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.

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]

Eplerenone is metabolized primarily by CYP3A4. Inhibitors of CYP3A4 cause increased exposure [see DRUG INTERACTIONS].

Drug-drug interaction studies were conducted with a 100 mg dose of eplerenone.

A pharmacokinetic study evaluating the administration of a single dose of INSPRA 100 mg with ketoconazole 200 mg two times a day, a strong 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.

Administration of eplerenone with moderate CYP3A4 inhibitors (e.g., erythromycin 500 mg BID, verapamil 240 mg once daily, saquinavir 1200 mg three times a day, fluconazole 200 mg once daily) resulted in increases in Cmax of eplerenone ranging from 1.4- to 1.6-fold and AUC from 2.0- to 2.9-fold.

Grapefruit juice caused only a small increase (about 25%) in exposure.

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. John's 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.

Clinical Studies

Congestive Heart Failure Post-Myocardial Infarction

The eplerenone post-acute myocardial infarction heart failure efficacy and survival study (EPHESUS) was a multinational, multicenter, double- blind, randomized, placebo-controlled study in patients clinically stable 3– 14 days after an acute myocardial infarction (MI) with left ventricular dysfunction (as measured by left ventricular ejection fraction [LVEF] ≤ 40%) and either diabetes or clinical evidence of congestive heart failure (CHF) (pulmonary congestion by exam or chest x-ray or S₃). Patients with CHF of valvular or congenital etiology, patients with unstable post-infarct angina, and patients with serum potassium > 5.0 mEq/L or serum creatinine > 2.5 mg/dL were to be excluded. Patients were allowed to receive standard post-MI drug therapy and to undergo revascularization by angioplasty or coronary artery bypass graft surgery.

Patients randomized to INSPRA were given an initial dose of 25 mg once daily and titrated to the target dose of 50 mg once daily after 4 weeks if serum potassium was < 5.0 mEq/L. Dosage was reduced or suspended anytime during the study if serum potassium levels were 5.5 mEq/L. [See DOSAGE AND ADMINISTRATION]

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