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INSPRA (eplerenone)

Health Professional Information

SUMMARY PRODUCT INFORMATION

Route of Administration

Dosage Form / Strength

All Nonmedicinal Ingredients

Oral

Tablets 25 mg, 50 mg

Croscarmellose sodium, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium lauryl sulfate, talc, titanium dioxide, iron oxide yellow, and iron oxide red.

Indications And Clinical Use

INSPRA (eplerenone) is indicated as an adjunct to standard therapy to reduce the risk of cardiovascular mortality and hospitalization for heart failure in patients with NYHA class II systolic chronic heart failure and left ventricular systolic dysfunction.  In patients 75 years and older a reduction in cardiovascular mortality was not observed with INSPRA (see WARNINGS AND PRECAUTIONS - Special Populations - Geriatrics, and CLINICAL TRIALS – EMHASIS-HF Study).

INSPRA (eplerenone) is indicated as an adjunct to standard therapy to reduce the risk of mortality and hospitalization for heart failure following myocardial infarction in clinically stable adult patients who have evidence of heart failure and left ventricular systolic dysfunction (ejection fraction ≤40%). In patients 75 years and older a reduction in mortality was not observed with INSPRA (see WARNINGS AND PRECAUTIONS - Special Populations - Geriatrics, and CLINICAL TRIALS – EPHESUS Study).

INSPRA (eplerenone) is indicated for the treatment of mild and moderate essential hypertension, usually in combination with other drugs, for patients who cannot be treated adequately with other agents or for whom other agents are considered inappropriate.

Serum potassium level should be measured and glomerular filtration rate should be estimated before starting INSPRA therapy and INSPRA should not be administered if initial serum potassium is >5.0 mmol/L or if estimated glomerular filtration rate is <30 ml/min/1.73m2 (see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and DOSAGE AND ADMINISTRATION).

Contraindications

INSPRA (eplerenone) is contraindicated in all patients with the following:

  • hypersensitivity to INSPRA or any component of this medication (for a complete listing of the INSPRA components, see DOSAGE FORMS, COMPOSITION AND PACKAGING);
  • patients with clinically significant hyperkalemia;
  • severe hepatic impairment (Child-Pugh Class C);
  • serum potassium >5.0 mmol/L at initiation;
  • severe renal impairment [eGFR <30 mL/min/1.73m2];
  • concomitant use with potassium-sparing diuretics, potassium supplements or strong CYP3A4 inhibitors such as ketoconazole, itraconazole, nefazodone, telithromycin, clarithromycin, ritonavir, and nelfinavir (see DRUG INTERACTIONS and DOSAGE AND ADMINISTRATION).

INSPRA (eplerenone) is also contraindicated for the treatment of hypertension in patients with:

  • type 2 diabetes with microalbuminuria
  • serum creatinine >132µmol/L in males or > 115µmol/L in females
  •  moderate to severe renal impairment [eGFR<50 mL/min/1.73m2]

Warnings And Precautions

Hyperkalemia

The principal risk of INSPRA (eplerenone) is hyperkalemia. Hyperkalemia, if not recognized in a timely manner, can cause serious, sometimes fatal, arrhythmias. All patients prescribed INSPRA must have their serum potassium level measured before initiating INSPRA therapy, within one week and at one month after the first dose or after a dose adjustment, and measured periodically thereafter, as clinically warranted (see DOSAGE AND ADMINISTRATION).

Hyperkalemia can be minimized by appropriate patient selection, avoidance of certain concomitant treatments, thoroughly informing the patient and periodic monitoring until the effect of INSPRA has been established.

For patient selection and medications which should not be prescribed concomitantly with INSPRA or prescribed with caution, see CONTRAINDICATIONS, DRUG INTERACTIONS; and ADVERSE REACTIONS.

INSPRA should not be administered to heart failure patients with initial serum potassium >5.0 mmol/L, and/or eGFR <30mL/min/1.73m2. The incidence of hyperkalemia increases with declining renal function (see ADVERSE EVENTS, Tables 6 and 9).

INSPRA should not be administered to hypertensive patients with initial serum potassium >5.0 mmol/L, and/or eGFR <50 mL/min/1.73m2. In patients with hypertension who have reduced eGFR, serum potassium concentrations should be closely monitored when treated with INSPRA, especially when co-administrated with other antihypertensive drugs. Even in hypertensive patients with normal renal function, hyperkalemia may occur when treated with INSPRA (see ADVERSE REACTIONS, Table 11). Overdose is associated with a significantly increased frequency of hyperkalemia (serum potassium > 5.5mmol/L).

Diabetic patients with heart failure (HF) who are treated with INSPRA, especially those with proteinuria or renal impairment, should also be treated with caution as they have an increased risk of hyperkalemia. Patients with either diabetes or renal impairment / proteinuria also have an increased risk of hyperkalemia, however the incidence remains lower than in patients with both of these comorbidities (see ADVERSE REACTIONS, Tables 7 and 10).

Impaired Hepatic Function

In 16 subjects with mild-to-moderate hepatic impairment (Child-Pugh Class B) who received 400 mg of INSPRA, no elevations of serum potassium above 5.5 mmol/L were observed. Cmax was not significantly changed but AUC was increased by 42% and INSPRA clearance 30% lower compared to matched controls. The dose recommended is 8 times smaller and, therefore, no dose adjustment is necessary in patients with mild to moderate hepatic impairment.

The use of INSPRA in patients with severe hepatic impairment has not been evaluated and therefore, INSPRA is contraindicated in these patients (see CONTRAINDICATIONS, DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions).

Impaired Renal Function

See CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS – Hyperkalemia, ADVERSE REACTIONS.

Carcinogenesis, Mutagenesis

Preclinical studies of safety pharmacology, genotoxicity, carcinogenic potential and toxicity to reproduction revealed no special hazard for humans.

In repeat dose toxicity studies, prostate atrophy was observed in rats and dogs at exposure levels several-fold above clinical exposure levels. The prostatic changes were not associated with adverse functional consequences. The clinical relevance of these findings is unknown.

Studies in rats and rabbits showed no teratogenic effects, although decreased body weight in maternal rabbits and increased rabbit fetal resorptions and post-implantation loss were observed at the highest administered dosage.

Special Populations

Pregnant Women

There are no INSPRA studies in pregnant women. Eplerenone did not impair fertility and was not teratogenic in animals but the risk to the fetus of pregnant women is not known. Therefore, INSPRA should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus (see TOXICOLOGY).

Nursing Women

It has not been determined if INSPRA is present in human breast milk, however it was present in rat breast milk at a milk to plasma ratio of 0.85. 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 (see TOXICOLOGY).

Pediatrics

The safety and effectiveness of INSPRA have not been established in pediatric patients and INSPRA is not recommended in this patient population.

Geriatrics

There were 1641 (46%) patients treated with INSPRA in EPHESUS who were 65 and over, while 616 (18.6%) were 75 and over. Patients greater than 75 years did not appear to benefit from the use of INSPRA (see CLINICAL TRIALS – EPHESUS study).

There were 1854 (68%) patients treated with INSPRA in EMPHASIS-HF who were 65 years and over, while 657 (24%) were 75 years and over.Both subgroups of patients appeared to benefit from the use of INSPRA compared to placebo-treated patients, based on the results from the primary endpoint (composite endpoint CV mortality or hospitalization for heart failure) but these results were driven by a significant reduction of hospitalization for heart failure. While hospitalization for heart failure was reduced in all age groups, the study did not show a reduction in cardiovascular mortality with INSPRA in patients 75 years and older (see CLINICAL TRIALS – EMPHASIS-HF study).

Of the patients treated with INSPRA in hypertension studies, 629 (22%) were 65 years old and over, and 104 (3.7%) were 75 years old and over. No differences in safety or effectiveness were observed between elderly patients and younger subjects.

No initial dose adjustment is required in the elderly. Due to an age-related decline in renal function, the risk of hyperkalemia is increased in elderly patients. This risk may be further increased when co-morbidity associated with increased systemic exposure is also present, in particular mild-to-moderate hepatic impairment. Periodic monitoring of serum potassium is recommended.

Adverse Reactions

Clinical Trial Adverse Events

Because clinical trials are conducted under very specific conditions the adverse drug reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

NYHA Class II Chronic Heart Failure

EMPHASIS-HF study: NYHA Class II chronic heart failure

In the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF), safety was evaluated in 1364 patients treated with INSPRA and followed-up for a median duration of 675 days, and 1372 placebo-treated patients, followed-up for a median of 615 days during the double-blind phase of the trial. All causality adverse events that occurred in >2% of subjects treated with INSPRA (also incidence higher than placebo) are presented in Table 1.

Table 1. Incidence of Adverse Events ≥ 2% of Subjects in the INSPRA arm and more frequent than placebo, in the EMPHASIS-HF Study.
*
Judged as an adverse event by the investigator regardless of specific serum potassium value.
A dash indicates no statistically significant difference between treatment groups (p>0.05).

Body System

Adverse Event

INSPRA
25-50 mg QD
N=1364

Placebo
N=1372

P-value†

Blood and Lymphatic System Disorders

Anemia

32

(2.3%)

28

(2.0%)

-

Cardiac Disorders

Myocardial infarction

36

(2.6%)


34

(2.5%)

-

Gastrointestinal Disorders
Constipation

32

(2.3%)


15


(1.1%)

0.0123

Infections and Infestations
Nasopharyngitis
Upper respiratory tract infection

49

39

(3.6%)

(2.9%)


48

35

(3.5%)

(2.6%)

-

-

Metabolism and Nutrition Disorders
Diabetes mellitus
Hyperkalemia*

33

118

(2.4%)

(8.7%)


28

55


(2.0%)

(4.0%)

-

< 0.0001

Musculoskeletal and Connective Tissue Disorders

Pain in extremity

30

(2.2%)

29

(2.1%)

-

Nervous System Disorders

Dizziness

Headache

Syncope

66

35

37

(4.8%)

(2.6%)

(2.7%)

65

32

31

(4.7%)

(2.3%)

(2.3%)

-

-

-

Renal and Urinary Disorders

Renal impairment

68

(5.0%)

44

(3.2%)

0.0205

Respiratory, Thoracic and Mediastinal Disorders

Cough

57

(4.2%)

48

(3.5%)

-

Skin and Subcutaneous Tissue Disorders

Pruritus

29

(2.1%)

15

(1.1%)

0.0338

Vascular Disorders

Hypotension

55

(4.0%)

42

(3.1%)

-

The overall incidence of treatment-related adverse events reported with eplerenone versus placebo was 21.3% and 17.1%, respectively. The only treatment‑related AE that occurred in ≥ 2% of subjects in either treatment group was hyperkalemia (7.0% in the eplerenone group vs 2.9% in the placebo group).

A total of 1272 subjects reported serious adverse events (SAE); 586 subjects (43.0%) in the INSPRA group and 686 subjects (50.0%) in the placebo group.

A total of 472 subjects discontinued from the study due to adverse events; 215 subjects (15.8%) in the INSPRA group and 257 subjects (18.7%) in the placebo group. A total of 32 subjects discontinued due to hyperkalemia; 19 subjects (1.4%) in the INSPRA group and 13 subjects (0.9%) in the placebo group.

A summary of the incidence of hyperkalemia and hypokalemia is provided in Table 5.

Heart Failure following Myocardial Infarction

EPHESUS study: Post-myocardial infarction heart failure

In the eplerenone post-acute myocardial infarction heart failure efficacy and survival study (EPHESUS), safety was evaluated in 3307 patients treated with INSPRA and 3301 placebo-treated patients. Patients were followed for an average of 16 months (see CLINICAL TRIALS). Vital status was confirmed for 99.7% of patients.

The most serious adverse events in EPHESUS were endpoint events (e.g., death, cardiac failure) and these were significantly more frequent in the placebo treatment group. Serious adverse events that were significantly associated with eplerenone treatment included dehydration, arterial leg thrombosis, increased creatinine, and pyelonephritis; the incidence of these was low ( ≤ 0.5%).

Headache was the most frequent adverse reaction among eplerenone subjects in single- and multiple-dose trials. Adverse events that occurred more frequently in patients treated with INSPRA than placebo were hyperkalemia (summarized in Table 7). Eplerenone-treated patients also experienced more postural hypotension (0.7% vs 0.3% on placebo). Other adverse events more frequent during eplerenone treatment were increased blood urea nitrogen (BUN), increased creatinine, hypothyroidism, gastroesophageal reflux, pancreatitis, ketosis, arterial leg thrombosis, sepsis, and varicose veins. Hypokalemia (<3.5 mmol/l) occurred less frequently in patients treated with INSPRA (8.4% vs. 13.1%).

Elevation of serum potassium led to appropriate dose adjustments of eplerenone (see Table 16, Dose adjustment). Permanent discontinuations of eplerenone treatment due to hyperkalemia were infrequent (0.7% eplerenone vs 0.3% placebo); no eplerenone patient died from hyperkalemia. Sepsis led to permanent discontinuation of study medication in 2 eplerenone patients. No patients permanently discontinued study medication due to postural hypotension.

Adverse events experienced by ≥ 2.0% of subjects treated with INSPRA (also incidence higher than placebo) are presented in Table 2.

Table 2. Incidence of Adverse Events ≥ 2% of Subjects in the eplerenone arm and more frequent than placebo, in the EPHESUS Study.
From Fisher’s exact test. A dash indicates no statistically significant difference between treatment groups (p>0.05).

Body System

Adverse Event

INSPRA
25-50 mg QD
N=3307

Placebo
N=3301

P-value†

Autonomic Nervous System Disorders

Hypotension

Syncope

119

71

(3.6%)

(2.1%)

109

58

(3.3%)

(1.8%)

-

-

Body as a Whole - General Disorders

Asthenia

Chest Pain Non-Cardiac

Fatigue

Fever

89

213

95

67

(2.7%)

(6.4%)

(2.9%)

(2.4%)


68

206

91

65

(2.1%)

(6.2%)

(2.8%)

(2.0%)

-

-

-

-

Central and Peripheral Nervous System Disorders

Dizziness

Headache

214

126

(6.5%)

(3.8%)

197

119

(6.0%)

(3.6%)

-

-

Gastrointestinal System Disorders
Constipation

Diarrhea

Dyspepsia

Nausea

Vomiting

98

115

129

139

76

(3.0%)

(3.5%)

(3.9%)

(4.2%)

(2.3%)


92

113

120

133

59


(2.8%)

(3.4%)

(3.6%)

(4.0%)

(1.8%)

-

-

-

-

-

Heart Rate and Rhythm Disorders
Tachycardia Ventricular

70

(2.1%)


63

(1.9%)

-

Metabolism and Nutritional Disorders
Hyperkalemia

113

(3.4%)


66

(2.0%)

0.0005

Myo Endo Pericardial & Valve Disorders

Angina Pectoris

Coronary Artery Disorder

459

100

(13.9%)

(3.0%)

415

91

(12.6%)

(2.8%)

-

-

Red Blood Cell Disorders

Anemia

115

(3.5%)

98

(3.0%)

-

Urinary System Disorders

Creatinine Increase

Hematuria

Renal Function Abnormal

81

70

96

(2.4%)

(2.1%)

(2.9%)

51

55

79

(1.5%)

(1.7%)

(2.4%)

0.0105

-

-

Vascular (Extracardiac) Disorders

Cerebrovascular Disorder

103

(3.1%)

101

(3.1%)

-

The incidences of sex hormone-related adverse events are shown in Table 3.

Table 3. Rates of Sex Hormone-Related Adverse Events in EPHESUS
 

Rates in Males

Rates in Females

 

Gynecomastia

Mastodynia

Abnormal Vaginal Bleeding

Inspra

0.4%

0.1%

0.4%

Placebo

0.5%

0.1%

0.4%

Hypertension:

INSPRA has been evaluated for safety in 3,299 patients as either monotherapy or co-administration therapy in the hypertension clinical trials. A total of approximately 499 patients were treated with INSPRA for over 6 months and more than 176 patients were treated for over 1 year. The most commonly reported adverse events were headache (11.2%) and upper respiratory tract infection (7.6%).

In placebo-controlled fixed-dose trials, the overall rates of adverse events were 46% with recommended doses of INSPRA and 48% % with placebo. Adverse events occurred at a similar rate regardless of age, gender, or race. Therapy was discontinued due to an adverse event in 2.5% of patients treated with INSPRA and 2.7% of patients given placebo.

The adverse events that were reported at a rate of at least 1% of patients and at a higher rate in patients treated with INSPRA versus placebo are shown in Table 4.

Table 4. Incidence of Adverse Events ≥1% of Subjects in the INSPRA pooled arms and More Frequent than Placebo in the Placebo-Controlled Fixed-Dose Monotherapy Trials

Placebo

INSPRA

25 mg/day

50 mg/day

100 mg/day

Subjects

244

97

294

239

Body as a Whole – General disorders

Edema peripheral

4 (1.6%)

3 (3.1%)

5 (1.7%)

2 (0.8%)

Fatigue

1 (0.4%)

1 (1.0%)

4 (1.4%)

2 (0.8%)

Influenza-like symptoms

3 (1.2%)

2 (2.1%)

5 (1.7%)

5 (2.1%)

Cardiovascular Disorders

Palpitation

1 (0.4%)

1 (1.0%)

3 (1.0%)

3 (1.3%)

Central and Peripheral Nervous System Disorders

Dizziness

5 (2.0%)

3 (3.1%)

8 (2.7%)

7 (2.9%)

Gastrointestinal System Disorders

Abdominal pain

2 (0.8%)

3 (3.1%)

2 (0.7%)

4 (1.7%)

Liver and Biliary system Disorders

Bilirubinemia

0

0

1 (0.3%)

5 (2.1%)

Increased GGT

2 (0.8%)

1 (1.0%)

5 (1.7%)

3 (1.3%)

SGOT increased

2 (0.8%)

1 (1.0%)

4 (1.4%)

2 (0.8%)

SGPT increased

1 (0.4%)

1 (1.0%)

7 (2.4%)

3 (1.3%)

Metabolic

Creatine Phosphokinases Increased

2 (0.8%)

0

4 (1.4%)

4 (1.7%)

Hypercholesterolemia

0

0

5 (1.7%)

3 (1.3%)

Hypertriglyceridemia

3 (1.2%)

0

4 (1.4%)

6 (2.5%)

Hyperuricemia

2 (0.8%)

0

4 (1.4%)

4 (1.7%)

Musculoskeletal System Disorders

Arthralgia

1 (0.4%)

0

4 (1.4%)

3 (1.3%)

Respiratory System Disorders

Bronchitis

3 (1.2%)

1 (1.0%)

2 (0.7%)

4 (1.7%)

Coughing

2 (0.8%)

0

3 (1.0%)

3 (1.3%)

Sinusitis

5 (2.0%)

3 (3.1%)

6 (2.0%)

8 (3.3%)

Upper respiratory Tract Infection

10 (4.1%)

5 (5.2%)

17 (5.8%)

13 (5.4%)

Urinary System Disorders

Albuminuria

2 (0.8%)

0

3 (1.0%)

3 (1.3%)

Gynecomastia and abnormal vaginal bleeding were reported with INSPRA (around 1%) but not with placebo. The rates increased with increasing duration of therapy.

Clinical Chemistry Findings

EMPHASIS-HF study: NYHA Class II chronic heart failure

A summary of the incidence of hyperkalemia and hypokalemia is provided in Table 5.

Table 5. Rates of Hyperkalemia and Hypokalemia - Treated Patients in EMPHASIS-HF Study

Serum potassium

mmol/L

INSPRA

N=1344

Placebo

N=1349

P-value

>6.0

2.7%

2.1%

0.3141

>5.5

12.9%

8.2%

<0.0001

<4.0

42.0%

51.7%

<0.0001

<3.5

9.0%

12.3%

0.0060

>5.5 at least 2 consecutive measurements

1.6%

0.9%

0.1182

The higher risk of hyperkalemia in patients with renal impairment and, low estimated glomerular filtration rate (eGFR) and history of diabetes mellitus (EMPHASIS-HF study) are shown in Table 6 and Table 7 respectively.

Table 6. Rates of Hyperkalemia (>5.5 mmol/L) in EMPHASIS-HF by Baseline Creatinine Clearance*
*
Estimated using the Cockroft-Gault formula.

Baseline Creatinine Clearance

INSPRA

Placebo

≤ 30 mL/min

21.4%

5.6%

31–50 mL/min

15.8%

11.8%

51–70 mL/min

13.8%

7.9%

>70 mL/min

10.0%

6.7%

Table 7. Rates of Hyperkalemia (> 5.5 mmol/L) in EMPHASIS-HF by baseline eGFR 30-50* and History of Diabetes
 

INSPRA

Placebo

eGFR 30-<50, No Diabetes

15.4%

7.6%

eGFR >50, Diabetes

13.6%

8.6%

eGFR 30-<50, Diabetes

21.8%

17.6%

eGFR >50, No Diabetes

10.7%

7.0%

EPHESUS study: Post-myocardial infarction heart failure

A summary of the incidence of hyperkalemia and hypokalemia is provided in Table 8.

Table 8. Rates of Hyperkalemia and Hypokalemia - Treated Patients in EPHESUS Study

Serum potassium

mmol/L

INSPRA

N=1344

Placebo

N=1349

P-value

>6.0

4.2%

2.7%

0.001

>5.5

15.6%

11.2%

<0.001

<4.0

42.6%

52.2%

<0.001

<3.5

8.4%

13.1%

<0.001

>5.5 at least 2 consecutive measurements

3.0%

1.7%

<0.001

The higher risk of hyperkalemia in patients with renal impairment and, proteinuria and history of diabetes mellitus (EPHESUS study) are shown in Table 9 and Table 10 respectively.

Table 9. Rates of Hyperkalemia ( >5.5 mmol/L) in EPHESUS by Baseline Creatinine Clearance*
*
Estimated using the Cockroft-Gault formula.

Baseline Creatinine Clearance

INSPRA

Placebo

≤ 30 mL/min

31.5%

22.6%

31–50 mL/min

24.1%

12.7%

51–70 mL/min

16.9%

13.1%

>70 mL/min

10.8%

8.7%

Table 10. Rates of Hyperkalemia ( >5.5 mmol/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.
 

INSPRA

Placebo

Proteinuria, No Diabetes

16.1%

10.8%

No Proteinuria, Diabetes

18.0%

12.9%

Proteinuria and Diabetes

26.0%

15.9%

No Proteinuria, No Diabetes

12.8%

10.3%

Creatinine: Increases of more than 44 umol/L were reported in 6.5% of patients administered INSPRA and in 4.9% of placebo-treated patients.

Blood Urea Nitrogen: In EPHESUS, a mean increase of 0.17 mmol/L in blood urea nitrogen (BUN) was reported in patients treated with INSPRA and a mean 0.31 mmol/L decrease for placebo-treated patients. BUN increased in 1.6% and 1.0% of subjects, respectively. The incidence of patients with a value of 1.3xULN for BUN is 36.0% for the eplerenone group compared to 30.5% for placebo.

Abnormal Hematologic and Clinical Chemistry Findings in Hypertension Trials

Potassium: In the combined controlled trials, hyperkalemia rate increased with decreasing renal function, and increased with the co-administration with other antihypertensive drugs as shown in Table 11 below. It is noted that in the trial some patients were treated with higher than the maximal recommended dose of 50 mg twice daily.

Table 11. Maximal Serum Potassium >5.5 mmol/L and >5.9 mmol/L by Baseline Creatinine Clearance in the Combined Controlled Hypertension Trials*
*
It is noted that in these trials some patients were treated with higher than maximal recommended dose of 50 mg twice daily.

Baseline Creatinine Clearance

Maximum Potassium (mmol/L)

Placebo

% (patient #)

INSPRA monotherapy

% (patient #)

Co-Administration

therapy

% (patient #)

<50 mL/min

>5.5

0 (0/6)

18.2% (6/33)

33.3 (3/9)

>5.9

0 (0/6)

6.1 % (2/33)

11.1 (1/24)

50 – 70 mL/min

>5.5

0 (0/35)

7.5 (12/160)

17.2 (15/87)

>5.9

0 (0/35)

2.5% (4/160)

4.6 (4/87)

>70 – 100 mL/min

>5.5

2.5 (3/121)

5.0 (31/624)

12.1 (33/272)

>5.9

1.7 (2/121)

1.1 (7/624)

2.6 (7/272)

>100 mL/min

>5.5

0.8 (2/252)

2.7 (27/1014)

3.9 (22/563)

>5.9

0.4 (1/252)

0.7 (7/1014)

1.2 (7/563)

Sodium: Hyponatremia (<135 mmol/L) was reported for 0% of placebo-treated patients, 0% in 25 mg daily INSPRA group, 0.7% in 50 mg daily INSPRA group and 2.1% in 100 mg daily INSPRA group.

Triglycerides: Increases in triglycerides (above 2.83 mmol/L) were reported for 6.5% in placebo group, 9.2% in 25 mg INSPRA group, 6.0% in 50 mg daily INSPRA group and 7.8% in 100 mg daily INSPRA group.

Cholesterol: Increases in serum cholesterol values greater than 5.17mmol/L were reported for 0% in placebo group, 0% in 25 mg daily INSPRA group, 1.7% in 50 mg daily INSPRA group and 1.3% in 100 mg daily INSPRA group.

Less Common Clinical Trial Adverse Events

EMPHASIS-HF study: NYHA Class II chronic heart failure

Table 12. Incidence of Adverse Events < 2%* of Subjects in the INSPRA arm and more frequent than placebo, in the EMPHASIS-HF Study
*
[common : >1% - < 2%; uncommon >0.1%<1%)]

Blood and lymphatic system disorders

Uncommon: Thrombocytopenia

Cardiac Disorders

Common: Bradycardia

Uncommon: Acute myocardial infarction, Cardiac asthma, Cardiogenic shock, Cardiovascular disorder, Congestive cardiomyopathy, Coronary artery disease, Extrasystoles, Mitral valve incompetence, Sinus tachycardia, Supraventricular tachycardia, Tachycardia, Ventricular arrhythmia, Ventricular fibrillation

Eye disorders

Uncommon: Conjunctival hemorrhage, Glaucoma, Vision blurred

Gastrointestinal disorders

Common: Dyspepsia, Gastritis,

Uncommon: Abdominal pain upper, Anal fissure, Ascites, Duodenitis, Hemorrhoids, Inguinal hernia, Toothache

General disorders and administration site conditions

Uncommon: Influenza like illness, Malaise, Pain

Immune system disorders

Uncommon: Hypersensitivity

Infections and infestations

Common: Gastroenteritis, Influenza

Uncommon: Cellulitis, Gangrene, Gastroenteritis viral, Gastrointestinal infection, Herpes zoster, Implant site infection, Localised infection, Lung infection, Pharyngitis, Pyelonephritis, Sinusitis, Tooth abscess, Tooth infection, Viral infection

Injury, poisoning and procedural complications

Common: Fall

Uncommon: Laceration, Ligament sprain, Radius fracture, Road traffic accident, Upper limb fracture

Investigations

Common: Blood creatinine increased, Blood urea increased

Uncommon: Alanine aminotransferase increase, Blood glucose increased, Blood potassium increased, Blood uric acid increased, Epidermal growth factor receptor, Glomerular filtration rate decrease, Hemoglobin decreased, Hepatic enzyme increased, International normalised ratio increase, Liver function test abnormal, Weight decreased, Weight increased

Metabolism and nutrition disorders

Common: Dehydration

Uncommon: Decreased appetite, Dyslipidemia, Hyponatremia, Hypovolemia, Iron deficiency

Musculoskeletal and connective tissue disorders

Common: Arthralgia, Muscle spasms, Osteoarthritis

Uncommon: Bursitis, Muscular weakness, Musculoskeletal chest pain, Musculoskeletal pain, Osteitis, Osteochondrosis, Osteoporosis

Neoplasms benign, malignant and unspecified

Uncommon: Bronchial carcinoma, Colon neoplasm, Lung neoplasm

Nervous system disorders

Uncommon: Carotid artery stenosis, Carpal tunnel syndrome, Dementia, Diabetic neuropathy, Dizziness postural, Dysarthria, Hypoesthesia, Neuralgia, Neuropathy peripheral, Paresthesia, Polyneuropathy

Psychiatric disorders

Uncommon: Anxiety, Depressed mood

Renal and urinary disorders

Uncommon: Nocturia, Pollakiuria, Renal failure chronic, Urinary retention

Respiratory, thoracic and mediastinal disorders

Uncommon: Acute pulmonary oedema, Hemoptysis, Lung disorder, Nasal congestion, Pneumothorax, Productive cough

Skin and subcutaneous tissue disorders

Uncommon: Dermatitis allergic, Psoriasis, Rash, Skin lesion

Surgical and medical procedures

Uncommon: Cardiac pacemaker replacement, Prophylaxis

Vascular disorders

Uncommon: Extremity necrosis, Intermittent claudication, Peripheral coldness, Phlebitis

EPHESUS study: Post-myocardial infarction heart failure

Table 13. Incidence of Adverse Events < 2%* of Subjects in the INSPRA arm and more frequent than placebo, in the EPHESUS Study
*
[common : >1% - < 2%; uncommon >0.1%<1%)]

Application Site Disorders

Uncommon: Injection site reaction

Autonomic Nervous System Disorders

Uncommon: Hypotension Postural, Pre-syncope

Body as a Whole - General Disorders

Common: Influenza-like symptoms, Vertigo

Uncommon: Chills, Cyst NOS, Edema, Edema generalized, Face edema, Hot flushes, Laboratory test abnormal, Malaise, Pain, Post-operative incision pain, Respite care, Sternal wound infection

Cardiovascular Disorders, General

Uncommon: Circulatory failure, Intra-cardiac thrombus

Central and Peripheral Nervous System Disorders

Common: Cramps legs

Uncommon: Aphasia, Ataxia, Dementia, Dysphonia, Encephalopathy, Hemiparesis, Hypotonia, Paresthesia, Tremor

Disorders, Female

Uncommon: Breast neoplasm female, Breast neoplasm malignant female, Leukorrhea, Mastitis acute female, Menstrual disorder, Uterine disorder NOS, Vaginitis, Vaginitis atrophic,

Disorders, Male

Uncommon: Benign prostatic hyperplasia, Impotence

Endocrine Disorders

Uncommon: Hyperthyroidism, Hypothyroidism

Gastro-intestinal System Disorders

Common: Gastritis

Uncommon: Abdominal distension, Appendicitis, Duodenal ulcer, Duodenitis, Dysphagia, Flatulence, Gastric ulcer, Gastroenteritis, Gastroesophageal reflux, Hematemesis, Hemorrhage rectum, Hemorrhoids, Hernia, Hiatal hernia, Pancreatitis, Peptic ulcer

Hearing and Vestibular Disorders

Uncommon: Earache, Tinnitus

Heart Rate and Rhythm Disorders

Common: Arrhythmia atrial, Fibrillation ventricular, Palpitation

Uncommon: AV block, Tachycardia, Tachycardia supraventricular

Liver and Biliary System Disorders

Uncommon: Biliary pain, Cholecystitis, Cholelithiasis, Jaundice, Liver fatty

Metabolic and Nutritional Disorders

Uncommon: Acidosis, Dehydration, Hypertriglyceridemia, Hypoproteinemia, Ketosis, Weight decrease

Musculo-Skeletal System Disorders

Common: Fracture accidental

Uncommon: Arthrosis, Osteoporosis, Tendonitis,

Myo Endo Pericardial & Valve Disorders

Common: Myocardial ischemia

Uncommon: Cardiomyopathy, Pericardial effusion,

Neoplasm

Uncommon: GI neoplasm malignant, Neoplasm, Pulmonary carcinoma

Platelet, Bleeding & Clotting Disorders

Uncommon: Ecchymosis, Prothrombin decreased, Thrombosis arterial leg

Psychiatric Disorders

Uncommon: Apathy, Neurosis, Thinking abnormal

Resistance Mechanism Disorders

Uncommon: Herpes Zoster, Infection, Infection viral, Moniliasis, Moniliasis genital, Otitis media, Sepsis

Respiratory System Disorders

Uncommon: Abnormal breath sounds, Atelectasis, Hyperventilation, Laryngitis, Pharyngitis, Respiratory arrest, Respiratory disorder, Respiratory insufficiency, Rhinitis, Sinusitis, Sputum increased

Skin and Appendages Disorders

Common: Pruritus

Uncommon: Alopecia, Angioedema, Dermatitis, Inflammation, Rash Maculo-papular, Skin dry, Sweating increased, Urticaria

Special Senses Other, Disorders

Uncommon: Taste perversion

Urinary System Disorders

Common: Albuminuria, Bun increased

Uncommon: Bladder carcinoma, Hydronephrosis, Micturition frequency, Nocturia, Polyuria, Pyelonephritis, Renal calculus, Renal cyst, Urinary incontinence, Urinary retention

Vascular (Extracardiac) Disorders

Uncommon: Cerebral hemorrhage, Claudication intermittent, Gangrene, Peripheral ischemia, Peripheral vascular disease, Phlebitis, Thrombophlebitis, Vein varicose

Vision Disorders

Uncommon: Diplopia, Retinal disorder,

White Cell and RES Disorders

Uncommon: Eosinophilia, Leukocytosis, Leukopenia, Lymphadenopathy, Lymphocytosis

Hypertension Trials: the pooled placebo-controlled, fixed-dose INSPRA hypertension studies data

Table 14. Incidence of Adverse Events < 1% of Subjects in the INSPRA arms and more frequent than placebo, in the placebo-controlled, fixed-dose Study

Application Site Disorders

Cellulitis

Autonomic Nervous System

Syncope, Glaucoma, Mouth Dry

Body as A Whole – General Disordoers

Allergy, Chills, Laboratory test abnormal, Pain

Cardiovascular Disorders

Angina pectoris, ECG abnormal, Myocardial infarction, Arrhythmia (atrial and ventricular), Fibrillation atrial

Central and Peripheral Nervous System Disorders

Cramps legs, Migraine, Neuralgia, Paresthesia, Scotoma, Vertigo

Collagen Disorders

Arthritis Rheumatoid

Female Patients Disorders

Menstrual disorder,

Male Patients Disorders

Libido decreased

Endocrine Disorders

Sialoadenitis

Gastro-Intestinal System Disorders

Diverticulitis, Esophagitis, Gastroesophageal reflux, H Pylori , Hemorrhoids, Oral pain, Stomatitis, Vomiting

Hearing and Vestibular Disorders

Labyrinthine disorder, Tinnitus

Metabolic and Nutritional Disorders

Gout, Hypercalcemia, Hyperchloremia

Musculoskeletal System Disorders

Arthritis, Myalgia

Platelet, Bleeding & Clotting Disorders

Prothrombin decreased, Thrombocytopenia

Psychiatric Disorders

Agitation, Confusion, Depression, Anxiety

Red Blood Cell Disorders

Anemia, Hyperhemoglobinemia

Resistance Mechanism Disorders

Herpes zoster, Infection bacterial, Moniliasis genital, Otitis Media, Sepsis

Respiratory System Disorders

Bronchospasm, Laryngitis, Rhinitis, Sputum Increased

Skin and appendages Disorders

Eczema, Nail disorder, Rash macolo-papular

Urinary System Disorders

BUN increased, Cystitis, Hematuria, Oligura, Renal function abnormal, Renal pain, Urine abnormal, Micturition Frequency

Vision Disorders

Blurred vision, Vision abnormal

White Cell and RES Disorders

Eosinophilia, Granulocytosis, Leukopenia, Monocytosis

Drug Interactions

Overview

Inhibitors of CYP3A4

INSPRA (eplerenone) metabolism is predominantly mediated via CYP3A4 and therefore, INSPRA should not be used with drugs described as strong inhibitors of CYP3A4 in their labeling (see CONTRAINDICATIONS, Drug-Drug Interactions – Table 15, and DOSAGE AND ADMINISTRATION).

Caution should be used in patients treated with mild to moderate CYP3A4 inhibitors; dosing should not exceed 25mg QD in patients with an eGFR ≥ 50 ml/min/1.73m2. For patients with moderate renal impairment (eGFR 30-49 ml/min/1.73 m2), INSPRA is not recommended because a lower dose than 25 mg once daily has not been studied.

Inducers of CYP3A4

St. John’s Wort was found to decrease exposure and to increase clearance of INSPRA significantly indicating that concomitant use of strong inducers of CYP3A4 such as phenobarbital, phenytoin, rifampicin, carbamazepine should be avoided.

ACE Inhibitors and Angiotensin II Receptor Antagonists

In EPHESUS and EMPHASIS-HF, 3020 (91%) and 1282 (94%) patients, respectively, receiving INSPRA 25 to 50 mg, also received ACE inhibitors or angiotensin II receptor antagonists (ACEI/ARB). Rates of patients with maximum potassium levels >5.5 mmol/L were similar regardless of the use of ACEI/ARB. However, as ACEI/ARB can also increase serum potassium levels in some patients, concomitant use with INSPRA dictates that greater caution should be exercised.

Lithium

A drug interaction study of INSPRA with lithium has not been conducted.  However, lithium toxicity has been reported in patients receiving lithium concomitantly with diuretics and ACE inhibitors and concomitant administration of INSPRA may worsen lithium toxicity. Serum lithium levels should be monitored frequently if INSPRA is administered concomitantly with lithium, as excretion may be altered as a result of modifications in sodium balance induced by the aldosterone antagonist. Lithium has also been reported to increase plasma renin activity and aldosterone levels.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

A drug interaction study of INSPRA with an NSAID has not been conducted. The administration of potassium-sparing antihypertensive drugs 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 INSPRA and NSAIDs including COX-2 Inhibitors, are used concomitantly, blood pressure, renal function and serum potassium should be closely monitored.

Herbal Preparations and Salt Substitutes

The full consequence of using INSPRA in patients taking herbal preparations and/or salt substitutes has not been established, and caution should be exercised. Theoretically, patients who are taking herbal preparations that affect blood pressure or contain high levels of potassium may be at risk of hypotension/hypertension or hyperkalemia (see WARNINGS and PRECAUTIONS). Clinicians should consider discontinuing the herbal preparation or salt substitute or closely monitoring patients using such a combination. Such preparations may include (but not limited to): dandelion, potassium iodine, laminaria, morinda, oleander, phosphate salts and potassium preparations, cat’s claw, cod liver oil, and licorice.

Drug-Drug Interactions

Drug-drug interaction studies were conducted with a 100 mg dose of INSPRA and the outcomes are summarized in Table 15.

Table 15. Established or Potential Drug-Drug Interactions
 
Legend: C = Case Study; CT = Clinical Trial; T = Theoretical

Proper name

Ref

Effect

Clinical comment

Digoxin

CT

no clinically significant interactions

Systemic Exposure (AUC) to digoxin increases by 16% (90% CI: 4-30%) when co-administered with INSPRA. Caution is warranted when digoxin is dosed near the upper limit of the therapeutic range.

Warfarin

CT

no clinically significant interactions

 

CYP3A4 substrates (e.g. midazolam, cisapride)

T and CT

no clinically significant interactions

 

Potent CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin, telithromycin, nefazodone)

T and CT

significant increases in eplerenone AUC

Concomitant use is contraindicated (see CONTRAINDICATIONS)

Mild to Moderate CYP3A4 inhibitors (erythromycin, saquinavir, amiodarone, diltiazem, verapamil, fluconazole)

T and CT

significant increases in eplerenone AUC

Eplerenone dosing should not exceed 25 mg daily when mild to moderate inhibitors of CYP3A4 are co-administered (see DOSAGE AND ADMINISTRATION). For patients with moderate renal impairment (eGFR 30-49 ml/min/1.73 m2) INSPRA is not recommended.

For hypertension, reduce the dose to 25 mg once daily when used with mild to moderate CYP3A4 inhibitors (e.g.,verapamil, erythromycin, saquinavir, fluconazole).

Potent CYP3A4 Inducers (e.g. carbamazepine, phenytoin, Phenobarbital, St John’s Wort, rifampicin)

T andCT

decreases eplerenone AUC

Due to the risk of decreased eplerenone efficacy, concomitant use of strong CYP3A4 inducers with INSPRA is not recommended because a lower dose than 25 mg once daily has not been studied.

Aluminum and magnesium-containing antacids

CT

No significant changes in eplerenone pharmacokinetics

 

Drug-Food Interactions

INSPRA may be administered with or without food.

Dosage And Administration

Glomerular filtration rate should be estimated (eGFR) and serum potassium measured before initiating INSPRA (eplerenone) therapy since INSPRA dosing depends on these variables.

INSPRA should not be administered to heart failure patients with initial serum potassium >5.0 mmol/L, serum creatinine >221umol/L and/or eGFR <30mL/min/1.73m2.

Serum potassium should be measured before initiating INSPRA (eplerenone) therapy, within the first week and at one month after the start of treatment or after a dose adjustment. Serum potassium should be measured periodically thereafter, as clinically warranted. Hyperkalemia can be expected at any time during treatment with INSPRA.

Efforts should be made to decrease the dietary potassium intake. Patients should be asked about their use of potassium containing salt substitutes and dietary supplements. Factors, such as patient characteristics, serum potassium levels and concomitant medications, may indicate that additional monitoring of serum potassium is appropriate (see WARNINGS AND PRECAUTIONS - Hyperkalemia, ADVERSE REACTIONS, and DRUG INTERACTIONS). INSPRA may be administered with or without food.

Recommended Dose and Dosage Adjustment

Heart failure

Renal Impairment

Patients with eGFR of ≥50 ml/min/1.73m2:

For chronic heart failure NYHA Class II and post-myocardial infarction heart failure patients with serum potassium ≤ 5 mmol/L, treatment should be initiated at a dose of 25 mg once daily and titrated to the target dose of 50 mg once daily preferably within 4 weeks, taking into account the serum potassium level (see Table 16). Following myocardial infarction INSPRA should be initiated 3 – 14 days after MI.

The maximum daily dose in patients with eGFR of ≥50 ml/min/1.73m2 is 50 mg daily. In patients using a mild to moderate CYP3A4 inhibitor, the maximum daily dose of INSPRA is 25 mg.

Patients with eGFR of 30-49 ml/min/1.73m2 :
For chronic heart failure NYHA Class II and post-myocardial infarction heart failure patients with serum potassium ≤ 5 mmol/L, treatment should be initiated at a dose of 25 mg once every other day and titrated to the target dose of 25 mg once daily preferably within 4 weeks, taking into account the serum potassium level (see Table 16). Following myocardial infarction INSPRA should be initiated 3 – 14 days after MI.

The maximum dose in patients with an eGFR 30-49 ml/min/1.73m2 is 25 mg once daily. INSPRA should not be given to patients on a mild to moderate CYP3A4 inhibitor because a lower dose than 25 mg once daily has not been studied.

Patients with eGFR of <30 ml/min/1.73m2: INSPRA is contraindicated in patients with severe renal impairment.

Hepatic Impairment

Mild-to-Moderate Hepatic Impairment: No initial dosage adjustment is necessary. Severe Hepatic Impairment (see CONTRAINDICATIONS and WARNINGS and PRECAUTIONS).

Dose adjustment based on serum potassium levels for heart failure patients

Patients who develop hyperkalemia (>5.5 mmol/L) may still benefit from INSPRA with proper dose adjustment. The dose should be adjusted based on the serum potassium level and the dose adjustment table shown in Table 16.

Table 16 Dose Adjustment recommendations after initiation
 
*QOD: every other day; **QD: every day

Serum Potassium (mmol/L)

Action

Dose Adjustment

< 5.0

Increase

If 25mg QOD* to 25mg QD**

If 25mg QD to 50mg QD; except (no increase) if:

- concurrent mild-moderate CYP3A4 inhibitor or

- patients with an eGFR 30-49 ml/min/1.73m2

5.0-5.4

Maintain

No adjustment

5.5-5.9

Decrease

If 50mg QD to 25mg QD

If 25mg QD to 25mg QOD

If 25mg QOD to withhold; restart ONLY if K+ falls <5.0

≥ 6.0

Withhold

Restart at a lower dose ONLY when K+ falls <5.0

Following withholding INSPRA due to serum potassium ≥ 6.0 mmol/L and the return of potassium levels within acceptable limits, INSPRA can be restarted at a test dose of 25 mg every other day. There are no data to demonstrate that 25mg every other day is effective and such dosing should be considered to be only a temporary situation. After a test period of one week on 25mg every other day, serum potassium levels should be measured. If potassium levels return within acceptable limits, the dose can be increased to 25 mg every day and serum potassium should be measured after one week. It could then be determined if INSPRA therapy should be continued or stopped.

Hypertension

INSPRA should not be administered to hypertensive patients with initial serum potassium >5.0 mmol/L, serum creatinine >132 µmol/L in males or >115 µmol/L in females, and/or eGFR <50 mL/min/1.73m2.

In patients with hypertension who have reduced eGFR, serum potassium concentrations should be closely monitored when treated with INSPRA, especially when co-administrated with other antihypertensive drugs).

For hypertension, the recommended starting dose of INSPRA is 50 mg administered once daily. The full therapeutic effect of INSPRA is apparent within 4 weeks. For patients with an inadequate blood pressure response to 50 mg once daily the dosage of INSPRA should be increased to 50 mg twice daily. Higher dosages of INSPRA are not recommended because they have no greater effect on blood pressure and are associated with an increased risk of adverse reactions, including hyperkalemia. (See CLINICAL TRIALS)

Specific Populations

Patients with hypertension: for patients with hypertension receiving mild to moderate CYP3A4 inhibitors (e.g.erythromycin, saquinavir, verapamil, and fluconazole), the dose of INSPRA should be reduced to 25 mg once daily. (See DRUG INTERACTIONS).

Overdosage

For the management of a suspected drug overdose, contact your regional Poison Control Centre.

In the hypertension clinical trials, increased incidence of hyperkalemia, hyponatremia, hyperglycemia, hypertriglyceridemia, increased GGT, and increased creatinine have been observed with the higher than maximal recommended doses (over 100 mg daily)

No cases of adverse events associated with overdose of INSPRA (eplerenone) in humans 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 and/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.

Action And Clinical Pharmacology

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 through both genomic and non-genomic effects.

Pharmacodynamics

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

In dose-ranging studies of chronic heart failure (NYHA classification II-IV), the addition of eplerenone to standard therapy resulted in expected dose-dependent increases in aldosterone. Similarly, in a cardiorenal substudy of EPHESUS, therapy with eplerenone led to a significant increase in aldosterone. These results are consistent with blockade of the mineralocorticoid receptor in these populations.

No consistent effects of eplerenone on heart rate, QRS duration, or PR or QT interval were observed in 147 normal subjects evaluated for electrocardiographic changes during pharmacokinetic studies.

Pharmacokinetics

General:  Eplerenone is cleared predominantly by cytochrome P450 (CYP) 3A4 metabolism, with an elimination half-life of 4 to 6 hours.  Steady state is reached within 2 days. Absorption is not affected by food.  Inhibitors of CYP3A4 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. 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 to 100 mg and less than proportional at doses above 100 mg.

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 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.

Special Populations and Conditions

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. The pharmacokinetics of eplerenone did not differ significantly between males and females. At steady state, elderly subjects had increases in Cmax (22%) and AUC (45%) compared with younger subjects (18 to 45 years). At steady state, Cmax was 19% lower and AUC was 26% lower in blacks (see WARNINGS AND PRECAUTIONS, Geriatric Use and DOSAGE AND ADMINISTRATION).

Renal Insufficiency: The pharmacokinetics of eplerenone was evaluated in patients with varying degrees of renal insufficiency 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, Hyperkalemia).

Hepatic Insufficiency: 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 (see DOSAGE AND ADMINISTRATION).

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 

(see DRUG INTERACTIONS)
Drug-drug interaction studies were conducted with a 100 mg dose of eplerenone.

Eplerenone is metabolized primarily by CYP3A4. A potent inhibitor of CYP3A4 (ketoconazole) caused increased exposure of 5.4 fold; while less potent CYP3A4 inhibitors (erythromycin, saquinavir, verapamil, and fluconazole) resulted in increases ranging from 2.0-2.9 fold. Grapefruit juice caused only a small increase (about 25%) in exposure (see DRUG INTERACTIONS).

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, and 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. Johns Wort (a CYP3A4 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.

Storage And Stability

Store at controlled room temperature (15–30ºC).

Special Handling Instructions

Not Applicable.

Dosage Forms, Composition And Packaging

Dosage Forms

INSPRA (eplerenone) tablets are formulated for oral administration and are available in tablet doses of 25 mg and 50 mg.

Composition

INSPRA tablets contain either 25 mg or 50 mg of eplerenone as the active ingredient.
The non-medicinal ingredients are as follows:  lactose, microcrystalline cellulose, croscarmellose sodium, hypromellose, sodium lauryl sulfate, talc, magnesium stearate, titanium dioxide, polyethylene glycol, polysorbate 80, iron oxide yellow and iron oxide red.

Packaging

INSPRA tablets, 25 mg, are yellow, diamond, biconvex film-coated tablets.  They are debossed with Pfizer on one side and NSR over 25 on the other.  They are available in blister packs of 30.

INSPRA tablets, 50 mg, are yellow, diamond, biconvex film-coated tablets.  They are debossed with Pfizer on one side and NSR over 50 on the other.  They are available in blister packs of 30.

 

Control #: 197413
27 October 2016

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