Eplerenone Side Effects

Brand Names: Inspra

Please note - some side effects for Eplerenone may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Eplerenone - for the Consumer

Eplerenone

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Eplerenone:

Cough; diarrhea; dizziness; flu-like symptoms (fever, chills, muscle ache, tiredness); headache; stomach pain.

Seek medical attention right away if any of these SEVERE side effects occur when using Eplerenone:

Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); abnormal vaginal discharge; chest pain; enlarged or swollen breasts; irregular heartbeat; severe muscle weakness.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Eplerenone Side Effects - for the Professional

Eplerenone

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.

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 %

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*

* Estimated 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 Diabetes*

* Diabetes 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.

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.

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

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Side Effects by Body System - for Healthcare Professionals

Metabolic

Metabolic side effects have included hyperkalemia (>5.5 mEq/L). Hyperkalemia was observed in 2.6% of patients with creatinine clearance greater than 100 mL/min, in 5.6% of patients with creatinine clearance of 70 to 100 mL/min, and in 10.4% of patients with creatinine clearance less than 70 mL/min. The principal risk of eplerenone is hyperkalemia, which can result in serious, sometimes fatal arrhythmias.

Other metabolic side effects have included hypercholesterolemia and hypertriglyceridemia in 1% of patients.

Nervous system

Nervous system side effects have included dizziness (3%) and headache. In a pharmacokinetic study, headache was reported in 14% to 63% of patients.

General

General side effects have included fatigue and influenza-like symptoms.

Renal

Renal side effects have included albuminuria in 1% of patients.

Respiratory

Respiratory side effects have included cough in 2% of patients.

Gastrointestinal

Gastrointestinal side effects have included diarrhea in 2% and abdominal pain in 1% of patients.

Endocrine

Endocrine side effects have included gynecomastia (up to 1%) and mastodynia (up to 1.3%) of male patients. Abnormal vaginal bleeding was reported in 2.5% of female patients.

Hepatic

Hepatic side effects have included increases in serum alanine aminotransferase (ALT) and gamma glutamyl transpeptidase (GGT).

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