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-, Î³-lactone, methyl ester, (7alpha,11alpha,17alpha)-. 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.
Mechanism of Action
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.
Eplerenone is cleared predominantly by cytochrome P450 (CYP) 3A4 metabolism, with an elimination half-life of 4 to 6 hours. Steady state is reached within 2 days. Absorption is not affected by food. Inhibitors of CYP3A4 (e.g., ketoconazole, saquinavir) increase blood levels of eplerenone.
Absorption and Distribution
Mean peak plasma concentrations of eplerenone are reached approximately 1.5 hours following oral administration. The absolute bioavailability of eplerenone is 69% following administration of a 100 mg oral tablet. Both peak plasma levels (Cmax) and area under the curve (AUC) are dose proportional for doses of 25 to 100 mg and less than proportional at doses above 100 mg.
The plasma protein binding of eplerenone is about 50% and it is primarily bound to alpha 1-acid glycoproteins. The apparent volume of distribution at steady state ranged from 43 to 90 L. Eplerenone does not preferentially bind to red blood cells.
Metabolism and Excretion
Eplerenone metabolism is primarily mediated via CYP3A4. No active metabolites of eplerenone have been identified in human plasma.
Less than 5% of an eplerenone dose is recovered as unchanged drug in the urine and feces. Following a single oral dose of radiolabeled drug, approximately 32% of the dose was excreted in the feces and approximately 67% was excreted in the urine. The elimination half-life of eplerenone is approximately 4 to 6 hours. The apparent plasma clearance is approximately 10 L/hr.
Age, Gender, and Race
The pharmacokinetics of eplerenone at a dose of 100 mg once daily has been investigated in the elderly (≥65 years), in males and females, and in Blacks. At steady state, elderly subjects had increases in Cmax (22%) and AUC (45%) compared with younger subjects (18 to 45 years). The pharmacokinetics of eplerenone did not differ significantly between males and females. At steady state, Cmax was 19% lower and AUC was 26% lower in Blacks. [See DOSAGE AND ADMINISTRATION and USE IN SPECIFIC POPULATIONS.]
The pharmacokinetics of eplerenone was evaluated in patients with varying degrees of renal impairment and in patients undergoing hemodialysis. Compared with control subjects, steady state AUC and Cmax were increased by 38% and 24%, respectively, in patients with severe renal impairment and were decreased by 26% and 3%, respectively, in patients undergoing hemodialysis. No correlation was observed between plasma clearance of eplerenone and creatinine clearance. Eplerenone is not removed by hemodialysis. [See WARNINGS AND PRECAUTIONS.]
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.
The pharmacokinetics of eplerenone 50 mg was evaluated in 8 patients with heart failure (NYHA classification IIâ€“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 (7).]
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, 17alpha-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.
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.
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 314 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.]
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, 2294 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 CHF (15%).
The mean dose of INSPRA was 43 mg/day. Patients also received standard care including aspirin (92%), ACE inhibitors (90%), Ÿ-blockers (83%), nitrates (72%), loop diuretics (66%), or HMG-CoA reductase inhibitors (60%).
Patients were followed for an average of 16 months (range, 033 months). The ascertainment rate for vital status was 99.7%.
The co-primary endpoints for EPHESUS were the time to death from any cause, and 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 9.
Figure 1. Kaplan-Meier Estimates of All-Cause Mortality
Table 9. Components of All-Cause Mortality in EPHESUS
| ||INSPRA |
|Death from any cause ||478 (14.4) ||554 (16.7) ||0.85 ||0.008 |
| CV Death ||407 (12.3) ||483 (14.6) ||0.83 ||0.005 |
| Non-CV Death ||60 (1.8) ||54 (1.6) || || |
| Unknown or unwitnessed death ||11 (0.3) ||17 (0.5) || || |
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 10.
Table 10. Rates of Death or Hospitalization in EPHESUS
|Event ||INSPRA |
|CV death or hospitalization for progression of CHF, stroke, MI or ventricular arrhythmia
||885 (26.7) ||993 (30.0) |
| Death ||407 (12.3) ||483 (14.6) |
| Hospitalization ||606 (18.3) ||649 (19.6) |
|CV death or hospitalization for progression of CHF, stroke, MI, ventricular arrhythmia, atrial arrhythmia, angina, CV procedures, or other CV causes (PVD; Hypotension) ||1516 (45.7) ||1610 (48.6) |
| Death ||407 (12.3) ||483 (14.6) |
| Hospitalization ||1281 (38.6) ||1307 (39.5) |
|All-cause death or hospitalization ||1734 (52.2) ||1833 (55.3) |
| Death ||478 (14.4) ||554 (16.7) |
| Hospitalization ||1497 (45.1) ||1530 (46.2) |
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 613 mm Hg (systolic) and 37 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.
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