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warnings and cautions
5 WARNINGS AND PRECAUTIONS Hyperkalemia: Patients with decreased renal function, diabetes, proteinuria or patients who are taking ACEs and ARBs, NSAIDs or moderate CYP3A inhibitors are at increased risk. Monitor serum potassium levels and adjust dose as needed. ( 5.1 ) 5.1 Hyperkalemia 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. Minimize the risk of hyperkalemia with proper patient selection and monitoring [see DOSAGE AND ADMINISTRATION (2.1) , CONTRAINDICATIONS (4) , ADVERSE REACTIONS (6.2) , and DRUG INTERACTIONS (7) ]. Monitor patients for the development of hyperkalemia until the effect of eplerenone is established. Patients who develop hyperkalemia (5.5 mEq/L to 5.9 mEq/L) may continue eplerenone 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) ].
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) ] HFrEF Post-MI: Most common adverse reactions (greater than 2% and more frequent than with placebo): hyperkalemia and increased creatinine. ( 6.1 ) Hypertension: In clinical studies, adverse reactions with eplerenone were uncommon. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AvKARE at 1-855-361-3993 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. 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, 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 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/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. 6.2 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 6.3 Clinical Laboratory Test Findings 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 (less than 3.5 mEq/L or greater than 5.5 mEq/L or greater than or equal to 6.0 mEq/L) receiving eplerenone compared with placebo are displayed in Table 2. Table 2. Hypokalemia (less than 3.5 mEq/L) or Hyperkalemia (greater than 5.5 or greater than or equal to 6.0 mEq/L) in EPHESUS Potassium (mEq/L) Eplerenone (N=3,251) n (%) Placebo (N=3,237) n (%) Rates of hyperkalemia increased with decreasing renal function. less than 3.5 273 (8.4) 424 (13.1) greater than 5.5 508 (15.6) 363 (11.2) Greater than or equal to 6.0 180 (5.5) 126 (3.9) Table 3. Rates of Hyperkalemia (greater than 5.5 mEq/L) in EPHESUS by Baseline Creatinine Clearance Estimated using the Cockroft-Gault formula. Baseline Creatinine Clearance Eplerenone (N=508) n (%) Placebo (N=363) n (%) less than or equal to 30 mL/min 160 (32) 82 (23) 31 mL/min to 50 mL/min 122 (24) 46 (13) 51mL/min to 70 mL/min 86 (17) 48 (13) greater than 70 mL/min 56 (11) 32 (9) 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 greater than 5.5 mEq/L. Table 4. Increases in Serum Potassium in the Placebo-Controlled, Fixed-Dose Hypertension Studies of Eplerenone Mean Increase mEq/L % greater than 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 To report SUSPECTED ADVERSE REACTIONS contact AvKARE at 1-855-361-3993; email drugsafety@avkare.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
adverse reactions table
<table width="80%"><caption>Table 2. Hypokalemia (less than 3.5 mEq/L) or Hyperkalemia (greater than 5.5 or greater than or equal to 6.0 mEq/L) in EPHESUS</caption><col width="33%" align="center" valign="top"/><col width="34%" align="center" valign="top"/><col width="33%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule">Potassium (mEq/L) </th><th styleCode="Rrule">Eplerenone (N=3,251) n (%) </th><th styleCode="Rrule">Placebo (N=3,237) n (%) </th></tr></thead><tfoot><tr><td colspan="3" align="left" valign="top">Rates of hyperkalemia increased with decreasing renal function.</td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">less than 3.5</td><td styleCode="Rrule">273 (8.4)</td><td styleCode="Rrule">424 (13.1)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">greater than 5.5</td><td styleCode="Rrule">508 (15.6)</td><td styleCode="Rrule">363 (11.2)</td></tr><tr><td styleCode="Lrule Rrule">Greater than or equal to 6.0</td><td styleCode="Rrule">180 (5.5)</td><td styleCode="Rrule">126 (3.9)</td></tr></tbody></table>
adverse reactions table
<table width="80%"><caption>Table 3. Rates of Hyperkalemia (greater than 5.5 mEq/L) in EPHESUS by Baseline Creatinine Clearance <footnote ID="K1452">Estimated using the Cockroft-Gault formula.</footnote></caption><col width="33%" align="center" valign="top"/><col width="34%" align="center" valign="top"/><col width="33%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule">Baseline Creatinine Clearance</th><th styleCode="Rrule">Eplerenone (N=508) n (%) </th><th styleCode="Rrule">Placebo (N=363) n (%) </th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">less than or equal to 30 mL/min</td><td styleCode="Rrule">160 (32)</td><td styleCode="Rrule">82 (23)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">31 mL/min to 50 mL/min</td><td styleCode="Rrule">122 (24)</td><td styleCode="Rrule">46 (13)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">51mL/min to 70 mL/min</td><td styleCode="Rrule">86 (17)</td><td styleCode="Rrule">48 (13)</td></tr><tr><td styleCode="Lrule Rrule">greater than 70 mL/min</td><td styleCode="Rrule">56 (11)</td><td styleCode="Rrule">32 (9)</td></tr></tbody></table>