Renotor

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

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; magnesium stearate; talc; titanium dioxide (E 171); polyethylene glycol 6000 (macrogol 6000).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white or almost white, round, biconvex tablets, film-coated.

Pharmacotherapeutic group.

Diuretics. Potassium-sparing diuretics. Aldosterone antagonists. Eplerenone.

ATC code C03DA04.

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 receptor binding by aldosterone — a key hormone of the renin-angiotensin-aldosterone system (RAAS) involved in blood pressure regulation and implicated in the pathophysiological mechanisms of cardiovascular diseases.

Pharmacodynamic effects

Eplerenone has been shown to cause sustained increases in plasma renin levels and serum aldosterone levels, consistent with inhibition of the negative feedback pathway of aldosterone on renin secretion. However, these increases in plasma renin activity and serum aldosterone levels do not diminish the efficacy 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 Survival Study of Eplerenone in Patients with Acute Myocardial Infarction Complicated by Left Ventricular Dysfunction and Heart Failure), treatment with eplerenone significantly increased serum aldosterone levels. These findings confirm mineralocorticoid receptor blockade in this patient population. In the EPHESUS trial, eplerenone reduced the risk of all-cause mortality by 15% compared to placebo, primarily due to a reduction in cardiovascular mortality. The risk of cardiovascular death or hospitalization was reduced by 13%. 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 of treatment in patients aged 75 years and older has not been well established. A statistically significant greater proportion of patients receiving eplerenone showed improvement or stabilization in NYHA functional class compared to placebo. The incidence of hyperkalemia was 3.4% in the eplerenone group and 2% in the placebo group. The incidence of hypokalemia was 0.5% in the eplerenone group and 1.5% in the placebo group.

In a study of 147 healthy volunteers assessing ECG changes during pharmacokinetic studies, eplerenone showed no consistent effects on heart rate, QRS complex duration, or PR and QT intervals.

In the EMPHASIS-HF study (Study of Hospitalization and Survival in Patients with Heart Failure and Mild Symptoms), the efficacy of eplerenone added to standard therapy was evaluated in patients with systolic heart failure and mild symptoms (NYHA functional class II). The primary endpoint (cardiovascular death or hospitalization due to heart failure) occurred in 249 patients (18.3%) in the eplerenone group and in 356 patients (25.9%) in the placebo group. The effect of eplerenone on the primary endpoint was consistent across all predefined subgroups. The secondary endpoint (all-cause mortality) occurred in 171 patients (12.5%) in the eplerenone group and in 213 patients (15.5%) in the placebo group. Cardiovascular death was recorded in 147 patients (10.8%) in the eplerenone group and in 185 patients (13.5%) in the placebo group. During the study, hyperkalemia (serum potassium > 5.5 mmol/L) occurred in 158 patients (11.8%) in the eplerenone group and in 96 patients (7.2%) in the placebo group. Hypokalemia (serum potassium < 4 mmol/L) occurred with statistically significantly lower frequency in the eplerenone group compared to the placebo group (38.9% vs. 48.4%).

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 trials 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 of eplerenone 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 the absorption of eplerenone.

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 about 67% was eliminated in urine. The elimination half-life of eplerenone is approximately 3–6 hours. Apparent plasma clearance is approximately 10 L/h.

Specific populations

Age, gender, and race

Pharmacokinetic studies of eplerenone at a dose of 100 mg once daily were conducted in elderly patients (≥65 years), male patients, female patients, and non-black patients. No significant differences in eplerenone pharmacokinetics were observed based on gender. In elderly patients, steady-state Cmax was 22% higher and AUC was 45% higher compared to younger patients (18–45 years). In non-black patients, 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 has a statistically significant effect on the volume of distribution of eplerenone but not on its elimination. It is expected that the volume of distribution and peak exposure in children with higher body weight will be similar to that observed in adults with comparable body weight. In patients with a body weight of 45 kg, the volume of distribution is approximately 40% lower, and peak exposure is expected to be higher than typically observed in adults. Children were administered 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.

Patients with renal impairment

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

Patients with hepatic impairment

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

Patients with 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. According to these results, population pharmacokinetic analysis conducted 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.

Adjunct to standard therapy with β-blockers for reduction of morbidity and mortality related to cardiovascular diseases in stable patients with left ventricular dysfunction (left ventricular ejection fraction ≤ 40%) and clinical signs of heart failure following a recent myocardial infarction.

Adjunct to standard optimal therapy for reduction of morbidity and mortality related to cardiovascular diseases 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 of the medicinal product;
• patients with serum potassium levels > 5 mmol/L at the start 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 strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, ritonavir, nelfinavir, clarithromycin, telithromycin, and nefazodone) (see section "Interaction with other medicinal products and other forms of interactions");
• concomitant use of eplerenone in triple combination with an ACE inhibitor and an angiotensin receptor blocker.

Interaction with other medicinal products and other forms of interactions.

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 enhance the antihypertensive 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 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 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 impairment 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").

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Due to direct effects on glomerular filtration, treatment with NSAIDs may lead to acute renal failure, particularly in patients at high risk (elderly, dehydrated, those taking diuretics, or patients with impaired renal function) due to reduced glomerular filtration (inhibition of vasodilatory prostaglandins by nonsteroidal anti-inflammatory agents). This effect is usually reversible. Additionally, a reduction in antihypertensive efficacy may occur. Patients receiving eplerenone and NSAIDs should be adequately hydrated before starting treatment, and renal function should be monitored at the beginning of treatment and regularly during combined 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)

Combining α1-blockers with eplerenone may increase the risk of enhanced hypotensive effect and/or orthostatic hypotension. Clinical status regarding orthostatic hypotension should be monitored 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 reduce the antihypertensive effect due to fluid and sodium retention.

Pharmacokinetic interactions

In vitro studies indicate that eplerenone is not an inhibitor of CYP1A2, CYP2C19, CYP2C9, CYP2D6, or CYP3A4 isoenzymes. 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 used with caution at doses approaching the upper limit of the therapeutic range.

Warfarin

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

CYP3A4 substrates

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

CYP3A4 inhibitors:

• Strong CYP3A4 inhibitors

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

• Weak and moderate CYP3A4 inhibitors

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

CYP3A4 inducers

Concomitant use of eplerenone with St. John's wort (a strong CYP3A4 inducer) resulted in a 30% reduction in eplerenone AUC. Use of more potent CYP3A4 inducers (e.g., rifampicin) may lead to a more pronounced decrease in eplerenone AUC. Due to the risk of reduced efficacy, concomitant use of strong CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, phenobarbital, St. John's wort) with eplerenone is not recommended (see section "Special 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. Serum potassium levels should be monitored in all patients at the beginning of treatment and during any dose adjustments. Thereafter, periodic monitoring is recommended, especially in patients who are at increased risk of 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 initiation of 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 levels.

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

Renal impairment

Serum potassium levels should be monitored regularly in patients with renal impairment (including those with diabetic microalbuminuria). Reduced renal function is associated with an increased risk of hyperkalemia. Although data from the EPHESUS study involving patients with type 2 diabetes and microalbuminuria are limited, these patients experienced a higher incidence of hyperkalemia. Therefore, treatment of such patients should be carried out with caution.

Eplerenone is contraindicated in patients with severe renal impairment (see section "Contraindications"). Eplerenone is not removed by hemodialysis.

Hepatic impairment

In patients with mild to moderate hepatic impairment (Child-Pugh classes A and B), serum potassium levels did not exceed 5.5 mmol/L. These patients require monitoring of electrolyte levels.

Studies on the use of eplerenone in patients with severe hepatic impairment have not been conducted; therefore, eplerenone is contraindicated in such patients (see section "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").

Lithium, cyclosporine, tacrolimus

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

Excipients

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

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

Use during pregnancy or breastfeeding.

Pregnancy

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

Breastfeeding

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

Fertility

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

Ability to affect reaction speed when driving or operating machinery.

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

Dosage and Administration.

Adults

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

The medicinal product 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 target dose should preferably be reached within 4 weeks, taking into account serum potassium levels (see Table 1).

Eplerenone treatment 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. This target dose should preferably be reached within 4 weeks, taking into account serum potassium levels (see Table 1 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. If necessary, serum potassium levels should be monitored periodically thereafter throughout the course of treatment.

After initiation of treatment, the dose should be adjusted according to serum potassium concentration as outlined in Table 1 below.

Dose Adjustment After Initiation of Treatment

Table 1

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 below 5 mmol/L.

Elderly patients

No initial dose adjustment of eplerenone 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 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 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 the dose should be adjusted according to Table 1.

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, and the dose should be adjusted based on potassium concentration (see Table 1). Periodic monitoring of serum potassium levels is recommended (see section "Special precautions for use").

Experience with the use of the drug 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 in these patients, and particularly in elderly patients, frequent and regular monitoring of serum potassium concentration is recommended (see section "Special precautions for use").

Studies on the use of eplerenone in patients with severe hepatic impairment have not been conducted; therefore, eplerenone is contraindicated in such patients (see section "Contraindications").

Combination therapy

When co-administered with weak or moderate CYP3A4 inhibitors (e.g., amiodarone, diltiazem, and verapamil), eplerenone treatment may be initiated at an initial 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. Current available information is provided in the section "Pharmacological properties".

Overdose

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

The adverse reactions listed below are possibly related to eplerenone use and occurred more frequently during treatment than with placebo, or were serious adverse reactions occurring more frequently during treatment than with placebo, or were reported during post-marketing surveillance.

Adverse reactions are classified according to the MedDRA standardized medical terminology system organ classes, with the following frequency: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 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 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 – peripheral arterial thrombosis, 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 – angioneurotic oedema, hyperhidrosis.

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 precautions for use").

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 numerically higher number of stroke cases was observed in the group of patients aged ≥ 75 years. However, there was no statistically significant difference in the incidence of stroke between the eplerenone group (30) and the placebo group (22). 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 important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions according to local requirements.

Shelf life.

2 years.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

10 tablets in a blister, 3 blisters in a cardboard pack.

Prescription category.

Prescription only.

Manufacturer.

MICROCHEM LLC

(responsible for batch release, excluding batch control/testing)

Manufacturer's address and location of operations.

5, Budynsturiyi Street, Kyiv, 01013, Ukraine.

INSTRUCTION

for medical use of the medicinal product

RENOTOR

(RENOTOR)

Composition:

Active ingredient: eplerenone;

One tablet contains 25 mg or 50 mg of eplerenone;

Excipients: lactose monohydrate; microcrystalline cellulose; sodium croscarmellose; hypromellose; sodium lauryl sulfate; magnesium stearate; talc; titanium dioxide (E 171); polyethylene glycol 6000 (macrogol 6000).

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties: round, biconvex tablets, white or almost white, film-coated.

Pharmacotherapeutic group.

Diuretics. Potassium-sparing diuretics. Aldosterone antagonists. Eplerenone.

ATC code C03D A04.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Eplerenone has relative selectivity for binding to recombinant human mineralocorticoid receptors compared to its interaction with recombinant human glucocorticoid, progesterone, and androgen receptors. Eplerenone prevents the binding of receptors to aldosterone—a key hormone of the renin-angiotensin-aldosterone system (RAAS) 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 sustained increases 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 serum aldosterone levels does not diminish the efficacy 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 (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study), treatment with eplerenone significantly increased serum aldosterone levels. These findings confirm mineralocorticoid receptor blockade in this patient population. In the EPHESUS study, eplerenone reduced the risk of all-cause mortality by 15% compared to placebo, primarily due to a reduction in cardiovascular mortality. The risk of cardiovascular death or hospitalization due to cardiovascular events was reduced by 13%. The absolute risk reduction was 2.3% for the endpoint of all-cause mortality and 3.3% for the endpoint of cardiovascular death or hospitalization due to cardiovascular events. The clinical efficacy of eplerenone was primarily demonstrated in patients under 75 years of age. The benefit of treatment in patients aged 75 years and older has not been well established. Improvement or stabilization of NYHA functional class was observed in a statistically significantly higher proportion of patients receiving eplerenone compared to placebo. The incidence of hyperkalemia was 3.4% in the eplerenone group and 2% in the placebo group. The incidence of hypokalemia was 0.5% in the eplerenone group and 1.5% in the placebo group.

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

In the EMPHASIS-HF study (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure), the efficacy of eplerenone added to standard therapy was evaluated in patients with systolic heart failure and mild symptoms (NYHA functional class II). The primary endpoint (cardiovascular death or hospitalization due to heart failure) occurred in 249 patients (18.3%) in the eplerenone group and in 356 patients (25.9%) in the placebo group. The effect of eplerenone on the primary endpoint was consistent across all predefined subgroups. The secondary endpoint (all-cause mortality) occurred in 171 patients (12.5%) in the eplerenone group and in 213 patients (15.5%) in the placebo group. Cardiovascular death was recorded in 147 patients (10.8%) in the eplerenone group and in 185 patients (13.5%) in the placebo group. During the study, hyperkalemia (serum potassium > 5.5 mmol/L) occurred in 158 patients (11.8%) in the eplerenone group and in 96 patients (7.2%) in the placebo group. Hypokalemia (serum potassium < 4 mmol/L) occurred significantly less frequently in the eplerenone group than in the placebo group (38.9% in the eplerenone group vs. 48.4% in the placebo group).

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), administration of eplerenone 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%.

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

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

Elimination

Less than 5% of the administered dose of eplerenone 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 about 67% was eliminated in urine. The elimination half-life of eplerenone is approximately 3–6 hours. Apparent plasma clearance is approximately 10 L/h.

Specific Populations

Age, Gender, and Race

Pharmacokinetic studies of eplerenone at a dose of 100 mg once daily were conducted in elderly patients (aged 65 years and older), male and female patients, and patients of non-black race. No significant differences in eplerenone pharmacokinetics were observed based on gender. In elderly patients, steady-state C_max was 22% higher and AUC was 45% higher compared to younger patients (18–45 years). In non-black patients, steady-state C_max 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 patient body weight has a statistically significant effect on the volume of distribution of eplerenone but not on its elimination. It is expected that the volume of distribution and peak exposure in children with higher body weight will be similar to those observed 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 were administered 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.

Patients with Renal Impairment

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

Patients with Hepatic Impairment

The pharmacokinetics of eplerenone 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 C_max 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, eplerenone is contraindicated in such patients (see section "Contraindications").

Patients with 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 C_max 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. According to these results, population pharmacokinetic analysis conducted 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.

Adjunct to standard therapy with β-blockers for reduction of morbidity and mortality related to cardiovascular diseases in stable patients with left ventricular dysfunction (left ventricular ejection fraction ≤ 40%) and clinical signs of heart failure following recent myocardial infarction.

Adjunct to standard optimal therapy for reduction of morbidity and mortality related to cardiovascular diseases 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 of the medicinal product;
• patients with serum potassium levels > 5 mmol/L at the start 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 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 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 diuretic drugs.

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 increase. 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 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 impairment 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").

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Due to direct effects on glomerular filtration, treatment with NSAIDs may lead to acute renal failure, particularly in patients at high risk (elderly, dehydrated, those taking diuretics, or those 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 receiving eplerenone and NSAIDs should be adequately hydrated before starting treatment, and renal function should be monitored at the beginning 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, particularly in elderly patients and patients with renal impairment.

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

Combining α1-blockers with eplerenone may increase the risk of enhanced hypotensive effect and/or orthostatic hypotension. Clinical status regarding orthostatic hypotension should be monitored during concomitant use of α1-blockers.

Tricyclic antidepressants, neuroleptics, amifostine, baclofen

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

Glucocorticoids, tetracosactide

Concomitant administration of these medicinal products with eplerenone may reduce 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 co-administered with eplerenone. Digoxin should be prescribed with caution at doses near the upper limit of the therapeutic range.

Warfarin

Clinically significant pharmacokinetic interactions with warfarin have not been reported. Warfarin should be prescribed with caution at doses 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 show evidence of significant pharmacokinetic interactions when co-administered with eplerenone.

Inhibitors of CYP3A4:

• Strong inhibitors of CYP3A4

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

• Weak and moderate inhibitors of CYP3A4

Concomitant use with erythromycin, saquinavir, amiodarone, diltiazem, verapamil, or fluconazole resulted in significant 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 once daily (see section "Dosage and administration").

Inducers of CYP3A4

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

Antacids

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

Special precautions for use.

Hyperkalemia

Due to its mechanism of action, treatment with eplerenone may lead to the development of hyperkalemia. Serum potassium levels should be monitored in all patients at the beginning of treatment and during any dose adjustments. Periodic monitoring is subsequently recommended, particularly in patients who are at increased risk of developing 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 counteracted the increase in serum potassium levels.

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

Renal impairment

Serum potassium levels should be monitored regularly in patients with renal impairment (including those with diabetic microalbuminuria). Reduced renal function is associated with an increased risk of hyperkalemia. Although data from the EPHESUS study involving patients with type 2 diabetes and microalbuminuria are limited, an increased incidence of hyperkalemia was observed in these patients. Therefore, treatment of such patients should be undertaken with caution.

Eplerenone is contraindicated in patients with severe renal impairment (see section "Contraindications"). Eplerenone is not removed by hemodialysis.

Hepatic impairment

In patients with mild to moderate hepatic impairment (Child-Pugh classes A and B), serum potassium levels exceeding 5.5 mmol/L were not observed. However, these patients still require monitoring of electrolyte levels.

Studies on the use of eplerenone in patients with severe hepatic impairment have not been conducted; therefore, eplerenone is contraindicated in such patients (see section "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 interactions").

Lithium, cyclosporine, tacrolimus

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

Excipients

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

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

Use during pregnancy or breastfeeding.

Pregnancy

There are no adequate data on the use of eplerenone in pregnant women. Animal studies do not indicate any direct or indirect adverse effects on pregnancy, embryonic and fetal development, parturition, or postnatal development. Eplerenone should be used during pregnancy only with caution.

Breastfeeding

It is unknown whether eplerenone is excreted in human breast milk after oral administration. However, preclinical data indicate the presence of eplerenone and/or its metabolites in the milk of rats and show normal development of offspring exposed in this way. Since the potential for adverse effects in breastfed infants has not been studied, a decision should be made whether to discontinue breastfeeding or to discontinue eplerenone therapy, taking into account the importance of the drug for the mother.

Fertility

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

Ability to affect reaction speed when driving or operating machinery.

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 due to the use of the drug should be taken into account.

Dosage and Administration

Adults

For individual dose adjustment, the medicinal product RENOTOR is available in doses of 25 mg and 50 mg. The maximum daily dose of RENOTOR is 50 mg per day.

The medicinal product 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. This dose level should preferably be reached within 4 weeks, taking into account serum potassium levels (see Table 1).

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. This dose level should preferably be reached within 4 weeks, taking into account serum potassium levels (see Table 1 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. If necessary, serum potassium levels should be monitored periodically throughout the course of treatment.

After initiation of treatment, the drug dose should be adjusted according to serum potassium concentration as outlined in Table 1 below.

Dose Adjustment After Initiation of Treatment

Table 1

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 below 5 mmol/L.

Elderly patients

No initial dose adjustment of eplerenone 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 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 warnings and precautions for use").

Renal impairment

Patients with mild renal impairment do not require initial dose adjustment. Periodic monitoring of serum potassium levels is recommended, and the dose should be adjusted according to Table 1.

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 1). Periodic monitoring of serum potassium levels is recommended (see section "Special warnings and precautions for use").

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 daily have not been studied in patients with creatinine clearance < 50 mL/min.

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

Hepatic impairment

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

Studies on the use of eplerenone in patients with severe hepatic impairment have not been conducted; therefore, eplerenone is contraindicated in such patients (see section "Contraindications").

Combination therapy

When used concomitantly with weak or moderate CYP3A4 inhibitors (e.g., amiodarone, diltiazem, and verapamil), treatment with eplerenone 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. Current available information is provided in the section "Pharmacological properties".

Overdose

There have been no reports of adverse reactions associated with eplerenone overdose in humans. The most likely manifestations of eplerenone overdose 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 initiated according to standard guidelines.

Adverse reactions.

In two studies (EPHESUS and EMPHASIS-HF), it has been 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 and which occurred during treatment more frequently than with placebo, or serious adverse reactions that occurred more frequently during treatment than with placebo, or those reported during post-marketing surveillance.

Adverse reactions are classified according to the MedDRA standardized medical terminology dictionary by system organ classes with the following frequency: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000), 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.

Metalbolism 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 – angioneurotic oedema, hyperhidrosis.

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: common – asthenia; uncommon – malaise.

Investigations: common – increased blood urea, increased creatinine level; uncommon – decreased epidermal growth factor receptor count, increased blood glucose level.

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 frequency of strokes between the eplerenone group (30) and the placebo group (22). In the EMPHASIS-HF study, the number of strokes 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 continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals are requested to report any suspected adverse reactions in accordance with local requirements.

Shelf life.

2 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

10 tablets in a blister, 3 blisters in a cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

MICROCHEM LLC (production operations)

Manufacturer's address and location of its business activities.

24-v Promyslova St., Severodonetsk, Luhansk Oblast, 93400, Ukraine