Hyperkalemia in Patients Treated for Congestive Heart Failure Post-Myocardial Infarction
The principal risk of INSPRA is hyperkalemia. Hyperkalemia can cause serious, sometimes
fatal, arrhythmias. Patients who develop hyperkalemia (>5.5 mEq/L) may still
benefit from INSPRA with proper dose adjustment. Hyperkalemia can be minimized by
patient selection, avoidance of certain concomitant treatments, and periodic monitoring
until the effect of INSPRA has been established.
For patient selection and avoidance of certain concomitant medications, see CONTRAINDICATIONS;
PRECAUTIONS, Congestive Heart Failure Post-Myocardial Infarction and Hypertension,
Drug Interactions; and ADVERSE REACTIONS, Clinical Laboratory Test Findings,
Congestive Heart Failure Post-Myocardial Infarction, Potassium. Dose
reduction of INSPRA has been shown to decrease potassium levels. (See DOSAGE AND
ADMINISTRATION, Congestive Heart Failure Post-Myocardial Infarction.)
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
caution. The rates of hyperkalemia increased with declining renal function. (See
ADVERSE REACTIONS, Clinical Laboratory Test Findings, Congestive Heart Failure Post-Myocardial
Infarction, Potassium.)
Diabetic patients with CHF post-MI, including those with proteinuria, should also
be treated with caution. The subset of patients in EPHESUS with both diabetes and
proteinuria on the baseline urinalysis had increased rates of hyperkalemia. (See
ADVERSE REACTIONS, Clinical Laboratory Test Findings, Congestive Heart Failure Post-Myocardial
Infarction, Potassium.)
Congestive Heart Failure Post-Myocardial Infarction and Hypertension
Impaired Hepatic Function: 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 DOSAGE AND
ADMINISTRATION and CLINICAL PHARMACOLOGY, Special Populations.)
Impaired Renal Function: (See CONTRAINDICATIONS; WARNINGS;
and PRECAUTIONS.)
Information for Patients: Patients receiving INSPRA should be informed
not to use potassium supplements, salt substitutes containing potassium, or contraindicated
drugs without consulting the prescribing physician. (See CONTRAINDICATIONS; WARNINGS;
and PRECAUTIONS.)
Drug Interactions:
Inhibitors of CYP3A4- Eplerenone metabolism is predominantly mediated via
CYP3A4. A pharmacokinetic study evaluating the administration of a single dose of
INSPRA 100 mg with ketoconazole 200 mg BID, a potent inhibitor of the CYP3A4 pathway,
showed a 1.7-fold increase in Cmax of eplerenone and a
5.4-fold increase in AUC of eplerenone. INSPRA should not be used with drugs described
as strong inhibitors of CYP3A4 in their labeling. (See CONTRAINDICATIONS.)
Administration of eplerenone with other CYP3A4 inhibitors (e.g., erythromycin 500
mg BID, verapamil 240 mg QD, saquinavir 1200 mg TID, fluconazole 200 mg QD) resulted
in increases in Cmax of eplerenone ranging from 1.4- to
1.6-fold and AUC from 2.0- to 2.9-fold. (See CLINICAL PHARMACOLOGY, Pharmacokinetics,
Drug-Drug Interactions and DOSAGE AND ADMINISTRATION, Hypertension.)
ACE Inhibitors and Angiotensin II Receptor Antagonists (Congestive Heart Failure
Post-Myocardial Infarction)- In EPHESUS, 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.
ACE Inhibitors and Angiotensin II Receptor Antagonists (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%.
(See CONTRAINDICATIONS.)
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.
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: The safety and effectiveness of INSPRA has not been
established in pediatric patients.
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, Congestive Heart Failure Post-Myocardial Infarction.)
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 PRECAUTIONS, Hyperkalemia in Patients Treated for Congestive Heart
Failure.)
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.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Eplerenone was
non-genotoxic in a battery of assays including in vitro bacterial mutagenesis
(Ames test in Salmonella spp. and E.Coli), in vitro mammalian
cell mutagenesis (mouse lymphoma cells), in vitro chromosomal aberration
(Chinese hamster ovary cells), in vivo rat bone marrow micronucleus formation,
and in vivo/ex vivo unscheduled DNA synthesis in rat liver.
There was no drug-related tumor response in heterozygous P53 deficient mice when
tested for 6 months at dosages up to 1000 mg/kg/day (systemic AUC exposures up to
9 times the exposure in humans receiving the 100-mg/day therapeutic dose). Statistically
significant increases in benign thyroid tumors were observed after 2 years in both
male and female rats when administered eplerenone 250 mg/kg/day (highest dose tested)
and in male rats only at 75 mg/kg/day. These dosages provided systemic AUC exposures
approximately 2 to 12 times higher than the average human therapeutic exposure at
100 mg/day. Repeat dose administration of eplerenone to rats increases the hepatic
conjugation and clearance of thyroxin, which results in increased levels of TSH
by a compensatory mechanism. Drugs that have produced thyroid tumors by this rodent-specific
mechanism have not shown a similar effect in humans.
Male rats treated with eplerenone at 1000 mg/kg/day for 10 weeks (AUC 17 times that
at the 100-mg/day human therapeutic dose) had decreased weights of seminal vesicles
and epididymides and slightly decreased fertility. Dogs administered eplerenone
at dosages of 15 mg/kg/day and higher (AUC 5 times that at the 100-mg/day human
therapeutic dose) had dose-related prostate atrophy. The prostate atrophy was reversible
after daily treatment for 1 year at 100 mg/kg/day. Dogs with prostate atrophy showed
no decline in libido, sexual performance, or semen quality. Testicular weight and
histology were not affected by eplerenone in any test animal species at any dosage.