Eplerenone

Eon Labs, Inc.

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use Eplerenone Tablets safely and effectively. See full prescribing information for Eplerenone Tablets.Initial U.S. Approval: 2002RECENT MAJOR CHANGESIndications and Usage: Benefits of lowering blood pressure (1.3) 06/2012Warnings and Precautions: Hyperkalemia (5.1) 05/2013Drug Interactions: ACE Inhibitors and Angiotension II Receptor Antagonists (7.2) 05/2012INDICATIONS AND USAGEEplerenone tablets are an aldosterone antagonist indicated for: •Improving survival of stable patients with LV systolic dysfunction (LVEF ≤40%) and CHF after an acute myocardial infarction. (1.2) •Hypertension, alone or combined with other agents. (1.3) Eplerenone tablets are 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.DOSAGE AND ADMINISTRATION CHF Post-MI: Initiate treatment with 25 mg once daily. Titrate to maximum of 50 mg once daily within 4 weeks, as tolerated. Dose adjustments may be required based on potassium levels. (2.1) Hypertension : 50 mg once daily, alone or combined with other antihypertensive agents. 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 STRENGTHSTablets: 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 2% and more frequent than with placebo): hyperkalemia and increased creatinine. (6.1) Hypertension : Most common adverse reactions (≥2% and more frequent than with placebo): dizziness, diarrhea, coughing, fatigue and flu-like symptoms. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS •CYP3A4 Inhibitors: Reduce the starting dose for hypertension to 25 mg once daily when used with moderate CYP3A4 inhibitors (e.g., verapamil, erythromycin, saquinavir, fluconazole). (2.4, 7.1, 12.3)

FULL PRESCRIBING INFORMATION: CONTENTS*

• 1 EPLERENONE INDICATIONS AND USAGE
  • 1.1 Patient Selection Considerations
  • 1.2 Congestive Heart Failure Post-Myocardial Infarction
  • 1.3 Hypertension
• 2 EPLERENONE DOSAGE AND ADMINISTRATION
  • 2.1 Congestive Heart Failure Post-Myocardial Infarction
  • 2.2 Hypertension
  • 2.3 Recommended Monitoring
  • 2.4 Dose Modifications for Specific Populations
• 3 DOSAGE FORMS AND STRENGTHS
• 4 EPLERENONE CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Hyperkalemia
  • 5.2 Impaired Hepatic Function
  • 5.3 Impaired Renal Function
  • 5.4 Allergic Reaction
• 6 EPLERENONE ADVERSE REACTIONS
  • 6.1 Clinical Trials Experience
  • 6.2 Clinical Laboratory Test Findings
  • 6.3 Post-Marketing Experience
• 7 DRUG INTERACTIONS
  • 7.1 CYP3A4 Inhibitors
  • 7.2 ACE Inhibitors and Angiotensin II Receptor Antagonists
  • 7.3 Lithium
  • 7.4 Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
• 10 OVERDOSAGE
• 11 EPLERENONE DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.3 Pharmacokinetics
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
• 14 CLINICAL STUDIES
  • 14.1 Congestive Heart Failure Post-Myocardial Infarction
  • 14.2 Hypertension
• 16 HOW SUPPLIED/STORAGE AND HANDLING
• 17 PATIENT COUNSELING INFORMATION
• Eplerenone 25 mg x 30 Tablets - Label
• Eplerenone 50 mg x 30 Tablets - Label

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Patient Selection Considerations

Serum potassium levels should be measured before initiating eplerenone tablet therapy and eplerenone tablets should not be prescribed if serum potassium is >5.5 mEq/L [see 4 CONTRAINDICATIONS].

1.2 Congestive Heart Failure Post-Myocardial Infarction

Eplerenone tablets are indicated to improve survival of stable patients with left ventricular (LV) systolic dysfunction (ejection fraction ≤40%) and clinical evidence of congestive heart failure (CHF) after an acute myocardial infarction (MI).

1.3 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 events, primarily strokes and myocardial infarctions. 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 cardiovascular 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 cardiovascular 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 cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular 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.

Eplerenone tablets may be used alone or in combination with other antihypertensive agents.

2 DOSAGE AND ADMINISTRATION

2.1 Congestive Heart Failure Post-Myocardial Infarction

Treatment should be initiated at 25 mg once daily and titrated to the recommended dose of 50 mg once daily, preferably within 4 weeks as tolerated by the patient. Eplerenone tablets may be administered with or without food.

Once treatment with eplerenone tablets has begun, adjust the dose based on the serum potassium level as shown in Table 1.

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 the dosage of eplerenone tablets should be increased 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 Hypertension ].

2.3 Recommended Monitoring

Serum potassium should be measured before initiating eplerenone tablet therapy, within the first week, and at one month after the start of treatment or dose adjustment. Serum potassium should be assessed periodically thereafter. Patient characteristics and serum potassium levels may indicate that additional monitoring is appropriate [see WARNINGS AND PRECAUTIONS, 5.1 Hyperkalemia, ADVERSE REACTIONS, 6.2 Clinical Laboratory Test Findings]. In the EPHESUS study [see CLINICAL STUDIES, 14.1 Congestive Heart Failure Post-Myocardial Infarction], the majority of hyperkalemia was observed within the first three months after randomization.

In all patients taking eplerenone tablets who start taking a moderate CYP3A4 inhibitor, check serum potassium and serum creatinine in 3 to 7 days.

2.4 Dose Modifications for Specific Populations

For hypertensive patients receiving moderate CYP3A4 inhibitors (e.g., erythromycin, saquinavir, verapamil and fluconazole), the starting dose of eplerenone tablets should be reduced to 25 mg once daily [see DRUG INTERACTIONS, 7.1 CYP3A4 Inhibitors].

No adjustment of the starting dose is recommended for the elderly or for patients with mild-to-moderate hepatic impairment [see CLINICAL PHARMACOLOGY, 12.3 Pharmacokinetics].

3 DOSAGE FORMS AND STRENGTHS

• •25 mg tablets: round, white, film-coated tablets debossed with "SZ" on one side and "12" on the other.
• •50 mg tablets: round, yellow, film-coated tablets debossed with "SZ" on one side and "16" on the other.

4 CONTRAINDICATIONS

For All Patients

Eplerenone is contraindicated in all patients with:

• •serum potassium >5.5 mEq/L at initiation,
• •creatinine clearance ≤30 mL/min, or
• •concomitant administration of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, and nelfinavir) [see DRUG INTERACTIONS, 7.1 CYP3A4 Inhibitors, CLINICAL PHARMACOLOGY, 12.3 Pharmacokinetics].

For Patients Treated for Hypertension

Eplerenone is 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 Hyperkalemia , ADVERSE REACTIONS, 6.2 Clinical Laboratory Test Findings , 7 DRUG INTERACTIONS, and CLINICAL PHARMACOLOGY, 12.3 Pharmacokinetics].

5 WARNINGS AND PRECAUTIONS

5.1 Hyperkalemia

Minimize the risk of hyperkalemia with proper patient selection and monitoring and avoidance of certain concomitant medications [see 4 CONTRAINDICATIONS, ADVERSE REACTIONS, 6.2 Clinical Laboratory Test Findings and 7 DRUG INTERACTIONS]. Monitor patients for the development of hyperkalemia until the effect of eplerenone is established. Patients who develop hyperkalemia (>5.5 mEq/L) may continue eplerenone therapy with proper dose adjustment. Dose reduction decreases potassium levels [see DOSAGE AND ADMINISTRATION, 2.1 Congestive Heart Failure Post-Myocardial Infarction ].

The rates of hyperkalemia increase with declining renal function [see ADVERSE REACTIONS, 6.2 Clinical Laboratory Test Findings]. Patients with hypertension who have serum creatinine levels >2.0 mg/dL (males) or >1.8 mg/dL (females) or creatinine clearance ≤50mL/min should not be treated with eplerenone [see 4 CONTRAINDICATIONS]. Patients with CHF post-MI who have serum creatinine levels >2.0 mg/dL (males) or >1.8 mg/dL (females) or creatinine clearance ≤50mL/min should be treated with eplerenone with caution.

Diabetic patients with CHF post-MI should also be treated with caution, especially those with proteinuria. The subset of patients in the EPHESUS study with both diabetes and proteinuria on the baseline urinalysis had increased rates of hyperkalemia compared to patients with either diabetes or proteinuria [see ADVERSE REACTIONS, 6.2 Clinical Laboratory Test Findings ].

The risk of hyperkalaemia may increase when eplerenone is used in combination with an angiotensin converting enzyme (ACE) inhibitor and/or an angiotensin receptor blocker (ARB) [see DRUG INTERACTIONS, (7.2)].

5.2 Impaired Hepatic Function

Mild-to-moderate hepatic impairment did not increase the incidence of hyperkalemia. In 16 subjects with mild-to-moderate hepatic impairment who received 400 mg of eplerenone, no elevations of serum potassium above 5.5 mEq/L were observed. The mean increase in serum potassium was 0.12 mEq/L in patients with hepatic impairment and 0.13 mEq/L in normal controls. The use of eplerenone in patients with severe hepatic impairment has not been evaluated [see CLINICAL PHARMACOLOGY, 12 CLINICAL PHARMACOLOGY ].

5.3 Impaired Renal Function

Patients with decreased renal function are at increased risk of hyperkalemia [see 4 CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, 5.1 Hyperkalemia , and ADVERSE REACTIONS, 6.1 Clinical Trials Experience].

5.4 Allergic Reaction

Eplerenone Tablets 50 mg contain FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

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 Hyperkalemia ]

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.

6.1 Clinical Trials Experience

Congestive Heart Failure Post-Myocardial Infarction

In EPHESUS, safety was evaluated in 3,307 patients treated with eplerenone and 3,301 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, myocardial infarction, 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. Hypokalemia occurred less frequently in patients treated with eplerenone (0.6% vs. 1.6%).

The rates of sex hormone-related adverse events are shown in Table 2.

Hypertension

Eplerenone has been evaluated for safety in 3,091 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/myocardial infarction, and increased GGT. The adverse events that were reported at a rate of at least 1% of patients and at a higher rate in patients treated with eplerenone in daily doses of 25 mg to 400 mg versus placebo are shown in Table 3.

Note: Adverse events that are too general to be informative or are very common in the treated population are excluded.

Gynecomastia and abnormal vaginal bleeding were reported with eplerenone but not with placebo. The rates of these sex hormone-related adverse events are shown in Table 4. The rates increased slightly with increasing duration of therapy. In females, abnormal vaginal bleeding was also reported in 0.8% of patients on antihypertensive medications (other than spironolactone) in active control arms of the studies with eplerenone.

6.2 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 Congestive Heart Failure Post-Myocardial Infarction ], 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 5.

Table 6 shows the rates of hyperkalemia in EPHESUS as assessed by baseline renal function (creatinine clearance).

Table 6: Rates of Hyperkalemia (>5.5 mEq/L)in EPHESUS by Baseline Creatinine ClearanceEstimated using the Cockroft-Gault formula.

Baseline Creatinine Clearance	Eplerenone (N=508) n (%)	Placebo (N=363) n (%)
≤30 mL/min	160 (32)	82 (23)
31–50 mL/min	122 (24)	46 (13)
51–70 mL/min	86 (17)	48 (13)
>70 mL/min	56 (11)	32 (9)

Table 7 shows the rates of hyperkalemia in EPHESUS as assessed by two baseline characteristics: presence/absence of proteinuria from baseline urinalysis and presence/absence of diabetes [see WARNINGS AND PRECAUTIONS, 5.1 Hyperkalemia ].

Table 7: Rates of Hyperkalemia ( >5.5 mEq/L)in EPHESUS by Proteinuria and History of DiabetesDiabetes assessed as positive medical history at baseline; proteinuria assessed by positive dipstick urinalysis at baseline.

	Eplerenone (N=508) n (%)	Placebo (N=363) n (%)
Proteinuria, no Diabetes	81 (16)	40 (11)
Diabetes, no Proteinuria	91 (18)	47 (13)
Proteinuria and Diabetes	132 (26)	58 (16)

Hypertension

Potassium: In placebo-controlled fixed-dose studies, the mean increases in serum potassium were dose-related and are shown in Table 8 along with the frequencies of values >5.5 mEq/L.

Patients with both type 2 diabetes and microalbuminuria are at increased risk of developing persistent hyperkalemia. In a study of such patients taking eplerenone 200 mg, the frequencies of maximum serum potassium levels >5.5 mEq/L were 33% with eplerenone given alone and 38% when eplerenone was given with enalapril.

Rates of hyperkalemia increased with decreasing renal function. In all studies, serum potassium elevations >5.5 mEq/L were observed in 10.4% of patients treated with eplerenone with baseline calculated creatinine clearance <70 mL/min, 5.6% of patients with baseline creatinine clearance of 70 mL/min to 100 mL/min, and 2.6% of patients with baseline creatinine clearance of >100 mL/min [see WARNINGS AND PRECAUTIONS, 5.1 Hyperkalemia ].

Sodium: Serum sodium decreased in a dose-related manner. Mean decreases ranged from 0.7 mEq/L at 50 mg daily to 1.7 mEq/L at 400 mg daily. Decreases in sodium (<135 mEq/L) were reported for 2.3% of patients administered eplerenone and 0.6% of placebo-treated patients.

Triglycerides: Serum triglycerides increased in a dose-related manner. Mean increases ranged from 7.1 mg/dL at 50 mg daily to 26.6 mg/dL at 400 mg daily. Increases in triglycerides (above 252 mg/dL) were reported for 15% of patients administered eplerenone and 12% of placebo-treated patients.

Cholesterol: Serum cholesterol increased in a dose-related manner. Mean changes ranged from a decrease of 0.4 mg/dL at 50 mg daily to an increase of 11.6 mg/dL at 400 mg daily. Increases in serum cholesterol values greater than 200 mg/dL were reported for 0.3% of patients administered eplerenone and 0% of placebo-treated patients.

Liver Function Tests: Serum alanine aminotransferase (ALT) and gamma glutamyl transpeptidase (GGT) increased in a dose-related manner. Mean increases ranged from 0.8 U/L at 50 mg daily to 4.8 U/L at 400 mg daily for ALT and 3.1 U/L at 50 mg daily to 11.3 U/L at 400 mg daily for GGT. Increases in ALT levels greater than 120 U/L (3 times upper limit of normal) were reported for 15/2,259 patients administered eplerenone and 1/351 placebo-treated patients. Increases in ALT levels greater than 200 U/L (5 times upper limit of normal) were reported for 5/2,259 of patients administered eplerenone and 1/351 placebo-treated patients. Increases of ALT greater than 120 U/L and bilirubin greater than 1.2 mg/dL were reported 1/2,259 patients administered eplerenone and 0/351 placebo-treated patients. Hepatic failure was not reported in patients receiving eplerenone.

BUN/ Creatinine : Serum creatinine increased in a dose-related manner. Mean increases ranged from 0.01 mg/dL at 50 mg daily to 0.03 mg/dL at 400 mg daily. Increases in blood urea nitrogen to greater than 30 mg/dL and serum creatinine to greater than 2 mg/dL were reported for 0.5% and 0.2%, respectively, of patients administered eplerenone and 0% of placebo-treated patients.

Uric Acid: Increases in uric acid to greater than 9 mg/dL were reported in 0.3% of patients administered eplerenone and 0% of placebo-treated patients.

6.3 Post-Marketing Experience

The following adverse reactions have been identified during post-approval 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

7 DRUG INTERACTIONS

7.1 CYP3A4 Inhibitors

Because eplerenone metabolism is predominantly mediated via CYP3A4, do not use eplerenone with drugs that are strong inhibitors of CYP3A4 [see 4 CONTRAINDICATIONS and CLINICAL PHARMACOLOGY, 12.3 Pharmacokinetics].

In patients with hypertension taking moderate CYP3A4 inhibitors, reduce the starting dose of eplerenone to 25 mg once daily [see DOSAGE AND ADMINISTRATION, 2.4 Dose Modifications for Specific Populations) and CLINICAL PHARMACOLOGY, 12.3 Pharmacokinetics].

7.2 ACE Inhibitors and Angiotensin II Receptor Antagonists

The risk of hyperkalaemia may increase when eplerenone is used in combination with an angiotensin converting enzyme (ACE) inhibitor and/or an angiotensin receptor blocker (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 Hyperkalemia ].

Congestive Heart Failure Post-Myocardial Infarction

In EPHESUS [see CLINICAL STUDIES, 14.1 Congestive Heart Failure Post-Myocardial Infarction], 3,020 (91%) patients receiving eplerenone 25 mg to 50 mg also received ACE inhibitors or angiotensin II receptor antagonists (ACEI/ARB). Rates of patients with maximum potassium levels >5.5 mEq/L were similar regardless of the use of ACEI/ARB.

Hypertension

In clinical studies of patients with hypertension, the addition of eplerenone 50 mg to 100 mg to ACE inhibitors and angiotensin II receptor antagonists increased mean serum potassium slightly (about 0.09 mEq/L to 0.13 mEq/L). In a study in diabetics with microalbuminuria, eplerenone 200 mg combined with the ACE inhibitor enalapril 10 mg increased the frequency of hyperkalemia (serum potassium >5.5 mEq/L) from 17% on enalapril alone to 38%.

7.3 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.

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 and NSAIDs are used concomitantly, patients should be observed to determine whether the desired effect on blood pressure is obtained and monitored for changes in serum potassium levels.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

There are no adequate and well-controlled studies in pregnant women. Eplerenone 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 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, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

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

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

Eplerenone has not been studied in pediatric patients with heart failure.

8.5 Geriatric Use

Congestive Heart Failure Post-Myocardial Infarction

Of the total number of patients in EPHESUS, 3,340 (50%) were 65 and over, while 1,326 (20%) were 75 and over. Patients greater than 75 years did not appear to benefit from the use of eplerenone [see CLINICAL STUDIES, 14.1 Congestive Heart Failure Post-Myocardial Infarction ].

No differences in overall incidence of adverse events were observed between elderly and younger patients. However, due to age-related decreases in creatinine clearance, the incidence of laboratory-documented hyperkalemia was increased in patients 65 and older [see WARNINGS AND PRECAUTIONS, 5.1 Hyperkalemia ].

Hypertension

Of the total number of subjects in clinical hypertension studies of eplerenone, 1,123 (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.

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 C_max exposures at least 25 times higher than in humans receiving eplerenone 100 mg/day. Dogs showed emesis, salivation, and tremors at a C_max 41 times the human therapeutic C_max, 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.

11 DESCRIPTION

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

Eplerenone is chemically described as Pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy-17-hydroxy-3-oxo-, γ-lactone, methyl ester, (7α,11α,17α)-. Its empirical formula is C₂₄H₃₀O₆ and it has a molecular weight of 414.50.

The structural formula of eplerenone is represented below: