Eplerenone-mb

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT EPLERENONE-MB (EPLERENONE-MB)

Composition:

Active substance: eplerenone;

1 tablet contains 25 mg or 50 mg of eplerenone;

Excipients: lactose monohydrate; microcrystalline cellulose; sodium croscarmellose; sodium lauryl sulfate; hypromellose; talc; magnesium stearate; film coating: Opadry II white OY-L-28900 (lactose monohydrate; hypromellose; titanium dioxide (E171); polyethylene glycol 4000).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties.

25 mg: film-coated tablets, white to almost white, round, biconvex, with engraving «CG3» on one side, the other side without engraving.

50 mg: film-coated tablets, white to almost white, round, biconvex, with engraving «CG4» on one side, the other side without engraving.

Pharmacotherapeutic group.

Potassium-sparing diuretics. Aldosterone antagonists. Eplerenone.

ATC code C03D A04.

Pharmacological Properties

Pharmacodynamics.

Mechanism of action. 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 receptor binding by aldosterone—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.

Pharmacodynamic effects. Eplerenone causes a sustained increase in plasma renin levels and serum aldosterone levels, consistent with suppression of the negative feedback pathway of aldosterone on renin secretion. However, this increase in plasma renin activity and serum aldosterone levels does not reduce the efficacy of eplerenone.

It has been reported that adding eplerenone to standard therapy in patients with chronic heart failure (NYHA classes II–IV) resulted in the expected dose-dependent increase in aldosterone levels. Similarly, in a cardiorenal study, eplerenone treatment led to a significant increase in aldosterone levels. These findings confirm mineralocorticoid receptor blockade in this patient population.

A mortality and efficacy study of eplerenone in patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure has been reported. Eplerenone reduced the risk of death from any cause by 15% compared to placebo, primarily due to a reduction in cardiovascular mortality. The risk of death or hospitalization due to cardiovascular events was reduced by 13% with eplerenone. The absolute risk reduction was 2.3% for all-cause mortality and 3.3% for death or hospitalization due to cardiovascular events. The clinical efficacy of eplerenone was primarily demonstrated in patients under 75 years of age. The benefit of treatment in patients aged 75 years and older has not been well established. A greater proportion of patients receiving eplerenone showed improvement or stabilization in NYHA functional class compared to placebo. The incidence of hyperkalemia was 3.4% in the eplerenone group and 2% in the placebo group (p < 0.001). The incidence of hypokalemia was 0.5% in the eplerenone group and 1.5% in the placebo group (p < 0.001).

No sustained effects of eplerenone on heart rate, QRS complex duration, or PR and QT intervals were observed.

A study evaluating the efficacy of eplerenone added to standard therapy on clinical outcomes in patients with systolic heart failure and mild symptoms (NYHA functional class II) has been reported.

The initial dose of eplerenone was 25 mg once daily. After 4 weeks, the dose was increased to 50 mg once daily if serum potassium levels did not reach 5 mmol/L. Alternatively, if the estimated glomerular filtration rate (eGFR) was 30–49 mL/min/1.73 m², the initial dose of eplerenone was 25 mg every other day, subsequently increased to 25 mg once daily.

The primary endpoint (cardiovascular death or hospitalization due to heart failure) occurred in 249 patients (18.3%) in the eplerenone group and 356 patients (25.9%) in the placebo group. The effect of eplerenone on the primary endpoint (cardiovascular death or hospitalization due to heart failure) was consistently observed across all predefined subgroups.

The secondary endpoint (all-cause mortality) occurred in 171 patients (12.5%) in the eplerenone group and 213 patients (15.5%) in the placebo group. Cardiovascular death was recorded in 147 patients (10.8%) in the eplerenone group and 185 patients (13.5%) in the placebo group.

During the study, hyperkalemia (serum potassium > 5.5 mmol/L) occurred in 158 patients (11.8%) in the eplerenone group and 96 patients (7.2%) in the placebo group (p < 0.001). Hypokalemia (serum potassium < 4 mmol/L) occurred with statistically significantly lower frequency in the eplerenone group compared to placebo (38.9% in the eplerenone group vs. 48.4% in the placebo group, p < 0.0001).

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

A study of eplerenone use at doses of 25–100 mg daily in children aged 4–17 years with hypertension has been reported. Effective reduction in blood pressure 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 showed lack of efficacy (see section "Dosage and administration").

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

Pharmacokinetics.

Absorption. The absolute bioavailability of eplerenone is unknown. Maximum plasma concentration is reached approximately 2 hours after administration. The maximum plasma concentration (Cmax) and area under the pharmacokinetic curve (AUC) increase proportionally with dose in the range of 10–100 mg, and less than proportionally at doses above 100 mg. Steady state is achieved within 2 days of starting treatment. Food does not affect drug absorption.

Distribution. Eplerenone is approximately 50% bound to plasma proteins, primarily to α-1-acid glycoprotein. The apparent volume of distribution at steady state is 50 ± 7 L. Eplerenone does not bind to erythrocytes.

Biotransformation. Eplerenone metabolism is primarily mediated 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 oral administration of a single radiolabeled dose, approximately 32% of the dose was eliminated in feces and about 67% was excreted in urine. The elimination half-life of eplerenone is approximately 3–5 hours. The apparent plasma clearance is approximately 10 L/h.

Use in special patient populations.

Age, sex, and race. Pharmacokinetic studies of eplerenone at a dose of 100 mg once daily have been reported in individuals aged 65 years and older, in both men and women, and in African Americans. No significant differences in eplerenone pharmacokinetics between men and women were observed. In elderly patients, steady-state Cmax was 22% higher and AUC was 45% higher compared to younger patients (18–45 years). In African Americans, steady-state Cmax was 19% lower and AUC was 26% lower (see section "Dosage and administration").

Children. It has been established that patient 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 patients 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; 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 doses, peak eplerenone concentrations in children were not substantially higher than those observed in adults receiving an initial dose of 50 mg once daily.

Renal impairment. 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 values were reduced by 26% and 3%, respectively, compared to the control group. No correlation was observed between plasma eplerenone clearance and creatinine clearance. Eplerenone is not removed by hemodialysis (see section "Special precautions").

Hepatic impairment. 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 subjects of comparable age, body weight, and sex. Eplerenone clearance in patients with heart failure does not differ from that in healthy elderly volunteers.

Clinical characteristics.

Indications

• As an adjunct to standard therapy with β-blockers 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 following a recent myocardial infarction.
• As an adjunct to optimal standard 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%) (see section "Pharmacodynamics").

Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in the section "Composition".
• Patients with serum potassium levels > 5 mmol/L at the start of treatment.
• Patients with severe renal impairment (estimated 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-containing supplements. Eplerenone should not be administered to patients receiving other potassium-sparing diuretics or potassium-containing supplements due to an 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. The risk of hyperkalemia increases when eplerenone is used in combination with an ACE inhibitor and/or an angiotensin receptor blocker. Careful monitoring of serum potassium levels and renal function is recommended, especially in patients at risk of renal impairment, such as elderly patients. Concomitant use of eplerenone in triple combination with an ACE inhibitor and an angiotensin receptor blocker is contraindicated (see sections "Contraindications" and "Special precautions for use").

Lithium. Studies on the interaction between eplerenone and lithium have not been conducted. However, lithium toxicity has been observed in patients receiving lithium concomitantly with ACE inhibitors and diuretics (see section "Special precautions for use"). Concomitant use of eplerenone and lithium-containing medications should be avoided. If avoidance is not possible, plasma lithium levels should be monitored (see section "Special precautions for use").

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

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

Trimethoprim. Concomitant administration of trimethoprim and eplerenone increases the risk of hyperkalemia. Serum potassium levels and renal function should be monitored, especially in elderly patients and patients with renal impairment.

α-1-blockers (e.g., prazosin, alfuzosin). When α-1-blockers are combined with eplerenone, there is a potential for enhanced antihypertensive effect and/or development of orthostatic hypotension. The clinical status of patients should be monitored for orthostatic hypotension during concomitant use of α-1-blockers.

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

Glucocorticoids, tetracosactide. When these medicinal products are administered concomitantly with eplerenone, there is a possibility of reduced antihypertensive effect due to fluid and sodium retention.

Pharmacokinetic interactions

In vitro studies have shown 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. Systemic exposure (AUC) to digoxin increases by 16% (90% CI 4–30%) when administered concomitantly with eplerenone. Digoxin should be used 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 used with caution at doses close to the upper limit of the therapeutic range.

Substrates of CYP3A4. No significant pharmacokinetic interactions were observed when eplerenone was co-administered with probe substrates of CYP3A4 (midazolam and cisapride).

Inhibitors of CYP3A4.

• Strong inhibitors of CYP3A4: concomitant use of eplerenone with agents that inhibit CYP3A4 enzyme activity may lead to pronounced pharmacokinetic interactions. With 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").
• Weak and moderate inhibitors of CYP3A4: co-administration with erythromycin, saquinavir, amiodarone, diltiazem, verapamil, and fluconazole resulted in significant pharmacokinetic interactions, increasing AUC levels by 98–187%. Therefore, when eplerenone is co-administered with weak or moderate CYP3A4 inhibitors, the dose of eplerenone should not exceed 25 mg (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% reduction 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, concomitant use of eplerenone with strong CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, phenobarbital, St. John's wort) is not recommended (see section "Special precautions for use").

Antacids. No significant interactions are expected when eplerenone is administered concomitantly with antacids.

Special precautions for use.

Hyperkalemia. Hyperkalemia may occur during treatment with eplerenone. Serum potassium levels should be monitored in all patients at the beginning of treatment and during any dose adjustments. Periodic monitoring is further recommended, especially in patients at increased risk of hyperkalemia (such as elderly patients, patients with renal impairment (see section "Dosage and administration") and diabetes). Potassium supplements are not recommended after initiating eplerenone therapy due to an increased risk of hyperkalemia. Reducing the dose 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.

When eplerenone is used in combination with an ACE inhibitor and/or an angiotensin receptor blocker, the risk of hyperkalemia increases. Eplerenone should not be used concomitantly in triple combination with an ACE inhibitor and an angiotensin receptor blocker (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Renal function impairment. In patients with renal dysfunction (including diabetic microalbuminuria), serum potassium levels should be monitored regularly. Impaired renal function is associated with an increased risk of hyperkalemia. In patients with type 2 diabetes and microalbuminuria, an increased incidence of hyperkalemia has been observed. 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 exceeding 5.5 mmol/L were not observed. Such 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 these patients (see sections "Dosage and administration" and "Contraindications").

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

Lithium, cyclosporine, tacrolimus should not be prescribed during eplerenone treatment (see section "Interaction with other medicinal products and other forms of interaction").

Fertility. There is no information available regarding the effect on human fertility.

The medicinal product contains lactose monohydrate and therefore should not be administered to patients with rare hereditary disorders such as 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 not available. Animal studies do not indicate a direct or indirect adverse effect on pregnancy, embryonic and fetal development, parturition, or postnatal development. Eplerenone should be used during pregnancy only with caution.

Breastfeeding. It is unknown 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 established, a clinical decision should be made whether to discontinue breastfeeding or discontinue eplerenone therapy, taking into account the importance of the drug to the mother.

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

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

Dosage and Administration

Adults.

The medicinal product is available in 25 mg and 50 mg doses. The maximum recommended daily dose is 50 mg once daily.

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

Patients with heart failure following myocardial infarction. The recommended maintenance dose of eplerenone is 50 mg once daily. Treatment should be initiated at a dose of 25 mg once daily and gradually increased to the target dose of 50 mg once daily. This target dose should preferably be reached within 4 weeks, 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 25 mg once daily, with gradual dose titration to the target dose of 50 mg once daily. This target dose should preferably be achieved within 4 weeks, considering serum potassium levels (see table below and section "Special Warnings and Precautions").

Eplerenone treatment should not be initiated in patients with serum potassium levels exceeding 5 mmol/L (see section "Contraindications").

Serum potassium levels should be measured before starting eplerenone treatment, during the first week of treatment, and one month after initiation of treatment or dose adjustment. Periodic monitoring of serum potassium should be performed throughout treatment as clinically indicated.

Dose adjustments after initiation of treatment should be based on serum potassium concentration as outlined in the table below.

Dose adjustment after initiation of treatment.

After temporary discontinuation of eplerenone due to an increase in potassium levels to ≥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 drug 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").

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"), and dosage should be adjusted according to the table above.

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

Experience with use of the drug in patients with creatinine clearance <50 mL/min and heart failure following myocardial infarction is limited. 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 eliminated from the body by dialysis.

Hepatic impairment. Patients with mild or moderate hepatic impairment do not require initial dose adjustment; however, due to increased systemic exposure to eplerenone, frequent and regular monitoring of serum potassium concentration is recommended in these patients, particularly in elderly patients (see section "Special precautions").

Combination therapy. When used concomitantly with weak or moderate CYP3A4 inhibitors (e.g., amiodarone, diltiazem, verapamil), eplerenone therapy may be initiated at the starting dose of 25 mg once daily. The dose of the drug should not exceed 25 mg once daily (see section "Interaction with other medicinal products and other forms of interaction").

Children. Safety and efficacy of eplerenone in children have not been established. Available information is presented in sections "Pharmacodynamics" and "Pharmacokinetics".

Overdose.

There have been no reports of adverse reactions associated with eplerenone overdose in humans. The most likely manifestations of eplerenone overdose in humans would be hypotension or hyperkalemia. Eplerenone cannot be removed from the body by hemodialysis. It has been demonstrated that eplerenone is effectively bound by activated charcoal. In cases of hypotension, supportive treatment should be initiated. In cases of hyperkalemia, treatment should be started according to standard guidelines.

Side effects.

Side effects are classified by organ systems and by absolute frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

Infections and infestations.

Uncommon: pyelonephritis, infections, pharyngitis.

Blood and lymphatic system disorders.

Uncommon: eosinophilia.

Endocrine disorders.

Uncommon: hypothyroidism.

Metabolism and nutrition disorders.

Common: hyperkalaemia (see sections “Contraindications” and “Special warnings and precautions for use”), hypercholesterolaemia.

Uncommon: hyponatraemia, dehydration, hypertriglyceridaemia.

Psychiatric disorders.

Uncommon: insomnia.

Nervous system disorders.

Common: dizziness, syncope, headache.

Uncommon: paraesthesia.

Cardiac disorders.

Common: left ventricular dysfunction, atrial fibrillation.

Uncommon: tachycardia.

Vascular disorders.

Common: hypotension.

Uncommon: limb artery thrombosis, orthostatic hypotension.

Respiratory, thoracic and mediastinal disorders.

Common: cough.

Gastrointestinal disorders.

Common: diarrhoea, nausea, constipation.

Uncommon: vomiting, abdominal distension.

Skin and subcutaneous tissue disorders.

Common: rash, pruritus.

Uncommon: hyperhidrosis, angioneurotic oedema.

Musculoskeletal and connective tissue disorders.

Common: muscle spasms, musculoskeletal pain.

Uncommon: back pain.

Renal and urinary disorders.

Common: renal function impairment (see sections “Special warnings and precautions for use” and “Interaction with other medicinal products and other forms of interaction”).

Hepatobiliary disorders.

Uncommon: cholecystitis.

Reproductive system and breast disorders.

Uncommon: gynaecomastia.

General disorders.

Uncommon: asthenia, malaise.

Investigations.

Common: increased blood urea, increased creatinine levels.

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

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

Shelf life. 3 years.

Storage conditions.

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

Keep out of the reach of children.

Incompatibilities.

None.

Packaging.

10 tablets per blister, 3 blisters per cardboard pack.

Prescription category. Prescription only.

Manufacturer.

LABORATORIOS LICONSA, S.A.
LABORATORIOS LICONSA, S.A.

Manufacturer's address.

Avda. Miralcampo, 7, Pol. Ind. Miralcampo, Azuqueca de Henares, 19200, Guadalajara, Spain

Marketing Authorisation Holder.

M. BIOTECH LIMITED
M. BIOTECH LIMITED

Address of the Marketing Authorisation Holder.

Gladstone House, 77-79 High Street, Egham TW20 9HY, Surrey, United Kingdom