378-1031-10, 0378-1031-77, 0378-1031-93
  • Packager: Mylan Pharmaceuticals Inc.
  • Category: HUMAN PRESCRIPTION DRUG LABEL
  • DEA Schedule: None
  • Marketing Status: Abbreviated New Drug Application

Drug Label Information

Updated January 4, 2017

If you are a consumer or patient please visit this version.

  • HIGHLIGHTS OF PRESCRIBING INFORMATION
    These highlights do not include all the information needed to use EPLERENONE TABLETS safely and effectively. See full prescribing information for EPLERENONE TABLETS.

    EPLERENONE tablets, for oral use
    Initial U.S. Approval: 2002

    INDICATIONS AND USAGE

    Eplerenone tablets are an aldosterone antagonist indicated for:

    the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. ( 1.2)

    DOSAGE AND ADMINISTRATION

    Hypertension: 50 mg once daily. For inadequate response, increase to 50 mg twice daily. Higher dosages are not recommended. (2.2)

    For all patients:

    Measure serum potassium before starting eplerenone tablets and periodically thereafter. (2.3)

    DOSAGE FORMS AND STRENGTHS

    Tablets: 25 mg, 50 mg (3)

    CONTRAINDICATIONS

    For all patients:

    Serum potassium > 5.5 mEq/L at initiation ( 4)
    Creatinine clearance ≤ 30 mL/min ( 4)
    Concomitant use with strong CYP3A4 inhibitors ( 4, 7.1)

    For the treatment of hypertension:

    Type 2 diabetes with microalbuminuria ( 4)
    Serum creatinine > 2.0 mg/dL in males, > 1.8 mg/dL in females ( 4)
    Creatinine clearance < 50 mL/min ( 4)
    Concomitant use of potassium supplements or potassium-sparing diuretics ( 4)

    WARNINGS AND PRECAUTIONS

    Hyperkalemia: Patients with decreased renal function, diabetes, proteinuria or patients who are taking ARBs, NSAIDs or moderate CYP3A inhibitors are at increased risk. Monitor serum potassium levels and adjust dose as needed. ( 5.1)

    ADVERSE REACTIONS

    Hypertension: In clinical studies, adverse reactions with eplerenone tablets were uncommon. (6.1)

        

    To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

    DRUG INTERACTIONS

    CYP3A4 Inhibitors: In patients with hypertension initiate at 25 mg once daily. For inadequate blood pressure response, dosing may be increased to a maximum of 25 mg twice daily. (2.4, 7.1, 12.3)

    See 17 for PATIENT COUNSELING INFORMATION.

    Revised: 1/2017

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  • FULL PRESCRIBING INFORMATION: CONTENTS*
  • 1 INDICATIONS AND USAGE

    1.2 Hypertension

    Eplerenone tablets are indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular (CV) events, primarily strokes and MI. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes.

    Control of high blood pressure should be part of comprehensive CV risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

    Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce CV morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent CV outcome benefit has been a reduction in the risk of stroke, but reductions in MI and CV mortality also have been seen regularly.

    Elevated systolic or diastolic pressure causes increased CV risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

    Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.

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  • 2 DOSAGE AND ADMINISTRATION

    2.2 Hypertension

    The recommended starting dose of eplerenone tablets is 50 mg administered once daily. The full therapeutic effect of eplerenone tablets is apparent within 4 weeks. For patients with an inadequate blood pressure response to 50 mg once daily increase the dosage of eplerenone tablets to 50 mg twice daily. Higher dosages of eplerenone tablets are not recommended because they have no greater effect on blood pressure than 100 mg and are associated with an increased risk of hyperkalemia [see Clinical Studies (14.2)].

    2.3 Recommended Monitoring

    Measure serum potassium before initiating eplerenone tablet therapy, within the first week, and at one month after the start of treatment or dose adjustment. Assess serum potassium periodically thereafter.

    Check serum potassium and serum creatinine within 3 to 7 days of a patient initiating a moderate CYP3A inhibitor, angiotensin-II blockers or nonsteroidal anti-inflammatories.

    2.4 Dose Modifications for Use with Moderate CYP3A Inhibitors

    In patients with hypertension receiving 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 Drug Interactions (7.1)].

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  • 3 DOSAGE FORMS AND STRENGTHS

    Eplerenone Tablets are available containing 25 mg or 50 mg of eplerenone.

    The 25 mg tablets are yellow, film-coated, round, unscored tablets debossed with M on one side of the tablet and EP1 on the other side.
    The 50 mg tablets are yellow, film-coated, round, unscored tablets debossed with M on one side of the tablet and EP2  on the other side.
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  • 4 CONTRAINDICATIONS

    For All Patients: Eplerenone tablets are contraindicated in all patients with:

    serum potassium > 5.5 mEq/L at initiation,
    creatinine clearance ≤ 30 mL/min, or
    concomitant administration of strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, and nelfinavir) [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

    For Patients Treated for Hypertension: Eplerenone tablets are contraindicated for the treatment of hypertension in patients with:

    type 2 diabetes with microalbuminuria,
    serum creatinine > 2.0 mg/dL in males or > 1.8 mg/dL in females,
    creatinine clearance < 50 mL/min, or
    concomitant administration of potassium supplements or potassium-sparing diuretics (e.g., amiloride, spironolactone, or triamterene) [see Warnings and Precautions (5.1), Adverse Reactions (6.2), Drug Interactions (7), and Clinical Pharmacology (12.3)].
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  • 5 WARNINGS AND PRECAUTIONS

    5.1 Hyperkalemia

    The risk of hyperkalemia is higher in patients with impaired renal function, proteinuria, diabetes and those concomitantly treated with ARBs, NSAIDs and moderate CYP3A inhibitors. Minimize the risk of hyperkalemia with proper patient selection and monitoring [see Contraindications (4), Adverse Reactions (6.2), and Drug Interactions (7)]. Monitor patients for the development of hyperkalemia until the effect of eplerenone tablets is established. Patients who develop hyperkalemia (5.5 to 5.9 mEq/L) may continue eplerenone tablet therapy with proper dose adjustment. Dose reduction decreases potassium levels. Patients on moderate CYP3A inhibitors that cannot be avoided should have their dose of eplerenone reduced [see Drug Interactions (7.2)].

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  • 6 ADVERSE REACTIONS

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

    Hyperkalemia [see Warnings and Precautions (5.1)]

    6.1 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.

    Hypertension

    Eplerenone tablets have 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 tablets 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 tablets and 3% of patients given placebo. The most common reasons for discontinuation of eplerenone tablets were headache, dizziness, angina pectoris/MI, and increased GGT.

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

    6.2 Postmarketing Experience

    The following adverse reactions have been identified during postapproval use of eplerenone tablets. 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

       

    6.3 Clinical Laboratory Test Findings

    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.

    Table 4. Increases in Serum Potassium in the Placebo-Controlled, Fixed-Dose Hypertension Studies of Eplerenone Tablets

    Mean Increase mEq/L

    % > 5.5 mEq/L

    Daily Dosage

    n

    Placebo

    194

    0

    1

    25

    97

    0.08

    0

    50

    245

    0.14

    0

    100

    193

    0.09

    1

     

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  • 7 DRUG INTERACTIONS

    7.1 CYP3A Inhibitors

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

    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)].

    7.2 Angiotensin II Receptor Antagonists

    The risk of hyperkalemia increases when eplerenone is used in combination with 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)].

    7.3 Lithium

    A drug interaction study of eplerenone with lithium has not been conducted. Serum lithium levels should be monitored frequently if eplerenone tablets are administered concomitantly with lithium.

    7.4 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 tablets and NSAIDs are used concomitantly, monitor blood pressure and serum potassium levels.

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  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Pregnancy Category B

    There are no adequate and well-controlled studies in pregnant women. Eplerenone tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

    Teratogenic Effects

    Embryo-fetal development studies were conducted with doses up to 1000 mg/kg/day in rats and 300 mg/kg/day in rabbits (exposures up to 32 and 31 times the human AUC for the 100 mg/day therapeutic dose, respectively). No teratogenic effects were seen in rats or rabbits, although decreased body weight in maternal rabbits and increased rabbit fetal resorptions and post-implantation loss were observed at the highest administered dosage. Because animal reproduction studies are not always predictive of human response, eplerenone tablets should be used during pregnancy only if clearly needed.

    8.3 Nursing Mothers

    The concentration of eplerenone in human breast milk after oral administration is unknown. However, preclinical data show that eplerenone and/or metabolites are present in rat breast milk (0.85:1 [milk:plasma] AUC ratio) obtained after a single oral dose. Peak concentrations in plasma and milk were obtained from 0.5 to 1 hour after dosing. Rat pups exposed by this route developed normally. Because many drugs are excreted in human milk and because of the unknown potential for adverse effects on the nursing infant, decide whether to discontinue nursing or discontinue the drug.

    8.4 Pediatric Use

    In a 10-week study of 304 hypertensive pediatric patients age 4 to 16 years treated with eplerenone tablets up to 100 mg per day, doses that produced exposure similar to that in adults, eplerenone tablets did not lower blood pressure effectively. In this study and in a 1-year pediatric safety study in 149 patients (age range 5 to 17 years), the incidence of reported adverse events was similar to that of adults.

    Eplerenone tablets have not been studied in hypertensive patients less than 4 years old because the study in older pediatric patients did not demonstrate effectiveness.

    Eplerenone tablets have not been studied in pediatric patients with heart failure.

    8.5 Geriatric Use

    Hypertension

    Of the total number of subjects in clinical hypertension studies of eplerenone tablets, 1123 (23%) were 65 and over, while 212 (4%) were 75 and over. No overall differences in safety or effectiveness were observed between elderly subjects and younger subjects, however due to age-related decreases in creatine clearance, the risk of hyperkalemia may be increased [see Warnings and Precautions (5.1)].

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  • 10 OVERDOSAGE

    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.

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  • 11 DESCRIPTION

    Eplerenone tablets contain eplerenone, a blocker of aldosterone binding at the mineralocorticoid receptor.

    Eplerenone is chemically described as 9α,11α-Epoxy-17β-hydroxy-3-oxo-17α-pregn-4-ene-7α,21-dicarboxylic acid γ-lactone 7- methyl ester. Its molecular formula is C24H30O6 and it has a molecular weight of 414.50. The structural formula of eplerenone is represented below:

    Eplerenone Structural Formula

    eplerenone

    Eplerenone is an odorless, white, almost white or slightly yellow crystalline powder. It is very slightly soluble in water, with its solubility essentially pH-independent. The octanol/water partition coefficient of eplerenone is approximately 7.1 at pH 7.0.

    Eplerenone tablets for oral administration contain 25 mg or 50 mg of eplerenone and the following inactive ingredients: croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, red iron oxide, sodium lauryl sulfate, talc, titanium dioxide and yellow iron oxide.

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  • 12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    Eplerenone binds to the mineralocorticoid receptor and blocks the binding of aldosterone, a component of the renin-angiotensin-aldosterone-system (RAAS). Aldosterone synthesis, which occurs primarily in the adrenal gland, is modulated by multiple factors, including angiotensin II and non-RAAS mediators such as adrenocorticotropic hormone (ACTH) and potassium. Aldosterone binds to mineralocorticoid receptors in both epithelial (e.g., kidney) and nonepithelial (e.g., heart, blood vessels, and brain) tissues and increases blood pressure through induction of sodium reabsorption and possibly other mechanisms.

    Eplerenone has been shown to produce sustained increases in plasma renin and serum aldosterone, consistent with inhibition of the negative regulatory feedback of aldosterone on renin secretion. The resulting increased plasma renin activity and aldosterone circulating levels do not overcome the effects of eplerenone.

    Eplerenone selectively binds to human mineralocorticoid receptors relative to its binding to recombinant human glucocorticoid, progesterone, and androgen receptors.

    12.3 Pharmacokinetics

    Eplerenone is cleared predominantly by cytochrome P450 (CYP) 3A4 metabolism, with an elimination half-life of 3 to 6 hours. Steady state is reached within 2 days. Absorption is not affected by food. Inhibitors of CYP3A (e.g., ketoconazole, saquinavir) increase blood levels of eplerenone.

    Absorption and Distribution

    Mean peak plasma concentrations of eplerenone are reached approximately 1.5 to 2 hours following oral administration. Absorption is not affected by food. The absolute bioavailability of eplerenone is 69% following administration of a 100 mg oral tablet. Both peak plasma levels (Cmax) and area under the curve (AUC) are dose proportional for doses of 25 mg to 100 mg and less than proportional at doses above 100 mg. Upon repeat dosing, steady state levels are reached within 2 days.

    The plasma protein binding of eplerenone is about 50% and it is primarily bound to alpha 1-acid glycoproteins. The apparent volume of distribution at steady state ranged from 42 L to 90 L. Eplerenone does not preferentially bind to red blood cells.

    Metabolism and Excretion

    Eplerenone metabolism is primarily mediated via CYP3A4. No active metabolites of eplerenone have been identified in human plasma.

    Less than 5% of an eplerenone dose is recovered as unchanged drug in the urine and feces. Following a single oral dose of radiolabeled drug, approximately 32% of the dose was excreted in the feces and approximately 67% was excreted in the urine. The elimination half-life of eplerenone is approximately 3 to 6 hours. The apparent plasma clearance is approximately 10 L/hr.

    Age, Gender, and Race

    The pharmacokinetics of eplerenone at a dose of 100 mg once daily has been investigated in the elderly (≥ 65 years), in males and females, and in Blacks. At steady state, elderly subjects had increases in Cmax (22%) and AUC (45%) compared with younger subjects (18 to 45 years). The pharmacokinetics of eplerenone did not differ significantly between males and females. At steady state, Cmax was 19% lower and AUC was 26% lower in Blacks [see Dosage and Administration (2.4) and Use in Specific Populations (8.5)].

    Renal Impairment

    The pharmacokinetics of eplerenone was evaluated in patients with varying degrees of renal impairment and in patients undergoing hemodialysis. Compared with control subjects, steady state AUC and Cmax were increased by 38% and 24%, respectively, in patients with severe renal impairment and were decreased by 26% and 3%, respectively, in patients undergoing hemodialysis. No correlation was observed between plasma clearance of eplerenone and creatinine clearance. Eplerenone is not removed by hemodialysis [see Warnings and Precautions (5.3)].

    Hepatic Impairment

    The pharmacokinetics of eplerenone 400 mg has been investigated in patients with moderate (Child-Pugh Class B) hepatic impairment and compared with normal subjects. Steady state Cmax and AUC of eplerenone were increased by 3.6% and 42%, respectively.

    Heart Failure

    The pharmacokinetics of eplerenone 50 mg was evaluated in 8 patients with heart failure (NYHA classification II–IV) and 8 matched (gender, age, weight) healthy controls. Compared with the controls, steady state AUC and Cmax in patients with stable heart failure were 38% and 30% higher, respectively.

    Drug-Drug Interactions

    Eplerenone is metabolized primarily by CYP3A4. Inhibitors of CYP3A cause increased exposure [see Drug Interactions (7.1)].

    Drug-drug interaction studies were conducted with a 100 mg dose of eplerenone.

    Following a single dose of eplerenone tablets 100 mg and CYP3A inhibitor ketoconazole 200 mg twice a day, eplerenone’s Cmax was 1.7-fold and AUC was 5.4-fold compared with eplerenone alone.

    Administration of eplerenone with moderate CYP3A inhibitors (e.g., erythromycin 500 mg BID, verapamil 240 mg once daily, saquinavir 1200 mg three times a day, fluconazole 200 mg once daily) resulted in increases in Cmax of eplerenone ranging from 40% to 60% and AUC from 100% to 190%.

    Grapefruit juice caused a 25% increase in exposure.

    Eplerenone is not an inhibitor of CYP1A2, CYP3A4, CYP2C19, CYP2C9, or CYP2D6. Eplerenone did not inhibit the metabolism of amiodarone, amlodipine, astemizole, chlorzoxazone, cisapride, dexamethasone, dextromethorphan, diclofenac, 17α-ethinyl estradiol, fluoxetine, losartan, lovastatin, mephobarbital, methylphenidate, methylprednisolone, metoprolol, midazolam, nifedipine, phenacetin, phenytoin, simvastatin, tolbutamide, triazolam, verapamil, or warfarin in vitro. Eplerenone is not a substrate or an inhibitor of P-Glycoprotein at clinically relevant doses.

    No clinically significant drug-drug pharmacokinetic interactions were observed when eplerenone was administered with cisapride, cyclosporine, digoxin, glyburide, midazolam, oral contraceptives (norethindrone/ethinyl estradiol), simvastatin, or warfarin. St. John’s wort (a CYP3A inducer) caused a small (about 30%) decrease in eplerenone AUC.

    No significant changes in eplerenone pharmacokinetics were observed when eplerenone was administered with aluminum- and magnesium-containing antacids.

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  • 13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    Eplerenone was non-genotoxic in a battery of assays including in vitro bacterial mutagenesis (Ames test in Salmonella spp. and E. Coli), in vitro mammalian cell mutagenesis (mouse lymphoma cells), in vitro chromosomal aberration (Chinese hamster ovary cells), in vivo rat bone marrow micronucleus formation, and in vivo/ex vivo unscheduled DNA synthesis in rat liver.

    There was no drug-related tumor response in heterozygous P53 deficient mice when tested for 6 months at dosages up to 1000 mg/kg/day (systemic AUC exposures up to 9 times the exposure in humans receiving the 100 mg/day therapeutic dose). Statistically significant increases in benign thyroid tumors were observed after 2 years in both male and female rats when administered eplerenone 250 mg/kg/day (highest dose tested) and in male rats only at 75 mg/kg/day. These dosages provided systemic AUC exposures approximately 2 to 12 times higher than the average human therapeutic exposure at 100 mg/day. Repeat dose administration of eplerenone to rats increases the hepatic conjugation and clearance of thyroxin, which results in increased levels of TSH by a compensatory mechanism. Drugs that have produced thyroid tumors by this rodent-specific mechanism have not shown a similar effect in humans.

    Male rats treated with eplerenone at 1000 mg/kg/day for 10 weeks (AUC 17 times that at the 100 mg/day human therapeutic dose) had decreased weights of seminal vesicles and epididymides and slightly decreased fertility. Dogs administered eplerenone at dosages of 15 mg/kg/day and higher (AUC 5 times that at the 100 mg/day human therapeutic dose) had dose-related prostate atrophy. The prostate atrophy was reversible after daily treatment for 1 year at 100 mg/kg/day. Dogs with prostate atrophy showed no decline in libido, sexual performance, or semen quality. Testicular weight and histology were not affected by eplerenone in any test animal species at any dosage.

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  • 14 CLINICAL STUDIES

    14.2 Hypertension

    The safety and efficacy of eplerenone tablets have been evaluated 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 mmHg were conducted to assess the antihypertensive effect of eplerenone tablets. In these two studies, 611 patients were randomized to eplerenone tablets and 140 patients to placebo. Patients received eplerenone tablets 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 tablets in these studies at doses up to 200 mg are shown in Figures 3 and 4. 

    Figure 3. Eplerenone Dose Response – Trough Cuff SBP Placebo-Subtracted Adjusted Mean Change from Baseline in Hypertension Studies

    Figure 3. Eplerenone Tablets Dose Response – Trough Cuff SBP Placebo-Subtracted Adjusted Mean Change from Baseline in Hypertension Studies

       

    Figure 4. Eplerenone Dose Response – Trough Cuff DBP Placebo-Subtracted Adjusted Mean Change from Baseline in Hypertension Studies

    Figure 4. Eplerenone Tablets Dose Response – Trough Cuff DBP Placebo-Subtracted Adjusted Mean Change from Baseline in Hypertension Studies

    Patients treated with eplerenone tablets 50 mg to 200 mg daily experienced significant decreases in sitting systolic and diastolic blood pressure at trough with differences from placebo of 6 to 13 mmHg (systolic) and 3 to 7 mmHg (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 tablets, administered once or twice daily, maintained antihypertensive efficacy over the entire dosing interval. However, at a total daily dose of 100 mg, eplerenone tablets administered as 50 mg twice per day produced greater trough cuff (4/3 mmHg) and ABPM (2/1 mmHg) blood pressure reductions than 100 mg given once daily.

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

    Blood pressure reductions with eplerenone tablets 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 tablets.

    Eplerenone tablets have been studied concomitantly with treatment with ARBs, calcium channel blockers, and beta-blockers. When administered concomitantly with one of these drugs, eplerenone tablets usually produced its expected antihypertensive effects.

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

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  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    Eplerenone Tablets are available containing 25 mg or 50 mg of eplerenone.

    The 25 mg tablets are yellow, film-coated, round, unscored tablets debossed with M on one side of the tablet and EP1 on the other side. They are available as follows:

    NDC 0378-1030-93
    bottles of 30 tablets

    NDC 0378-1030-77
    bottles of 90 tablets

    NDC 0378-1030-05
    bottles of 500 tablets

    NDC 0378-1030-10
    bottles of 1000 tablets

    The 50 mg tablets are yellow, film-coated, round, unscored tablets debossed with M on one side of the tablet and EP2 on the other side. They are available as follows:

    NDC 0378-1031-93
    bottles of 30 tablets

    NDC 0378-1031-77
    bottles of 90 tablets

    NDC 0378-1031-05
    bottles of 500 tablets

    NDC 0378-1031-10
    bottles of 1000 tablets

    Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

    Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

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  • 17 PATIENT COUNSELING INFORMATION

    Advise patients receiving eplerenone tablets:

    Not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing physician [see Warnings and Precautions (5.1)].
    To call their physician if they experience dizziness, diarrhea, vomiting, rapid or irregular heartbeat, lower extremity edema, or difficulty breathing [see Warnings and Precautions (5.1)].

    Manufactured for:
    Mylan Pharmaceuticals Inc.
    Morgantown, WV 26505 U.S.A.

    Manufactured by:
    Unichem Laboratories Limited
    Plot No. 17 & 18, Pilerne Industrial Estate, Pilerne,
    Bardez, Pilerne, Goa 403511, India

    Code No.: GO/DRUGS/321

    13009206

    Revised: 1/2017
    UN:EPLR:R5

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  • PRINCIPAL DISPLAY PANEL – 25 mg

    NDC 0378-1030-93

    Eplerenone
    Tablets
    25 mg

    Rx only     30 Tablets

    Each film-coated tablet contains:
    Eplerenone          25 mg

    Usual Dosage: See accompanying
    prescribing information.

    Keep this and all medication out of
    the reach of children.

    Store at 20° to 25°C (68° to 77°F). [See
    USP Controlled Room Temperature.]

    Manufactured for:
    Mylan Pharmaceuticals Inc.
    Morgantown, WV 26505 U.S.A.

    Made in India

    Mylan.com

    RUN1030H1

    Dispense in a tight, light-resistant
    container as defined in the USP
    using a child-resistant closure.

    Keep container tightly closed.

    Code No. GO/DRUGS/321

    Eplerenone Tablets 25 mg Bottle Label
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  • PRINCIPAL DISPLAY PANEL – 50 mg

    NDC 0378-1031-93

    Eplerenone
    Tablets
    50 mg

    Rx only     30 Tablets

    Each film-coated tablet contains:
    Eplerenone          50 mg

    Usual Dosage: See accompanying
    prescribing information.

    Keep this and all medication out of
    the reach of children.

    Store at 20° to 25°C (68° to 77°F). [See
    USP Controlled Room Temperature.]

    Manufactured for:
    Mylan Pharmaceuticals Inc.
    Morgantown, WV 26505 U.S.A.

    Made in India

    Mylan.com

    RUN1031H1

    Dispense in a tight, light-resistant
    container as defined in the USP
    using a child-resistant closure.

    Keep container tightly closed.

    Code No. GO/DRUGS/321

    Eplerenone Tablets 50 mg Bottle Label
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  • INGREDIENTS AND APPEARANCE
    EPLERENONE 
    eplerenone tablet, film coated
    Product Information
    Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0378-1030
    Route of Administration ORAL
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    EPLERENONE (UNII: 6995V82D0B) (EPLERENONE - UNII:6995V82D0B) EPLERENONE 25 mg
    Inactive Ingredients
    Ingredient Name Strength
    CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)  
    HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)  
    LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)  
    POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A)  
    POLYSORBATE 80 (UNII: 6OZP39ZG8H)  
    FERRIC OXIDE RED (UNII: 1K09F3G675)  
    SODIUM LAURYL SULFATE (UNII: 368GB5141J)  
    TALC (UNII: 7SEV7J4R1U)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    FERRIC OXIDE YELLOW (UNII: EX438O2MRT)  
    Product Characteristics
    Color YELLOW Score no score
    Shape ROUND Size 6mm
    Flavor Imprint Code M;EP1
    Contains     
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:0378-1030-93 30 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 10/03/2017
    2 NDC:0378-1030-77 90 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 10/03/2017
    3 NDC:0378-1030-05 500 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 10/03/2027
    4 NDC:0378-1030-10 1000 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 10/03/2027
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    ANDA ANDA203896 10/03/2017
    EPLERENONE 
    eplerenone tablet, film coated
    Product Information
    Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0378-1031
    Route of Administration ORAL
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    EPLERENONE (UNII: 6995V82D0B) (EPLERENONE - UNII:6995V82D0B) EPLERENONE 50 mg
    Inactive Ingredients
    Ingredient Name Strength
    CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)  
    HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)  
    LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)  
    POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A)  
    POLYSORBATE 80 (UNII: 6OZP39ZG8H)  
    FERRIC OXIDE RED (UNII: 1K09F3G675)  
    SODIUM LAURYL SULFATE (UNII: 368GB5141J)  
    TALC (UNII: 7SEV7J4R1U)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    FERRIC OXIDE YELLOW (UNII: EX438O2MRT)  
    Product Characteristics
    Color YELLOW Score no score
    Shape ROUND Size 8mm
    Flavor Imprint Code M;EP2
    Contains     
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:0378-1031-93 30 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 10/03/2017
    2 NDC:0378-1031-77 90 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 10/03/2017
    3 NDC:0378-1031-05 500 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 10/03/2027
    4 NDC:0378-1031-10 1000 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 10/03/2027
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    ANDA ANDA203896 10/03/2017
    Labeler - Mylan Pharmaceuticals Inc. (059295980)
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