Eplerenone

Pharmacological properties

eplerenone is relatively selective for the binding of recombinant human mineralocorticoid receptors compared to the binding of recombinant human glucocorticoid, progesterone and androgen receptors. eplerenone prevents the binding of aldosterone, a key hormone of the renin-angiotensin-aldosterone system (raas), which is involved in the regulation of hell and the pathophysiology of cardiovascular disease.

Eplerenone causes a prolonged increase in plasma renin and aldosterone levels, which is associated with the regulation of renin secretion by aldosterone according to the principle of negative feedback. Moreover, an increase in plasma renin activity and the level of circulating aldosterone does not reduce the effect of eplerenone.

In studies of various doses of eplerenone in chronic heart failure (NYHA functional class II-IV), the addition of eplerenone to standard therapy led to a predicted dose-dependent increase in aldosterone levels.

Eplerenone treatment in patients with acute myocardial infarction (MI) complicated by left ventricular dysfunction and heart failure led to a significant increase in aldosterone levels. Long-term treatment with eplerenone in a dose of 12.5 to 50 mg per day under the control of potassium levels, begun 3-14 days after acute myocardial infarction in patients with left ventricular dysfunction (ejection fraction of the left ventricle ≤40%) and clinical signs of heart failure in addition to standard treatment (aspirin, β-adrenoreceptor blocker, ACE inhibitor) led to a decrease in mortality from all causes and the prevention of cardiovascular complications. The clinical effectiveness of eplerenone was primarily demonstrated when prescribing treatment to patients under the age of 75 years. The benefits of treating patients over the age of 75 are not well understood. A decrease or stabilization of the functional class of heart failure according to NYHA classification in the group receiving eplerenone was observed in a larger statistically significant percentage of patients than in the group receiving placebo.

The incidence of hyperkalemia was 3.4% in the eplerenone group compared with 2% in the placebo group (p 0.001). The incidence of hypokalemia was 0.5% in the eplerenone group compared with 1.5% in the placebo group (p 0.001).

During pharmacokinetic studies on the study of electrocardiographic changes, no stable effect of eplerenone on heart rate, QRS complex duration, or P – R and Q – T intervals was revealed.

Pharmacokinetics Suction and distribution. The absolute bioavailability of eplerenone after taking a dose of 100 mg orally is 69%. The maximum concentration of the drug in plasma is reached after about 2 hours. The maximum concentration in the blood plasma (C_max) and the area under the pharmacokinetic curve (AUC) change in proportion to the dose in the range of 10–100 mg and less in proportion to the dose when doses exceeding 100 mg are used. The equilibrium state is reached within 2 days from the start of treatment. Food does not affect the absorption of the drug.

Eplerenone binds to plasma proteins by approximately 50% and mainly binds to alpha-1-acid glycoproteins. The volume of distribution of eplerenone in equilibrium is 50 ± 7 l. Eplerenone is not prone to binding to red blood cells.

Metabolism and excretion. Eplerenone metabolism is predominantly due to the enzyme CYP 3A4. In human blood plasma, no active metabolites of eplerenone were detected.

Less than 5% of the dose of eplerenone is excreted unchanged in urine and feces. After oral administration of a single dose of a radiolabeled drug, about 32% of the dose was excreted in the feces and about 67% in the urine. T_½ eplerenone is about 3-5 hours. Estimated plasma clearance is about 10 l / h.

Use in special patient groups

Age, gender and race.The pharmacokinetics of eplerenone at a dose of 100 mg once a day was studied in elderly patients (aged 65 years and older), men and women, as well as individuals of the Negroid race. The pharmacokinetics of eplerenone in men and women did not differ significantly. Elderly people have equilibrium indicators C_max (22%) and AUC (45%) were increased compared to younger patients (18–45 years old). Equilibrium indices C_max and AUC in individuals of the Negroid race were reduced by 19 and 26%, respectively.

Renal failure. The pharmacokinetics of eplerenone was evaluated in patients with various degrees of impaired renal function and in patients who were on hemodialysis.

In patients with severe renal failure AUC and C_max in equilibrium were increased by 38 and 24%, respectively, compared with the control group. In patients who were on hemodialysis, these indicators were reduced by 26 and 3%, respectively, compared with the control group of patients. No correlation between eplerenone clearance in plasma and creatinine clearance was found. Eplerenone is not removed by hemodialysis (see SPECIAL INSTRUCTIONS).

Liver failure. The pharmacokinetics of eplerenone at a dose of 400 mg were studied in patients with moderate liver damage (class B according to the Child-Pugh classification) and the results were compared with the results obtained in patients without impaired liver function. C_max and AUC of eplerenone in equilibrium were increased by 3.6 and 42%, respectively (see APPLICATION). Since studies of the use of eplerenone for the treatment of patients with severely impaired liver function have not been carried out, eplerenone is contraindicated in such patients (see CONTRAINDICATIONS).

Heart failure. In patients with heart failure (NYHA classes II-IV), the pharmacokinetics of eplerenone were studied at a dose of 50 mg. C value_max and AUC in equilibrium in patients with heart failure were 38 and 30% respectively higher than in healthy patients of the corresponding age, body weight and gender. According to these results, a population analysis of the pharmacokinetics of eplerenone suggests that eplerenone clearance in patients with heart failure does not differ from that in healthy elderly volunteers.

Indications

Addition to standard treatment with β-adrenoreceptor blockers to reduce the risk of morbidity and mortality associated with cardiovascular disease in patients with stable condition with left ventricular dysfunction (left ventricular ejection fraction ≤40%) and clinical signs of heart failure after recently myocardial infarction.

Addition 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%).

Application

The tablets of the drug contain doses of 25 or 50 mg. the maximum daily dose is 50 mg / day.

Eplerenone can be taken both with food and regardless of food intake (see Pharmacokinetics).

Patients with heart failure after myocardial infarction. The recommended maintenance dose of eplerenone is 50 mg once daily. Treatment should begin with a dose of 25 mg 1 time per day and gradually increase to a target dose of 50 mg 1 time per day. It is advisable to achieve this dose level in 4 weeks, given the level of potassium in the blood plasma (table). Treatment with eplerenone usually needs to be started 3-14 days after acute myocardial infarction.

NYHA Class II Chronic Heart Failure Patients. The treatment of patients with NYHA class II chronic heart failure should begin with a dose of 25 mg once a day and gradually increase to a target dose of 50 mg once a day.It is advisable to achieve this dose level in 4 weeks, given the level of potassium in the blood plasma (see table below and SPECIAL INSTRUCTIONS).

Patients whose plasma potassium level exceeds 5 mmol / L should not start treatment with eplerenone (see CONTRAINDICATIONS).

The level of potassium in the blood plasma should be determined before starting treatment with eplerenone, during the 1st week of treatment and one month after the start of treatment or dose adjustment. If necessary, you should periodically determine the level of potassium in the blood plasma throughout the treatment.

After the start of treatment, the dose of the drug should be adjusted taking into account the concentration of potassium in the blood plasma, as indicated in the table below.

Dose adjustment after the start of treatment.

After the temporary discontinuation of eplerenone due to an increase in potassium level of 6 mmol / L, treatment can be resumed at a dose of 25 mg once every 2 days after a decrease in potassium concentration below 5 mmol / L.

Elderly patients. For elderly patients, there is no need to adjust the initial dose of the drug. Due to the age-related decrease in the intensity of renal function, the risk of developing hyperkalemia in elderly patients increases. The risk also increases in the presence of a concomitant disease, accompanied by an increase in systemic exposure of the drug, in particular impaired liver function of mild to moderate severity. It is recommended to periodically monitor the level of potassium in the blood plasma (see SPECIAL INSTRUCTIONS).

Impaired renal function. Patients with mild renal impairment do not require an initial dose adjustment. It is recommended to periodically monitor the level of potassium in the blood plasma (see SPECIAL INSTRUCTIONS) and adjust the dose of the drug in accordance with the table above.

Patients with impaired renal function of moderate severity (creatinine clearance 30-60 mg / ml) should start with a dose of 25 mg once every 2 days and adjust the dose depending on the concentration of potassium (see table above). It is recommended to periodically monitor the level of potassium in the blood plasma (see SPECIAL INSTRUCTIONS).

There is no experience with the use of the drug in patients with creatinine clearance of 50 ml / min and heart failure after myocardial infarction. Eplerenone should be used with caution to treat such patients.

The use of doses exceeding 25 mg per day was not studied in patients with creatinine clearance of 50 ml / min.

Eplerenone is contraindicated in patients with severe kidney damage (creatinine clearance 30 ml / min) (see CONTRAINDICATIONS). Eplerenone is not excreted by dialysis.

Impaired liver function. Patients with mild or moderate hepatic impairment do not need to adjust the initial dose, however, due to an increase in the systemic exposure level of eplerenone in this category of patients, especially elderly patients, it is recommended that frequent and regular monitoring of potassium concentration in blood plasma is performed (see SPECIAL INSTRUCTIONS).

Combined use. In case of simultaneous use with mild or moderate CYP 3A4 inhibitors (for example, amiodarone, diltiazem and verapamil), treatment with eplerenone can be started with an initial dose of 25 mg once a day. The dose of the drug should not exceed 25 mg 1 time per day (see INTERACTIONS).

Contraindications

Hypersensitivity to eplerenone or any of the excipients. plasma potassium level of 5 mmol / l at the start of treatment. severe renal failure (estimated glomerular filtration rate of 30 ml / min / 1.73 m2). severe liver failure (class with child-drink scale).the simultaneous use of potassium-sparing diuretics, potassium preparations, or potent cyp 3a4 inhibitors (e.g. itraconazole, ketoconazole, ritonavir, nelfinavir, clarithromycin, telithromycin, and nefazodone) (see interactions). the simultaneous use of eplerenone in a triple combination together with an apf inhibitor and angiotensin receptor blocker.

Side effects

Adverse reactions are presented that are possibly associated with the use of eplerenone and which occurred more frequently during treatment than with