Apleria
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT APLERIA (APLERIA)
Composition:
Active substance: eplerenone;
One film-coated tablet contains 25 mg or 50 mg of eplerenone;
Excipients: lactose monohydrate, microcrystalline cellulose, sodium croscarmellose, hypromellose, magnesium stearate, sodium lauryl sulfate;
film coating: hypromellose, titanium dioxide (E 171), polyethylene glycol 400, polysorbate 80, iron oxide yellow (E 172).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties:
25 mg tablets: yellow, round, biconvex, film-coated tablets, marked with "25" on one side;
50 mg tablets: yellow, round, biconvex, film-coated tablets, marked with "50" on one side.
Pharmacotherapeutic group. 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 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 serum renin and aldosterone levels, consistent with inhibition of the negative feedback pathway of aldosterone on renin secretion. Despite this elevation in plasma renin activity and circulating aldosterone levels, the efficacy of eplerenone is not diminished.
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 cardio-nephrological EPHESUS trial (Efficacy and Survival Study of Eplerenone in Patients with Acute Myocardial Infarction Complicated by Left Ventricular Dysfunction and Heart Failure), treatment with eplerenone led to a significant increase in aldosterone levels. These findings confirm mineralocorticoid receptor blockade in these patient populations.
Eplerenone was evaluated in the EPHESUS trial—a 3-year, double-blind, placebo-controlled study involving 6,632 subjects with acute myocardial infarction, left ventricular dysfunction (defined by left ventricular ejection fraction ≤ 40%) and clinical signs of heart failure. Within 3–14 days (mean 7 days) after acute myocardial infarction, subjects received either eplerenone or placebo in addition to standard therapy. The initial dose of epleren0ne was 25 mg once daily, increased after 4 weeks to a target dose of 50 mg once daily, provided serum potassium was <5 mmol/L. Throughout the study, standard therapy included acetylsalicylic acid (92%), angiotensin-converting enzyme (ACE) inhibitors (90%), β-blockers (83%), nitrates (72%), loop diuretics (66%), or HMG-CoA reductase inhibitors (60%).
The primary endpoints in the EPHESUS trial 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 trial, eplerenone reduced the risk of all-cause mortality by 15% (HR 0.85; 95% CI 0.75–0.96; p=0.008) compared to placebo, primarily due to a reduction in cardiovascular mortality. The risk of cardiovascular death or hospitalization was reduced by 13% (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. Clinical efficacy of eplerenone was demonstrated primarily in patients under 75 years of age. Benefit 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 classification compared to placebo. The incidence of hyperkalemia was 3.4% in the eplerenone group and 2% in the placebo group (p < 0.001). Hypokalemia occurred in 0.5% of the eplerenone group and 1.5% of the placebo group (p < 0.001).
In a pharmacokinetic study involving 147 healthy volunteers to assess ECG changes, eplerenone showed no consistent effect on heart rate, QRS duration, or PR and QT intervals.
The EMPHASIS-HF trial (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) evaluated the efficacy of eplerenone added to standard therapy on clinical outcomes in patients with systolic heart failure and mild symptoms (NYHA functional class II).
The study included patients aged ≥55 years with left ventricular ejection fraction ≤30%, or ≤35% if QRS duration was >130 milliseconds, and who had either been hospitalized for cardiovascular events within the prior 6 months or had plasma B-type natriuretic peptide (BNP) ≥250 pg/mL or N-terminal pro-BNP ≥500 pg/mL in men (≥750 pg/mL in women). The initial dose of eplerenone was 25 mg once daily, increased after 4 weeks to 50 mg once daily, provided 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, increased 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%). Mean left ventricular ejection fraction was ~26%, and mean QRS duration was ~122 ms. Most subjects (83.4%) had been hospitalized for cardiovascular events within the 6 months prior to randomization, approximately half due to heart failure. Approximately 20% of subjects had implanted defibrillators or were on cardiac resynchronization therapy.
The primary endpoint (cardiovascular death or hospitalization 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 benefit 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 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 (38.9%) compared to placebo (48.4%; p < 0.0001).
Children
The use of eplerenone in children with heart failure has not been studied.
In a 10-week study in children with hypertension (aged 4–16 years, n=304), eplerenone administered at doses resulting in exposure similar to adults (25–100 mg daily) did not effectively reduce blood pressure. In this study and in a 1-year safety study involving 149 children, 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 hormonal effects of eplerenone in children.
Pharmacokinetics
Absorption
The absolute bioavailability of eplerenone after a 100 mg oral dose is 69%. Maximum plasma concentration (Cmax) is reached approximately 1.5–2 hours after administration. Cmax and area under the plasma concentration-time curve (AUC) increase proportionally with dose in the range of 10–100 mg, but less than proportionally at doses above 100 mg. Steady-state concentrations are achieved within 2 days of starting therapy. Food does not affect drug absorption.
Distribution
Eplerenone is approximately 50% bound to plasma proteins, primarily to α1-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 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 67% in urine. The elimination half-life of eplerenone is approximately 3–6 hours. Apparent plasma clearance is approximately 10 L/hour.
Special Patient 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 and female patients, and non-black patients. No significant differences in 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 two studies involving 51 patients aged 4–16 years showed that body weight significantly affects the volume of distribution of eplerenone but not its clearance. The volume of distribution and peak exposure in patients with higher body weight are expected to be similar to those in adults with comparable body weight. In patients with body weight below 45 kg, the volume of distribution is approximately 40% lower; peak exposure is expected to be higher than typically observed in adults. Children received an initial dose of eplerenone 25 mg once daily, increased after 2 weeks 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 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 values were reduced by 26% and 3%, respectively, compared to control. 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").
Hepatic Impairment
The pharmacokinetics of a 400 mg dose of eplerenone were studied in patients with moderate hepatic impairment (Child-Pugh class B) 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 in patients with severe hepatic impairment, eplerenone is contraindicated in such patients (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 AUC and Cmax 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 the EPHESUS trial indicates that eplerenone clearance is similar in patients with heart failure and in elderly healthy volunteers.
Clinical characteristics.
Indications.
- As an adjunct to standard therapy with β-blockers to reduce the risk of cardiovascular events and mortality in stable patients with left ventricular dysfunction (left ventricular ejection fraction ≤40%) and clinical signs of heart failure following recent myocardial infarction (MI).
- As an adjunct to standard optimal therapy to reduce the risk of cardiovascular events and mortality in adult patients with NYHA Class II (chronic) heart failure and left ventricular dysfunction (left ventricular ejection fraction ≤30%) (see section "Pharmacodynamics").
Contraindications.
- Hypersensitivity to eplerenone or to any of the excipients of the medicinal product.
- Serum potassium level >5 mmol/L at the start of treatment.
- Severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m²).
- Severe hepatic impairment (Child-Pugh class C).
- Concomitant use of potassium-sparing diuretics, potassium supplements, or strong inhibitors of CYP3A4 (e.g., itraconazole, ketoconazole, ritonavir, nelfinavir, clarithromycin, telithromycin, and nefazodone) (see section "Interaction with other medicinal products and other forms of interaction").
- Concomitant use of eplerenone in triple combination with an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin receptor blocker (ARB).
Interaction with other medicinal products and other forms of interaction.
Pharmacodynamic interactions
Potassium-sparing diuretics and potassium-containing supplements
Due to the increased risk of hyperkalemia, eplerenone should not be administered to patients receiving other potassium-sparing diuretics or potassium-containing supplements (see section "Contraindications"). Potassium-sparing diuretics may also enhance the effects of antihypertensive agents and other diuretics.
ACE inhibitors, angiotensin receptor antagonists (ARBs)
The risk of hyperkalemia may be increased when eplerenone is used in combination with an ACE inhibitor and/or ARB. 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 ARB (see sections "Contraindications" and "Special precautions for use").
Lithium
Studies on the interaction between eplerenone and lithium have not been conducted. However, toxic effects of lithium 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 cyclosporine or tacrolimus must be administered during eplerenone therapy, serum potassium levels should be closely monitored (see section "Special precautions for use").
Nonsteroidal anti-inflammatory drugs (NSAIDs)
NSAID therapy may lead to acute renal failure due to direct effects on glomerular filtration, especially in patients at high risk (elderly patients and/or dehydration). Patients receiving eplerenone and NSAIDs should be adequately hydrated prior to initiation of therapy, and renal function should be monitored.
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 those with impaired renal function.
α1-blockers (e.g., prazosin, alfuzosin)
Combination of α1-blockers with eplerenone may increase the risk of enhanced hypotensive effects and/or orthostatic hypotension. Patients should be monitored for signs of orthostatic hypotension during concomitant use.
Tricyclic antidepressants, neuroleptics, amifostine, baclofen
Concomitant use of these medicinal products with eplerenone may potentially enhance hypotensive effects and increase the risk of orthostatic hypotension.
Glucocorticoids, tetracosactide
Concomitant use of these agents with eplerenone may lead to reduced antihypertensive efficacy due to fluid and sodium retention.
Pharmacokinetic interactions
In vitro studies indicate that eplerenone is not an inhibitor of the isoenzymes CYP1A2, CYP2C19, CYP2C9, CYP2D6, or CYP3A4. Eplerenone is neither a substrate nor an inhibitor of P-glycoprotein.
Digoxin
Systemic exposure (AUC) to digoxin increases by 16% (90% CI: 4–30%) when administered concomitantly with eplerenone. Digoxin should be prescribed with caution when doses are near the upper limit of the therapeutic range.
Warfarin
No clinically significant pharmacokinetic interactions with warfarin have been reported. Warfarin should be used with caution when doses are near the upper limit of the therapeutic range.
Substrates of CYP3A4
Pharmacokinetic studies using probe substrates of CYP3A4 (i.e., midazolam and cisapride) did not reveal evidence of significant pharmacokinetic interactions when coadministered 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. Under the influence of a strong CYP3A4 inhibitor (ketoconazole 200 mg twice daily), eplerenone AUC 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: coadministration with erythromycin, saquinavir, amiodarone, diltiazem, verapamil, or fluconazole resulted in significant pharmacokinetic interactions, increasing eplerenone AUC by 98–187%. Therefore, when eplerenone is coadministered with weak or moderate CYP3A4 inhibitors, the dose of eplerenone should not exceed 25 mg (see section "Dosage and administration").
Inducers of CYP3A4
Concomitant use of eplerenone with St. John’s wort (a strong 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 decrease in eplerenone AUC. Due to the risk of reduced efficacy, concomitant use of eplerenone with strong CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, phenobarbital, St. John’s wort) is not recommended (see section "Special precautions for use").
Antacids
Based on results from a clinical pharmacokinetic study, no significant interactions are expected when eplerenone is administered concomitantly with antacids.
Special precautions for use.
Hyperkalemia
During treatment with eplerenone, hyperkalemia may occur due to its mechanism of action. Serum potassium levels should be monitored in all patients at the beginning of treatment and following any dose adjustment. Periodic monitoring is subsequently recommended, particularly in patients at increased risk of developing hyperkalemia (elderly patients, patients with renal impairment (see section "Dosage and administration") and diabetes mellitus). Potassium supplements are not recommended during 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, concomitant 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 an angiotensin II receptor antagonist (ARA), the risk of hyperkalemia may increase. Concomitant use of eplerenone with both an ACE inhibitor and an ARA (triple combination therapy) is not recommended (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").
Renal impairment
In patients with renal impairment (including those with diabetic microalbuminuria), serum potassium levels should be monitored regularly. Impaired renal function is associated with an increased risk of hyperkalemia. Although data from the EPHESUS study in patients with type 2 diabetes and microalbuminuria are limited, an increased incidence of hyperkalemia was observed in this small patient group. Therefore, treatment of such patients should be undertaken with caution. 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 increase above 5.5 mmol/L. These patients require monitoring of electrolyte levels. The use of eplerenone in patients with severe hepatic impairment has not been studied; therefore, eplerenone is contraindicated in such patients (see sections "Contraindications" and "Dosage and administration").
CYP3A4 inducers: concomitant use of eplerenone with strong CYP3A4 inducers is not recommended (see section "Interaction with other medicinal products and other forms of 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").
Fertility
There is no information available on the effects of eplerenone on human fertility.
If you have known intolerance to certain sugars, consult your physician before taking this medicinal product.
Use during pregnancy or breastfeeding.
Pregnancy
There are insufficient data on the use of eplerenone in pregnant women. Animal studies do not indicate any direct or indirect adverse effects on pregnancy, embryonal/fetal development, parturition, or postnatal development. However, eplerenone should be used during pregnancy only with caution.
Breastfeeding
It is not known whether eplerenone is excreted into human breast milk following oral administration. However, preclinical data indicate the presence of eplerenone and/or its metabolites in the milk of rats and show normal development of offspring exposed via this route. Since the potential for adverse effects in breastfed infants has not been established, breastfeeding or eplerenone therapy should be discontinued, taking into account the benefit of treatment for the mother.
Effects on ability to drive and use machines.
No studies on the effects of eplerenone on the ability to drive or operate machinery have been conducted. Eplerenone does not cause drowsiness or impair cognitive function; however, the possibility of dizziness during treatment should be considered when driving or operating machinery.
Dosage and Administration
Adults
The medicine is available in 25 mg and 50 mg doses for individual dosage adjustment. The maximum daily dose is 50 mg once daily.
Eplerenone can be administered independently of food intake (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, preferably over 4 weeks, to the target dose of 50 mg once daily, based on serum potassium levels (see table).
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 25 mg once daily and gradually increased, preferably over 4 weeks, to the target dose of 50 mg once daily, based on serum potassium levels (see table and section "Special Warnings and Precautions for Use").
Eplerenone treatment should not be initiated in patients with serum potassium levels >5 mmol/L (see section "Contraindications").
Serum potassium levels should be measured before initiating eplerenone treatment, during the first week of treatment, and one month after initiation or dose adjustment. Thereafter, serum potassium should be monitored periodically during treatment as clinically indicated.
After treatment initiation, the dose should be adjusted according to serum potassium concentration as outlined in the table below.
Dose adjustment after treatment initiation
| Serum potassium concentration (mmol/l) |
Action |
Dose adjustment |
| <5.0 |
increase |
From 25 mg once every 2 days to 25 mg once daily From 25 mg once daily to 50 mg once daily |
| 5.0–5.4 |
no change |
do not change dose |
| 5.5–5.9 |
decrease |
From 50 mg once daily to 25 mg once daily From 25 mg once daily to 25 mg once every 2 days From 25 mg once every 2 days to temporary discontinuation |
| ≥6.0 |
temporary discontinuation |
- |
After temporary discontinuation of eplerenone due to elevated potassium levels ≥6 mmol/L, treatment may be resumed at a dose of 25 mg once every 2 days once potassium concentration has decreased below 5 mmol/L.
Elderly patients
No initial dose adjustment 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").
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.
For patients with moderate renal impairment (creatinine clearance 30–60 mL/min), treatment should be initiated at 25 mg once every 2 days, with subsequent dose adjustments based on potassium concentration (see table above). Periodic monitoring of serum potassium levels is recommended (see section "Special precautions").
There is no experience with the use of eplerenone in patients with creatinine clearance <50 mL/min and heart failure following myocardial infarction. Eplerenone should be used with caution in such patients. Doses exceeding 25 mg 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, particularly in elderly individuals, more frequent and regular monitoring of serum potassium concentration is recommended (see section "Special precautions").
Combination therapy
When used concomitantly with weak or moderate CYP3A4 inhibitors (e.g., amiodarone, diltiazem, 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. Available information is provided in the sections "Pharmacodynamics" and "Pharmacokinetics".
Overdose
There have been no reports of adverse reactions related to 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 cases of hypotension, supportive treatment should be initiated. In cases of hyperkalemia, treatment should be started according to standard guidelines.
Adverse Reactions
During 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 those possibly related to eplerenone use, occurring 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 class and frequency: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), frequency not known (cannot be estimated from available data).
Infections and infestations
Uncommon: pyelonephritis, infections, pharyngitis.
Blood and lymphatic system disorders
Uncommon: eosinophilia.
Endocrine disorders
Uncommon: hypothyroidism.
Metabolism and nutrition disorders
Common: hyperkalaemia (see sections "Contraindications" and "Special warnings and precautions for use"), hypercholesterolaemia.
Uncommon: hyponatraemia, dehydration, hypertriglyceridaemia.
Psychiatric disorders
Common: insomnia.
Nervous system disorders
Common: syncope, dizziness, headache.
Uncommon: paraesthesia.
Cardiac disorders
Common: left ventricular dysfunction, atrial fibrillation.
Uncommon: tachycardia.
Vascular disorders
Common: hypotension.
Uncommon: arterial thrombosis of limbs, orthostatic hypotension.
Respiratory, thoracic and mediastinal disorders
Common: cough.
Gastrointestinal disorders
Common: diarrhoea, nausea, constipation, vomiting.
Uncommon: abdominal distension.
Skin and subcutaneous tissue disorders
Common: rash, pruritus.
Uncommon: hyperhidrosis, angioneurotic oedema.
Musculoskeletal and connective tissue disorders
Common: muscle spasms, back pain.
Uncommon: musculoskeletal pain.
Renal and urinary disorders
Common: renal function impairment (see sections "Special warnings and precautions for use" and "Interaction with other medicinal products and other forms of interaction").
Hepatobiliary disorders
Uncommon: cholecystitis.
Reproductive system and breast disorders
Uncommon: gynaecomastia.
General disorders and administration site conditions
Common: asthenia.
Uncommon: malaise.
Investigations
Common: increased blood urea, increased creatinine.
Uncommon: decreased epidermal growth factor receptor count, increased blood glucose.
In the EPHESUS study, a numerically higher number of stroke events was observed in patients aged ≥75 years. However, there was no statistically significant difference in the incidence of stroke between the eplerenone group (30 events) and the placebo group (22 events). In the EMPHASIS-HF study, the number of stroke events in patients aged ≥75 years was 9 in the eplerenone treatment group and 8 in the placebo group.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Information on any suspected adverse reactions should be reported in accordance with applicable legal requirements.
Shelf life.
3 years.
Storage conditions.
No special storage conditions are required for this medicinal product. Keep out of the reach of children.
Packaging.
10 tablets in a blister pack, 3 blisters in a cardboard box.
Prescription status. Prescription only.
Manufacturer.
KRKA, d.d., Novo mesto, Slovenia / KRKA, d.d., Novo mesto, Slovenia.
Manufacturer's address and place of business.
Smarjeska cesta 6, 8501 Novo mesto, Slovenia / Smarjeska cesta 6, 8501 Novo mesto, Slovenia.