INSPRA^®

(eplerenone) tablets

INSPRA contains eplerenone, a blocker of aldosterone binding at the mineralocorticoid receptor.

Eplerenone is chemically described as Pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy-17-hydroxy-3-oxo-, γ-lactone, methyl ester, (7α,11α,17α)-. Its empirical formula is C₂₄H₃₀O₆ and it has a molecular weight of 414.50. The structural formula of eplerenone is represented below:

Eplerenone is an odorless, white to off-white crystalline powder. It is very slightly soluble in water, with its solubility essentially pH independent. The octanol/water partition coefficient of eplerenone is approximately 7.1 at pH 7.0.

INSPRA for oral administration contains 25 mg or 50 mg of eplerenone and the following inactive ingredients: lactose, microcrystalline cellulose, croscarmellose sodium, hypromellose, sodium lauryl sulfate, talc, magnesium stearate, titanium dioxide, polyethylene glycol, polysorbate 80, and iron oxide yellow and iron oxide red.

Eplerenone binds to the mineralocorticoid receptor and blocks the binding of aldosterone, a component of the renin-angiotensin-aldosterone-system (RAAS). Aldosterone synthesis, which occurs primarily in the adrenal gland, is modulated by multiple factors, including angiotensin II and non-RAAS mediators such as adrenocorticotropic hormone (ACTH) and potassium. Aldosterone binds to mineralocorticoid receptors in both epithelial (e.g., kidney) and nonepithelial (e.g., heart, blood vessels, and brain) tissues and increases blood pressure through induction of sodium reabsorption and possibly other mechanisms.

Eplerenone has been shown to produce sustained increases in plasma renin and serum aldosterone, consistent with inhibition of the negative regulatory feedback of aldosterone on renin secretion. The resulting increased plasma renin activity and aldosterone circulating levels do not overcome the effects of eplerenone.

Eplerenone selectively binds to recombinant human mineralocorticoid receptors relative to its binding to recombinant human glucocorticoid, progesterone and androgen receptors.

(See PRECAUTIONS, Congestive Heart Failure Post-Myocardial Infarction and Hypertension, Drug Interactions .)

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

Eplerenone is metabolized primarily by CYP3A4. A potent inhibitor of CYP3A4 (ketoconazole) caused increased exposure of about 5-fold while less potent CYP3A4 inhibitors (erythromycin, saquinavir, verapamil, and fluconazole) gave approximately 2-fold increases. Grapefruit juice caused only a small increase (about 25%) in exposure. (See PRECAUTIONS, Congestive Heart Failure Post-Myocardial Infarction and Hypertension, Drug Interactions and DOSAGE AND ADMINISTRATION, Hypertension .)

Eplerenone is not an inhibitor of CYP1A2, CYP3A4, CYP2C19, CYP2C9, or CYP2D6. Eplerenone did not inhibit the metabolism of chlorzoxazone, diclofenac, methylphenidate, losartan, amiodarone, dexamethasone, mephobarbital, phenytoin, phenacetin, dextromethorphan, metoprolol, tolbutamide, amlodipine, astemizole, cisapride, 17α-ethinyl estradiol, fluoxetine, lovastatin, methylprednisolone, midazolam, nifedipine, simvastatin, 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 digoxin, warfarin, midazolam, cisapride, cyclosporine, simvastatin, glyburide, or oral contraceptives (norethindrone/ethinyl estradiol). St. Johns 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.

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, Congestive Heart Failure Post-Myocardial Infarction .)

EPHESUS randomized 6,632 patients (9.3% U.S.) at 671 centers in 27 countries. The study population was primarily white (90%, with 1% black, 1% Asian, 6% Hispanic, 2% other) and male (71%). The mean age was 64 years (range, 22–94 years). The majority of patients had pulmonary congestion (75%) by exam or x-ray and were Killip Class II (64%). The mean ejection fraction was 33%. The average time to enrollment was 7 days post-MI. Medical histories prior to the index MI included hypertension (60%), coronary artery disease (62%), dyslipidemia (48%), angina (41%), type 2 diabetes (30%), previous MI (27%), and HF (15%).

The mean dose of INSPRA was 43 mg/day. Patients also received standard care including aspirin (92%), ACE inhibitors (90%), β-blockers (83%), nitrates (72%), loop diuretics (66%), or HMG-CoA reductase inhibitors (60%).

Patients were followed for an average of 16 months (range, 0–33 months). The ascertainment rate for vital status was 99.7%.

The co-primary endpoints for EPHESUS were (1) the time to death from any cause, and (2) the time to first occurrence of either cardiovascular (CV) mortality [defined as sudden cardiac death or death due to progression of congestive heart failure (CHF), stroke, or other CV causes] or CV hospitalization (defined as hospitalization for progression of CHF, ventricular arrhythmias, acute myocardial infarction, or stroke). For the co-primary endpoint for death from any cause, there were 478 deaths in the INSPRA group (14.4%) and 554 deaths in the placebo group (16.7%). The risk of death with INSPRA was reduced by 15% [hazard ratio equal to 0.85 (95% confidence interval 0.75 to 0.96; p = 0.008 by log rank test)]. Kaplan-Meier estimates of all-cause mortality are shown in Figure 1 and the components of mortality are provided in Table 1.

Figure 1. Kaplan-Meier Estimates of All-Cause Mortality

Most CV deaths were attributed to sudden death, acute MI, and CHF.

The time to first event for the co-primary endpoint of CV death or hospitalization as defined above, was longer in the INSPRA group (hazard ratio 0.87, 95% confidence interval 0.79 to 0.95, p = 0.002). An analysis that included the time to first occurrence of CV mortality and all CV hospitalizations (atrial arrhythmia, angina, CV procedures, progression of CHF, MI, stroke, ventricular arrhythmia, or other CV causes) showed a smaller effect with a hazard ratio of 0.92 (95% confidence interval 0.86 to 0.99; p = 0.028). The combined endpoints, including combined all-cause hospitalization and mortality were driven primarily by CV mortality. The combined endpoints in EPHESUS, including all-cause hospitalization and all-cause mortality, are presented in Table 2.

Mortality hazard ratios varied for some subgroups as shown in Figure 2. Mortality hazard ratios appeared favorable for INSPRA for both genders and for all races or ethnic groups, although the numbers of non-caucasians were low (648, 10%). Patients with diabetes without clinical evidence of CHF and patients greater than 75 years did not appear to benefit from the use of INSPRA. Such subgroup analyses must be interpreted cautiously.

Figure 2. Hazard Ratios of All-Cause Mortality by Subgroups

Analyses conducted for a variety of CV biomarkers did not confirm a mechanism of action by which mortality was reduced.

The safety and efficacy of INSPRA have been evaluated alone and in combination with other antihypertensive agents in clinical studies of 3091 hypertensive patients. The studies included 46% women, 14% blacks, and 22% elderly (age ≥65). The studies excluded patients with elevated baseline serum potassium (>5.0 mEq/L) and elevated baseline serum creatinine (generally >1.5 mg/dL in males and >1.3 mg/dL in females).

Two fixed-dose, placebo-controlled, 8- to 12-week monotherapy studies in patients with baseline diastolic blood pressures of 95 to 114 mm Hg were conducted to assess the antihypertensive effect of INSPRA. In these two studies, 611 patients were randomized to INSPRA and 140 patients to placebo. Patients received INSPRA in doses of 25 to 400 mg daily as either a single daily dose or divided into two daily doses. The mean placebo-subtracted reductions in trough cuff blood pressure achieved by INSPRA in these studies at doses up to 200 mg are shown in Figures 3 and 4.

Patients treated with INSPRA 50 to 200 mg daily experienced significant decreases in sitting systolic and diastolic blood pressure at trough with differences from placebo of 6–13 mm Hg (systolic) and 3–7 mm Hg (diastolic). These effects were confirmed by assessments with 24-hour ambulatory blood pressure monitoring (ABPM). In these studies, assessments of 24-hour ABPM data demonstrated that INSPRA, administered once or twice daily, maintained antihypertensive efficacy over the entire dosing interval. However, at a total daily dose of 100 mg, INSPRA administered as 50 mg twice per day produced greater trough cuff (4/3 mm Hg) and ABPM (2/1 mm Hg) blood pressure reductions than 100 mg given once daily.

Blood pressure lowering was apparent within 2 weeks from the start of therapy with INSPRA, with maximal antihypertensive effects achieved within 4 weeks. Stopping INSPRA following treatment for 8 to 24 weeks in six studies did not lead to adverse event rates in the week following withdrawal of INSPRA greater than following placebo or active control withdrawal. Blood pressures in patients not taking other antihypertensives rose 1 week after withdrawal of INSPRA by about 6/3 mm Hg, suggesting that the antihypertensive effect of INSPRA was maintained through 8 to 24 weeks.

Blood pressure reductions with INSPRA in the two fixed-dose monotherapy studies and other studies using titrated doses, as well as concomitant treatments, were not significantly different when analyzed by age, gender, or race with one exception. In a study in patients with low renin hypertension, blood pressure reductions in blacks were smaller than those in whites during the initial titration period with INSPRA.

INSPRA has been studied concomitantly with treatment with ACE inhibitors, angiotensin II receptor antagonists, calcium channel blockers, beta blockers, and hydrochlorothiazide. When administered concomitantly with one of these drugs INSPRA usually produced its expected antihypertensive effects.

There was no significant change in average heart rate among patients treated with INSPRA in the combined clinical studies. No consistent effects of INSPRA on heart rate, QRS duration, or PR or QT interval were observed in 147 normal subjects evaluated for electrocardiographic changes during pharmacokinetic studies.

INSPRA is indicated to improve survival of stable patients with left ventricular systolic dysfunction (ejection fraction ≤40%) and clinical evidence of congestive heart failure after an acute myocardial infarction. (See CLINICAL STUDIES, Congestive Heart Failure Post-Myocardial Infarction .)

INSPRA is indicated for the treatment of hypertension. INSPRA may be used alone or in combination with other antihypertensive agents. (See CLINICAL STUDIES, Hypertension .)

INSPRA is contraindicated in all patients with the following:

• serum potassium >5.5 mEq/L at initiation
• creatinine clearance ≤30 mL/min
• concomitant use with the following potent CYP3A4 inhibitors: ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, and nelfinavir. Inspra should also not be used with other drugs noted in the CONTRAINDICATIONS, WARNINGS or PRECAUTIONS sections of their labeling to be potent CYP3A4 inhibitors. (See CLINICAL PHARMACOLOGY, Drug-Drug Interactions; PRECAUTIONS, Congestive Heart Failure Post-Myocardial Infarction and Hypertension, Drug Interactions and DOSAGE AND ADMINISTRATION, Hypertension .)

INSPRA is also contraindicated for the treatment of hypertension in patients with the following:

• type 2 diabetes with microalbuminuria
• serum creatinine >2.0 mg/dL in males or >1.8 mg/dL in females
• creatinine clearance <50 mL/min
• concomitant use of potassium supplements or potassium-sparing diuretics (amiloride, spironolactone, or triamterene)

(See CLINICAL PHARMACOLOGY, Pharmacokinetics, Drug-Drug Interactions; WARNINGS, Hyperkalemia in Patients Treated for Hypertension; PRECAUTIONS, Congestive Heart Failure Post-Myocardial Infarction and Hypertension, Drug Interactions ; and ADVERSE REACTIONS, Clinical Laboratory Test Findings, Hypertension, Potassium .)

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 .)

In EPHESUS, safety was evaluated in 3307 patients treated with INSPRA and 3301 placebo-treated patients. The overall incidence of adverse events reported with INSPRA (78.9%) was similar to placebo (79.5%). Adverse events occurred at a similar rate regardless of age, gender, or race. Patients discontinued treatment due to an adverse event at similar rates in either treatment group (4.4% INSPRA vs. 4.3% placebo).

Adverse events that occurred more frequently in patients treated with INSPRA than placebo were hyperkalemia (3.4% vs 2.0%) and increased creatinine (2.4% vs 1.5%). Discontinuations due to hyperkalemia or abnormal renal function were less than 1.0% in both groups. Hypokalemia occurred less frequently in patients treated with INSPRA (0.6% vs. 1.6%).

The rates of sex hormone related adverse events are shown in Table 3.

INSPRA has been evaluated for safety in 3091 patients treated for hypertension. A total of 690 patients were treated for over 6 months and 106 patients were treated for over 1 year.

In placebo-controlled studies, the overall rates of adverse events were 47% with INSPRA and 45% with placebo. Adverse events occurred at a similar rate regardless of age, gender, or race. Therapy was discontinued due to an adverse event in 3% of patients treated with INSPRA and 3% of patients given placebo. The most common reasons for discontinuation of INSPRA were headache, dizziness, angina pectoris/myocardial infarction, and increased GGT. The adverse events that were reported at a rate of at least 1% of patients and at a higher rate in patients treated with INSPRA in daily doses of 25 to 400 mg versus placebo are shown in Table 4.

Gynecomastia and abnormal vaginal bleeding were reported with INSPRA but not with placebo. The rates of these sex hormone related adverse events are shown in Table 5. The rates increased slightly with increasing duration of therapy. In females, abnormal vaginal bleeding was also reported in 0.8% of patients on antihypertensive medications (other than spironolactone) in active control arms of the studies with INSPRA.

No cases of human overdosage with eplerenone have been reported. Lethality was not observed in mice, rats, or dogs after single oral doses that provided C_max exposures at least 25 times higher than in humans receiving eplerenone 100 mg/day. Dogs showed emesis, salivation, and tremors at a C_max 41 times the human therapeutic C_max, progressing to sedation and convulsions at higher exposures.

The most likely manifestation of human overdosage would be anticipated to be hypotension or hyperkalemia. Eplerenone cannot be removed by hemodialysis. Eplerenone has been shown to bind extensively to charcoal. If symptomatic hypotension should occur, supportive treatment should be instituted. If hyperkalemia develops, standard treatment should be initiated.

The recommended dose of INSPRA is 50 mg once daily. Treatment should be initiated at 25 mg once daily and titrated to the target dose of 50 mg once daily preferably within 4 weeks as tolerated by the patient. INSPRA may be administered with or without food.

Serum potassium should be measured before initiating INSPRA therapy, within the first week and at one month after the start of treatment or dose adjustment. Serum potassium should be assessed periodically thereafter. Factors such as patient characteristics and serum potassium levels may indicate that additional monitoring is appropriate. (See PRECAUTIONS, Hyperkalemia in Patients Treated for Congestive Heart Failure and ADVERSE REACTIONS, Clinical Laboratory Test Findings, Congestive Heart Failure Post-Myocardial Infarction, Potassium .) In EPHESUS, the majority of hyperkalemia was observed within the first three months after randomization. The dose should be adjusted based on the serum potassium level and the dose adjustment table shown below (Table 10).

Following withholding INSPRA due to serum potassium ≥6.0 mEq/L, INSPRA can be restarted at a dose of 25 mg QOD when serum potassium levels have fallen below 5.5 mEq/L.

INSPRA may be used alone or in combination with other antihypertensive agents. The recommended starting dose of INSPRA is 50 mg administered once daily. The full therapeutic effect of INSPRA is apparent within 4 weeks. For patients with an inadequate blood pressure response to 50 mg once daily the dosage of INSPRA should be increased to 50 mg twice daily. Higher dosages of INSPRA are not recommended either because they have no greater effect on blood pressure than 100 mg or because they are associated with an increased risk of hyperkalemia. (See CLINICAL STUDIES, Hypertension .)

No adjustment of the starting dose is recommended for the elderly or for patients with mild-to-moderate hepatic impairment. For patients receiving weak CYP3A4 inhibitors, such as erythromycin, saquinavir, verapamil, and fluconazole the starting dose should be reduced to 25 mg once daily. (See CONTRAINDICATIONS and PRECAUTIONS, Congestive Heart Failure Post-Myocardial Infarction and Hypertension, Drug Interactions .)

INSPRA Tablets, 25 mg, are yellow diamond biconvex film-coated tablets. They are debossed with Pfizer on one side and NSR over 25 on the other. They are supplied as follows:

NDC Number                                              Size

0025-1710-01                                  Bottle of 30 tablets

0025-1710-02                                  Bottle of 90 tablets

0025-1710-03                                  Hospital Unit Dose

INSPRA Tablets, 50 mg, are yellow diamond biconvex film-coated tablets. They are debossed with Pfizer on one side and NSR over 50 on the other. They are supplied as follows:

NDC Number                                              Size

0025-1720-03                                  Bottle of 30 tablets

0025-1720-01                                  Bottle of 90 tablets

Store at 25°C (77°F); excursions permitted to 15-30°C (59–86°F) [See USP Controlled Room Temperature].