Licepler

Licepler is indicated:

- in addition to standard therapy including beta-blockers, to reduce the risk of cardiovascular mortality and morbidity in stable patients with left ventricular dysfunction (LVEF ≤ 40 %) and clinical evidence of heart failure after recent myocardial infarction.

- in addition to standard optimal therapy, to reduce the risk of cardiovascular mortality and morbidity in adult patients with NYHA class II (chronic) heart failure and left ventricular systolic dysfunction (LVEF ≤30%).

Eplerenone is indicated:

- in addition to standard therapy including beta-blockers, to reduce the risk of cardiovascular (CV) mortality and morbidity in stable patients with left ventricular dysfunction (LVEF ≤ 40 %) and clinical evidence of heart failure after recent myocardial infarction (MI).

- in addition to standard optimal therapy, to reduce the risk of CV mortality and morbidity in adult patients with New York Heart Association (NYHA) class II (chronic) heart failure and left ventricular systolic dysfunction (LVEF ≤30%).

Posology

For the individual adjustment of dose, the strengths of 25 mg and 50 mg are available. The maximum dose regimen is 50 mg daily.

For post-myocardial infarction heart failure patients:

The recommended maintenance dose of Licepler is 50 mg once daily (OD). Treatment should be initiated at 25 mg once daily and titrated to the target dose of 50 mg once daily preferably within 4 weeks, taking into account the serum potassium level (see Table 1). Licepler therapy should usually be started within 3-14 days after an acute myocardial infarction.

For patients with NYHA class II (chronic) heart failure:

Patients with a serum potassium of > 5.0 mmol/L should not be started on Licepler.

Serum potassium should be measured before initiating Licepler therapy, within the first week and at one month after the start of treatment or dose adjustment. Serum potassium should be assessed as needed periodically thereafter.

After initiation, the dose should be adjusted based on the serum potassium level as shown in Table 1.

Table 1: Dose adjustment table after initiation

* EOD: Every Other Day

Following withholding Licepler due to serum potassium > 6.0 mmol/L, Licepler can be re-started at a dose of 25 mg every other day when potassium levels have fallen below 5.0 mmol/L.

Paediatric population

The safety and efficacy of Licepler in children and adolescents have not been established.2

Older People

No initial dose adjustment is required in the elderly. Due to an age-related decline in renal function, the risk of hyperkalaemia 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.

Renal impairment

No initial dose adjustment is required in patients with mild renal impairment. Periodic monitoring of serum potassium is recommended and doses adjusted according to Table 1.

Patients with moderate renal impairment (CrCl 30-60 ml/min) should be started at 25 mg every other day, and dose should be adjusted based on the potassium level (see Table 1). Periodic monitoring of serum potassium is recommended.

There is no experience in patients with CrCl <50 ml/min with post MI heart failure. The use of Licepler in these patients should be done cautiously.

Doses above 25 mg daily have not been studied in patients with CrCl <50 ml/min.

Patients with severe renal impairment (CrCl <30 ml/min) are contraindicated.

Licepler is not dialysable.

Hepatic impairment

No initial dosage adjustment is necessary for patients with mild-to-moderate hepatic impairment. Due to an increased systemic exposure to Licepler in patients with mild-to-moderate hepatic impairment, frequent and regular monitoring of serum potassium is recommended in these patients, especially when elderly.

Concomitant treatment

In case of concomitant treatment with mild to moderate CYP3A4 inhibitors, e.g. amiodarone, diltiazem and verapamil, a starting dose of 25 mg OD may be initiated. Dosing should not exceed 25 mg OD.

Method of administration

Licepler may be administered with or without food.

Posology

For the individual adjustment of dose, the strengths of 25 mg and 50 mg are available. The maximum dose regimen is 50 mg daily.

For post-MI heart failure patients

The recommended maintenance dose of eplerenone is 50 mg once daily (OD). Treatment should be initiated at 25 mg once daily and titrated to the target dose of 50 mg once daily preferably within 4 weeks, taking into account the serum potassium level (see Table 1). Eplerenone therapy should usually be started within 3-14 days after an acute MI.

For patients with NYHA class II (chronic) heart failure

Patients with a serum potassium of > 5.0 mmol/L should not be started on eplerenone.

Serum potassium should be measured before initiating eplerenone therapy, within the first week and at one month after the start of treatment or dose adjustment. Serum potassium should be assessed as needed periodically thereafter.

After initiation, the dose should be adjusted based on the serum potassium level as shown in Table 1.

Table 1: Dose adjustment table after initiation

* EOD: Every Other Day

Following withholding eplerenone due to serum potassium > 6.0 mmol/L, eplerenone can be re-started at a dose of 25 mg every other day when potassium levels have fallen below 5.0 mmol/L.

Paediatric population

The safety and efficacy of eplerenone in children and adolescents have not been established.2.

Elderly

No initial dose adjustment is required in the elderly. Due to an age-related decline in renal function, the risk of hyperkalaemia 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.

Renal impairment

No initial dose adjustment is required in patients with mild renal impairment. Periodic monitoring of serum potassium with dose adjustment according to Table 1 is recommended.

Patients with moderate renal impairment (CrCl 30-60 mL/min) should be started at 25 mg every other day, and dose should be adjusted based on the potassium level (see Table 1). Periodic monitoring of serum potassium is recommended.

There is no experience in patients with CrCl <50 mL/min with post MI heart failure. The use of eplerenone in these patients should be done cautiously. Doses above 25 mg daily have not been studied in patients with CrCl <50 mL/min.

Use in patients with severe renal impairment (CrCl <30 mL/min) is contraindicated.

Eplerenone is not dialysable.

Hepatic impairment

No initial dose adjustment is necessary for patients with mild-to-moderate hepatic impairment. Due to an increased systemic exposure to eplerenone in patients with mild-to-moderate hepatic impairment, frequent and regular monitoring of serum potassium is recommended in these patients, especially when elderly.

Concomitant treatment

In case of concomitant treatment with mild to moderate CYP3A4 inhibitors, e.g. amiodarone, diltiazem and verapamil, the dose of 25 mg OD may be initiated. Dosing should not exceed 25 mg OD.

Eplerenone may be administered with or without food.

- Patients with serum potassium level > 5.0 mmol/L at initiation

- Patients with severe renal insufficiency (eGFR <30 mL/minute/1.73 m2)

- Patients with severe hepatic insufficiency (Child-Pugh Class C)

- Patients receiving potassium-sparing diuretics, potassium-supplements or strong inhibitors of CYP3A4 (e.g. itraconazole, ketoconazole, ritonavir, nelfinavir, clarithromycin, telithromycin and nefazodone).

- The combination of an angiotensin converting enzyme (ACE) inhibitor and an angiotensin receptor blocker (ARB) with Licepler

-

- Patients with serum potassium level > 5.0 mmol/L at initiation

- Patients with severe renal insufficiency (eGFR <30 mL per minute per 1.73 m²)

- Patients with severe hepatic insufficiency (Child-Pugh Class C)

- Patients receiving potassium-sparing diuretics or strong inhibitors of CYP 3A4 (e.g., itraconazole, ketoconazole, ritonavir, nelfinavir, clarithromycin, telithromycin and nefazodone)

- The combination of an angiotensin converting enzyme (ACE) inhibitor and an angiotensin receptor blocker (ARB) with eplerenone

Hyperkalaemia

Consistent with its mechanism of action, hyperkalaemia may occur with Licepler. Serum potassium levels should be monitored in all patients at initiation of treatment and with a change in dosage. Thereafter, periodic monitoring is recommended especially in patients at risk for the development of hyperkalaemia, such as elderly patients, patients with renal insufficiency and patients with diabetes. The use of potassium supplements after initiation of Licepler therapy is not recommended, due to an increased risk of hyperkalaemia. Dose reduction of Licepler has been shown to decrease serum potassium levels. In one study, the addition of hydrochlorothiazide to Licepler therapy has been shown to offset increases in serum potassium.

The risk of hyperkalaemia may increase when Licepler is used in combination with an angiotensin converting enzyme (ACE) inhibitor and/or an angiotensin receptor blocker (ARB). The combination of an angiotensin converting enzyme (ACE) inhibitor and an angiotensin receptor blocker (ARB) with Licepler should not be used.

Impaired renal function

Potassium levels should be monitored regularly in patients with impaired renal function, including diabetic microalbuminuria. The risk of hyperkalaemia increases with decreasing renal function. While the data from EPHESUS in patients with type 2 diabetes and microalbuminuria is limited, an increased occurrence of hyperkalaemia was observed in this small number of patients. Therefore, these patients should be treated with caution. Licepler is not removed by haemodialysis.

Impaired hepatic function

No elevations of serum potassium above 5.5 mmol/L were observed in patients with mild to moderate hepatic impairment (Child Pugh class A and B). Electrolyte levels should be monitored in patients with mild to moderate hepatic impairment. The use of Licepler in patients with severe hepatic impairment has not been evaluated and its use is therefore contraindicated.

CYP3A4 inducers

Co-administration of Licepler with strong CYP3A4 inducers is not recommended.

Lithium, cyclosporin, tacrolimus should be avoided during treatment with Licepler.

Lactose

The tablets contain lactose and should not be administered in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.

Hyperkalaemia

Consistent with its mechanism of action, hyperkalaemia may occur with eplerenone. Serum potassium levels should be monitored in all patients at initiation of treatment and with a change in dosage. Thereafter, periodic monitoring is recommended especially in patients at risk for the development of hyperkalaemia, such as elderly patients, patients with renal insufficiency and patients with diabetes. The use of potassium supplements after initiation of eplerenone therapy is not recommended, due to an increased risk of hyperkalaemia. Dose reduction of eplerenone has been shown to decrease serum potassium levels. In one study, the addition of hydrochlorothiazide to eplerenone therapy has been shown to offset increases in serum potassium.

The risk of hyperkalaemia may increase when eplerenone is used in combination with an ACE inhibitor and/or an ARB. The combination of an ACE inhibitor and an ARB with eplerenone should not be used.

Impaired renal function

Potassium levels should be monitored regularly in patients with impaired renal function, including diabetic microalbuminuria. The risk of hyperkalaemia increases with decreasing renal function. While the data from Eplerenone Post-acute Myocardial Infarction Heart failure Efficacy and Survival Study (EPHESUS) in patients with Type 2 diabetes and microalbuminuria is limited, an increased occurrence of hyperkalaemia was observed in this small number of patients. Therefore, these patients should be treated with caution. Eplerenone is not removed by haemodialysis.

Impaired hepatic function

No elevations of serum potassium above 5.5 mmol/L were observed in patients with mild to moderate hepatic impairment (Child Pugh class A and B). Electrolyte levels should be monitored in patients with mild to moderate hepatic impairment. The use of eplerenone in patients with severe hepatic impairment has not been evaluated and its use is therefore contraindicated.

CYP3A4 inducers

Co-administration of eplerenone with strong CYP3A4 inducers is not recommended.

Lithium, cyclosporin, tacrolimus should be avoided during treatment with eplerenone.

Lactose

The tablets contain lactose and should not be administered in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.

No studies on the effect of Licepler on the ability to drive or use machines have been performed. Licepler does not cause drowsiness or impairment of cognitive function but when driving vehicles or operating machines it should be taken into account that dizziness may occur during treatment.

No studies on the effect of eplerenone on the ability to drive or use machines have been performed. Eplerenone does not cause drowsiness or impairment of cognitive function but when driving vehicles or operating machines it should be taken into account that dizziness may occur during treatment.

In two studies (Licepler Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study [EPHESUS] and Licepler in Mild Patients Hospitalization and Survival Study in Heart Failure [EMPHASIS-HF]), the overall incidence of adverse events reported with Licepler was similar to placebo. The most frequent adverse event reported in the EMPHASIS-HF study was hyperkalaemia with an incidence rate of 8.7% and 4% for Licepler and placebo respectively.

Adverse events reported below are those with suspected relationship to treatment and in excess of placebo or are serious and significantly in excess of placebo, or have been observed during post marketing surveillance. Adverse events are listed by body system and absolute frequency. Frequencies are defined as: very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1000 to < 1/100),.rare (> 1/10,000 to <1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data).

In EPHESUS, there were numerically more cases of stroke in the elderly group (> 75 years old). There was however no statistical significant difference between the occurrence of stroke in the Licepler (30) vs placebo (22) groups. In EMPHASIS-HF, the number of cases of stroke in the very elderly (> 75 years old) was 9 in the Licepler group and 8 in the placebo group.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

In two studies (EPHESUS and Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure [EMPHASIS-HF]), the overall incidence of adverse events reported with eplerenone was similar to placebo.

Adverse events reported below are those with suspected relationship to treatment and in excess of placebo or are serious and significantly in excess of placebo, or have been observed during post marketing surveillance. Adverse events are listed by body system and absolute frequency. Frequencies are defined as:

Very common (> 1/10)

Common (> 1/100 to < 1/10)

Uncommon (> 1/1,000 to < 1/100)

Rare (> 1/10,000 to < 1/1,000)

Very rare (< 1/10,000)

Not known (cannot be estimated from the available data).

Table 2: ADR Frequency in Eplerenone Placebo Controlled Studies

In EPHESUS, there were numerically more cases of stroke in the very elderly group (> 75 years old). There was however no statistical significant difference between the occurrence of stroke in the eplerenone (30) vs placebo (22) groups. In EMPHASIS-HF, the number of cases of stroke in the very elderly (> 75 years old) was 9 in the eplerenone group and 8 in the placebo group.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.

No cases of adverse events associated with overdose of Licepler in humans have been reported.

The most likely manifestation of human overdosage would be anticipated to be hypotension and/or hyperkalaemia.

Licepler cannot be removed by haemodialysis. Licepler has been shown to bind extensively to charcoal. If symptomatic hypotension should occur, supportive treatment should be initiated. If hyperkalaemia develops, standard treatment should be initiated.

No cases of adverse events associated with overdose of eplerenone in humans have been reported. The most likely manifestation of human overdose would be anticipated to be hypotension or hyperkalaemia. Eplerenone cannot be removed by haemodialysis. Eplerenone has been shown to bind extensively to charcoal. If symptomatic hypotension should occur, supportive treatment should be initiated. If hyperkalaemia develops, standard treatment should be initiated.

Pharmacotherapeutic group: aldosterone antagonists, ATC code: C03DA04

Mechanism of action

Licepler has relative selectivity in binding to recombinant human mineralocorticoid receptors compared to its binding to recombinant human glucocorticoid, progesterone and androgen receptors. Licepler 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 cardiovascular disease.

Pharmacodynamic effects

Licepler 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 Licepler.

In dose-ranging studies of chronic heart failure (NYHA classification II-IV), the addition of Licepler to standard therapy resulted in expected dose-dependent increases in aldosterone. Similarly, in a cardiorenal substudy of EPHESUS, therapy with Licepler led to a significant increase in aldosterone. These results confirm the blockade of the mineralocorticoid receptor in these populations.

Licepler was studied in the Licepler post-acute myocardial infarction heart failure efficacy and survival study (EPHESUS). EPHESUS was a double-blind, placebo-controlled study, of 3 year duration, in 6632 patients with acute myocardial infarction (MI), left ventricular dysfunction (as measured by left ventricular ejection fraction [LVEF] ≤ 40%), and clinical signs of heart failure. Within 3-14 days (median 7 days) after an acute MI, patients received Licepler or placebo in addition to standard therapies at an initial dose 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 patients received standard care including acetylsalicylic acid (92%), ACE inhibitors (90%), ß-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 patients assigned to Licepler and 16.7% of patients assigned to placebo died (all causes), while 26.7% of patients assigned to Licepler and 30.0% assigned to placebo met the combined endpoint of CV death or hospitalisation. Thus, in EPHESUS, Licepler 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 cardiovascular (CV) mortality. The risk of CV death or CV hospitalisation was reduced by 13% with Licepler (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 Licepler therapy was initiated in patients aged < 75 years old. The benefits of therapy in those patients over the age of 75 are unclear. NYHA functional classification improved or remained stable for a statistically significantly greater proportion of patients receiving Licepler compared to placebo. The incidence of hyperkalaemia was 3.4% in the Licepler group vs 2.0% in the placebo group (p < 0.001). The incidence of hypokalaemia was 0.5% in the Licepler group vs 1.5% in the placebo group (p < 0.001).

No consistent effects of Licepler 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 (Licepler in Mild Patients Hospitalization and Survival Study in Heart Failure) the effect of Licepler when added to standard therapy was investigated on clinical outcomes in patients with systolic heart failure and mild symptoms (NYHA functional class II).

Patients were included if they were at least 55 years old, had a left ventricular ejection fraction (LVEF) ≤ 30% or LVEF ≤ 35% in addition to QRS duration of > 130 msec, and were either hospitalized for cardiovascular (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). Licepler 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 GFR was 30-49 ml/min/1.73 m², Licepler was started at 25 mg on alternate days, and increased to 25 mg once daily.

In total, 2737 patients were randomized (double-blind) to the treatment with Licepler 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 patients (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 patients had implantable defibrillators or cardiac resynchronization therapy.

The primary endpoint, death from cardiovascular causes or hospitalization for heart failure occurred in 249 patients (18.3%) in the Licepler group and 356 patients (25.9%) in the placebo group (RR 0.63, 95% CI, 0.54-0.74; p<0.001). The effect of Licepler on the primary endpoint outcomes was consistent across all pre-specified subgroups.

The secondary endpoint of all cause mortality was met by 171 patients (12.5%) in the Licepler group and 213 patients (15.5%) 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%) patients in the Licepler group and 185 (13.5%) patients 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 patients (11.8%) in the Licepler group and 96 patients (7.2%) in the placebo group (p < 0.001). Hypokalaemia, defined as serum potassium levels < 4.0 mmol/L, was statistically lower with Licepler when compared to placebo (38.9% for Licepler compared to 48.4% for placebo, p<0.0001).

Paediatric population

Licepler has not been studied in pediatric patients with heart failure.

In a 10 week study of paediatric patients with hypertension (age range 4 to 17 years, n=304), Licepler, 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 patients, the safety profile was similar to that of adults. Licepler has not been studied in hypertensive patients less than 4 years old because the study in older paediatric patients showed a lack of efficacy.

Any (long term) effect on hormonal status in paediatric patients has not been studied.

Pharmacotherapeutic group: aldosterone antagonists, ATC code: C03DA04

Mechanism of action

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.

Pharmacodynamic effects

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).

Paediatric population:

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.

Any (long term) effect on hormonal status in paediatric subjects has not been studied.

Absorption

The absolute bioavailability of Licepler is unknown. Maximum plasma concentrations are reached after about 2 hours. Both peak plasma levels (C_max) and area under the curve (AUC) are dose proportional for doses of 10 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.

Distribution

The plasma protein binding of Licepler is about 50% and is primarily bound to alpha 1-acid glycoproteins. The apparent volume of distribution at steady state is estimated at 50 (±7) L. Licepler does not preferentially bind to red blood cells.

Biotransformation

Licepler metabolism is primarily mediated via CYP3A4. No active metabolites of Licepler have been identified in human plasma.

Elimination

Less than 5% of an Licepler 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 Licepler is approximately 3 to 5 hours. The apparent plasma clearance is approximately 10 L/hr.

Special Populations

Age, Gender, and Race:

The pharmacokinetics of Licepler 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 Licepler did not differ significantly between males and females. At steady state, elderly subjects had increases in C_max (22%) and AUC (45%) compared with younger subjects (18 to 45 years). At steady state, C_max was 19% lower and AUC was 26% lower in blacks.

Paediatric population

A population pharmacokinetic model for Licepler concentrations from two studies in 51 paediatric hypertensive patients of ages 4-16 years identified that patient body weight had a statistically significant effect on Licepler volume of distribution but not on its clearance. Licepler 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. Licepler 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 Licepler concentrations in paediatric subjects were not substantially higher than those in adults initiated at 50 mg once daily.

Renal Insufficiency:

The pharmacokinetics of Licepler were evaluated in patients with varying degrees of renal insufficiency and in patients undergoing haemodialysis. Compared with control subjects, steady-state AUC and C_max 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 Licepler and creatinine clearance. Licepler is not removed by haemodialysis.

Hepatic Insufficiency:

The pharmacokinetics of Licepler 400 mg have been investigated in patients with moderate (Child-Pugh Class B) hepatic impairment and compared with normal subjects. Steady-state C_max and AUC of Licepler were increased by 3.6% and 42%, respectively. Since the use of Licepler has not been investigated in patients with severe hepatic impairment, Licepler is contraindicated in this patients' group.

Heart Failure:

The pharmacokinetics of Licepler 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 C_max in heart failure patients were 38% and 30% higher, respectively. Consistent with these results, a population pharmacokinetic analysis of Licepler based on a subset of patients from EPHESUS indicates that clearance of Licepler in patients with heart failure was similar to that in healthy elderly subjects.

Absorption

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.

Distribution

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.

Biotransformation

Eplerenone metabolism is primarily mediated via CYP3A4. No active metabolites of eplerenone have been identified in human plasma.

Elimination

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.

Special populations

Age, gender, and race

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 C_max (22%) and AUC (45%) compared with younger subjects (18 to 45 years). At steady state, C_max was 19% lower and AUC was 26% lower in blacks.

Paediatric population

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.

Renal insufficiency

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.

Hepatic insufficiency

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. Since the use of eplerenone has not been investigated in patients with severe hepatic impairment, eplerenone is contraindicated in this patient group.

Heart failure

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 on safety pharmacology, genotoxicity, carcinogenic potential and toxicity to reproduction 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.

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.

Not applicable.

Not applicable.