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warnings and cautions
5 WARNINGS AND PRECAUTIONS Hyperkalemia: Patients with decreased renal function and diabetics with proteinuria are at increased risk. Proper patient selection and monitoring and avoiding certain concomitant medications can minimize the risk. (5.1) 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. (5.4) 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 .] 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 , 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. CHF Post-MI : Most common adverse reactions (>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 FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. Table 2: Rates of Sex Hormone-Related Adverse Events in EPHESUS Rates in Males Rates in Females Gynecomastia Mastodynia Either Abnormal Vaginal Bleeding Eplerenone 0.4 % 0.1% 0.5% 0.4% Placebo 0.5 % 0.1% 0.6% 0.4% 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. Table 3: Rates (%) of Adverse Events Occurring in Placebo-Controlled Hypertension Studies in ≥1% of Patients Treated with Eplerenone (25 mg to 400 mg) and at a More Frequent Rate than in Placebo-Treated Patients Eplerenone (n=945) Placebo (n=372) Metabolic Hypercholesterolemia Hypertriglyceridemia 1 1 0 0 Digestive Diarrhea Abdominal pain 2 1 1 0 Urinary Albuminuria 1 0 Respiratory Coughing 2 1 Central/Peripheral Nervous System Dizziness 3 2 Body as a Whole Fatigue Influenza-like symptoms 2 2 1 1 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. Table 4: Rates of Sex Hormone-Related Adverse Events with Eplerenone in Hypertension Clinical Studies Rates in Males Rates in Females Gynecomastia Mastodynia Either Abnormal Vaginal Bleeding All controlled studies 0.5% 0.8% 1.0% 0.6% Controlled studies lasting ≥ 6 months 0.7% 1.3% 1.6% 0.8% Open label, long-term study 1.0% 0.3 % 1.0 % 2.1 % 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 frequency 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 5: Hypokalemia (<3.5 mEq/L) or Hyperkalemia (>5.5 or ≥6.0 mEq/L) in EPHESUS Potassium (mEq/L) Eplerenone (N=3,251) n (%) Placebo (N=3,237) n (%) <3.5 273 (8.4) 424 (13.1) >5.5 508 (15.6) 363 (11.2) ≥ 6.0 180 (5.5) 126 (3.9) 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 Clearance 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 Diabetes 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. Table 8: Increases in Serum Potassium in the Placebo-Controlled, Fixed-Dose Hypertension Studies of Eplerenone 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 1 200 139 0.19 1 400 104 0.36 8.7 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