Eplerik

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT EPLERIK (EPLERIK)

Composition:

active ingredient: eplerenone;

one film-coated tablet contains 25 mg or 50 mg of eplerenone;

excipients: lactose monohydrate, microcrystalline cellulose (intragranular), microcrystalline cellulose (extragranular), sodium croscarmellose, hypromellose, sodium lauryl sulfate, talc, magnesium stearate, purified water; coating: hypromellose, polysorbate 80, macrogol (PEG 4000), titanium dioxide (E171), yellow iron oxide (E172), purified water.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

25 mg tablets: light-yellow, round, biconvex, film-coated tablets, with "E9RN" imprinted on one side and "25" on the other;

50 mg tablets: light-yellow, round, biconvex, film-coated tablets, with i mprint "E9RN" on one side and "50" on the other.

Pharmacotherapeutic group. Potassium-sparing diuretics. Aldosterone antagonists. Eplerenone. ATC code C03DA04.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Eplerenone has relative selectivity in binding to recombinant human mineralocorticoid receptors compared to its interaction with recombinant human glucocorticoid, progesterone, and androgen receptors. Eplerenone prevents the binding of receptors to aldosterone—a key hormone of the renin-angiotensin-aldosterone system involved in the regulation of blood pressure and implicated in the pathophysiological mechanisms of cardiovascular diseases.

Pharmacodynamic Effects

Eplerenone has been shown to cause sustained increases in plasma renin levels and serum aldosterone levels, consistent with inhibition of the negative feedback pathway of aldosterone on renin secretion. However, these increases in plasma renin activity and blood aldosterone levels do not diminish the effect of eplerenone.

In dose-ranging studies in chronic heart failure (NYHA classes II–IV), adding eplerenone to standard therapy resulted in the expected dose-dependent increase in aldosterone levels. Similarly, in the EPHESUS cardiovascular-renal sub-study (Efficacy and Mortality Evaluation of Eplerenone in patients with acute Myocardial Infarction complicated by Left Ventricular Dysfunction and Heart Failure), eplerenone treatment led to a significant increase in aldosterone levels. These findings confirm mineralocorticoid receptor blockade in this patient population.

Eplerenone was evaluated in the EPHESUS trial, a double-blind, placebo-controlled study lasting 3 years, involving 6,632 subjects with acute myocardial infarction, left ventricular dysfunction (defined as left ventricular ejection fraction ≤ 40%) and clinical signs of heart failure. Subjects received eplerenone or placebo in addition to standard therapy, starting 3–14 days (median 7 days) after acute myocardial infarction, at an initial dose of 25 mg once daily. The dose was gradually increased (over 4 weeks) to a target dose of 50 mg once daily, provided serum potassium levels remained below 5 mmol/L. Throughout the study, subjects received standard therapy, including acetylsalicylic acid (92%), ACE inhibitors (90%), β-blockers (83%), nitrates (72%), loop diuretics (66%), or HMG-CoA reductase inhibitors (60%).

Primary endpoints in the EPHESUS trial were all-cause mortality and a composite endpoint (cardiovascular death or hospitalization due to cardiovascular events). All-cause mortality occurred in 14.4% of subjects in the eplerenone group and 16.7% in the placebo group. The composite endpoint (cardiovascular death or hospitalization due to cardiovascular events) was reached in 26.7% of the eplerenone group and 30% of the placebo group. Thus, in the EPHESUS trial, eplerenone reduced the risk of all-cause mortality by 15% (HR 0.85; 95% CI 0.75–0.96; p = 0.008) compared to placebo, primarily due to a reduction in cardiovascular mortality. The risk of cardiovascular death or hospitalization was reduced by 13% with eplerenone (HR 0.87; 95% CI 0.79–0.95; p = 0.002). The absolute risk reduction was 2.3% for all-cause mortality and 3.3% for the composite endpoint of cardiovascular death or hospitalization. The clinical benefit of eplerenone was primarily demonstrated in patients under 75 years of age. The benefit in subjects aged 75 years and older has not been adequately studied. A statistically significant greater proportion of subjects receiving eplerenone showed improvement or stabilization in NYHA functional class compared to the placebo group. The incidence of hyperkalemia was 3.4% in the eplerenone group and 2% in the placebo group (p < 0.001). The incidence of hypokalemia was 0.5% in the eplerenone group and 1.5% in the placebo group (p < 0.001).

In a study involving 147 healthy volunteers to assess ECG changes during pharmacokinetic evaluations, eplerenone did not show a sustained effect on heart rate, QRS complex duration, or PR and QT intervals.

The EMPHASIS-HF trial (Eplerenone in Mild Patients Hospitalization and Survival Study) evaluated the efficacy of eplerenone added to standard therapy on clinical outcomes in subjects with systolic heart failure and mild symptoms (NYHA functional class II).

The study included subjects aged 55 years and older, with left ventricular ejection fraction ≤ 30%, or ≤ 35% if QRS duration was >130 milliseconds, who had been hospitalized for cardiovascular events within the preceding 6 months or had plasma B-type natriuretic peptide (BNP) levels ≥ 250 pg/mL, or N-terminal pro-BNP levels ≥ 500 pg/mL in men (750 pg/mL in women). The initial dose of eplerenone was 25 mg once daily. After 4 weeks, the dose was increased to 50 mg once daily if serum potassium remained below 5 mmol/L. Alternatively, if estimated glomerular filtration rate (eGFR) was 30–49 mL/min/1.73 m², the initial dose was 25 mg every other day, subsequently increased to 25 mg once daily.

A total of 2,737 subjects were randomized (in a double-blind design) to receive eplerenone or placebo in addition to background therapy, including diuretics (85%), ACE inhibitors (78%), angiotensin receptor blockers type II (19%), β-blockers (87%), antiplatelet agents (88%), lipid-lowering agents (63%), and digitalis glycosides (27%). Mean left ventricular ejection fraction was ~26%, and mean QRS duration was ~122 ms. The majority of subjects (83.4%) had been hospitalized for cardiovascular events within the 6 months prior to randomization, approximately half of them due to heart failure. Approximately 20% of subjects had implanted defibrillators or were on cardiac resynchronization therapy.

The primary endpoint (cardiovascular death or hospitalization due to heart failure) occurred in 249 subjects (18.3%) in the eplerenone group and 356 subjects (25.9%) in the placebo group (HR 0.63; 95% CI 0.54–0.74; p < 0.001). The effect of eplerenone on the primary endpoint was consistently observed across all predefined subgroups.

The secondary endpoint (all-cause mortality) occurred in 171 patients (12.5%) in the eplerenone group and 213 subjects (15.5%) in the placebo group (HR 0.76; 95% CI 0.62–0.93; p = 0.008). Cardiovascular death occurred in 147 subjects (10.8%) in the eplerenone group and 185 subjects (13.5%) in the placebo group (HR 0.76; 95% CI 0.61–0.93; p = 0.01).

During the study, hyperkalemia (serum potassium > 5.5 mmol/L) occurred in 158 subjects (11.8%) in the eplerenone group and 96 subjects (7.2%) in the placebo group (p < 0.001). Hypokalemia (serum potassium < 4 mmol/L) occurred significantly less frequently in the eplerenone group compared to placebo (38.9% vs. 48.4%; p < 0.0001).

Children

The use of eplerenone in children with heart failure has not been studied.

In a 10-week study involving hypertensive children (aged 4–16 years, n = 304), eplerenone administered at doses of 25–100 mg daily, resulting in exposure similar to that in adults, did not demonstrate effective blood pressure reduction. In this study and in a 1-year safety study involving 149 children aged 5–17 years, the safety profile was similar to that observed in adults. The use of eplerenone in children under 4 years of age with hypertension has not been studied, as trials in older children showed lack of efficacy (see section "Dosage and Administration").

No studies have been conducted on the (long-term) effects on hormonal status in children.

Pharmacokinetics

Absorption

The absolute bioavailability of eplerenone after a 100 mg oral dose is 69%.

Maximum plasma concentration is reached approximately 1.5–2 hours after administration. Maximum plasma concentration (Cmax) and area under the pharmacokinetic curve (AUC) increase proportionally with dose in the range of 10–100 mg and less than proportionally at doses above 100 mg. Steady state is achieved within 2 days of starting treatment. Food does not affect drug absorption.

Distribution

Eplerenone is approximately 50% bound to plasma proteins, primarily to α-1-acid glycoproteins. The apparent volume of distribution at steady state is estimated to be 42–90 L. Eplerenone does not bind significantly to red blood cells.

Biotransformation

Eplerenone metabolism is primarily mediated by the CYP3A4 enzyme. No active metabolites of eplerenone have been detected in human plasma.

Elimination

Less than 5% of the eplerenone dose is excreted unchanged in urine and feces. After oral administration of a single radiolabeled dose, approximately 32% of the dose was excreted in feces and about 67% in urine. The elimination half-life of eplerenone is approximately 3–6 hours. Apparent plasma clearance is approximately 10 L/h.

Use in Specific Patient Populations

Age, Gender, and Race

Pharmacokinetic studies of eplerenone at a dose of 100 mg once daily were conducted in subgroups including elderly patients (aged 65 years and older), male and female patients, and non-black patients. No significant differences in eplerenone pharmacokinetics were observed based on gender. In elderly subjects, steady-state Cmax was 22% higher and AUC was 45% higher compared to younger subjects (18–45 years). In non-black subjects, steady-state Cmax was 19% lower and AUC was 26% lower (see section "Dosage and Administration").

Children

Population pharmacokinetic modeling based on data from two studies involving 51 patients aged 4–16 years showed that body weight significantly affects the volume of distribution of eplerenone but not its elimination. The volume of distribution and peak exposure in children with higher body weight are expected to be similar to those in adults with comparable body weight. In patients weighing 45 kg, the volume of distribution is approximately 40% lower, and peak exposure is expected to be higher than typically observed in adults. Children received an initial dose of eplerenone 25 mg once daily; after 2 weeks, the dose was increased to 25 mg twice daily, and if clinically indicated, to 50 mg twice daily. With these doses, peak eplerenone concentrations in children were not significantly higher than those in adults receiving an initial dose of 50 mg once daily.

Renal Impairment

Eplerenone pharmacokinetics were evaluated in patients with varying degrees of renal dysfunction and in patients undergoing hemodialysis. In patients with severe renal impairment, steady-state AUC and Cmax were increased by 38% and 24%, respectively, compared to the control group. In patients on hemodialysis, these values were reduced by 26% and 3%, respectively, compared to the control group. No correlation was observed between plasma eplerenone clearance and creatinine clearance. Eplerenone is not removed by hemodialysis (see section "Special Warnings and Precautions for Use").

Hepatic Impairment

Eplerenone pharmacokinetics at a dose of 400 mg were studied in patients with moderate hepatic impairment (Child-Pugh class B) and compared to patients with normal liver function. Steady-state Cmax and AUC of eplerenone were increased by 3.6% and 42%, respectively (see section "Dosage and Administration"). Since studies on eplerenone use in patients with severe hepatic impairment have not been conducted, eplerenone is contraindicated in such patients (see section "Contraindications").

Heart Failure

Pharmacokinetic studies of eplerenone at a dose of 50 mg were conducted in patients with heart failure (NYHA classes II–IV). Steady-state Cmax and AUC values were 38% and 30% higher, respectively, compared to age-, weight-, and gender-matched healthy volunteers. However, population pharmacokinetic analysis in a subgroup of patients from the EPHESUS trial indicates that eplerenone clearance in heart failure patients does not differ from that in healthy elderly volunteers.

Clinical characteristics

Indications

The medicinal product Eplerenone is indicated as an adjunct to:

• Standard therapy with β-blockers to reduce the risk of morbidity and mortality associated with cardiovascular disease in stable patients with left ventricular dysfunction (left ventricular ejection fraction ≤ 40%) and clinical signs of heart failure following recent myocardial infarction;
• Standard optimal therapy to reduce the risk of morbidity and mortality associated with cardiovascular disease in adult patients with NYHA class II (chronic) heart failure and left ventricular dysfunction (left ventricular ejection fraction ≤ 30%) (see section "Pharmacodynamics").

Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in the section "Composition".
• Serum potassium level > 5 mmol/L at the start of treatment.
• Severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.73 m²).
• Severe hepatic impairment (Child-Pugh class C).
• Concomitant use of potassium-sparing diuretics or strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, ritonavir, nelfinavir, clarithromycin, telithromycin, and nefazodone) (see section "Interaction with other medicinal products and other types of interactions").
• Concomitant use of eplerenone in triple combination with an ACE inhibitor and an angiotensin receptor blocker.

Interaction with other medicinal products and other types of interactions

Pharmacodynamic interactions

Potassium-sparing diuretics and potassium supplements. Eplerenone should not be administered to patients receiving other potassium-sparing diuretics or potassium supplements due to increased risk of hyperkalemia (see section "Contraindications"). Potassium-sparing diuretics may also enhance the effect of antihypertensive agents and other diuretics.

ACE inhibitors, angiotensin receptor blockers

The risk of hyperkalemia may increase when eplerenone is used in combination with an ACE inhibitor and/or angiotensin receptor blocker. Careful monitoring of serum potassium levels and renal function is recommended, especially in patients at risk of renal dysfunction, such as elderly patients. Eplerenone should not be used concomitantly in triple combination with an ACE inhibitor and an angiotensin receptor blocker (see sections "Contraindications" and "Special warnings and precautions for use").

Lithium

Studies on the interaction between eplerenone and lithium have not been conducted. However, cases of lithium toxicity have been reported in patients receiving lithium concomitantly with ACE inhibitors and diuretics (see section "Special warnings and precautions for use"). Concomitant use of eplerenone and lithium-containing preparations should be avoided. If concomitant use cannot be avoided, plasma lithium levels should be monitored (see section "Special warnings and precautions for use").

Cyclosporine, tacrolimus

Cyclosporine and tacrolimus may cause renal dysfunction and increase the risk of hyperkalemia. Concomitant use of eplerenone with cyclosporine or tacrolimus should be avoided. If administration of cyclosporine or tacrolimus is necessary during eplerenone therapy, careful monitoring of serum potassium levels is recommended (see section "Special warnings and precautions for use").

Non-steroidal anti-inflammatory drugs (NSAIDs)

Acute renal failure may occur in patients at risk (elderly patients, dehydrated patients, patients taking diuretics, patients with impaired renal function) due to reduced glomerular filtration (inhibition of vasodilatory prostaglandins by non-steroidal anti-inflammatory drugs). This effect is usually reversible. In addition, a reduction in antihypertensive effect may occur. Patients should be adequately hydrated and renal function should be monitored at the start of treatment and regularly during combination therapy (see sections "Dosage and administration" and "Special warnings and precautions for use").

Trimethoprim

Concomitant administration of trimethoprim and eplerenone increases the risk of hyperkalemia. Serum potassium levels and renal function should be monitored, especially in elderly patients and patients with renal impairment.

α1-blockers (e.g., prazosin, alfuzosin)

Combination of α1-blockers with eplerenone may enhance hypotensive effects and/or lead to orthostatic hypotension. Clinical status of patients should be monitored for orthostatic hypotension during concomitant use of α1-blockers.

Tricyclic antidepressants, neuroleptics, amifostine, baclofen

Concomitant use of these medicinal products with eplerenone may potentially enhance hypotensive effects and increase the risk of orthostatic hypotension.

Glucocorticoids, tetracosactide

Concomitant administration of these medicinal products with eplerenone may lead to reduced antihypertensive effect due to fluid and sodium retention.

Pharmacokinetic interactions

In vitro studies indicate that eplerenone is not an inhibitor of the isoenzymes CYP1A2, CYP2C19, CYP2C9, CYP2D6, or CYP3A4. Eplerenone is neither a substrate nor an inhibitor of P-glycoprotein.

Digoxin

Systemic exposure (AUC) to digoxin increases by 16% (90% CI 4–30%) when administered concomitantly with eplerenone. Digoxin should be prescribed with caution at doses approaching the upper limit of the therapeutic range.

Warfarin

Clinically significant pharmacokinetic interactions with warfarin have not been reported. Warfarin should be prescribed with caution at doses approaching the upper limit of the therapeutic range.

Substrates of CYP3A4

Pharmacokinetic studies with probe substrates of CYP3A4 (i.e., midazolam and cisapride) did not reveal signs of significant pharmacokinetic interactions when administered concomitantly with eplerenone.

Inhibitors of CYP3A4

Strong CYP3A4 inhibitors

Concomitant use of eplerenone with agents that inhibit CYP3A4 enzyme activity may lead to significant pharmacokinetic interactions. With a strong CYP3A4 inhibitor (ketoconazole 200 mg twice daily), the AUC of eplerenone increased by 441% (see section "Contraindications"). Concomitant use of eplerenone with strong CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin, telithromycin, and nefazodone) is contraindicated (see section "Contraindications").

Weak and moderate CYP3A4 inhibitors

Concomitant use with erythromycin, saquinavir, amiodarone, diltiazem, verapamil, or fluconazole resulted in significant pharmacokinetic interactions, increasing AUC levels by 98–187%. Therefore, when eplerenone is used concomitantly with weak or moderate CYP3A4 inhibitors, the dose of eplerenone should not exceed 25 mg once daily (see section "Dosage and administration").

Inducers of CYP3A4

Concomitant use of eplerenone with St. John's wort (a strong CYP3A4 inducer) resulted in a 30% decrease in eplerenone AUC. Use of stronger CYP3A4 inducers (such as rifampicin) may lead to a more pronounced reduction in eplerenone AUC. Due to the risk of reduced efficacy, concomitant use of strong CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, phenobarbital, St. John's wort) with eplerenone is not recommended (see section "Special warnings and precautions for use").

Antacids

Based on results of clinical pharmacokinetic studies, no significant interactions are expected when eplerenone is administered concomitantly with antacids.

Special precautions for use

Hyperkalemia

Due to its mechanism of action, treatment with eplerenone may lead to the development of hyperkalemia. Serum potassium levels should be monitored in all patients at the beginning of treatment and during dose adjustments. Thereafter, periodic monitoring is recommended, particularly in patients at increased risk of hyperkalemia (such as elderly patients, patients with renal impairment (see section "Dosage and administration") and patients with diabetes mellitus). Potassium-containing supplements should not be used during eplerenone treatment due to the increased risk of hyperkalemia. Reduction of eplerenone dose has been shown to reduce serum potassium concentration. In one study, additional administration of hydrochlorothiazide during eplerenone treatment counterbalanced the increase in serum potassium levels.

When eplerenone is used in combination with an ACE inhibitor and/or angiotensin receptor blocker, the risk of hyperkalemia may increase. Eplerenone should not be used concomitantly in triple combination with an ACE inhibitor and an angiotensin receptor blocker (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Renal impairment

Serum potassium levels should be monitored regularly in patients with renal impairment (including those with diabetic microalbuminuria). Reduced renal function is associated with an increased risk of hyperkalemia. Although data from the EPHESUS study in patients with type 2 diabetes and microalbuminuria are limited, an increased incidence of hyperkalemia was observed in this small patient group. Therefore, treatment of such patients should be undertaken with caution. Eplerenone is not removed by hemodialysis.

Hepatic impairment

In patients with mild to moderate hepatic impairment (Child-Pugh classes A and B), serum potassium levels did not increase above 5.5 mmol/L. These patients require monitoring of electrolyte levels. The use of eplerenone in patients with severe hepatic impairment has not been studied; therefore, eplerenone is contraindicated in such patients (see sections "Dosage and administration" and "Contraindications").

CYP3A4 inducers

Concomitant use of eplerenone with strong CYP3A4 inducers is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use of lithium, cyclosporine, tacrolimus should be avoided during eplerenone treatment (see section "Interaction with other medicinal products and other forms of interaction").

Lactose

This medicinal product contains lactose and therefore should not be used in patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, i.e., is essentially "sodium-free".

Use during pregnancy or breastfeeding

Pregnancy

There are no adequate data on the use of eplerenone in pregnant women. Animal studies do not indicate a direct or indirect adverse effect on pregnancy, embryonal/fetal development, parturition, or postnatal development. Eplerenone should be used during pregnancy only if clearly needed and with caution.

Breastfeeding

It is not known whether eplerenone passes into human breast milk after oral administration. However, preclinical data indicate the presence of eplerenone and/or its metabolites in the milk of rats and normal development of offspring exposed via this route. Since the potential for adverse effects in breastfed infants has not been ruled out, a decision should be made whether to discontinue breastfeeding or to discontinue/abstain from eplerenone therapy, taking into account the benefits of the drug for the mother.

Fertility

There is no information available on the effect of eplerenone on human fertility.

Ability to affect reaction speed when driving or operating machinery

No studies on the effect of eplerenone on the ability to drive or operate machinery have been conducted. Eplerenone does not cause drowsiness or impair cognitive function; however, when driving or operating machinery, the possibility of dizziness related to treatment with the drug should be taken into account.

Dosage and Administration

Adults

The drug is available in 25 mg and 50 mg dosages to allow individual dose titration. The maximum daily dose is 50 mg once daily.

Eplerenone can be administered with or without food (see section "Pharmacokinetics").

Patients with heart failure following myocardial infarction

The recommended maintenance dose of eplerenone is 50 mg once daily. Treatment should be initiated at a dose of 25 mg once daily and gradually increased to the target dose of 50 mg once daily. Achievement of this dose level within 4 weeks is desirable, taking into account serum potassium levels (see table below).

Eplerenone therapy is usually initiated 3–14 days after acute myocardial infarction.

Patients with NYHA Class II (chronic) heart failure

Treatment of patients with chronic heart failure classified as NYHA Class II should be initiated at a dose of 25 mg once daily and gradually increased to the target dose of 50 mg once daily. Achievement of this dose level within 4 weeks is desirable, taking into account serum potassium levels (see table below and section "Special Warnings and Precautions for Use").

Eplerenone treatment should not be initiated in patients with serum potassium levels exceeding 5 mmol/L (see section "Contraindications").

Serum potassium levels should be measured before initiating eplerenone treatment, during the first week of treatment, and one month after initiation of treatment or dose adjustment. Thereafter, serum potassium levels should be monitored periodically as clinically indicated during treatment.

After initiation of treatment, the drug dose should be adjusted according to serum potassium concentration as outlined in the table below.

Dose adjustment after initiation of treatment

After temporary discontinuation of eplerenone due to serum potassium levels ≥ 6 mmol/L, treatment may be resumed at a dose of 25 mg once every 2 days after potassium concentration decreases below 5 mmol/L.

Elderly patients

No initial dose adjustment is required for elderly patients. However, due to age-related decline in renal function, the risk of hyperkalemia is increased in elderly patients. The risk may be further increased in the presence of concomitant conditions associated with elevated systemic exposure to the drug, such as mild to moderate hepatic impairment. Periodic monitoring of serum potassium levels is recommended (see section "Special precautions").

Renal impairment

Patients with mild renal impairment do not require initial dose adjustment. Periodic monitoring of serum potassium levels is recommended, and dose adjustments should be made according to the table above.

For patients with moderate renal impairment (creatinine clearance 30–60 mL/min), treatment should be initiated at a dose of 25 mg once every 2 days, with subsequent dose adjustments based on serum potassium levels (see table above). Periodic monitoring of serum potassium levels is recommended (see section "Special precautions").

Experience with eplerenone in patients with creatinine clearance < 50 mL/min and heart failure following myocardial infarction is limited. Eplerenone should be used with caution in such patients. Doses exceeding 25 mg daily have not been studied in patients with creatinine clearance < 50 mL/min.

Eplerenone is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see section "Contraindications"). Eplerenone is not removed from the body by dialysis.

Hepatic impairment

Patients with mild or moderate hepatic impairment do not require initial dose adjustment. However, due to increased systemic exposure to eplerenone in these patients—and particularly in elderly patients—frequent and regular monitoring of serum potassium concentration is recommended (see section "Special precautions").

Concomitant use

When used concomitantly with weak or moderate CYP3A4 inhibitors (e.g., amiodarone, diltiazem, and verapamil), eplerenone therapy may be initiated at a starting dose of 25 mg once daily. The dose of eplerenone should not exceed 25 mg once daily (see section "Interaction with other medicinal products and other forms of interaction").

Children

The safety and efficacy of eplerenone in children have not been established. Current available information is provided in the section "Pharmacological properties".

Overdose

There have been no reports of adverse reactions associated with eplerenone overdose in humans. The most likely manifestations of eplerenone overdose are expected to be hypotension or hyperkalemia. Eplerenone cannot be removed from the body by hemodialysis. Eplerenone has been shown to bind effectively to activated charcoal. In case of hypotension, supportive treatment should be initiated. In case of hyperkalemia, treatment should be started according to standard guidelines.

Adverse Reactions

Two studies (EPHESUS and EMPHASIS-HF) demonstrated that the overall incidence of adverse reactions with eplerenone was similar to that with placebo.

Listed below are adverse reactions possibly related to eplerenone use that occurred more frequently during treatment than with placebo, serious adverse reactions occurring more frequently during treatment than with placebo, or those reported during post-marketing surveillance.

Adverse reactions are classified by organ systems and by absolute frequency: 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), frequency not known (cannot be estimated from available data).

Infections and infestations

Uncommon: pyelonephritis, infections, pharyngitis.

Blood and lymphatic system disorders

Uncommon: eosinophilia.

Endocrine disorders

Uncommon: hypothyroidism.

Metabolism and nutrition disorders

Common: hyperkalaemia (see sections "Contraindications" and "Special warnings and precautions for use"), hypercholesterolaemia.

Uncommon: hyponatraemia, dehydration, hypertriglyceridaemia.

Psychiatric disorders

Common: insomnia.

Nervous system disorders

Common: syncope, dizziness, headache.

Uncommon: paraesthesia.

Cardiac disorders

Common: left ventricular dysfunction, atrial fibrillation.

Uncommon: tachycardia.

Vascular disorders

Common: hypotension.

Uncommon: arterial thrombosis of limbs, orthostatic hypotension.

Respiratory, thoracic and mediastinal disorders

Common: cough.

Gastrointestinal disorders

Common: diarrhoea, nausea, constipation, vomiting.

Uncommon: abdominal distension.

Skin and subcutaneous tissue disorders

Common: rash, pruritus.

Uncommon: angioedema, hyperhidrosis.

Musculoskeletal and connective tissue disorders

Common: muscle spasms, back pain.

Uncommon: musculoskeletal pain.

Renal and urinary disorders

Common: renal function impairment (see sections "Special warnings and precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Hepatobiliary disorders

Uncommon: cholecystitis.

Reproductive system and breast disorders

Uncommon: gynecomastia.

General disorders and administration site conditions

Common: asthenia.

Uncommon: malaise.

Investigations

Common: increased blood urea, increased creatinine levels.

Uncommon: decreased epidermal growth factor receptor count, increased blood glucose levels.

In the EPHESUS study, a numerically higher number of stroke cases was observed in the group of patients aged ≥ 75 years. However, there was no statistically significant difference in the frequency of strokes between the eplerenone group (30 cases) and the placebo group (22 cases). In the EMPHASIS-HF study, the number of stroke cases in patients aged ≥ 75 years was 9 in the eplerenone treatment group and 8 in the placebo group.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare and pharmacy professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions

No special storage conditions required. Keep out of reach of children.

Packaging

10 film-coated tablets in a blister; 3 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer

Sintrop Spain, S.L.

Manufacturer's address

C/Castello, no1, Sant Boi de Llobregat, Barcelona, 08830, Spain