Hyperkalemia
Minimize the risk of hyperkalemia with proper patient selection and monitoring, and avoidance
of certain concomitant medications [See CONTRAINDICATIONS, ADVERSE REACTIONS, and DRUG
INTERACTIONS]. Monitor patients for the development of hyperkalemia until the effect of
INSPRA is established. Patients who develop hyperkalemia (>5.5 mEq/L) may continue INSPRA
therapy with proper dose adjustment. Dose reduction decreases potassium levels.
[See DOSAGE AND ADMINISTRATION.]
The rates of hyperkalemia increase with declining renal function. [See ADVERSE REACTIONS.]
Patients with hypertension who have serum creatinine levels >2.0 mg/dL (males) or >1.8 mg/dL
(females) or creatinine clearance ≤50 mL/min should not be treated with INSPRA.
[See CONTRAINDICTIONS.] 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 INSPRA
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.]
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 INSPRA in patients with severe hepatic impairment has not been evaluated.
[See CLINICAL PHARMACOLOGY.]
Impaired Renal Function
Patients with decreased renal function are at increased risk of hyperkalemia.
[See CONTRAINDICATIONS,WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS.]
DRUG INTERACTIONS
CYP3A4 Inhibitors
Because eplerenone metabolism is predominantly mediated via CYP3A4, do not use INSPRA with drugs
that are strong inhibitors of CYP3A4. [See CONTRAINDICATIONS and CLINICAL PHARMACOLOGY.]
In patients with hypertension taking moderate CYP3A4 inhibitors, reduce the starting dose of
INSPRA to 25 mg once daily. [See DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY.]
ACE Inhibitors and Angiotensin II Receptor Antagonists
Congestive Heart Failure Post-Myocardial Infarction
In EPHESUS [see CLINICAL STUDIES], 3020 (91%) patients 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 mEq/L were similar regardless of the use of ACEI/ARB.
Hypertension
In clinical studies of patients with hypertension, the addition of INSPRA 50 to 100 mg to
ACE inhibitors and angiotensin II receptor antagonists increased mean serum potassium slightly
(about 0.09–0.13 mEq/L). In a study in diabetics with microalbuminuria, INSPRA 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%.
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 INSPRA is
administered concomitantly with lithium.
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 INSPRA 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.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category B
There are no adequate and well-controlled studies in pregnant women. INSPRA 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, INSPRA should be used during pregnancy only if clearly needed.
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.
Pediatric Use
In a 10-week study of 304 hypertensive pediatric patients age 4 to 17 years treated with
INSPRA up to 100 mg per day, doses that produced exposure similar to that in adults, INSPRA
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.
INSPRA has not been studied in hypertensive patients less than 4 years old because the study in
older pediatric patients did not demonstrate effectiveness.
INSPRA has not been studied in pediatric patients with heart failure.
Geriatric Use
Congestive Heart Failure Post-Myocardial Infarction
Of the total number of patients in EPHESUS, 3340 (50%) were 65 and over, while 1326 (20%) were 75
and over. Patients greater than 75 years did not appear to benefit from the use of INSPRA.
[See CLINICAL STUDIES.]
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.]
Hypertension
Of the total number of subjects in clinical hypertension studies of INSPRA, 1123 (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.
PATIENT COUNSELING INFORMATION
Patients receiving INSPRA should be informed:
- Not to use strong CYP3A4 inhibitors, such as ketoconazole, clarithromycin, nefazodone, ritonavir, and nelfinavir.
- Not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing physician.
- To call their physician if they experience dizziness, diarrhea, vomiting, rapid or irregular heartbeat, lower extremity edema, or difficulty breathing.
- That periodic monitoring of blood pressure and serum potassium is important.
[See CONTRAINDICATIONS; WARNINGS AND PRECAUTIONS; and DRUG INTERACTIONS.]