Espiro

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ESPERO (ESPIRO)

Composition:

Active substance: One film-coated tablet contains 25 or 50 mg of eplerenone;

Excipients: lactose monohydrate, microcrystalline cellulose, hypromellose 15 cP, sodium lauryl sulfate, sodium croscarmellose, magnesium stearate;

Coating: Opadry II Yellow 33G32578 [hypromellose 6 cP (E 464), titanium dioxide (E 171), lactose monohydrate, polyethylene glycol 3350, triacetin, iron oxide yellow (E 172)].

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

25 mg: film-coated tablets, yellow-colored, round, biconvex;

50 mg: film-coated tablets, yellow-colored, round, biconvex, with a break line on one side.

Pharmacotherapeutic group. Potassium-sparing diuretics. Aldosterone antagonists.

ATC code: C03D A04.

Pharmacological Properties

Pharmacodynamics

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

Pharmacodynamic effects. Eplerenone causes a sustained increase in plasma renin levels and serum aldosterone levels, consistent with inhibition of the negative feedback pathway of aldosterone on renin secretion. However, this increase in plasma renin activity and blood aldosterone levels does 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 cardionephrological substudy of EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study), treatment with eplerenone led to a significant increase in aldosterone levels in patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure. These findings confirm mineralocorticoid receptor blockade in this patient population.

The effect of eplerenone was evaluated in the EPHESUS study. This was a 3-year, double-blind, placebo-controlled trial involving 6,632 subjects with acute myocardial infarction, left ventricular dysfunction (defined as left ventricular ejection fraction ≤ 40%) and clinical signs of heart failure. Within 3–14 days (median 7 days) after acute myocardial infarction, subjects received either eplerenone or placebo in addition to standard therapy, starting at an initial dose of 25 mg once daily. The dose was then 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, standard therapy included acetylsalicylic acid (92%), angiotensin-converting enzyme (ACE) inhibitors (90%), β-blockers (83%), nitrates (72%), loop diuretics (66%), or HMG-CoA reductase inhibitors (60%).

The primary endpoints in the EPHESUS study 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, while 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 study, eplerenone reduced the risk of all-cause mortality by 15% (relative risk [RR] 0.85; 95% confidence interval [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% (RR 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 efficacy of eplerenone was primarily demonstrated in patients under 75 years of age. The benefit in patients aged 75 years and older has not been adequately established. A statistically significant greater proportion of subjects treated with 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, no consistent effect of eplerenone on heart rate, QRS complex duration, or PR and QT intervals was observed.

The EMPHASIS-HF study (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) 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 with left ventricular ejection fraction ≤ 30% or ≤ 35% if QRS duration was >130 milliseconds, and who had either been hospitalized for cardiovascular events within the preceding 6 months or had plasma levels of B-type natriuretic peptide ≥250 pg/mL or N-terminal pro-B-type natriuretic peptide ≥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 levels were 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, increased later to 25 mg once daily.

A total of 2,737 subjects were randomized (double-blind) to receive eplerenone or placebo in addition to background therapy, including diuretics (85%), ACE inhibitors (78%), angiotensin receptor blockers (ARBs) (19%), β-blockers (87%), antiplatelet agents (88%), lipid-lowering agents (63%), and digoxin (27%). The mean left ventricular ejection fraction was ~26%, and mean QRS duration was ~122 ms. Most subjects (83.4%) had been hospitalized for cardiovascular events within the 6 months prior to randomization, approximately half 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 (RR 0.63; 95% CI 0.54–0.74; p < 0.001). The effect of eplerenone on the primary endpoint was consistent across all predefined subgroups.

The secondary endpoint (all-cause mortality) occurred in 171 subjects (12.5%) in the eplerenone group and 213 subjects (15.5%) in the placebo group (RR 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 (RR 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 children with hypertension (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 studies in older children showed lack of efficacy (see section "Dosage and administration").

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

Pharmacokinetics

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

Peak 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 glycoprotein. The apparent volume of distribution at steady state is 42–90 L. Eplerenone does not bind to erythrocytes.

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

Elimination. Less than 5% of the dose is excreted unchanged in urine and feces. After oral administration of a single radiolabeled dose, approximately 32% of the dose was recovered 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 populations

Age, gender, and race. Pharmacokinetic studies of eplerenone at a dose of 100 mg once daily were conducted in elderly subjects (≥65 years), males, females, and non-black race subjects. 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 race 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 concentration 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 concentration 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 necessary, to 50 mg twice daily. With these doses, peak eplerenone concentrations in children were not substantially higher than those observed in adults receiving an initial dose of 50 mg once daily.

Renal impairment. The pharmacokinetics of eplerenone were evaluated in patients with varying degrees of renal dysfunction and in patients on 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 parameters were reduced by 26% and 3%, respectively, compared to the control group. No correlation was observed between eplerenone plasma clearance and creatinine clearance. Eplerenone is not removed by hemodialysis (see section "Special precautions").

Hepatic impairment. The pharmacokinetics of eplerenone 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 the use of eplerenone in patients with severe hepatic impairment have not been conducted, its use in such patients is contraindicated (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-, gender-, and body weight-matched healthy volunteers. Population pharmacokinetic analysis in a subgroup of patients from the EPHESUS study indicates that eplerenone clearance in patients with heart failure does not differ from that in healthy elderly volunteers.

Clinical Characteristics

Indications

• As an adjunct to standard therapy with β-blockers to reduce the risk of cardiovascular morbidity and mortality in stable patients with left ventricular dysfunction (left ventricular ejection fraction ≤ 40%) and clinical signs of heart failure following recent myocardial infarction.
• As an adjunct to standard optimal therapy to reduce the risk of cardiovascular morbidity and mortality 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 potent CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, ritonavir, nelfinavir, clarithromycin, telithromycin, and nefazodone) (see section "Interaction with other medicinal products and other forms of interaction").
• Concomitant use of eplerenone in triple combination with an ACE inhibitor and an angiotensin receptor blocker.

Interaction with other medicinal products and other forms of interaction

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 effects of antihypertensive agents and other diuretics.

ACE inhibitors, angiotensin receptor blockers. When eplerenone is used in combination with an ACE inhibitor and/or angiotensin receptor blocker, the risk of hyperkalemia may be increased. Serum potassium levels and renal function should be closely monitored, especially in patients at risk of impaired renal function, 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 medications 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 cyclosporine or tacrolimus must be administered during eplerenone therapy, serum potassium levels should be closely monitored (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, those taking diuretics, patients with impaired renal function) due to reduced glomerular filtration (inhibition of vasodilatory prostaglandins by NSAIDs). This effect is usually reversible. In addition, a reduction in antihypertensive efficacy 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 enhance hypotensive effects and increase the risk of orthostatic hypotension.

Glucocorticoids, tetracosactide. Concomitant use of these medicinal products with eplerenone may reduce antihypertensive efficacy 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 not a substrate or inhibitor of P-glycoprotein.

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

Warfarin. No clinically significant pharmacokinetic interactions with warfarin have been reported. Warfarin should be prescribed with caution when doses are near 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 evidence of significant pharmacokinetic interactions when co-administered with eplerenone.

Inhibitors of CYP3A4.

• Potent inhibitors of CYP3A4. Concomitant use of eplerenone with agents that inhibit CYP3A4 enzyme activity may result in pronounced pharmacokinetic interactions. With a potent CYP3A4 inhibitor (ketoconazole 200 mg twice daily), eplerenone AUC increased by 441% (see section "Contraindications"). Concomitant use of eplerenone with potent CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin, telithromycin, and nefazodone) is contraindicated (see section "Contraindications").
• Weak and moderate inhibitors of CYP3A4. Co-administration with erythromycin, saquinavir, amiodarone, diltiazem, verapamil, or fluconazole resulted in pronounced pharmacokinetic interactions with increases in AUC of 98–187%. Therefore, when eplerenone is used concomitantly with weak or moderate CYP3A4 inhibitors, the dose of eplerenone should not exceed 25 mg daily (see section "Dosage and administration").

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

Antacids. Based on results of a clinical pharmacokinetic study, 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. In all patients, serum potassium levels should be monitored at the beginning of treatment and during any dose adjustments. Periodic monitoring is recommended thereafter, especially in patients who are at increased risk of developing hyperkalemia (such as elderly patients, patients with renal impairment (see section "Posology and method of administration") and diabetes). Potassium-containing supplements are not recommended after initiating eplerenone therapy due to an increased risk of hyperkalemia. It has been demonstrated that reducing the dose of eplerenone leads to a decrease in serum potassium concentration. In one study, the addition of hydrochlorothiazide during eplerenone treatment counterbalanced the increase in serum potassium levels.

When eplerenone is used in combination with an ACE inhibitor and/or an angiotensin receptor blocker, the risk of hyperkalemia increases. Concomitant use of eplerenone with both an ACE inhibitor and an angiotensin receptor blocker (triple combination therapy) is not recommended (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

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

Hepatic function 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 "Posology and method of 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").

Fertility. There is no information available regarding the effect on human fertility.

Excipients

Lactose. The medicinal product contains lactose monohydrate (1 tablet of 25 mg – 39.51 mg, 1 tablet of 50 mg – 79.02 mg); therefore, it should not be administered to patients with rare hereditary disorders such as galactose intolerance, congenital lactase deficiency, or glucose-galactose malabsorption syndrome.

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

Use during pregnancy or breastfeeding

Pregnancy. Adequate data on the use of eplerenone in pregnant women are not available. Animal studies do not indicate a direct or indirect adverse effect on pregnancy, embryofetal 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 following 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 established, a decision must be made whether to discontinue breastfeeding or to discontinue eplerenone therapy, taking into account the importance of the drug to the mother.

Ability to affect performance while 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 cognitive impairment; however, dizziness associated with treatment should be taken into account when driving or operating machinery.

Dosage and Administration

Adults

The medicinal product is available in 25 mg and 50 mg dosage strengths to allow individual dose titration. The maximum recommended daily dose is 50 mg once daily.

Eplerenone may 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 the target dose within 4 weeks is desirable, taking into account serum potassium levels (see table below).

Eplerenone treatment is typically 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 the target dose within 4 weeks is desirable, with consideration of serum potassium levels (see table below and section "Special Warnings and Precautions for Use").

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

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

Dose adjustments after initiation of therapy should be based on serum potassium concentration, as outlined in the table below.

Dose adjustment after initiation of therapy

After temporary discontinuation of eplerenone due to an increase in potassium levels to ≥ 6 mmol/L, treatment may be resumed at a dose of 25 mg every other day once potassium concentration decreases below 5 mmol/L.

Elderly patients. No initial dose adjustment of the medicinal product is required for elderly patients. However, due to age-related decline in renal function, the risk of developing hyperkalemia is increased in elderly patients. The risk may be further increased in the presence of concomitant diseases 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 for use").

Renal impairment. Patients with mild renal impairment do not require adjustment of the initial dose. Periodic monitoring of serum potassium levels is recommended, and dosage should be adjusted 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 every other day, with subsequent dose adjustments based on potassium concentration (see table above). Periodic monitoring of serum potassium levels is recommended (see section "Special precautions for use").

Experience with the use of eplerenone in patients with creatinine clearance < 50 mL/min and heart failure following myocardial infarction is lacking. 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 adjustment of the initial dose. Due to increased systemic exposure to eplerenone, frequent regular monitoring of serum potassium concentration is recommended in these patients, particularly in elderly patients (see section "Special precautions for use").

Combination therapy. When used concomitantly with weak or moderate CYP3A4 inhibitors (e.g., amiodarone, diltiazem, verapamil), eplerenone treatment may be initiated at an initial dose of 25 mg once daily. The dose 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. The currently available information is presented in 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 in humans 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 administered according to standard guidelines.

Side effects

In two studies (EPHESUS and EMPHASIS-HF), it has been demonstrated that the overall incidence of adverse reactions with eplerenone was similar to that with placebo.

Below are the adverse reactions, including serious ones, that may be related to eplerenone use, occurring more frequently with eplerenone than with placebo, or those reported during post-marketing surveillance.

Adverse reactions are classified by system organ class and by absolute frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), 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: gynaecomastia.

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

Reporting suspected adverse reactions

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

Shelf life. 4 years.

Storage conditions

Store in a light-protected place at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Packaging

10 tablets in a blister pack, with 1, 2, 3, 5, or 9 blisters per cardboard box.

14 tablets in a blister pack, with 2 blisters per cardboard box.

30 tablets in a blister pack, with 1 blister per cardboard box.

Prescription status. Prescription only.

Manufacturer

Pharmaceutical Works “Polpharma” S.A., Poland.

Manufacturer's address and place of business

19, Pelplinska Str., 83-200 Starogard Gdanski, Poland.