Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: Pfizer Limited, Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom
Pharmacotherapeutic group: aldosterone antagonists
ATC code: C03DA04
Eplerenone has relative selectivity in binding to recombinant human mineralocorticoid receptors compared to its binding to recombinant human glucocorticoid, progesterone and androgen receptors. Eplerenone prevents the binding of aldosterone, a key hormone in the renin-angiotensin-aldosterone-system (RAAS), which is involved in the regulation of blood pressure and the pathophysiology of CV disease.
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.
In dose-ranging studies of chronic heart failure (NYHA classification II-IV), the addition of eplerenone to standard therapy resulted in expected dose-dependent increases in aldosterone. Similarly, in a cardiorenal substudy of EPHESUS, therapy with eplerenone led to a significant increase in aldosterone. These results confirm the blockade of the mineralocorticoid receptor in these populations.
Eplerenone was studied in the EPHESUS. EPHESUS was a double-blind, placebo-controlled study, of 3 year duration, in 6632 subjects with acute MI, left ventricular dysfunction (as measured by left ventricular ejection fraction [LVEF] ≤40%), and clinical signs of heart failure. Within 3 to 14 days (median 7 days) after an acute MI, subjects received eplerenone or placebo in addition to standard therapies at 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 mmol/L. During the study subjects received standard care including acetylsalicylic acid (92%), ACE inhibitors (90%), beta-blockers (83%), nitrates (72%), loop diuretics (66%), or HMG CoA reductase inhibitors (60%).
In EPHESUS, the co-primary endpoints were all-cause mortality and the combined endpoint of CV death or CV hospitalisation; 14.4% of subjects assigned to eplerenone and 16.7% of subjects assigned to placebo died (all causes), while 26.7% of subjects assigned to eplerenone and 30.0% assigned to placebo met the combined endpoint of CV death or hospitalisation. Thus, in EPHESUS, eplerenone reduced the risk of death from any cause by 15% (RR 0.85; 95% CI, 0.75-0.96; p =0.008) compared to placebo, primarily by reducing CV mortality. The risk of CV death or CV hospitalisation was reduced by 13% with eplerenone (RR 0.87; 95% CI, 0.79-0.95; p=0.002). The absolute risk reductions for the endpoints all cause mortality and CV mortality/hospitalisation were 2.3% and 3.3%, respectively. Clinical efficacy was primarily demonstrated when eplerenone therapy was initiated in subjects aged <75 years old. The benefits of therapy in those subjects over the age of 75 are unclear. NYHA functional classification improved or remained stable for a statistically significant greater proportion of subjects receiving eplerenone compared to placebo. The incidence of hyperkalaemia was 3.4% in the eplerenone group vs. 2.0% in the placebo group (p <0.001). The incidence of hypokalaemia was 0.5% in the eplerenone group vs 1.5% in the placebo group (p <0.001).
No consistent effects of eplerenone on heart rate, QRS duration, or PR or QT interval were observed in 147 normal subjects evaluated for electrocardiographic changes during pharmacokinetic studies.
In the EMPHASIS-HF trial the effect of eplerenone when added to standard therapy was investigated on clinical outcomes in subjects with systolic heart failure and mild symptoms (NYHA functional class II).
Subjects were included if they were at least 55 years old, had a LVEF ≤30% or LVEF ≤35% in addition to QRS duration of >130 msec, and were either hospitalized for CV reasons 6 months prior to inclusion or had a plasma level of B-type natriuretic peptide (BNP) of at least 250 pg/mL or a plasma level of N-terminal pro-BNP of at least 500 pg/mL in men (750 pg/mL in women). Eplerenone was started at a dose of 25 mg once daily and was increased after 4 weeks to 50 mg once daily if the serum potassium level was <5.0 mmol/L. Alternatively, if the estimated glomerular filtration rate (GFR) was 30-49 mL/min/1.73 m², eplerenone was started at 25 mg on alternate days, and increased to 25 mg once daily.
In total, 2737 subjects were randomized (double-blind) to treatment with eplerenone or placebo including baseline therapy of diuretics (85%), ACE inhibitors (78%), angiotensin II receptor blockers (19%), beta-blockers (87%), anti thrombotic drugs (88%), lipid lowering agents (63%), and digitalis glycosides (27%). The mean LVEF was ~26% and the mean QRS duration was ~122 msec. Most of the subjects (83.4%) were previously hospitalized for CV reasons within 6 months of randomization, with around 50% of them due to heart failure. Around 20% of the subjects had implantable defibrillators or cardiac resynchronization therapy.
The primary endpoint, death from CV causes or hospitalization for heart failure occurred in 249 (18.3%) subjects in the eplerenone group and 356 (25.9%) subjects in the placebo group (RR 0.63, 95% CI, 0.54-0.74; p<0.001). The effect of eplerenone on the primary endpoint outcomes was consistent across all pre-specified subgroups.
The secondary endpoint of all cause mortality was met by 171 (12.5%) subjects in the eplerenone group and 213 (15.5%) subjects in the placebo group (RR 0.76; 95% CI, 0.62-0.93; p =0.008). Death from CV causes was reported in 147 (10.8%) subjects in the eplerenone group and 185 (13.5%) subjects in the placebo group (RR 0.76; 95% CI, 0.61-0.94; p =0.01).
During the study, hyperkalaemia (serum potassium level >5.5 mmol/L) was reported in 158 (11.8%) subjects in the eplerenone group and 96 (7.2%) subjects in the placebo group (p <0.001). Hypokalaemia, defined as serum potassium levels <4.0 mmol/L, was statistically lower with eplerenone when compared to placebo (38.9% for eplerenone compared to 48.4% for placebo, p <0.0001).
Eplerenone has not been studied in pediatric subjects with heart failure.
In a 10-week study of paediatric subjects with hypertension (age range 4 to 16 years, n=304), eplerenone, at doses (from 25 mg up to 100 mg per day) that produced exposure similar to that in adults, did not lower blood pressure effectively. In this study and in a 1-year paediatric safety study in 149 subjects (age range 5 to 17 years), the safety profile was similar to that of adults. Eplerenone has not been studied in hypertensive subjects less than 4 years old because the study in older paediatric subjects showed a lack of efficacy (see section 4.2).
Any (long term) effect on hormonal status in paediatric subjects has not been studied.
The absolute bioavailability of eplerenone is 69% following administration of a 100 mg oral tablet.
Maximum plasma concentrations are reached after approximately 1.5 to 2 hours. Both peak plasma levels (Cmax) and area under the curve (AUC) are dose proportional for doses of 10 mg to 100 mg and less than proportional at doses above 100 mg. Steady state is reached within 2 days. Absorption is not affected by food.
The plasma protein binding of eplerenone is about 50% and is primarily bound to alpha 1-acid glycoproteins. The apparent volume of distribution at steady state is estimated to be 42-90 L. Eplerenone does not preferentially bind to red blood cells.
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 faeces. Following a single oral dose of radiolabeled drug, approximately 32% of the dose was excreted in the faeces and approximately 67% was excreted in the urine. The elimination half-life of eplerenone is approximately 3 to 6 hours. The apparent plasma clearance is approximately 10 L/hr.
The pharmacokinetics of eplerenone at a dose of 100 mg once daily have been investigated in the elderly (≥65 years), in males and females, and in blacks. The pharmacokinetics of eplerenone did not differ significantly between males and females. At steady state, elderly subjects had increases in Cmax (22%) and AUC (45%) compared with younger subjects (18 to 45 years). At steady state, Cmax was 19% lower and AUC was 26% lower in blacks (see section 4.2).
A population pharmacokinetic model for eplerenone concentrations from two studies in 51 paediatric hypertensive subjects of ages 4 to16 years identified that patient body weight had a statistically significant effect on eplerenone volume of distribution but not on its clearance. Eplerenone volume of distribution and peak exposure in a heavier paediatric patient are predicted to be similar to that in an adult of similar body weight; in a lighter 45 kg patient, the volume of distribution is about 40% lower and the peak exposure is predicted to be higher than typical adults. Eplerenone treatment was initiated at 25 mg once daily in paediatric patients and increased to 25 mg twice daily after 2 weeks and eventually to 50 mg twice daily, if clinically indicated. At these doses, the highest observed eplerenone concentrations in paediatric subjects were not substantially higher than those in adults initiated at 50 mg once daily.
The pharmacokinetics of eplerenone were evaluated in patients with varying degrees of renal insufficiency and in patients undergoing haemodialysis. 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 haemodialysis. No correlation was observed between plasma clearance of eplerenone and creatinine clearance. Eplerenone is not removed by haemodialysis (see section 4.4.).
The pharmacokinetics of eplerenone 400 mg have 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 (see section 4.2). Since the use of eplerenone has not been investigated in patients with severe hepatic impairment, eplerenone is contraindicated in this patient group (see section 4.3).
The pharmacokinetics of eplerenone 50 mg were evaluated in patients with heart failure (NYHA classification II-IV). Compared with healthy subjects matched according to age, weight and gender, steady state AUC and Cmax in heart failure patients were 38% and 30% higher, respectively. Consistent with these results, a population pharmacokinetic analysis of eplerenone based on a subset of patients from EPHESUS indicates that clearance of eplerenone in patients with heart failure was similar to that in healthy elderly subjects.
Preclinical studies of safety pharmacology, genotoxicity, carcinogenic potential and reproductive toxicity revealed no special hazard for humans.
In repeated dose toxicity studies, prostate atrophy was observed in rats and dogs at exposure levels slightly above clinical exposure levels. The prostatic changes were not associated with adverse functional consequences. The clinical relevance of these findings is unknown.
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