Epletor film-coated tablets 25 mg No. 30

Instructions for Epletor film-coated tablets 25 mg No. 30

Composition

active ingredient: eplerenone;

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

excipients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, 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)).

Dosage form

Film-coated tablets.

Main physicochemical properties: film-coated tablets, light yellow in color, round in shape, with a biconvex surface. The surface of the tablets contains an imprint of "Е9RN" on one side and "25" or "50" on the other side for tablets of 25 mg and 50 mg, respectively.

Pharmacotherapeutic group

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

Pharmacological properties

Pharmacodynamics

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

Eplerenone causes a sustained increase in plasma renin and aldosterone levels, which is due to the negative feedback regulation of renin secretion by aldosterone. However, the increase in plasma renin activity and circulating aldosterone levels does not affect the blood pressure effects of eplerenone.

In studies, eplerenone significantly reduced blood pressure (measured in the sitting position) compared with placebo. The hypotensive effect of the drug was evident after 2 weeks and reached a maximum after 4 weeks of use. The severity of the antihypertensive effect was maintained for 8-24 weeks and was independent of the age, sex or race of the patients, and of concomitant use with drugs such as ACE inhibitors, angiotensin-II receptor antagonists, calcium channel blockers, hydrochlorothiazide and β-blockers.

The drug significantly reduced mortality from cardiovascular diseases and the frequency of hospitalization for cardiovascular disease. This effect was especially pronounced at the beginning of therapy in patients under 75 years of age. The effect of the drug in patients over 75 years of age has not been studied sufficiently.

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

Pharmacokinetics

Absorption and distribution. The absolute bioavailability of eplerenone is 69% after oral administration of 100 mg. The maximum plasma concentration (Cmax) of the drug is reached 2 hours after administration. Cmax and area under the concentration-time curve (AUC) are proportional to the dose in the dose range of 10-100 mg and are not proportional at doses above 100 mg. Equilibrium concentrations are reached within 2 days. Absorption is independent of food intake.

The binding of eplerenone to plasma proteins is approximately 50%, mainly due to binding to α-1-acid glycoproteins. The approximate volume of distribution at steady state is 50±7 L. Eplerenone does not selectively bind to erythrocytes.

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

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

Pharmacokinetics in individual patient groups. Age, gender, and race. The pharmacokinetics of eplerenone in men and women are not fundamentally different. At steady-state concentrations, elderly patients have an increase in Cmax by 22% and AUC by 45% compared with those in individuals aged 18-45 years. At steady-state concentrations, there is a decrease in Cmax (19%) and AUC (26%) in patients of the Negroid race.

Renal impairment. Steady-state Cmax and AUC were increased by 38% and 24%, respectively, in patients with severe renal impairment and decreased by 26% and 3%, respectively, in patients on hemodialysis. No correlation was found between eplerenone clearance and plasma creatinine clearance. Eplerenone is not removed by hemodialysis.

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

Indication

Add-on to standard β-blocker therapy to reduce the risk of cardiovascular morbidity and mortality in stable patients with left ventricular dysfunction (left ventricular ejection fraction ≤ 40%) and clinical signs of heart failure after a recent myocardial infarction. Add-on to standard optimal therapy to reduce the risk of cardiovascular morbidity and mortality in adult patients with NYHA class II (chronic) heart failure and left ventricular dysfunction (left ventricular ejection fraction ≤ 30).

Contraindication

Hypersensitivity to eplerenone or to any component of the drug; clinically significant hyperkalemia or related conditions (serum potassium level greater than 5 mmol/L (mEq/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 with other potassium-sparing diuretics, potassium preparations/potassium supplements, or potent 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 types of interactions

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 and potassium supplements/potassium supplements. 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 ARBs. This combination requires caution. Close monitoring of serum potassium and renal function is recommended, especially in patients at risk of renal impairment, such as the elderly. Triple combination of ACE inhibitors and ARBs with eplerenone is contraindicated.

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

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

Nonsteroidal anti-inflammatory drugs (NSAIDs): NSAIDs may cause acute renal failure (direct effect on glomerular filtration rate), hyperkalemia, especially in patients at risk (elderly patients, patients with impaired renal function or dehydration). Patients receiving eplerenone and NSAIDs should be adequately hydrated, have renal function tested before starting treatment and should be closely monitored for renal function and serum potassium.

Trimethoprim: increased risk of hyperkalemia. Serum potassium and renal function should be monitored, particularly in patients with renal impairment and the elderly.

Alpha-1-adrenergic blockers (prazosin, alfuzosin), tricyclic antidepressants, neuroleptics, amifostine, baclofen: possible increase in the hypotensive effect and/or risk of postural hypotension. With concomitant administration, monitoring of patients is recommended to prevent these complications.

Glucocorticoids, tetracosactide: possible reduction of the antihypertensive effect (sodium and fluid retention).

Pharmacokinetic interactions

In vitro studies have shown that eplerenone does not inhibit CYP1A2, CYP2C19, CYP2C9, CYP2D6, or CYP3A4 isoenzymes. Eplerenone is not a substrate or inhibitor of P-glycoprotein.

Digoxin: No clinical drug interaction has been observed, although digoxin AUC is increased by 16% when combined with eplerenone. However, caution should be exercised when digoxin is dosed at the upper end 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 end of the therapeutic range.

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

potent inhibitors (ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin, telithromycin, nefazodone): significant pharmacokinetic interaction possible. Ketoconazole 200 mg twice daily caused a 441% increase in eplerenone AUC. Concomitant use of eplerenone with potent CYP3A4 inhibitors is contraindicated; weak and moderate CYP3A4 inhibitors (erythromycin, saquinavir, verapamil, fluconazole, amiodarone, diltiazem): significant pharmacokinetic interaction possible, manifested by a 98-187% increase in eplerenone AUC. The daily dose of eplerenone when used simultaneously with such drugs should not exceed 25 mg.

CYP3A4 inducers: Co-administration of St. John's wort (a strong CYP3A4 inducer) with eplerenone resulted in a 30% decrease in eplerenone AUC. A more significant decrease in eplerenone AUC may occur with more potent CYP3A4 inducers such as rifampicin. Due to the risk of decreased efficacy of eplerenone, co-administration of eplerenone with potent CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, phenobarbital, St. John's wort) is not recommended.

Antacids: No significant interactions are expected with the concomitant use of antacids and eplerenone.

Application features

Hyperkalemia

When using eplerenone, in accordance with its mechanism of action, the development of hyperkalemia is possible. The risk of hyperkalemia is reduced by eliminating polypharmacy and conducting careful monitoring of the patient's condition.

Serum potassium levels should be monitored in all patients at the start of treatment and when the dosage is changed. Periodic monitoring is recommended thereafter, especially in patients at risk of developing hyperkalemia, e.g., diabetics, the elderly, and patients with renal insufficiency.

Potassium supplements are contraindicated after initiation of eplerenone therapy due to the increased risk of hyperkalemia. Reducing the dose of eplerenone results in a decrease in serum potassium. It has been reported that the addition of hydrochlorothiazide to eplerenone therapy may compensate for the increase in serum potassium.

The risk of hyperkalemia may be increased when eplerenone is used in combination with ACE inhibitors and/or ARBs. The concomitant use of ACE inhibitors and ARBs with eplerenone in a triple combination is contraindicated.

Kidney dysfunction

Patients with impaired renal function (including diabetic microalbuminuria) should have their serum potassium levels monitored regularly. The risk of hyperkalemia increases with decreasing renal function. 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 heart failure after myocardial infarction. See also Hyperkalemia in this section and sections Contraindications, Dosage and Administration. Eplerenone is not removed by hemodialysis.

Liver dysfunction

In patients with mild to moderate hepatic impairment (Child-Pugh class A and B), no increase in serum potassium levels above 5.5 mmol/L was observed. Serum electrolyte levels should be monitored in such patients. The use of eplerenone in patients with severe hepatic impairment has not been evaluated and is therefore contraindicated.

CYP3A4 inducers

Concomitant administration of eplerenone and strong CYP3A4 inducers is contraindicated.

The use of lithium, cyclosporine, tacrolimus should be avoided during treatment with eplerenone.

Fertility

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

The drug contains lactose, therefore patients with rare hereditary forms of galactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome should not use the drug.

Information for patients

Patients taking eplerenone should be advised not to use potassium supplements, potassium supplements, salt substitutes containing potassium, or any other medications while taking eplerenone without consulting the physician who prescribed eplerenone.

Ability to influence reaction speed when driving vehicles or other mechanisms

Studies on the effect of eplerenone on the ability to drive or use machines have not been conducted. Eplerenone does not cause drowsiness or cognitive impairment, but when driving or operating machinery, the possibility of dizziness should be taken into account.

Use during pregnancy or breastfeeding

It is not known whether eplerenone is excreted in human milk after oral administration. The potential for adverse effects in breastfed infants has not been studied, so a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Method of administration and doses

The drug can be used regardless of meals.

Heart failure after myocardial infarction.

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

The recommended maintenance dose is 50 mg once daily. Treatment should be initiated at 25 mg once daily with subsequent dose titration over 4 weeks to a target dose of 50 mg once daily under the control 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 a target dose of 50 mg once daily over 4 weeks, taking into account serum potassium levels (see table).

Patients with serum potassium levels greater than 5 mmol/L should not initiate treatment with eplerenone (see section 4.3).

Serum potassium levels should be measured prior to initiation of eplerenone therapy, during the first week of treatment, and one month after initiation of treatment or dose adjustment. Serum potassium levels should be measured periodically thereafter as necessary during treatment.

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

After temporary discontinuation of the drug in case of an increase in serum potassium concentration above 6 mmol/l (mEq/l), Epletor at a dose of 25 mg once every 2 days can be re-administered when the potassium concentration decreases below 5 mmol/l (mEq/l).

Liver dysfunction

No initial dose adjustment is required for patients with mild to moderate hepatic impairment (Child-Pugh class A and B). Given the increased systemic exposure to eplerenone in such patients, regular monitoring of serum potassium 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.

Kidney dysfunction

In mild renal impairment, no adjustment of the initial dose is required. Periodic monitoring of serum potassium levels and, if necessary, dose adjustment is recommended (see table).

In patients with moderate renal insufficiency (creatinine clearance 30-60 ml/min), treatment should be initiated with 25 mg every other day, the dose should be adjusted according to serum potassium levels (see table).

There is no experience with eplerenone in patients with creatinine clearance < 50 ml/min and with heart failure after myocardial infarction. Eplerenone should be used with caution in these patients.

Doses above 25 mg/day 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 adjustment of the initial dose is required for this group of patients. Age-related decline in renal function increases the risk of hyperkalemia, especially in the presence of mild to moderate hepatic impairment. Periodic monitoring of serum potassium is recommended.

Concomitant treatment

With concomitant treatment with weak and moderate CYP3A4 inhibitors (e.g. amiodarone, diltiazem, verapamil, erythromycin, saquinavir, fluconazole), the initial recommended dose is 25 mg once daily, which should not be exceeded in the future.

Children

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

Overdose

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

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

If symptoms of overdose appear, standard symptomatic and supportive therapy should be administered.

Adverse reactions

Infections and infestations: infection, pyelonephritis, pharyngitis.

Blood and lymphatic system: eosinophilia.

Endocrine system: hypothyroidism.

Metabolic and trophic disorders: hyperkalemia, hyponatremia, dehydration, hypercholesterolemia, hypertriglyceridemia, dyslipidemia.

Mental disorders: insomnia.

Cardiovascular system: arterial hypotension, atrial fibrillation, left ventricular heart failure, tachycardia, postural hypotension, arterial thrombosis of the extremities.

Respiratory system: cough.

Digestive tract: diarrhea, nausea, constipation, vomiting, flatulence.

Hepatobiliary system: cholecystitis.

Skin and subcutaneous tissue: rash, itching, increased sweating, there have been reports of cases of angioedema.

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

Urinary system: renal dysfunction, increased levels of urea and creatinine in serum.

Reproductive system and breast disorders: gynecomastia.

General disorders: asthenia, malaise.

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

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

Expiration date

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 pack.

Vacation category

According to the recipe.

Producer

Public Joint Stock Company "Research and Production Center "Borshchagov Chemical and Pharmaceutical Plant".

Location of the manufacturer and its business address

Ukraine, 03134, Kyiv, Myru St., 17.