Renial

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

Composition:

Active substance: eplerenone;

1 tablet contains eplerenone equivalent to 100% substance 25 mg or 50 mg;

Excipients: lactose monohydrate; microcrystalline cellulose; sodium croscarmellose; hypromellose; sodium lauryl sulfate; talc; magnesium stearate;

film coating: hypromellose, polyethylene glycol 400; polysorbate 80; titanium dioxide (E 171); iron oxide yellow (E 172); iron oxide red (E 172).

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties: beige-colored, round, biconvex tablets with "25" or "50" marked on one side of the tablet.

Pharmacotherapeutic group.

Potassium-sparing diuretics. Aldosterone antagonists. Eplerenone.

ATC code C03D A04.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action. Eplerenone has relative selectivity for binding to human recombinant mineralocorticoid receptors compared to its interaction with human recombinant 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 arterial blood pressure and implicated in the pathophysiological mechanisms of cardiovascular diseases.

Pharmacodynamic effects. Eplerenone has been shown to cause 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 cardiology-nephrology 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. These findings confirm mineralocorticoid receptor blockade in this 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. Within 3–14 days (median 7 days) after acute myocardial infarction, subjects received either eplerenone or placebo in addition to standard therapy, starting at a 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, 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 study were all-cause mortality and a composite endpoint (cardiovascular death or hospitalization due to cardiovascular events). 14.4% of subjects in the eplerenone group and 16.7% in the placebo group died (from any cause), while 26.7% in the eplerenone group and 30% in the placebo group met the criteria for the composite endpoint (cardiovascular death or hospitalization due to cardiovascular events). Thus, in the EPHESUS study, 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 combined endpoint of cardiovascular death or hospitalization. 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 sufficiently established. 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 pharmacokinetic study involving 147 healthy volunteers to assess ECG changes, no consistent effects of eplerenone on heart rate, QRS duration, or PR and QT intervals were 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 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 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 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, increasing to 25 mg once daily.

Overall, 2,737 subjects were randomized (double-blind) to receive eplerenone or placebo in addition to background therapy with diuretics (85%), ACE inhibitors (78%), angiotensin receptor blockers (ARBs, 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 for 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 than in 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 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 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) are dose-proportional in the range of 10–100 mg and less than dose-proportional 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 estimated to be 42–90 L. Eplerenone does not bind 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 a single oral dose of radiolabeled eplerenone, approximately 32% of the dose was excreted in feces and approximately 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, sex, and race. Pharmacokinetic studies of eplerenone at a dose of 100 mg once daily were conducted in elderly subjects (≥65 years), male and female subjects, and non-black race subjects. No significant differences in eplerenone pharmacokinetics were observed based on sex. 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. A population pharmacokinetic model based on data from 2 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 necessary, to 50 mg twice daily. With these doses, peak eplerenone concentrations in children were not significantly 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 impairment 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 found between eplerenone plasma clearance and creatinine clearance. Eplerenone is not removed by hemodialysis (see section "Special precautions").

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"). As 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 sex. According to these results, 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 elderly healthy volunteers.

Clinical characteristics.

Indications.

• As an adjunct to standard therapy with β-blockers to reduce the risk of morbidity and mortality related to cardiovascular disease 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 morbidity and mortality related to 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 eplerenone or to any of the excipients of the medicinal product;
• Serum potassium level > 5 mmol/L at initiation of treatment;
• Severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.73 m²);
• Severe hepatic impairment (Child-Pugh class C);
• Treatment with potassium-sparing diuretics, potassium-containing supplements, or strong 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 angiotensin-converting enzyme (ACE) inhibitor and an angiotensin receptor blocker.

Interaction with other medicinal products and other forms of interaction.

Pharmacodynamic interactions.

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

ACE inhibitors, angiotensin receptor blockers. The risk of hyperkalemia may be increased 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 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 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 concomitant use cannot be avoided, 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 cyclosporine or tacrolimus must be administered during eplerenone therapy, careful monitoring of serum potassium levels is recommended (see section "Special precautions for use").

Nonsteroidal 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. Additionally, 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 precautions for use").

Trimethoprim. Concomitant use 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.

Alpha-1 blockers (e.g., prazosin, alfuzosin). When alpha-1 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 when alpha-1 blockers are used concomitantly.

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

Pharmacokinetic interactions.

Eplerenone is not an inhibitor of the CYP1A2, CYP2C19, CYP2C9, CYP2D6, or CYP3A4 isoenzymes, nor is it a substrate or inhibitor of P-glycoprotein.

Digoxin. The 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 using probe substrates of CYP3A4 (i.e., midazolam and cisapride) showed no evidence of significant pharmacokinetic interactions when these drugs were administered concomitantly with eplerenone.

Inhibitors of CYP3A4.

Strong CYP3A4 inhibitors. Concomitant use of eplerenone with drugs 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 increases by 441% (see section "Contraindications"). Concomitant use of eplerenone with strong CYP3A4 inhibitors such as 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, and fluconazole results in significant pharmacokinetic interactions, increasing AUC levels by 98–187%. Therefore, when eplerenone is co-administered with weak or moderate CYP3A4 inhibitors, the dose of eplerenone should not exceed 25 mg (see section "Dosage and administration").

Inducers of CYP3A4. Concomitant use of eplerenone with St. John's wort (a strong CYP3A4 inducer) results 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, concomitant use of eplerenone with strong CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, phenobarbital, St. John's wort) is not recommended (see section "Special 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. During treatment with eplerenone, hyperkalemia may occur 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 developing hyperkalemia, such as elderly patients, patients with renal impairment (see section "Dosage and administration") and patients with diabetes mellitus. Potassium-containing supplements are not recommended after initiating eplerenone therapy due to an increased risk of hyperkalemia. Reducing the dose of eplerenone leads to a decrease in serum potassium concentration. Data suggest that additional administration of hydrochlorothiazide during eplerenone treatment may counteract 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 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 interactions").

Renal function impairment. In patients with impaired renal function (including those with diabetic microalbuminuria), serum potassium levels should be monitored regularly. Decreased 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 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 do 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 "Contraindications" and "Dosage and administration").

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

Lithium, cyclosporine, tacrolimus should not be prescribed during eplerenone treatment (see section "Interaction with other medicinal products and other forms of interactions").

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

Lactose. The medicinal product contains lactose; therefore, it should not be administered to patients with rare hereditary disorders (galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption syndrome).

Use during pregnancy or breastfeeding.

Pregnancy. Adequate data on the use of eplerenone in pregnant women are lacking. 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 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 studied, a clinical decision should be made whether to discontinue breastfeeding or to discontinue eplerenone therapy, taking into account the importance of the drug for the mother.

Ability to affect 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, dizziness may occur during treatment, and this should be taken into account when driving or operating machinery.

Dosage and Administration

The drug is available in 25 mg and 50 mg dosages. The maximum daily dose of the drug is 50 mg.

Eplerenone can be taken 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. This dose level should preferably be reached within 4 weeks, taking into account serum potassium levels (see table below). Eplerenone treatment 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. This dose level should preferably be reached within 4 weeks, considering 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 starting 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.

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

Dose adjustment after initiation of treatment.

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 after potassium concentration decreases to 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 (see section "Special precautions"), 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 eplerenone 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 initial dose adjustment. However, due to increased systemic exposure to eplerenone, frequent and regular monitoring of serum potassium concentration is recommended in these patients, particularly in elderly patients (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 eplerenone should not exceed 25 mg once daily (see section "Interaction with other medicinal products and other forms of interaction").

Children.

There are no data on the use of eplerenone in children; therefore, administration of the drug to this patient group is not recommended.

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 arterial hypotension or hyperkalemia. Eplerenone cannot be removed from the body by hemodialysis. Eplerenone is effectively bound by 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 treatment was similar to that with placebo.

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

Adverse reactions are classified by system organ class and absolute frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), frequency not known (cannot be estimated from available data).

Infections and infestations: uncommon: infection, pyelonephritis, 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: uncommon – insomnia.

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

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 – hyperhidrosis, angioneurotic oedema.

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

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

Hepatobiliary disorders: uncommon – cholecystitis.

Reproductive system and breast disorders: uncommon – gynaecomastia.

General disorders and administration site conditions: uncommon – asthenia, 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 events was observed 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) and the placebo group (22). 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 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 professionals are asked to report any suspected adverse reactions according to local requirements.

Shelf life. 3 years from the date of manufacture in bulk.

Storage conditions.

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

Keep out of the reach of children.

Packaging.

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

Prescription category. Prescription only.

Manufacturer. JSC "Kyivmedpreparat".

Manufacturer's location and address of place of business activity.

139 Saksaganskogo Street, Kyiv, 01032, Ukraine.