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INSPRA (eplerenone) Warnings And Precautions

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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 <30 mL/min/1.73 m2. 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/1.73 m2. 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 > 5.5 mmol/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.

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