Epletore

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT EPLETOR (EPLETOR)

Composition:

Active substance: eplerenone;

1 tablet contains 25 mg or 50 mg of eplerenone (calculated as 100% anhydrous substance);

Excipients: lactose monohydrate, microcrystalline cellulose, sodium croscarmellose, hypromellose, sodium lauryl sulfate, talc, magnesium stearate;

Film coating: Opadry yellow 15 B220000 (hypromellose, polysorbate 80, macrogol (PEG 400), titanium dioxide (E 171), iron oxide yellow (E 172)).

Medicinal form. Film-coated tablets.

Main physico-chemical properties: film-coated tablets, light yellow in color, round-shaped, biconvex surface. The surface of the tablets has the imprint «E9RN» on one side and «25» or «50» on the other side for 25 mg and 50 mg tablets, respectively.

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

Pharmacological Properties

Pharmacodynamics

Eplerenone is a relatively selective agent for binding to human recombinant mineralocorticoid receptors compared to its binding to recombinant glucocorticoid, progesterone, and androgen receptors. Eplerenone prevents the binding of aldosterone—the key hormone of the renin-angiotensin-aldosterone system involved in the regulation of arterial blood pressure and the development of cardiovascular diseases.

Eplerenone causes a sustained increase in plasma levels of renin and aldosterone, which is related to the regulation of renin secretion by aldosterone via negative feedback mechanisms. However, increased plasma renin activity and circulating aldosterone levels do not affect the impact of eplerenone on arterial blood pressure.

In clinical studies, eplerenone significantly reduced arterial blood pressure (measured in the seated position) compared to placebo. The antihypertensive effect of the drug was evident within 2 weeks and reached maximum efficacy within 4 weeks of treatment. The magnitude of the antihypertensive effect was maintained throughout 8–24 weeks and was independent of patient age, sex, or race, as well as concomitant use of drugs such as ACE inhibitors, angiotensin-II receptor antagonists, calcium channel blockers, hydrochlorothiazide, and β-blockers.

Treatment with eplerenone was associated with a significant reduction in mortality due to cardiovascular diseases and in the frequency of hospitalizations for cardiovascular conditions. This effect was particularly evident early in therapy among patients under 75 years of age. The effect of the drug in patients aged 75 years and older has not been sufficiently studied.

The incidence of hyperkalemia or hypokalemia with eplerenone was not different from that observed with placebo. Eplerenone had no effect on heart rate or on the duration of QRS, PR, or QT intervals.

Pharmacokinetics

Absorption and Distribution. The absolute bioavailability of eplerenone is 69% after oral administration of 100 mg. Maximum plasma concentration (Cmax) is reached within 2 hours after administration. Cmax and the area under the plasma concentration-time curve (AUC) are dose-proportional within the dose range of 10–100 mg, but not at doses exceeding 100 mg. Steady-state concentrations are achieved within 2 days. Absorption is not affected by food intake.

Plasma protein binding of eplerenone is approximately 50%, primarily due to binding to α-1-acid glycoproteins. The apparent volume of distribution at steady state is approximately 50±7 L. Eplerenone does not selectively bind to erythrocytes.

Metabolism and Excretion. Eplerenone is primarily metabolized by CYP3A4. No active metabolites of eplerenone have been identified in plasma.

Less than 5% of the dose is excreted unchanged in urine and feces. After a single dose of radiolabeled eplerenone, approximately 32% of the dose is excreted in feces and approximately 67% in urine. The elimination half-life of eplerenone is 3–5 hours. Plasma clearance is approximately 10 L/hour.

Pharmacokinetics in Specific Patient Populations. Age, Sex, and Race. The pharmacokinetics of eplerenone in men and women are not fundamentally different. At steady-state, Cmax is increased by 22% and AUC by 45% in elderly patients compared to individuals aged 18–45 years. At steady-state, Cmax is reduced by 19% and AUC by 26% in patients of Black race.

Renal Impairment. Steady-state Cmax and AUC values are increased by 38% and 24%, respectively, in patients with severe renal dysfunction, and decreased by 26% and 3%, respectively, in patients undergoing hemodialysis. No correlation was observed between eplerenone clearance and creatinine clearance in plasma. Eplerenone is not removed by hemodialysis.

Hepatic Impairment. Steady-state Cmax and AUC values of eplerenone in patients with moderate hepatic impairment (Child-Pugh class B) are increased by 3.6% and 42%, respectively, compared to healthy volunteers. Since the use of the drug has not been studied in patients with severe hepatic impairment, eplerenone is contraindicated in such patients.

Heart Failure. The pharmacokinetics of eplerenone at a dose of 50 mg were studied in patients with heart failure (NYHA classification II–IV). Steady-state AUC and Cmax in patients with heart failure were increased by 38% and 30%, respectively, compared to age-, sex-, and race-matched healthy volunteers. Drug clearance in patients with heart failure is similar to that in healthy elderly volunteers.

Clinical characteristics.

Indications.

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

Contraindications.

• Hypersensitivity to eplerenone or to any component of the medicinal product;
• Clinically significant hyperkalemia or associated conditions (serum potassium level above 5 mmol/L (mEq/L)) at initiation of treatment;
• Severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.73 m²);
• Severe hepatic impairment (Child-Pugh class C);
• Concomitant use with other potassium-sparing diuretics, potassium supplements/potassium-containing salt substitutes, or strong CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin, telithromycin, nefazodone;
• Triple combination of ACE inhibitors, angiotensin receptor blockers (ARBs), and eplerenone.

Interaction with other medicinal products and other forms of interaction.

Pharmacodynamic interactions.

Potassium-sparing diuretics and potassium supplements: Due to the increased risk of hyperkalemia, eplerenone should not be administered to patients receiving other potassium-sparing diuretics or potassium supplements/potassium-containing salt substitutes. Potassium-sparing diuretics may also potentiate the effects of antihypertensive agents and other diuretics.

ACE inhibitors, ARBs: The risk of hyperkalemia is increased when eplerenone is combined with an ACE inhibitor and/or ARB. Such combinations require caution. Careful monitoring of serum potassium levels and renal function is recommended, especially in patients at potential risk of renal impairment, such as elderly patients. Triple combination of ACE inhibitors, ARBs, and eplerenone is contraindicated.

Lithium: No interaction studies between eplerenone and lithium have been conducted. However, cases of lithium toxicity have been reported in patients receiving lithium concomitantly with diuretics and ACE inhibitors. Concomitant use of eplerenone with lithium should be avoided. If such combination is necessary, plasma lithium levels should be monitored.

Cyclosporine, tacrolimus: Possible impairment of renal function and increased risk of hyperkalemia. Concomitant use with eplerenone should be avoided. If such combination is necessary, careful monitoring of renal function and serum potassium levels is recommended.

Nonsteroidal anti-inflammatory drugs (NSAIDs): NSAID use may precipitate acute kidney injury (direct effect on glomerular filtration), hyperkalemia, particularly in patients at risk (elderly patients, patients with renal impairment or dehydration). In patients receiving eplerenone and NSAIDs, adequate hydration should be ensured, renal function parameters should be assessed before initiating treatment, and close monitoring of renal function and serum potassium levels is required.

Trimethoprim: Increased risk of hyperkalemia. Monitoring of serum potassium levels and renal function is necessary, especially in patients with renal impairment and elderly patients.

Alpha-1-adrenergic blockers (prazosin, alfuzosin), tricyclic antidepressants, neuroleptics, amifostine, baclofen: Possible increase in hypotensive effect and/or risk of postural hypotension. Monitoring of patients is recommended when these agents are co-administered to prevent such complications.

Glucocorticoids, tetracosactide: Possible reduction in antihypertensive effect (sodium and fluid retention).

Pharmacokinetic interactions.

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

Digoxin: No clinical manifestations of drug interaction were observed, although digoxin AUC increases by 16% when combined with eplerenone. However, caution is advised if digoxin is dosed at the upper limit of the therapeutic range.

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

CYP3A4 substrates (e.g., midazolam, cisapride): No significant pharmacokinetic interactions were observed when co-administered with eplerenone.

CYP3A4 inhibitors:

• Strong inhibitors (ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin, telithromycin, nefazodone): A significant pharmacokinetic interaction is possible. Administration of ketoconazole 200 mg twice daily resulted in a 441% increase in eplerenone AUC. Concomitant use of eplerenone with strong CYP3A4 inhibitors is contraindicated;
• Weak and moderate CYP3A4 inhibitors (erythromycin, saquinavir, verapamil, fluconazole, amiodarone, diltiazem): A significant pharmacokinetic interaction is possible, manifested by an increase in eplerenone AUC by 98–187%. The daily dose of eplerenone when co-administered with these agents should not exceed 25 mg.

CYP3A4 inducers: Concomitant administration of St. John’s wort (a strong CYP3A4 inducer) with eplerenone resulted in a 30% decrease in eplerenone AUC. A more pronounced reduction in eplerenone AUC may occur with stronger CYP3A4 inducers such as rifampicin. Due to the risk of reduced efficacy of eplerenone, concomitant use with strong CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, phenobarbital, St. John’s wort preparations) is not recommended.

Antacids: Significant interactions with antacids and eplerenone are not expected.

Special precautions for use.

Hyperkalemia.

Due to its mechanism of action, hyperkalemia may occur during administration of eplerenone. The risk of hyperkalemia can be reduced by avoiding polypharmacy and by careful patient monitoring.

Serum potassium levels should be monitored in all patients at the start of treatment and when the dose is changed. Thereafter, periodic monitoring is recommended, especially in patients at risk of developing hyperkalemia, such as those with diabetes mellitus, elderly patients, and patients with renal impairment.

The use of potassium-containing supplements after initiation of eplerenone therapy is contraindicated due to the increased risk of hyperkalemia. Reducing the dose of eplerenone leads to a decrease in serum potassium levels. It has been reported that adding hydrochlorothiazide to eplerenone therapy may counteract the increase in serum potassium levels.

The risk of hyperkalemia may be increased when eplerenone is used concomitantly with ACE inhibitors and/or angiotensin II receptor antagonists (ARBs). Triple combination therapy with ACE inhibitors, ARBs, and eplerenone is contraindicated.

Renal impairment.

Patients with impaired renal function (including diabetic microalbuminuria) should have serum potassium levels monitored regularly. The risk of hyperkalemia increases as renal function declines. An increased incidence of hyperkalemia has been observed in patients with type 2 diabetes and microalbuminuria. Eplerenone should be used with caution in such patients, in patients with creatinine clearance < 50 mL/min, and in patients with heart failure following myocardial infarction. See also the section “Hyperkalemia” and sections “Contraindications”, “Dosage and administration”. Eplerenone is not removed by hemodialysis.

Hepatic impairment.

In patients with mild to moderate hepatic impairment (Child-Pugh class A and B), serum potassium levels above 5.5 mmol/L were not observed. Serum electrolyte levels should be monitored in these patients. The use of eplerenone in patients with severe hepatic impairment has not been evaluated and is therefore contraindicated.

Inducers of CYP3A4.

Concomitant administration of eplerenone and strong inducers of CYP3A4 is contraindicated.

Concomitant use of lithium, cyclosporine, tacrolimus should be avoided during eplerenone therapy.

Fertility.

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

The product contains lactose; therefore, patients with rare hereditary problems of galactose intolerance, severe lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Patient information.

Patients taking eplerenone should be informed that they must not take potassium supplements, potassium-containing salt substitutes, or any other medications without consulting the physician who prescribed eplerenone.

Use during pregnancy or breastfeeding.

Animal studies have not indicated any direct or indirect adverse effects on pregnancy, embryonic and fetal development, parturition, or postnatal development. Adequate data on the use of eplerenone in pregnant women are lacking. Therefore, eplerenone should be used during pregnancy only if clearly needed, with careful consideration of the benefit-risk balance for the mother and the fetus.

It is unknown whether eplerenone is excreted in human breast milk following oral administration. The possibility of adverse effects in breastfed infants has not been studied; therefore, the decision to discontinue breastfeeding or to discontinue/abstain from eplerenone therapy should be based on the importance of the drug to the mother.

Ability to affect reaction speed when driving vehicles or operating machinery.

No studies on the effects of eplerenone on the ability to drive vehicles or operate machinery have been conducted. Eplerenone does not cause drowsiness or impair cognitive function; however, when driving vehicles or operating machinery, the possibility of dizziness during treatment should be taken into account.

Method of Administration and Dosage

The drug can be administered independently of food intake.

Heart failure following myocardial infarction

Treatment with the drug should usually be initiated within 3–14 days after acute myocardial infarction.

The recommended maintenance dose of the drug is 50 mg once daily. Therapy should be initiated at a dose of 25 mg once daily, with subsequent dose titration over 4 weeks to reach the target dose of 50 mg once daily, under monitoring of serum potassium levels, as shown in the table.

Chronic heart failure (NYHA Class II)

Treatment should be initiated at a dose of 25 mg once daily and titrated to the target dose of 50 mg once daily over 4 weeks, taking into account serum potassium levels (see table).

Patients with serum potassium levels exceeding 5 mmol/L should not initiate eplerenone treatment (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 periodically monitored as needed during treatment.

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

After temporary discontinuation of the drug due to an increase in serum potassium concentration above 6 mmol/L (mEq/L), Eplitor at a dose of 25 mg once every 2 days may be reinitiated when the potassium concentration decreases below 5 mmol/L (mEq/L).

Impaired liver function.

Dose adjustment is not required for patients with mild to moderate hepatic impairment (Child-Pugh class A and B). Due to increased systemic exposure to eplerenone in these patients, regular monitoring of serum potassium concentration is recommended, especially in elderly patients. The use of eplerenone in patients with severe hepatic impairment (Child-Pugh class C) has not been studied and is therefore contraindicated.

Impaired renal function.

No initial dose adjustment is required in patients with mild renal impairment. Periodic monitoring of serum potassium levels is recommended, and dose adjustment may be necessary if needed (see table).

For patients with moderate renal impairment (creatinine clearance 30–60 mL/min), treatment should be initiated at 25 mg every other day, with dose adjustments based on serum potassium levels (see table).

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 these patients.

Doses higher than 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).

Eplerenone is not dialyzable.

Elderly patients.

No initial dose adjustment is required for this patient group. However, due to age-related decline in renal function, the risk of hyperkalemia is increased, especially in the presence of concomitant mild to moderate hepatic impairment. Periodic monitoring of serum potassium levels is recommended.

Concomitant therapy.

When used concomitantly with weak or moderate CYP3A4 inhibitors (e.g., amiodarone, diltiazem, verapamil, erythromycin, saquinavir, fluconazole), the recommended initial dose is 25 mg once daily, which should not be exceeded.

Children.

There are no data to support the use of eplerenone in pediatric patients. Therefore, the use of this drug in this age group is not recommended.

Overdose.

There have been no reports of eplerenone overdose. The most likely manifestations of overdose would be hypotension and/or hyperkalemia.

Eplerenone is significantly bound to activated charcoal. The drug is not removed by hemodialysis.

In case of overdose symptoms, standard symptomatic and supportive treatment should be administered.

Adverse reactions.

Infections and infestations: infection, pyelonephritis, pharyngitis.

Blood and lymphatic system disorders: eosinophilia.

Endocrine disorders: hypothyroidism.

Metabolism and nutrition disorders: hyperkalemia, hyponatremia, dehydration, hypercholesterolemia, hypertriglyceridemia, dyslipidemia.

Psychiatric disorders: insomnia.

Nervous system disorders: dizziness, syncope, headache, hypesthesia.

Cardiac disorders: arterial hypotension, atrial fibrillation, left ventricular heart failure, tachycardia, postural hypotension, arterial thrombosis of limbs.

Respiratory system disorders: cough.

Gastrointestinal disorders: diarrhea, nausea, constipation, vomiting, flatulence.

Hepatobiliary disorders: cholecystitis.

Skin and subcutaneous tissue disorders: rash, pruritus, increased sweating, cases of angioneurotic edema have been reported.

Musculoskeletal and connective tissue disorders: muscle spasms, musculoskeletal pain, back pain.

Renal and urinary disorders: renal dysfunction, increased serum urea and creatinine levels.

Reproductive system and breast disorders: gynecomastia.

General disorders: asthenia, malaise.

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

During the study of the active substance eplerenone (EPHESUS) in patients aged 75 years, cases of stroke were reported.

Shelf life. 3 years.

Do not use after the expiry date stated on the packaging.

Storage conditions. In the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging. 10 tablets in a blister, 3 blisters in a carton.

Prescription category. Prescription only.

Manufacturer. Public joint-stock company "Scientific and Production Center "Borshchagovskiy Chemical and Pharmaceutical Plant".

Manufacturer's address.

17 Miru Street, Kyiv, 03134, Ukraine.