Renial
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT RENIAL® (RENIAL)
Composition:
Active substance: eplerenone;
1 tablet contains eplerenone equivalent to 100% substance 25 mg or 50 mg;
Excipients: lactose monohydrate; microcrystalline cellulose, sodium croscarmellose, hypromellose, sodium lauryl sulfate, talc, magnesium stearate;
Film-coating suspension: titanium dioxide (E 171), polyethylene glycol (macrogol), hypromellose, iron oxide yellow (E 172), polysorbate 80, yellow FCF (E 110), quinoline yellow (E 104), indigo carmine (E 132).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties: film-coated tablets, yellow in colour, diamond-shaped, with a biconvex surface.
Pharmacotherapeutic group.
Potassium-sparing diuretics. Aldosterone antagonists. Eplerenone. ATC code C03DA04.
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 receptor binding by aldosterone—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, this increase in plasma renin activity and blood 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 (Efficacy and Mortality Evaluation of Eplerenone in patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure), treatment with eplerenone led to a significant increase in aldosterone levels. These findings confirm mineralocorticoid receptor blockade in this patient population.
Eplerenone was evaluated in the EPHESUS trial, a double-blind, placebo-controlled study lasting 3 years, involving 6632 patients with acute myocardial infarction, left ventricular dysfunction (defined by left ventricular ejection fraction ≤ 40%) and clinical signs of heart failure. Starting 3–14 days (median 7 days) after acute myocardial infarction, patients received either eplerenone or placebo in addition to standard therapy, beginning 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, patients received standard therapy, including acetylsalicylic acid (92%), ACE inhibitors (90%), β-blockers (83%), loop diuretics (66%), nitrates (72%), 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 patients in the eplerenone group and 16.7% in the placebo group, while the composite endpoint (cardiovascular death or hospitalization due to cardiovascular events) was reached in 26.7% of patients 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 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. Clinical efficacy of eplerenone was primarily demonstrated in patients under 75 years of age. The benefit in patients aged 75 years and older has not been sufficiently established. Improvement or stabilization of NYHA functional class was observed in a statistically significantly higher proportion of patients receiving eplerenone compared to those in the placebo group. The incidence of hyperkalemia was 3.4% in the eplerenone group and 2% in the placebo group (p < 0.001). The incidence of hypokalemia was 0.5% in the eplerenone group and 1.5% in the placebo group (p < 0.001).
In a study involving 147 healthy volunteers to assess ECG changes during pharmacokinetic evaluations, eplerenone showed no consistent effect on heart rate, QRS complex 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 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 prior 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 provided serum potassium levels remained below 5 mmol/L. Alternatively, if estimated glomerular filtration rate (eGFR) was 30–49 mL/min/1.73 m², the initial dose of eplerenone was 25 mg every other day, increased later to 25 mg once daily.
A total of 2737 adult patients were randomized (in a double-blind design) to receive either eplerenone or placebo in addition to background therapy, including diuretics (85%), ACE inhibitors (78%), angiotensin receptor blockers type II (19%), β-blockers (87%), antiplatelet agents (88%), lipid-lowering agents (63%), and digitalis glycosides (27%). Mean left ventricular ejection fraction was ~26%, and mean QRS duration was ~122 ms. The majority of patients (83.4%) had been hospitalized for cardiovascular events within the 6 months prior to randomization, approximately half of them due to heart failure. Approximately 20% of patients had implanted defibrillators or were on cardiac resynchronization therapy.
The primary endpoint (cardiovascular death or hospitalization for heart failure) occurred in 249 patients (18.3%) in the eplerenone group and 356 patients (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 patients (12.5%) in the eplerenone group and 213 patients (15.5%) in the placebo group (HR 0.76; 95% CI 0.62–0.93; p = 0.008). Cardiovascular death occurred in 147 patients (10.8%) in the eplerenone group and 185 patients (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 patients (11.8%) in the eplerenone group and 96 patients (7.2%) in the placebo group (p < 0.001). Hypokalemia (serum potassium < 4 mmol/L) occurred significantly less frequently in the eplerenone group compared to the placebo group (38.9% vs. 48.4%, p < 0.0001).
Children. The use of eplerenone in children with heart failure has not been studied.
In a 10-week study 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 (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 and less than proportionally at doses above 100 mg. Steady-state is achieved within 2 days of starting therapy. Food does not affect drug absorption.
Distribution. Eplerenone is approximately 50% bound to plasma proteins, primarily to α-1-acid glycoproteins. The apparent volume of distribution at steady state is estimated to be 42–90 L. Eplerenone does not bind to erythrocytes.
Biotransformation. Eplerenone is metabolized primarily 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 recovered in feces and about 67% in urine. The elimination half-life of eplerenone is approximately 3–6 hours. Apparent plasma clearance is approximately 10 L/h.
Use in specific populations
Age, gender, and race. Pharmacokinetic studies of eplerenone at a dose of 100 mg once daily were conducted in elderly patients (aged ≥65 years), male and 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 significantly affects the volume of distribution of eplerenone but not its elimination. The volume of distribution and peak exposure in children with higher body weight are expected to be similar to those 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 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 dosing regimens, 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 the control group. In patients on hemodialysis, these values were reduced by 26% and 3%, respectively, compared to the control group. No correlation was observed between plasma eplerenone clearance and creatinine clearance. Eplerenone is not removed by hemodialysis (see section "Special precautions").
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 eplerenone use in patients with severe hepatic impairment have not been conducted, 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 Cmax and AUC values in patients with heart failure were 38% and 30% higher, respectively, than in age-, body weight-, and gender-matched healthy volunteers. 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 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.
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 GFR < 30 mL/min/1.73 m²).
- Patients with severe hepatic impairment (Child-Pugh class C).
- Patients taking potassium-sparing diuretics or potent CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, ritonavir, nelfinavir, clarithromycin, telithromycin, and nefazodone) (see section "Interaction with other medicinal products and other forms of interaction").
- Concomitant use of eplerenone in triple combination with an ACE inhibitor and an angiotensin receptor blocker.
Interaction with other medicinal products and other forms of interaction.
Pharmacodynamic interactions
Potassium-sparing diuretics and potassium supplements. Eplerenone should not be administered to patients receiving other potassium-sparing diuretics or potassium supplements due to an increased risk of hyperkalemia (see section "Contraindications"). The antihypertensive effect of 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 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. Additionally, a reduction in antihypertensive efficacy is possible. Patients should be adequately hydrated, and renal function should be monitored at the start of treatment and regularly during combination therapy (see sections "Special precautions for use" and "Method of administration and dosage").
Trimethoprim. Concomitant use of trimethoprim and eplerenone increases the risk of hyperkalemia. Serum potassium levels and renal function should be monitored, especially in elderly patients and patients with 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. The AUC of digoxin increases by 16% (90% CI 4–30%) when co-administered 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) did not reveal signs of significant pharmacokinetic interactions when these medicinal products were used concomitantly with eplerenone.
Inhibitors of CYP3A4
- Potent inhibitors of CYP3A4. When eplerenone is used concomitantly with medicinal products that inhibit the activity of the CYP3A4 enzyme, significant pharmacokinetic interactions may occur. Under the influence of a potent CYP3A4 inhibitor (ketoconazole 200 mg twice daily), the AUC of eplerenone increased by 441% (see section "Contraindications"). Concomitant use of eplerenone with potent CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin, telithromycin, and nefazodone) is contraindicated (see section "Contraindications").
- Weak and moderate inhibitors of CYP3A4. Concomitant use with erythromycin, saquinavir, amiodarone, diltiazem, verapamil, or fluconazole resulted in significant pharmacokinetic interactions, increasing AUC 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 "Method of administration and dosage").
Inducers of CYP3A4. Concomitant use of eplerenone with St. John's wort (a potent CYP3A4 inducer) resulted in a 30% reduction in eplerenone AUC. Use of more potent CYP3A4 inducers (such as rifampicin) may lead to a more pronounced reduction in eplerenone AUC. Due to the risk of reduced efficacy, concomitant use of potent CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, phenobarbital, St. John's wort) with eplerenone is not recommended (see section "Special precautions for use").
Antacids. Based on results of a clinical pharmacokinetic study, significant interactions are not expected when eplerenone is used 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 recommended thereafter, particularly in patients at increased risk of hyperkalemia (elderly patients, patients with renal impairment (see section "Dosage and administration") and diabetes). Potassium-containing supplements should not be used 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, 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 an angiotensin receptor blocker, the risk of hyperkalemia may increase. Eplerenone should not be used concomitantly in triple combination with an ACE inhibitor and an angiotensin receptor blocker (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").
Renal function impairment. In patients with impaired renal function (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 in patients with type 2 diabetes and microalbuminuria are limited, an increased incidence of hyperkalemia was observed in this small patient group. Therefore, treatment of such patients should be carried out with caution. Eplerenone is not removed by hemodialysis.
Hepatic function impairment. In patients with mild to moderate hepatic impairment (Child-Pugh classes A and B), serum potassium levels 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").
Inducers of CYP3A4. Concomitant use of eplerenone and strong inducers of CYP3A4 is not recommended (see section "Interaction with other medicinal products and other forms of interaction").
Concomitant use of lithium, cyclosporine, tacrolimus should be avoided during eplerenone therapy (see section "Interaction with other medicinal products and other forms of interaction").
Sodium. This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, i.e. it is practically sodium-free.
Lactose. The product contains lactose monohydrate and therefore should not be administered to patients with rare hereditary problems such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.
Azo dyes. The medicinal product contains the azo dye sunset yellow FCF (E 110), which may cause allergic reactions.
Use during pregnancy or breastfeeding.
Pregnancy. There are no adequate data on the use of eplerenone in pregnant women. Animal studies have not shown any direct or indirect adverse effects on pregnancy, embryonic/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 reactions in breastfed infants has not been ruled out, a decision must be made whether to discontinue breastfeeding or to discontinue eplerenone therapy, taking into account the importance of the drug to 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 associated with the use of the drug should be taken into account.
Dosage and Administration
Adults
The drug is available in 25 mg and 50 mg doses to allow individual dose titration. The maximum daily dose is 50 mg once daily.
Eplerenone may be taken 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 to the target dose of 50 mg once daily. This dose level should preferably be reached within 4 weeks, taking into account serum potassium levels (see table below).
Eplerenone treatment is usually initiated 3–14 days after acute myocardial infarction.
Patients with NYHA class II (chronic) heart failure. Treatment of patients with chronic heart failure classified as NYHA class II should be initiated at a dose of 25 mg once daily and gradually increased to the target dose of 50 mg once daily. This dose level should preferably be reached within 4 weeks, taking into account serum potassium levels (see table below and section "Special Warnings and Precautions for Use").
Eplerenone treatment should not be initiated in patients with serum potassium levels exceeding 5 mmol/L (see section "Contraindications").
Serum potassium levels should be measured before starting eplerenone treatment, during the first week of treatment, and one month after initiation of treatment or dose adjustment. Thereafter, serum potassium levels should be monitored periodically as clinically indicated during treatment.
After initiation of treatment, the drug dose should be adjusted according to serum potassium concentration as indicated in the table below.
Dose adjustment after initiation of treatment
| Serum potassium concentration (mmol/l) |
Action |
Dose adjustment |
| < 5.0 |
increase |
from 25 mg once every 2 days to 25 mg once daily. |
| 5.0–5.4 |
unchanged |
dose remains unchanged |
| 5.5–5.9 |
decrease |
from 50 mg once daily to 25 mg once daily. |
| ≥ 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 after potassium concentration decreases 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. This risk may be further increased in the presence of concomitant conditions associated with 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.
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 for use").
Experience with eplerenone 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 initial dose adjustment. Due to increased systemic exposure to eplerenone in these patients, and particularly in elderly patients, more frequent and regular monitoring of serum potassium concentration is recommended (see section "Special precautions for use").
Combination therapy. When used concomitantly with weak or moderate CYP3A4 inhibitors (e.g., amiodarone, diltiazem, and verapamil), eplerenone treatment may be initiated at a starting dose of 25 mg once daily. The dose of eplerenone should not exceed 25 mg once daily (see section "Interaction with other medicinal products and other forms of interaction").
Children.
The safety and efficacy of eplerenone in children have not been established. Available information is presented in the sections "Pharmacodynamics" and "Pharmacokinetics".
Overdose.
There have been no reports of adverse reactions associated with eplerenone overdose in humans. The most likely manifestations of 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 started according to standard guidelines.
Adverse reactions.
In two studies (EPHESUS and EMPHASIS-HF), it has been 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, 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 absolute 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 based on available information).
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: arterial 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 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 cases) and the placebo group (22 cases). In the EMPHASIS-HF study, the number of stroke cases in patients aged ≥ 75 years was 9 in the eplerenone treatment group and 8 in the placebo group.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.
Shelf life.
2 years.
Storage conditions.
Store in the original packaging at a temperature not exceeding 25°C.
Keep out of reach and sight of children.
Packaging.
10 tablets per blister. 3 blisters per carton.
Prescription category. Prescription only.
Manufacturer. JSC "Kyivmedpreparat".
Manufacturer's address and location of its business activities.
139 Saksaganskogo Street, Kyiv, 01032, Ukraine.