Inspra

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

Composition:

Active substance: eplerenone;

One tablet contains 25 mg or 50 mg of eplerenone;

Excipients: lactose monohydrate; microcrystalline cellulose; sodium croscarmellose; hypromellose; sodium lauryl sulfate; talc; magnesium stearate; Opadry yellow YS-1-12524-A.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated tablets, yellow in color, rhomboid in shape, with embossing "VLE" on one side of the tablet and "NSR" over "25" or "50" on the other side for 25 mg and 50 mg tablets, respectively.

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

Pharmacological Properties.

Pharmacodynamics.

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

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

In dose-ranging studies in patients with 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 (Efficacy and Mortality Evaluation of Eplerenone in Patients with Acute Myocardial Infarction Complicated by Left Ventricular Dysfunction and Heart Failure), eplerenone treatment led to a significant increase in aldosterone levels. These findings confirm mineralocorticoid receptor blockade in this patient population.

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

The primary endpoints in the EPHESUS study were all-cause mortality and a composite endpoint (cardiovascular death or hospitalization due to cardiovascular events). All-cause mortality occurred in 14.4% of subjects in the eplerenone group and 16.7% in the placebo group. The composite endpoint (cardiovascular death or hospitalization due to cardiovascular events) was reached in 26.7% of subjects in the eplerenone group and 30% in the placebo group. 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 due to cardiovascular events was reduced by 13% with eplerenone (HR 0.87; 95% CI 0.79–0.95; p=0.002). The absolute risk reduction was 2.3% for all-cause mortality and 3.3% for the composite endpoint of cardiovascular death or hospitalization. The clinical benefit of eplerenone was primarily demonstrated in patients under 75 years of age. The benefit in subjects aged 75 years and older has not been well 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 study involving 147 healthy volunteers to assess ECG changes during pharmacokinetic evaluations, no sustained 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 <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.

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

The primary endpoint (cardiovascular death or hospitalization 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 consistent across all predefined subgroups.

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

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

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

In a 10-week study involving 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 the long-term effects of eplerenone 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 plasma concentration-time curve (AUC) increase proportionally with dose in the range of 10–100 mg and less than proportionally at doses above 100 mg. Steady-state is achieved within 2 days of starting treatment. Food does not affect drug absorption.

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

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 dose is excreted unchanged in urine and feces. After oral administration of a single radiolabeled dose, approximately 32% of the dose was recovered in feces and 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, gender, 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 subjects. No significant differences in eplerenone pharmacokinetics were observed based on gender. In elderly subjects, steady-state Cmax was 22% higher and AUC was 45% higher compared to younger subjects (18–45 years). In non-black subjects, steady-state Cmax was 19% lower and AUC was 26% lower (see section "Dosage and administration").

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

Renal impairment. The pharmacokinetics of eplerenone 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 control subjects. In patients on hemodialysis, these values were decreased by 26% and 3%, respectively, compared to control subjects. No correlation was observed between plasma clearance of eplerenone and creatinine clearance. Eplerenone is not removed by hemodialysis (see section "Special precautions for use").

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 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 were 38% and 30% higher, respectively, in patients with heart failure compared to age-, weight-, and gender-matched healthy volunteers. However, population pharmacokinetic analysis from a subgroup of patients in the EPHESUS study indicates that eplerenone clearance in patients with heart failure does not differ from that in healthy elderly volunteers.

Clinical characteristics.

Indications.

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

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients listed in the section "Composition".
• Patients with serum potassium levels > 5 mmol/L at the 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 taking 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 an increased risk of hyperkalemia (see section "Contraindications"). The effects of antihypertensive agents and other diuretics may also be enhanced under the influence of potassium-sparing diuretics.

ACE inhibitors, angiotensin receptor blockers. When eplerenone is used in combination with an ACE inhibitor and/or angiotensin receptor blocker, the risk of hyperkalemia may 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-containing preparations should be avoided. If avoidance is not possible, plasma lithium levels should be monitored (see section "Special precautions for use").

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

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. In addition, a reduction in antihypertensive effect may occur. Patients should be adequately hydrated 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 parameters should be monitored, especially in elderly patients and patients with impaired renal function.

α1-Blockers (e.g., prazosin, alfuzosin). When α1-blockers are combined with eplerenone, there is a possibility of enhanced hypotensive effect and/or development of 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. When these medicinal products are used concomitantly with eplerenone, there is a possibility of reduced antihypertensive effect due to fluid and sodium retention.

Pharmacokinetic interactions.

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

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

Warfarin. No clinically significant pharmacokinetic interactions with warfarin have been reported. Warfarin should be prescribed with caution at doses close to the upper limit of the therapeutic range.

Substrates of CYP3A4. Pharmacokinetic studies with probe substrates of CYP3A4 (i.e., midazolam and cisapride) showed no evidence of significant pharmacokinetic interactions when these agents were used concomitantly with eplerenone.

Inhibitors of CYP3A4.

• Strong inhibitors of CYP3A4. When eplerenone is used concomitantly with agents that inhibit the activity of the CYP3A4 enzyme, significant pharmacokinetic interactions may occur. Under the influence of 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, increasing AUC levels by 98–187%. Therefore, when eplerenone is used concomitantly with weak or moderate CYP3A4 inhibitors, the dose of eplerenone should not exceed 25 mg once daily (see section "Dosage and administration").

Inducers of CYP3A4. Concomitant use of eplerenone with St. John's wort (a strong inducer of CYP3A4) resulted in a 30% reduction in eplerenone AUC. Use of stronger CYP3A4 inducers (such as rifampicin) may lead to a more pronounced reduction in eplerenone AUC. Due to the risk of reduced efficacy of eplerenone, concomitant use 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 clinical pharmacokinetic studies, significant interactions are not expected when eplerenone is used concomitantly with antacids.

Special precautions for use.

Hyperkalemia. Due to its mechanism of action, hyperkalemia may occur during treatment with eplerenone. Serum potassium levels should be monitored in all patients at the beginning of treatment and during dose adjustments. Thereafter, periodic monitoring is recommended, especially in patients 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 initiation of eplerenone therapy due to an increased risk of hyperkalemia. It has been demonstrated that reducing the dose of eplerenone leads to a decrease in serum potassium concentration. In one study, additional administration of hydrochlorothiazide during eplerenone treatment counterbalanced the increase in serum potassium concentration.

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

Renal function impairment. In patients with impaired renal function (including those with diabetic microalbuminuria), serum potassium levels should be monitored regularly. Reduced renal function is associated with an increased risk of hyperkalemia. Although data from the EPHESUS study involving patients with type 2 diabetes and microalbuminuria are limited, an increased incidence of hyperkalemia was observed in this 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 exceeding 5.5 mmol/L were not observed. These patients require monitoring of electrolyte levels. The use of eplerenone in patients with severe hepatic impairment has not been studied; therefore, eplerenone is contraindicated in such patients (see sections "Dosage and administration" and "Contraindications").

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

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

Lactose.

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

Sodium.

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

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

Use during pregnancy or breastfeeding.

Pregnancy. Adequate data on the use of eplerenone in pregnant women are not available. Animal studies do not indicate a direct or indirect adverse effect on pregnancy, embryonal/fetal development, parturition, or postnatal development. Eplerenone should be used during pregnancy only if clearly needed and with caution.

Breastfeeding. It is not known whether eplerenone passes into human breast milk after oral administration. However, preclinical data indicate the presence of eplerenone and/or its metabolites in the milk of rats and normal development of offspring exposed via this route. Since the potential for adverse effects in breastfed infants has not been established, 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.

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 related to treatment with the drug should be taken into account.

Method of Administration and Dosage.

Adults.

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

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

Patients with heart failure following myocardial infarction. The recommended maintenance dose of eplerenone is 50 mg once daily. Treatment should be initiated at a dose of 25 mg once daily and gradually increased to the target dose of 50 mg once daily. This dose level should preferably be reached within 4 weeks, taking into account serum potassium levels (see table below).

Eplerenone treatment is typically initiated 3–14 days after acute myocardial infarction.

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

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

Serum potassium levels should be measured before 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 during treatment.

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

Dose adjustment after initiation of therapy

After temporary discontinuation of eplerenone due to an increase in potassium levels to ≥ 6 mmol/L, treatment may be resumed at a dose of 25 mg once every 2 days following a decrease in potassium concentration 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. This risk may be further increased in the presence of concomitant conditions leading to increased 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 initial dose adjustment. Periodic monitoring of serum potassium levels is recommended, and dosage should be adjusted according to the table above.

Patients with moderate renal impairment (creatinine clearance 30–60 mL/min) should start treatment 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 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 precautions for use").

Combination therapy. When co-administered 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 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. Currently available information is presented in the sections "Pharmacodynamics" and "Pharmacokinetics".

Overdose.

There have been no reports of adverse reactions associated with eplerenone overdose in humans. The most likely manifestations of 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. Supportive treatment should be initiated in case of hypotension. Treatment of hyperkalemia 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 during treatment with eplerenone was similar to that with placebo.

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

Adverse reactions are classified by system organ classes and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

Infections and infestations.

Uncommon: pyelonephritis, infections, pharyngitis.

Blood and lymphatic system disorders.

Uncommon: eosinophilia.

Endocrine disorders.

Uncommon: hypothyroidism.

Metabolism and nutrition disorders.

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

Uncommon: hyponatremia, dehydration, hypertriglyceridemia.

Psychiatric disorders.

Common: insomnia.

Nervous system disorders.

Common: syncope, dizziness, headache.

Uncommon: paresthesia.

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: diarrhea, nausea, constipation, vomiting.

Uncommon: abdominal distension.

Skin and subcutaneous tissue disorders.

Common: rash, pruritus.

Uncommon: angioneurotic edema, hyperhidrosis.

Musculoskeletal and connective tissue disorders.

Common: muscle spasms, back pain.

Uncommon: musculoskeletal pain.

Renal and urinary disorders.

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

Hepatobiliary disorders.

Uncommon: cholecystitis.

Reproductive system and breast disorders.

Uncommon: gynecomastia.

General disorders and administration site conditions.

Common: asthenia.

Uncommon: malaise.

Investigations.

Common: increased blood urea, increased creatinine levels.

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

In the EPHESUS study, a numerically higher number of stroke 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 events) and the placebo group (22 events). In the EMPHASIS-HF study, the number of stroke events in patients aged ≥ 75 years was 9 in the eplerenone treatment group and 8 in the placebo group.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after marketing authorization is important. It allows continuous 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.

3 years.

Storage conditions.

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

Packaging.

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

Prescription status.

Prescription only.

Manufacturer.

Fareva Amboise / Fareva Amboise.

Manufacturer's address and place of business.

Zone Industrielle, 29 route des Industries, 37530 Poce-sur-Cisse, France /
Zone Industrielle, 29 route des Industries, 37530 Poce-sur-Cisse, France.