Efez

APPROVED
Order of the Ministry of Health of Ukraine No. 1547 of August 29, 2022
Marketing Authorisation No. UA/19629/01/01, No.UA/19629/01/02

INSTRUCTION
for Medical Use
EFEZ

Composition:

active substances: eplerenone;

Each film-coated tablet contains 25 mg or 50 mg of eplerenone.;

Excipients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hypromellose, sodium lauryl sulphate, talc, magnesium stearate, Opadry^® ІІ 33G270003 yellow-brown.

Pharmaceutical form. Film-coated tablet.

Main physicochemical properties: Yellow-brown round biconvex film-coated tablet.

Pharmacotherapeutic group. Potassium-sparing diuretics. Aldosterone antagonists. Eplerenone. ATC code C03D A04.

Pharmacological properties.

Pharmacodynamic properties.

Mechanism of action. Eplerenone has relative selectivity in binding to recombinant human mineralocorticoid receptors compared to its binding to recombinant human glucocorticoid, progesterone and androgen receptors. Eplerenone prevents the binding of aldosterone, a key hormone in the renin-angiotensin-aldosterone-system (RAAS), which is involved in the regulation of blood pressure and the pathophysiology of cardiovascular disease.

Pharmacodynamic effects. Eplerenone has been shown to produce sustained increases in plasma renin and serum aldosterone, consistent with inhibition of the negative regulatory feedback of aldosterone on renin secretion. The resulting increased plasma renin activity and aldosterone circulating levels do not overcome the effects of eplerenone.

In dose-ranging studies of chronic heart failure (New York Heart Association (NYHA) classification II-IV), the addition of eplerenone to standard therapy resulted in expected dose-dependent increases in aldosterone. Similarly, in a cardiorenal sub-study of EPHESUS (efficacy and survival study of the effect of eplerenone among patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure), therapy with eplerenone led to a significant increase in aldosterone. These results confirm the blockade of the mineralocorticoid receptor in these populations.

 

Eplerenone was studied in the EPHESUS trial. EPHESUS was a double-blind, placebo-controlled study, of 3-year duration, in 6 632 subjects with acute myocardial infarction, left ventricular dysfunction (as measured by left ventricular ejection fraction ≤ 40%), and clinical signs of heart failure. Within 3 to 14 days (median 7 days) after an acute myocardial infarction, subjects received eplerenone or placebo in addition to standard therapies at an initial dose of 25 mg once daily. It was further titrated (during 4 weeks) to the target dose of 50 mg once daily if serum potassium was < 5.0 mmol/L. During the study subjects received standard care including acetylsalicylic acid (92%), ACE inhibitors (90%), β-blockers (83%), nitrates (72%), loop diuretics (66%), or HMG CoA reductase inhibitors (60%).

In EPHESUS, the co-primary endpoints were all-cause mortality and the combined endpoint (cardiovascular death or hospitalisation). 14.4 % of subjects assigned to eplerenone and 16.7 % of subjects assigned to placebo died (all causes), while 26.7 % of subjects assigned to eplerenone and 30.0 % assigned to placebo met the combined endpoint (cardiovascular death or hospitalisation). Thus, in EPHESUS, eplerenone reduced the risk of death from any cause by 15% (RR 0.85; 95% CI, 0.75-0.96; p= 0.008) compared to placebo, primarily by reducing cardiovascular mortality. The risk of cardiovascular death or cardiovascular hospitalisation was reduced by 13% with eplerenone (RR 0.87; 95% CI, 0.79-0.95; p=0.002). The absolute risk reductions for the endpoints all-cause mortality and cardiovascular mortality or hospitalisation were 2.3% and 3.3%, respectively. Clinical efficacy was primarily demonstrated when eplerenone therapy was initiated in subjects aged < 75 years old. The benefits of therapy in those subjects over the age of 75 are unclear. NYHA functional classification improved or remained stable for a statistically significant greater proportion of subjects receiving eplerenone compared to placebo. The incidence of hyperkalaemia was 3.4 % in the eplerenone group vs. 2.0 % in the placebo group (p < 0.001). The incidence of hypokalaemia was 0.5 % in the eplerenone group vs. 1.5 % in the placebo group (p < 0.001).

No consistent effects of eplerenone on heart rate, QRS duration, or PR or QT interval were observed in 147 normal subjects evaluated for electrocardiographic changes during pharmacokinetic studies.

In the EMPHASIS-HF (eplerenone in mild patients hospitalization and survival study in heart failure) trial the effect of eplerenone when added to standard therapy was investigated on clinical outcomes in subjects with systolic heart failure and mild symptoms (NYHA functional class II).

Subjects were included aged 55 years old and above who had a left ventricular ejection fraction ≤ 30% or ≤ 35% in addition to QRS duration of > 130 msec, and who were either hospitalized for cardiovascular reasons 6 months prior to inclusion or had a plasma level of B-type natriuretic peptide (BNP) of at least 250 pg/mL or a plasma level of N-terminal pro-BNP of at least 500 pg/mL in men (750 pg/mL in women). Eplerenone was started at a dose of 25 mg once daily and was increased after 4 weeks to 50 mg once daily if the serum potassium level was < 5.0 mmol/L. Alternatively, if the estimated glomerular filtration rate (GFR) was 30-49 mL/min/1.73 m², eplerenone was started at 25 mg on alternate days, and increased to 25 mg once daily.

In total, 2 737 subjects were randomized (double-blind) to treatment with eplerenone or placebo including baseline therapy of diuretics (85%), ACE inhibitors (78%), angiotensin II receptor blockers (19%), β-blockers (87%), anti-thrombotic agents (88%), lipid lowering agents (63%), and digitalis glycosides (27%). The mean left ventricular ejection fraction was ~26% and the mean QRS duration was ~122 msec. Most of the subjects (83.4%) were previously hospitalized for cardiovascular reasons within 6 months of randomization, with around 50% of them due to heart failure. Around 20% of the subjects had implantable defibrillators or cardiac resynchronization therapy.

 

The primary endpoint (death from cardiovascular causes or hospitalization for heart failure) occurred in 249 (18.3%) subjects in the eplerenone group and 356 (25.9%) subjects in the placebo group (RR 0.63, 95% CI, 0.54-0.74; p<0.001). The effect of eplerenone on the primary endpoint outcomes was consistent across all pre-specified subgroups.

The secondary endpoint (all-cause mortality) was met by 171 (12.5%) subjects in the eplerenone group and 213 (15.5%) subjects in the placebo group (RR 0.76; 95% CI, 0.62-0.93; p = 0.008). Death from cardiovascular causes was reported in 147 (10.8%) subjects in the eplerenone group and 185 (13.5%) subjects in the placebo group (RR 0.76; 95% CI, 0.610.94; p = 0.01).

During the study, hyperkalaemia (serum potassium level > 5.5 mmol/L) was reported in 158 (11.8%) subjects in the eplerenone group and 96 (7.2%) subjects in the placebo group (p < 0.001). Hypokalaemia (serum potassium levels < 4.0 mmol/L) was statistically lower with eplerenone when compared to placebo (38.9% for eplerenone compared to 48.4% for placebo, p<0.0001).

Paediatric population. Eplerenone has not been studied in paediatric subjects with heart failure.

In a 10-week study of paediatric subjects with hypertension (age range 4 to 16 years, n=304), eplerenone, at doses from 25 mg up to 100 mg per day that produced exposure similar to that in adults, did not lower blood pressure effectively. In this study and in a 1-year paediatric safety study in 149 subjects aged from 5 to 17 years, the safety profile was similar to that of adults. Eplerenone has not been studied in hypertensive subjects less than 4 years old because the study in older paediatric subjects showed a lack of efficacy (see the section ‘Posology and method of administration’).

Any (long term) effect on hormonal status in paediatric subjects has not been studied.

Pharmacokinetic properties.

Absorption. The absolute bioavailability of eplerenone is 69% following administration of a 100 mg oral tablet.

Maximum plasma concentrations of the medicinal product are reached after approximately 1.5 to 2 hours. Both peak plasma levels (C_max) and area under the curve (AUC) are dose proportional for doses of 10 mg to 100 mg and less than proportional at doses above 100 mg. Steady state is reached within 2 days. Absorption is not affected by food.

Distribution. The plasma protein binding of eplerenone is about 50% and is primarily bound to α-1-acid glycoproteins. The apparent volume of distribution at steady state is estimated to be 42-90 L. Eplerenone does not preferentially bind to red blood cells.

Biotransformation. Eplerenone metabolism is primarily mediated via CYP3A4. No active metabolites of eplerenone have been identified in human plasma.

Elimination. Less than 5% of an eplerenone dose is recovered as unchanged product in the urine and faeces. Following a single oral dose of radiolabelled product, approximately 32% of the dose was excreted in the faeces and approximately 67% was excreted in the urine. The elimination half-life of eplerenone is approximately 3 to 6 hours. The apparent plasma clearance is approximately 10 L/hr.

 

Special populations.

Age, gender, and race. The pharmacokinetics of eplerenone at a dose of 100 mg once daily have been investigated in the elderly (≥ 65 years), in males and females, and in blacks. The pharmacokinetics of eplerenone did not differ significantly between males and females. At steady state, elderly subjects had increases in C_max (22%) and AUC (45%) compared with younger subjects (18 to 45 years). At steady state, C_max was 19% lower and AUC was 26% lower in blacks (see the section ‘Posology and method of administration’).

Paediatric population. A population pharmacokinetic model for eplerenone concentrations from two studies in 51 paediatric hypertensive subjects of ages 4 to 16 years identified that patient body weight had a statistically significant effect on eplerenone volume of distribution but not on its clearance. Eplerenone volume of distribution and peak exposure in a heavier paediatric patient are predicted to be similar to that in an adult of similar body weight. In a lighter 45 kg patient, the volume of distribution is about 40% lower and the peak exposure is predicted to be higher than typical adults. Eplerenone treatment was initiated at 25 mg once daily in paediatric patients and increased to 25 mg twice daily after 2 weeks and eventually to 50 mg twice daily, if clinically indicated. At these doses, the highest observed eplerenone concentrations in paediatric subjects were not substantially higher than those in adults initiated at 50 mg once daily.

Renal insufficiency. The pharmacokinetics of eplerenone were evaluated in patients with varying degrees of renal insufficiency and in patients undergoing haemodialysis. Compared with control subjects, steady-state AUC and C_max were increased by 38% and 24%, respectively, in patients with severe renal impairment and were decreased by 26% and 3%, respectively, in patients undergoing haemodialysis. No correlation was observed between plasma clearance of eplerenone and creatinine clearance. Eplerenone is not removed by haemodialysis (see the section ‘Special warnings and precautions for use’).

Hepatic insufficiency. The pharmacokinetics of eplerenone 400 mg have been investigated in patients with moderate (Child-Pugh Class B) hepatic impairment and compared with normal subjects. Steady-state C_max and AUC of eplerenone were increased by 3.6% and 42%, respectively (see the section ‘Posology and method of administration’). Since the use of eplerenone has not been investigated in patients with severe hepatic impairment, eplerenone is contraindicated in this patient group (see the section ‘Contraindications’).

Heart failure. The pharmacokinetics of eplerenone 50 mg were evaluated in patients with heart failure (NYHA classification II-IV). Compared with healthy subjects matched according to age, weight and gender, steady state AUC and C_max in heart failure patients were 38% and 30% higher, respectively. Consistent with these results, a population pharmacokinetic analysis of eplerenone based on a subset of patients from EPHESUS indicates that clearance of eplerenone in patients with heart failure was similar to that in healthy elderly subjects.

Clinical particulars.

Therapeutic indications.

‒ In addition to standard therapy including β-blockers, to reduce the risk of cardiovascular mortality and morbidity in stable patients with left ventricular dysfunction (left ventricular ejection fraction ≤ 40 %) and clinical evidence of heart failure after recent myocardial infarction.

‒ In addition to standard optimal therapy, to reduce the risk of cardiovascular mortality and morbidity in adult patients with NYHA class II (chronic) heart failure and left ventricular systolic dysfunction (left ventricular ejection fraction ≤ 30%) (see the section ‘Pharmacodynamic properties’).

 

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients listed in section ‘Composition.’
• Patients with serum potassium level > 5.0 mmol/L at initiation of the treatment.
• Patients with severe renal insufficiency (estimated glomerular filtration rate <30 mL/min/1.73 m²)
• Patients with severe hepatic insufficiency (Child-Pugh Class C)
• Patients receiving potassium-sparing diuretics or strong inhibitors of CYP 3A4 (e.g., itraconazole, ketoconazole, ritonavir, nelfinavir, clarithromycin, telithromycin and nefazodone) (see the section ‘Interaction with other medicinal products and other forms of interaction’)
• The combination of an angiotensin converting enzyme (ACE) inhibitor and an angiotensin receptor blocker (ARB) with eplerenone

Interaction with other medicinal products and other forms of interaction.

Pharmacodynamic interactions.

Potassium-sparing diuretics and potassium supplements. Due to increased risk of hyperkalaemia, eplerenone should not be administered to patients receiving other potassium sparing diuretics and potassium supplements (see the section ‘Contraindications’). Potassium-sparing diuretics may also potentiate the effect of anti-hypertensive agents and other diuretics.

ACE inhibitors, angiotensin receptor blockers. The risk of hyperkalaemia may increase when eplerenone is used in combination with an ACE inhibitor and/or an angiotensin receptor blocker. A close monitoring of serum potassium and renal function is recommended, especially in patients at risk for impaired renal function, e.g., the elderly. The triple combination of an ACE inhibitor and an angiotensin receptor blocker with eplerenone should not be used (see the sections ‘Contraindications’ and ‘Special warnings and precautions for use’).

Lithium. Drug interaction studies of eplerenone have not been conducted with lithium. However, lithium toxicity has been reported in patients receiving lithium concomitantly with ACE inhibitors and diuretics (see the section ‘Special warnings and precautions for use’). Coadministration of eplerenone and lithium should be avoided. If this combination appears necessary, lithium plasma concentrations should be monitored (see the section ‘Special warnings and precautions for use’).

Cyclosporin, tacrolimus. Cyclosporin and tacrolimus may lead to impaired renal function and increase the risk of hyperkalaemia. The concomitant use of eplerenone and cyclosporin or tacrolimus should be avoided. If needed, close monitoring of serum potassium and renal function are recommended when cyclosporine and tacrolimus are to be administered during treatment with eplerenone (see the section ‘Special warnings and precautions for use’).

Non-steroidal anti-inflammatory drugs (NSAIDs). Acute renal failure may occur in at risk patients (elderly, dehydrated subjects, using diuretics, with impaired renal function) due to decreased glomerular filtration (inhibition of vasodilatory prostaglandins due to non-steroidal anti-inflammatory drugs). These effects are generally reversible. Furthermore, there may be a reduction of the antihypertensive effect. Hydrate the patient and monitor renal function at the beginning of treatment and regularly during the combination (see the sections ‘Posology and method of administration’ and ‘Special warnings and precautions for use’).

 

Trimethoprim. The concomitant administration of trimethoprim with eplerenone increases the risk of hyperkalaemia. Monitoring of serum potassium and renal function should be made, particularly in patients with renal impairment and in the elderly.

α₁-blockers (e.g. prazosin, alfuzosine). When α₁-blockers are combined with eplerenone, there is the potential for increased hypotensive effect and/or postural hypotension. Clinical monitoring for postural hypotension is recommended during α₁-blocker coadministration.

Tricyclic anti-depressants, neuroleptics, amifostine, baclofen. Co-administration of these agents with eplerenone may potentially increase antihypertensive effects and risk of postural hypotension.

Glucocorticoids, tetracosactide. Co-administration of these agents with eplerenone may potentially decrease antihypertensive effects (sodium and fluid retention).

Pharmacokinetic interactions

In vitro studies indicate that eplerenone is not an inhibitor of CYP1A2, CYP2C19, CYP2C9, CYP2D6 or CYP3A4 isozymes. Eplerenone is not a substrate or an inhibitor of P-Glycoprotein.

Digoxin. Systemic exposure (AUC) to digoxin increases by 16% (90% CI: 4%-30%) when co-administered with eplerenone. Caution is warranted when digoxin is dosed near the upper limit of therapeutic range.

Warfarin. No clinically significant pharmacokinetic interactions have been observed with warfarin. Caution is warranted when warfarin is dosed near the upper limit of therapeutic range.

CYP3A4 substrates. Results of pharmacokinetic studies with CYP3A4 probe-substrates (i.e. midazolam and cisapride) showed no significant pharmacokinetic interactions when these agents were co-administered with eplerenone.

CYP3A4 inhibitors.

Strong CYP3A4 inhibitors. Significant pharmacokinetic interactions may occur when eplerenone is co-administered with agents that inhibit the CYP3A4 enzyme. A strong inhibitor of CYP3A4 (ketoconazole 200 mg BID) led to a 441% increase in AUC of eplerenone (see the section ‘Contraindications’). The concomitant use of eplerenone with strong CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin, telithromycin and nefazadone) is contraindicated (see the section ‘Contraindications’).

Mild to moderate CYP3A4 inhibitors. Co-administration with erythromycin, saquinavir, amiodarone, diltiazem, verapamil, or fluconazole has led to significant pharmacokinetic interactions with rank order increases in AUC ranging from 98% to 187%. Eplerenone dosing should therefore not exceed 25 mg daily when mild to moderate inhibitors of CYP3A4 are co-administered with eplerenone (see the section ‘Posology and method of administration’).

CYP3A4 inducers. Co-administration of St John’s wort (a strong CYP3A4 inducer) with eplerenone caused a 30% decrease in eplerenone AUC. A more pronounced decrease in eplerenone AUC may occur with stronger CYP3A4 inducers (such as rifampicin). Due to the risk of decreased eplerenone efficacy, the concomitant use of strong CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, phenobarbital, St John’s wort) with eplerenone is not recommended (see the section ‘Special warnings and precautions for use’).

Antacids. Based on the results of a pharmacokinetic clinical study, no significant interaction is expected when antacids are co-administered with eplerenone.

Special warnings and precautions for use.

Hyperkalaemia. Consistent with its mechanism of action, hyperkalaemia may occur with eplerenone. Serum potassium levels should be monitored in all patients at initiation of treatment and with a change in dosage. Thereafter, periodic monitoring is recommended especially in patients at risk for the development of hyperkalaemia (such as elderly patients, patients with renal insufficiency) (see the section ‘Posology and method of administration’) and patients with diabetes). The use of potassium supplements after initiation of eplerenone therapy is not recommended, due to an increased risk of hyperkalaemia. Dose reduction of eplerenone has been shown to decrease serum potassium levels. In one study, the addition of hydrochlorothiazide to eplerenone therapy has been shown to offset increases in serum potassium.

The risk of hyperkalaemia may increase when eplerenone is used in combination with an ACE inhibitor and/or an angiotensin receptor blocker. The combination of an ACE inhibitor and an angiotensin receptor blocker with eplerenone should not be used (see the sections ‘Contraindications’ and ‘Interaction with other medicinal products and other forms of interaction’).

Impaired renal function. Potassium levels should be monitored regularly in patients with impaired renal function (including diabetic microalbuminuria). The risk of hyperkalaemia increases with decreasing renal function. While the data from the EPHESUS study in patients with Type 2 diabetes and microalbuminuria is limited, an increased occurrence of hyperkalaemia was observed in this small number of patients. Therefore, these patients should be treated with caution. Eplerenone is not removed by haemodialysis.

Impaired hepatic function. No elevations of serum potassium above 5.5 mmol/L were observed in patients with mild to moderate hepatic impairment (Child Pugh class A and B). Electrolyte levels should be monitored in patients with mild to moderate hepatic impairment. The use of eplerenone in patients with severe hepatic impairment has not been evaluated and its use is therefore contraindicated (see the sections ‘Posology and method of administration’ and ‘Contraindications’).

CYP3A4 inducers. Co-administration of eplerenone with strong CYP3A4 inducers is not recommended (see the section ‘Interaction with other medicinal products and other forms of interaction’).

Lithium, cyclosporin, tacrolimus should be avoided during treatment with eplerenone (see the section ‘Interaction with other medicinal products and other forms of interaction’).

Fertility. There are no human data available on fertility.

Important information on the excipients.

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains less than 1 mmol sodium (23 mg) per dosage that is to say essentially sodium free.

Pregnancy and lactation.

Pregnancy. There are no adequate data on the use of eplerenone in pregnant women. Animal studies did not indicate direct or indirect adverse effects with respect to pregnancy, embryofoetal development, parturition and postnatal development. Caution should be exercised prescribing eplerenone to pregnant women.

Breast-feeding. It is unknown if eplerenone is excreted in human breast milk after oral administration. However, preclinical data show that eplerenone and/or metabolites are present in rat milk and that rat pups exposed by this route developed normally. Because of the unknown potential for adverse effects on the breast fed infant, a decision should be made whether to discontinue breast-feeding or discontinue the product, considering the importance of the product to the mother.

 

Effects on ability to drive and use machines.

No studies on the effect of eplerenone on the ability to drive or use machines have been performed. Eplerenone does not cause drowsiness or impairment of cognitive function but when driving vehicles or operating machines it should be considered that dizziness may occur during treatment with the product.

Posology and method of administration.

Adults.

For the individual adjustment of dose, the strengths of 25 mg and 50 mg are available. The maximum dose regimen is 50 mg daily.

Eplerenone may be administered with or without food (see the section ‘Pharmacokinetic properties’).

For post-myocardial infarction heart failure patients. The recommended maintenance dose of eplerenone is 50 mg once daily. Treatment should be initiated at 25 mg once daily and titrated to the target dose of 50 mg once daily preferably within 4 weeks, considering the serum potassium level (see the table below).

Eplerenone therapy should usually be started within 3-14 days after an acute myocardial infarction.

For patients with NYHA class II (chronic) heart failure. For chronic heart failure NYHA class II patients, treatment should be initiated at a dose of 25 mg once daily and titrated to the target dose of 50 mg once daily preferably within 4 weeks; considering the serum potassium level (see the table below and section ‘Special warnings and precautions for use’).

Patients with a serum potassium of > 5.0 mmol/L should not be started on eplerenone (see the section ‘Contraindications’).

Serum potassium should be measured before initiating eplerenone therapy, within the first week and at one month after the start of treatment or dose adjustment. Serum potassium should be assessed as needed periodically thereafter.

After initiation, the dose should be adjusted based on the serum potassium level as shown in the table below.

Table: Dose adjustment table after initiation

Serum potassium (mmol/L)	Action	Dose adjustment
< 5.0	Increase	25 mg every other day to 25 mg once daily 25 mg every other day to 50 mg once daily
5.0–5.4	Maintain	No dose adjustment
5.5–5.9	Decrease	50 mg once daily to 25 mg once daily 25 mg once daily to 25 mg every other day 25 mg every other day to withhold
³ 6.0	Withhold	–

Following withholding eplerenone due to serum potassium ≥ 6.0 mmol/L, eplerenone can be re-started at a dose of 25 mg every other day when potassium levels have fallen below 5.0 mmol/L.

Elderly. No initial dose adjustment is required in the elderly. Due to an age-related decline in renal function, the risk of hyperkalaemia is increased in elderly patients. This risk may be further increased when co-morbidity associated with increased systemic exposure is also present, in particular mild-to-moderate hepatic impairment. Periodic monitoring of serum potassium is recommended (see the section ‘Special warnings and precautions for use’).

 

Renal impairment. No initial dose adjustment is required in patients with mild renal impairment. Periodic monitoring of serum potassium with dose adjustment according to the table above is recommended.

Patients with moderate renal impairment (creatinine clearance 30-60 mL/min) should be started at 25 mg every other day, and dose should be adjusted based on the potassium level (see the table). Periodic monitoring of serum potassium is recommended (see the section ‘Special warnings and precautions for use’).

There is no experience in patients with creatinine clearance < 50 mL/min with post myocardial infarction heart failure. The use of eplerenone in these patients should be done cautiously. Doses above 25 mg daily have not been studied in patients with creatinine clearance < 50 mL/min.

Use in patients with severe renal impairment (creatinine clearance < 30 mL/min) is contraindicated (see the section ‘Contraindications’). Eplerenone is not dialyzable.

Hepatic impairment. No initial dose adjustment is necessary for patients with mild-to-moderate hepatic impairment. Due to an increased systemic exposure to eplerenone in patients with mild-to-moderate hepatic impairment, frequent and regular monitoring of serum potassium is recommended in these patients, especially when elderly (see the section ‘Special warnings and precautions for use’).

Concomitant treatment. In case of concomitant treatment with mild to moderate CYP3A4 inhibitors, (amiodarone, diltiazem and verapamil), the dose of 25 mg once daily may be initiated. Dosing should not exceed 25 mg once daily (see the section ‘Interaction with other medicinal products and other forms of interaction’).

Paediatric population.

The safety and efficacy of eplerenone in children and adolescents have not been established. Currently available data are described in the sections ‘Pharmacodynamic properties’ and ‘Pharmacokinetic properties.’

Overdose.

No cases of adverse events associated with overdose of eplerenone in humans have been reported. The most likely manifestation of human overdose would be anticipated to be hypotension or hyperkalaemia. Eplerenone cannot be removed by haemodialysis. Eplerenone has been shown to bind extensively to charcoal. If symptomatic hypotension should occur, supportive treatment should be initiated. If hyperkalaemia develops, standard treatment should be initiated.

Undesirable effects.

In two studies (EPHESUS and EMPHASIS-HF), the overall incidence of adverse events reported with eplerenone was similar to placebo.

Adverse events reported below are those with suspected relationship to eplerenone and in excess of placebo or are serious and significantly in excess of placebo, or have been observed during post marketing surveillance.

Adverse events are listed by body system and absolute frequency: very common (≥ 1/10), common (≥ 1/100 – < 1/10), uncommon (≥ 1/1 000 – < 1/100), rare (≥ 1/10 000 – < 1/1 000), very rare (< 1/10 000), not known (cannot be estimated from the available data).

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

Respiratory, thoracic and mediastinal disorders: common – cough.

 

Gastrointestinal disorders: common – diarrhoea, nausea, constipation, vomiting; uncommon – flatulence.

Hepatobiliary disorders: uncommon – cholecystitis.

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

Endocrine disorders: uncommon – hypothyroidism.

Metabolism and nutrition disorders: common – hyperkalaemia (see the sections ‘Contraindications’ and ‘Special warnings and precautions for use’), hypercholesterolaemia; uncommon – hyponatraemia, dehydration, hypertriglyceridaemia.

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

Psychiatric disorders: common – insomnia.

Cardiac disorders: common – left ventricular failure, atrial fibrillation; uncommon – tachycardia, limb arterial thrombosis, orthostatic hypotension.

Blood and lymphatic system disorders: uncommon – eosinophilia.

Skin and subcutaneous tissue disorders: common – rash, pruritus; uncommon – angioedema, hyperhidrosis.

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

Reproductive system and breast disorders: uncommon – gynaecomastia.

General disorders: common – asthenia; uncommon – malaise.

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

In EPHESUS, there were numerically more cases of stroke in the group of patients ≥ 75 years old. There was however no statistically significant difference between the occurrence of stroke in the eplerenone (30) vs. placebo (22) groups. In EMPHASIS-HF, the number of cases of stroke in in the group of patients ≥ 75 years old was 9 in the eplerenone group and 8 in the placebo group.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.

Shelf life. 1.5 year.

Storage conditions.

Keep in the original packaging below 25°C.

Keep out of reach of children.

Nature and type of a container. 10 tablets in a blister; 3 blisters in a pack.

Prescription status.Prescription only.

Manufacturer. PRJSC Pharmaceutical Firm Darnitsa.

Manufacturer. 13, Boryspilska Street, 02093, City of Kyiv, Ukraine.

Date of the last revision. 29.08.2022.