Inspra Warnings, Precautions, Pregnancy, Nursing, Abuse - Eplerenone

Inspra Warnings, Precautions, Pregnancy, Nursing, Abuse - Eplerenone

WARNINGS

The principal risk of INSPRA is hyperkalemia. Hyperkalemia can cause serious, sometimes fatal, arrhythmias. This risk can be minimized by patient selection, avoidance of certain concomitant treatments, and monitoring. 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 and Hypertension, Potassium. Periodic monitoring is recommended in patients at risk for the development of hyperkalemia (including patients receiving concomitant ACE inhibitors or angiotensin II receptor antagonists) until the effect of INSPRA is established. Dose reduction of INSPRA has been shown to decrease potassium levels. (See DOSAGE AND ADMINISTRATION, Congestive Heart Failure Post-Myocardial Infarction and Hypertension.)

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.)

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.) 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.