Eplepress

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT EPLEPRES (EPLEPRES)

Composition:

Active substance: eplerenone;

1 tablet contains eplerenone 25 mg or 50 mg;

Excipients: lactose monohydrate; microcrystalline cellulose; sodium croscarmellose; hypromellose (hydroxypropylmethylcellulose); sodium lauryl sulfate; talc; magnesium stearate;

Coating: Opadry II Yellow 33G32799: hypromellose (hydroxypropylmethylcellulose); lactose monohydrate; polyethylene glycol; triacetin; titanium dioxide (E 171); iron oxide yellow (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, biconvex tablets, film-coated, light brownish-yellow to light yellow in color.

Pharmacological properties.

Pharmacodynamics.

Eplerenone has relative selectivity for binding to human recombinant mineralocorticoid receptors compared to its interaction with human recombinant glucocorticoid, progesterone, and androgen receptors. Eplerenone prevents aldosterone binding to its receptors — a key hormone of the renin-angiotensin-aldosterone system involved in the regulation of arterial blood pressure and implicated in the pathophysiological mechanisms of cardiovascular diseases.

Eplerenone causes a sustained increase 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 serum aldosterone levels does not diminish the effect of eplerenone.

In chronic heart failure (NYHA classes II–IV), adding eplerenone to standard therapy resulted in the expected dose-dependent increase in aldosterone levels.

It is known that in the EPHESUS trial (a study evaluating efficacy and mortality with 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.

No consistent effects of eplerenone on heart rate, QRS complex duration, or PR and QT intervals were observed in clinical studies.

Studies have reported the efficacy of adding eplerenone to standard therapy on clinical outcomes in patients with systolic heart failure and mild symptoms (NYHA functional class II).

Pediatric population. The use of eplerenone in children with heart failure has not been studied.

Studies of eplerenone administered at doses of 25–100 mg once daily in children aged 4–16 years with hypertension have been reported. Effective blood pressure reduction was not achieved. The use of eplerenone in children under 4 years of age with hypertension has not been studied, as trials in older children demonstrated lack of efficacy (see section "Dosage and administration").

No studies evaluating any (long-term) effects on hormonal status in children have been conducted.

Pharmacokinetics.

Absorption. Absolute bioavailability of eplerenone following 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 pharmacokinetic curve (AUC) increase proportionally with doses in the range of 10–100 mg, and less than proportionally with doses exceeding 100 mg. Steady-state levels are achieved within 2 days of starting therapy. Food does not affect the absorption of the drug.

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 significantly to erythrocytes.

Biotransformation. Eplerenone is metabolized predominantly 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 eliminated 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 the following patient groups: elderly patients (aged 65 years and older), male and female patients, and patients of non-black race. 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").

Pediatric population. It has been established that body weight has a statistically significant effect on the volume of distribution of eplerenone, but not on its elimination. It is expected that the volume of distribution and peak exposure in children with higher body weight will 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 were administered an initial dose of eplerenone 25 mg once daily; after 2 weeks, the dose was increased to 25 mg twice daily, and if clinically necessary, to 50 mg twice daily. With these dosing regimens, peak eplerenone concentrations in children were not substantially higher than those observed in adults receiving the initial dose of 50 mg once daily.

Renal impairment. The pharmacokinetics of eplerenone were evaluated in patients with varying degrees of renal impairment and in patients undergoing hemodialysis. In patients with severe renal impairment, steady-state AUC and Cmax were increased by 38% and 24%, respectively, compared to the control group. In patients undergoing hemodialysis, these parameters were reduced by 26% and 3%, respectively, compared to the control group. No correlation was found between plasma clearance of eplerenone 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 results in 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 of 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 in patients with heart failure (NYHA classes II–IV) have been reported. Steady-state Cmax and AUC values in patients with heart failure were 38% and 30% higher, respectively, than in healthy volunteers of comparable age, body weight, and gender. Eplerenone clearance in patients with heart failure does not differ from that in healthy elderly volunteers.

Clinical characteristics.

Indications.

Adjunct to standard therapy with beta-blockers for reduction of the risk of morbidity and mortality related to cardiovascular disease in stable patients with left ventricular dysfunction (left ventricular ejection fraction ≤ 40%) and clinical signs of heart failure following recent myocardial infarction.

Adjunct to standard optimal therapy for reduction of the risk of morbidity and mortality related to 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 eplerenone or to any of the excipients of the medicinal product.
• Patients with serum potassium levels > 5 mmol/L at the start of treatment.
• Patients with severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.73 m²).
• Patients with severe hepatic impairment (Child-Pugh class C).
• Patients taking potassium-sparing diuretics or strong 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 increased risk of hyperkalemia (see section "Contraindications").

Potassium-sparing diuretics may also enhance the effect of antihypertensive agents and other 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-containing products should be avoided. If concomitant use cannot be avoided, plasma lithium levels should be monitored (see section "Special precautions for use").

Cyclosporine, tacrolimus. Cyclosporine and tacrolimus may cause renal dysfunction and increase the risk of hyperkalemia. Concomitant use of eplerenone with cyclosporine or tacrolimus should be avoided. If cyclosporine or tacrolimus must be administered during eplerenone therapy, careful monitoring of serum potassium levels is recommended (see section "Special precautions for use").

Non-steroidal anti-inflammatory drugs (NSAIDs). Due to direct effects on glomerular filtration, NSAID therapy may lead to acute renal failure, particularly in patients at high risk (elderly and/or dehydrated). Patients receiving eplerenone and NSAIDs should be adequately hydrated before initiating treatment, and renal function should be monitored.

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 in patients with renal impairment.

α1-blockers (e.g., prazosin, alfuzosin). Combination of α1-blockers with eplerenone may enhance hypotensive effects and/or lead to orthostatic hypotension. Clinical status should be monitored for orthostatic hypotension during concomitant use of α1-blockers.

Tricyclic antidepressants, neuroleptics, amifostine, baclofen. Concomitant use of these medicinal products with eplerenone may potentially enhance hypotensive effects and increase the risk of orthostatic hypotension.

Glucocorticoids, tetracosactide. Concomitant use of these medicinal products with eplerenone may potentially reduce antihypertensive efficacy due to fluid and sodium retention.

Pharmacokinetic interactions.

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

Digoxin. The AUC of digoxin increases by 16% (90% CI 4–30%) when administered concomitantly 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) showed no evidence of significant pharmacokinetic interactions when these medicinal products were administered concomitantly with eplerenone.

Inhibitors of CYP3A4.

Strong inhibitors of CYP3A4. Concomitant use of eplerenone with medicinal products that inhibit CYP3A4 enzyme activity may lead to significant pharmacokinetic interactions. Under the influence of a strong CYP3A4 inhibitor (ketoconazole 200 mg twice daily), the AUC of eplerenone increased by 441% (see section "Contraindications"). Concomitant use of eplerenone with strong CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin, telithromycin, and nefazodone) is contraindicated (see section "Contraindications").

Mild and moderate inhibitors of CYP3A4. Concomitant use with erythromycin, saquinavir, amiodarone, diltiazem, verapamil, or fluconazole resulted in significant pharmacokinetic interactions, with increases in AUC by 98–187%. Therefore, when eplerenone is used concomitantly with mild or moderate CYP3A4 inhibitors, the dose of eplerenone should not exceed 25 mg once daily (see section "Dosage and administration").

Inducers of CYP3A4. Concomitant use of eplerenone with St. John's wort (a strong CYP3A4 inducer) resulted in a 30% decrease in eplerenone AUC. Use of stronger CYP3A4 inducers (such as rifampicin) may lead to a more pronounced reduction in eplerenone AUC. Due to the risk of reduced efficacy of eplerenone, concomitant use with strong CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, phenobarbital, St. John's wort) is not recommended (see section "Special precautions for use").

Antacids. Based on results of a clinical pharmacokinetic study, no significant interactions are expected when antacids are used concomitantly with eplerenone.

Special precautions for use.

Hyperkalemia. Due to its mechanism of action, hyperkalemia may occur during treatment with eplerenone. Serum potassium levels should be monitored in all patients at the beginning of treatment and following any dose adjustment. Periodic monitoring is subsequently recommended, especially in patients who are at increased risk of developing hyperkalemia (such as elderly patients, patients with renal impairment (see section "Dosage and administration") and diabetes). Potassium-containing supplements should not be used after initiating eplerenone therapy due to the increased risk of hyperkalemia. Dose reduction of eplerenone leads to a decrease in serum potassium concentration. In one study, additional administration of hydrochlorothiazide during eplerenone treatment counterbalanced the increase in serum potassium concentration.

The risk of hyperkalemia may be increased when eplerenone is used in combination with an ACE inhibitor and/or an angiotensin receptor blocker.

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. Serum potassium levels should be monitored regularly in patients with renal function impairment (including those with diabetic microalbuminuria). Impaired renal function is associated with an increased risk of hyperkalemia. An increased incidence of hyperkalemia has been observed in patients with type 2 diabetes and microalbuminuria. 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 "Dosage and administration" and "Contraindications").

CYP3A4 inducers. Concomitant use of eplerenone and strong CYP3A4 inducers is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use of lithium, cyclosporine, tacrolimus should be avoided during eplerenone therapy (see section "Interaction with other medicinal products and other forms of interaction").

Fertility. There is no information available on the effects of eplerenone on human fertility.

The medicinal product contains lactose and therefore should not be administered to patients with rare hereditary disorders (galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption syndrome).

Use during pregnancy or breastfeeding.

Pregnancy. Adequate data on the use of eplerenone in pregnant women are lacking. Animal studies do not indicate a direct or indirect adverse effect 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 show 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 effects in breastfed infants has not been ruled out, a decision should be made whether to discontinue breastfeeding or to discontinue eplerenone therapy, taking into account the importance of the drug for the mother.

Ability to influence the reaction rate when driving or operating machinery.

Studies on the effect of eplerenone on the ability to drive or operate machinery have not been conducted. Eplerenone does not cause drowsiness or cognitive impairment; however, dizziness may occur during treatment, and this should be taken into account when driving or operating machinery.

Dosage and Administration

Adults.

Eplerenone may be administered with or without food (see section "Pharmacokinetics").

The maximum daily dose of the medicinal product is 50 mg.

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. Achievement of this dose level within 4 weeks is recommended, taking into account serum potassium levels (see table below).

Eplerenone treatment is typically 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. Achievement of this dose level within 4 weeks is recommended, 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 initiating 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 based on serum potassium concentration as outlined in the table below.

Dose adjustment after initiation of treatment

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 of the medicinal product is required for elderly patients. However, due to age-related decline in renal function, the risk of hyperkalemia is increased in elderly patients. The risk may be further increased in the presence of concomitant conditions associated with elevated systemic exposure to the drug, such as mild to moderate hepatic impairment. Periodic monitoring of serum potassium levels is recommended (see section "Special precautions for use").

Renal impairment.

Patients with mild renal impairment do not require initial dose adjustment. Periodic monitoring of serum potassium levels is recommended (see section "Special precautions for use"), and dose adjustment should be performed according to the table above.

For patients with moderate renal impairment (creatinine clearance 30–60 mL/min), treatment should be initiated at a dose of 25 mg once every 2 days, with subsequent dose adjustment based on potassium concentration (see table above). Periodic monitoring of serum potassium levels is recommended (see section "Special precautions for use").

Experience with the use of the medicinal product 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, 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, verapamil), eplerenone therapy may be initiated at an initial dose of 25 mg once daily. The dose of the medicinal product 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.

Symptoms. There have been no reports of adverse reactions associated with eplerenone overdose in humans. The most likely manifestations of eplerenone overdose in humans would be hypotension or hyperkalemia.

Treatment. Eplerenone cannot be removed from the body by hemodialysis. Eplerenone binds effectively to activated charcoal. If hypotension develops, supportive treatment should be initiated. In case of hyperkalemia, treatment should be started according to standard guidelines.

Adverse Reactions

Blood and lymphatic system disorders: eosinophilia.

Endocrine disorders: hypothyroidism.

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

Cardiac disorders: left ventricular dysfunction, atrial fibrillation, tachycardia, arterial hypotension, arterial thrombosis of limbs, orthostatic hypotension.

Respiratory, thoracic and mediastinal disorders: cough.

Gastrointestinal disorders: diarrhea, nausea, constipation, vomiting, abdominal distension.

Skin and subcutaneous tissue disorders: rash, pruritus, hyperhidrosis, angioneurotic edema.

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

Renal and urinary disorders: renal impairment (see sections “Contraindications” and “Special warnings and precautions for use”).

Hepatobiliary disorders: cholecystitis.

Reproductive system and breast disorders: gynecomastia.

Psychiatric disorders: insomnia.

Metabolism and nutrition disorders: hyperkalemia (see sections “Contraindications” and “Special warnings and precautions for use”); hyponatremia, dehydration, hypercholesterolemia, hypertriglyceridemia.

General disorders: asthenia, malaise.

Infections and infestations: infections, pyelonephritis, pharyngitis.

Investigations: increased blood urea, increased creatinine levels, decreased epidermal growth factor receptor count, increased blood glucose levels.

A study in patients aged ≥75 years reported a numerically higher number of stroke cases. However, there was no statistically significant difference in the incidence of stroke between the eplerenone group (30) and placebo group (22).

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 are encouraged to report any suspected adverse reactions in accordance with local requirements.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25°C.

Keep out of the reach and sight of children.

Packaging.

10 tablets per blister; 3 blisters per carton.

Prescription status. Prescription only.

Manufacturer: JSC "KYIV VITAMIN PLANT".

Manufacturer’s address and location of its operations:

38 Kopilivska Street, Kyiv, 04073, Ukraine.

Web-site: www.vitamin.com.ua