Efez®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT EFEZ® (EFEZ)

Composition:

Active substance: eplerenone;

1 tablet contains 25 mg or 50 mg of eplerenone;

Excipients: lactose monohydrate, microcrystalline cellulose, sodium croscarmellose, hypromellose, sodium lauryl sulfate, talc, magnesium stearate, Opadry® II 33G270003 yellow-brown.

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties: round, biconvex tablets coated with a film coating, yellowish-brown in color.

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 receptor binding by aldosterone—a key hormone of the renin-angiotensin-aldosterone system (RAAS) involved in regulation of arterial 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, the increases in plasma renin activity and serum 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 cardiovascular-renal sub-study of EPHESUS (Efficacy and Mortality Evaluation of Eplerenone in Patients with Acute Myocardial Infarction Complicated by Left Ventricular Dysfunction and Heart Failure), treatment with eplerenone 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. This was a 3-year, double-blind, placebo-controlled study involving 6,632 subjects with acute myocardial infarction, left ventricular dysfunction (defined by left ventricular ejection fraction ≤ 40%) and clinical signs of heart failure. Between 3 and 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 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%).

The primary endpoints in the EPHESUS trial were all-cause mortality and a composite endpoint (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 (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 death or hospitalization due to cardiovascular events 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 death or hospitalization due to cardiovascular events. The clinical efficacy of eplerenone was primarily demonstrated in patients under 75 years of age. The benefit in subjects aged 75 years and older has not been well established. A greater proportion of subjects receiving eplerenone showed improvement or stabilization in NYHA functional class compared to those in 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 (a study of hospitalization and mortality rates with eplerenone in patients with heart failure and mild symptoms) evaluated the effectiveness 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, and who had either been hospitalized for cardiovascular events within the preceding 6 months or had plasma levels of B-type natriuretic peptide (BNP) ≥ 250 pg/mL or N-terminal pro-BNP ≥ 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 was 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 (ARBs, 19%), β-blockers (87%), antiplatelet agents (88%), lipid-lowering agents (63%), and digitalis glycosides (27%). The mean left ventricular ejection fraction was approximately 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, about 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 benefit 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 was recorded 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 the placebo group (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 in 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 studies in older children showed lack of efficacy (see section "Dosage and administration").

No studies have been conducted on any (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 drug 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 erythrocytes.

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 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 (aged 65 years and older), male and female subjects, and subjects of non-black race. 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 substantially higher than those observed 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 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 values were reduced by 26% and 3%, respectively, compared to the control group. No correlation was found between eplerenone plasma clearance and creatinine clearance. Eplerenone is not removed by hemodialysis (see section "Special precautions").

Hepatic impairment. Eplerenone pharmacokinetics were studied at a dose of 400 mg 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 no studies have been conducted on the use of eplerenone in patients with severe hepatic impairment, 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 in patients with heart failure were 38% and 30% higher, respectively, than in healthy volunteers of comparable age, body weight, and gender. However, 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 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 a recent myocardial infarction.

‒ As an adjunct to 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".
• Patients with serum potassium levels > 5 mmol/L at the initiation of treatment.
• Patients with severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.73 m²).
• Patients with severe hepatic impairment (Child–Pugh Class C).
• Patients receiving 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 the increased risk of hyperkalemia (see section "Contraindications"). Potassium-sparing diuretics may also enhance the hypotensive effect and the diuretic effect of other antihypertensive agents.

ACE inhibitors, angiotensin receptor blockers. When eplerenone is used in combination with an ACE inhibitor and/or an angiotensin receptor blocker, the risk of hyperkalemia may increase. Careful monitoring of serum potassium levels and renal function is recommended, especially in patients at risk of renal impairment, such as elderly patients. Concomitant use of eplerenone with an ACE inhibitor and an angiotensin receptor blocker in a triple combination is contraindicated (see sections "Contraindications" and "Special 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 precautions for use"). Concomitant use of eplerenone and lithium-containing preparations should be avoided. If avoidance is not possible, plasma lithium levels should be monitored (see section "Special 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 treatment, careful monitoring of serum potassium levels is recommended (see section "Special precautions for use").

Non-steroidal anti-inflammatory drugs (NSAIDs). Acute renal failure may occur in patients at risk (elderly patients, dehydrated patients, patients receiving 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 the 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 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). When α1-blockers are combined with eplerenone, there is a potential for enhanced hypotensive effect and/or development of orthostatic hypotension. Clinical status 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 the hypotensive effect and increase the risk of orthostatic hypotension.

Glucocorticoids, tetracosactide. Concomitant administration of these medicinal products with eplerenone may lead to attenuation of the 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 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.

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

CYP3A4 inhibitors.

Potent CYP3A4 inhibitors. Concomitant administration of eplerenone with agents that inhibit CYP3A4 enzyme activity may result in significant pharmacokinetic interactions. Under the influence of a potent CYP3A4 inhibitor (ketoconazole 200 mg twice daily), the AUC of eplerenone 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").

Mild 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 mild or moderate CYP3A4 inhibitors, the dose of eplerenone should not exceed 25 mg once daily (see section "Dosage and administration").

CYP3A4 inducers. Concomitant administration of eplerenone with St. John's wort (a potent CYP3A4 inducer) resulted in a 30% reduction in eplerenone AUC. Administration 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, concomitant use of potent CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, phenobarbital, St. John's wort) with eplerenone is not recommended (see section "Special precautions for use").

Antacids. Based on the results of a clinical pharmacokinetic study, significant interactions are not expected when eplerenone is administered concomitantly with antacids.

Special precautions for use.

Hyperkalemia. During treatment with eplerenone, hyperkalemia may develop due to its mechanism of action. Serum potassium levels should be monitored in all patients at the beginning of treatment and during dose adjustments. Periodic monitoring is recommended thereafter, especially in patients at increased risk of hyperkalemia (such as elderly patients, patients with renal impairment (see section "Dosage and administration") and diabetes). Potassium-containing supplements are not recommended after initiating eplerenone therapy due to the 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, additional administration of hydrochlorothiazide during eplerenone treatment counterbalanced the increase in serum potassium concentration.

When eplerenone is used in combination with an ACE inhibitor and/or angiotensin receptor blocker, the risk of hyperkalemia may be increased. 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 function impairment. In patients with impaired renal function (particularly 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 small patient group. Therefore, treatment of such patients should be conducted 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 exceed 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").

Inducers of CYP3A4. Concomitant use of eplerenone and strong inducers of CYP3A4 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 on the effect of eplerenone on human fertility.

Important information on excipients.

This medicinal product contains lactose; therefore, it should not be administered to patients with rare hereditary conditions such as galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.

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

Use during pregnancy or breastfeeding.

Pregnancy. Adequate data on the use of eplerenone in pregnant women are lacking. Animal studies do not indicate any direct or indirect adverse effects on pregnancy, embryofetal development, parturition, or postnatal development. Eplerenone should be used during pregnancy only if clearly needed and with caution.

Breastfeeding. It is unknown whether eplerenone passes into human breast milk after oral administration. However, preclinical data show 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 should be made whether to discontinue breastfeeding or to discontinue eplerenone therapy, taking into account the importance of the therapy for the mother.

Ability to influence reaction speed when driving or operating machinery.

Studies on the effect of eplerenone on the ability to drive or operate machinery have not been conducted. Eplerenone does not cause drowsiness or cognitive impairment; however, when driving or operating machinery, the possibility of dizziness related to treatment should be taken into account.

Dosage and Administration

Adults.

For individual dose titration of the medicinal product, 25 mg and 50 mg dosage strengths are available. The maximum daily dose of the medicinal product is 50 mg.

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 this dose level within 4 weeks is recommended, taking into account serum potassium levels (see table below).

Eplerenone therapy should usually be 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 recommended, considering 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 initiating eplerenone therapy, during the first week of treatment, and one month after initiation of therapy or dose adjustment. Thereafter, serum potassium levels should be monitored periodically as clinically indicated during treatment.

After initiation of therapy, the drug dose should be adjusted according to serum potassium concentration as specified 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 once every 2 days once potassium concentration has decreased below 5 mmol/L.

Elderly patients. There is no need for adjustment of the initial dose of the drug in 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 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 adjustment of the initial dose. Periodic monitoring of serum potassium levels is recommended, and the dose 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 once every 2 days, with subsequent dose adjustments based on potassium concentration (see table above). Periodic monitoring of serum potassium levels is recommended (see section "Special precautions").

There is no experience with the use of the drug in patients with creatinine clearance < 50 mL/min and heart failure following myocardial infarction. Eplerenone should be used with caution in such patients. Doses exceeding 25 mg per day 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 in these patients, and particularly in elderly patients, more frequent and regular monitoring of serum potassium concentration is recommended (see section "Special precautions").

Combination therapy. When used concomitantly with weak or moderate CYP3A4 inhibitors (e.g., amiodarone, diltiazem, and verapamil), treatment with eplerenone may be initiated at a starting dose of 25 mg once daily. The dose of the drug 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. Available information is presented in the sections "Pharmacodynamics" and "Pharmacokinetics".

Overdose.

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

Adverse Reactions

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

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

Adverse reactions are classified by system organ classes and 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.

Respiratory, thoracic and mediastinal disorders: common – cough.

Gastrointestinal disorders: common – diarrhea, nausea, constipation, vomiting; uncommon – abdominal distension.

Hepatobiliary disorders: uncommon – cholecystitis.

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").

Endocrine disorders: uncommon – hypothyroidism.

Metabolism and nutrition disorders: common – hyperkalemia (see sections "Contraindications" and "Special Warnings and Precautions for Use"), hypercholesterolemia; uncommon – hyponatremia, dehydration, hypertriglyceridemia.

Nervous system disorders: common – syncope, dizziness, headache; uncommon – paresthesia.

Psychiatric disorders: common – insomnia.

Cardiac disorders: common – left ventricular dysfunction, atrial fibrillation, hypotension; uncommon – tachycardia, arterial thrombosis of limbs, orthostatic hypotension.

Blood and lymphatic system disorders: uncommon – eosinophilia.

Skin and subcutaneous tissue disorders: common – rash, pruritus; uncommon – angioedema, hyperhidrosis.

Musculoskeletal and connective tissue disorders: common – muscle spasms, back pain; uncommon – musculoskeletal pain.

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 recorded in the group of patients aged ≥ 75 years. However, there was no statistically significant difference in the incidence of stroke 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 marketing authorization is an important procedure. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions via the national reporting system.

Shelf life. 1.5 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging. 10 tablets in a blister; 3 blisters in a carton.

Prescription status. Prescription only.

Manufacturer. JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's address and location of operations.

13, Borispilska Street, Kyiv, 02093, Ukraine.