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Active ingredients
Eplerenone
Release form
Pills
Composition
Active ingredient: Eplerenone (Eplerenone) Active ingredient concentration (mg): 25
Pharmacological effect
Potassium-sparing diuretic. Eplerenone has a high selectivity to the mineralocorticoid receptors in humans unlike the glucocorticoid, progesterone and androgen receptors, and inhibits the binding of the mineralocorticoid aldosterone-key hormone of the renin-angiotensin-aldosterone system (RAAS), which is involved in the regulation of blood pressure (BP) and the pathogenesis cardiovascular -vascular diseases. Eplerenone causes a persistent increase in plasma renin activity and serum aldosterone. Subsequently, renin secretion is inhibited by aldosterone via a feedback mechanism. An increase in renin activity or concentration of circulating aldosterone does not affect the effects of eplerenone. The efficacy of eplerenone was studied in a double-blind, placebo-controlled study EPHESUS (Eplerenone Postacute myocardial infarction Heart failure Efficacy and SUrvival Study) in 6632 patients with acute infarction heart failure in 6632 patients with acute infarction Heart failure Efficacy and SUrvival Study) 66 left ventricle (LV) (ejection fraction (EF) is less than 40%) and with clinical signs of heart failure. For 3–14 days (an average of 7 days) after acute myocardial infarction, patients were prescribed eplerenone or placebo in addition to standard therapy. The treatment was started with a dose of 25 mg 1 time / day and by the end of 4 weeks it was increased to 50 mg 1 time / day if the content of potassium in the blood serum remained less than 5 mmol / L. During the study, patients received standard therapy using acetylsalicylic acid (92%), ACE inhibitors (90%), beta-blockers (83%), nitrates (72%), loop diuretics (66%) or 3-hydroxy-3 inhibitors -methylglutaryl coenzyme A reductase (HMG-KoA reductase) (60%). The primary endpoint in the study was total mortality, and the combined endpoint was mortality or hospitalization for cardiovascular disease. As a result of eplerenone therapy, the risk of total mortality was reduced by 15% (relative risk 0.85; 95% confidence interval (CI), 0.75–0.96; p = 0.008) compared with placebo, mainly due to a decrease in mortality due to cardiovascular diseases .The risk of death or hospitalization for cardiovascular diseases when using eplerenone was reduced by 13% (relative risk 0.87; 95% CI, 0.79–0.95; p = 0.002). The absolute risk reduction for the two endpoints — total mortality and mortality / hospitalization for cardiovascular diseases — was 2.3 and 3.3%, respectively. 2 were included in the EMPHASIS-HF clinical study (Eplerenone in Mild Patients Hospitalization and SurvIval Study in Heart Failure). 737 patients with chronic heart failure (CHF) of the II functional class (FC) according to the NYHA (New York Heart Association) classification and severe systolic dysfunction (the mean LV EF in the study was 26.1%). The average follow-up period is 21 months. In the active treatment group with eplerenone, before inclusion, patients took ACE inhibitors or angiotensin II receptor blockers (94%), beta-blockers (86.6%). Primary endpoint: death from cardiovascular causes or hospitalization for heart failure (HF). A clinical study of EMPHASIS-HF demonstrated that the use of eplerenone in an average dose of 39.1 ± 13.8 mg / day (25-50 mg) in patients with CHF II FC according to the NYHA classification reduces the mortality associated with cardiovascular diseases by 37% (less than 0.001 ). Clinical efficacy has been demonstrated mainly in the use of eplerenone in patients under the age of 75 years. The effectiveness of therapy in patients over the age of 75 years has not been studied. Electrocardiography In studies of the dynamics of ECG in healthy volunteers, no significant effect of eplerenone on heart rate (HR), the duration of QRS, PR or QT intervals was found.
Pharmacokinetics
Absorption and distribution. The absolute bioavailability of eplerenone is 69% after taking 100 mg of eplerenone orally in the form of pills. The maximum plasma concentration (Cmax) is reached in approximately 2 hours. The Cmax and the area under the concentration-time curve (AUC) linearly depend on the dose in the range from 10 to 100 mg and nonlinearly in a dose of more than 100 mg. The equilibrium state is reached within 2 days. Food intake does not affect absorption. Eplerenone is approximately 50% bound to plasma proteins, primarily the alpha 1 acid group of glycoproteins. The calculated Vd in the equilibrium state is 50 (± 7) l. Eplerenone does not bind to erythrocytes. Metabolism and elimination Metabolism of eplerenone is carried out mainly by the action of the isoenzyme SUR3A4.The active metabolites of eplerenone in plasma are not identified. In an unchanged form, less than 5% of the dose of eplerenone is excreted through the kidneys and intestines. After a single intake of labeled eplerenone, about 32% of the dose was excreted through the intestines and about 67% through the kidneys. T1 / 2 eplerenone is about 3-5 hours, plasma clearance is about 10 l / h. Pharmacokinetics in special groups of patients Age, sex and race: the pharmacokinetics of eplerenone at a dose of 100 mg 1 time / day was studied in elderly patients (over 65 years of age) ), men and women. The pharmacokinetics of eplerenone were not significantly different in men and women. In equilibrium, elderly patients Cmax and AUC were 22% and 45% higher, respectively, than young patients (18-45 years). The pharmacokinetics of eplerenone were studied in patients with renal insufficiency of varying severity and in patients on hemodialysis. Compared to patients in the control group, patients with severe renal insufficiency showed an increase in equilibrium AUC and Cmax by 38% and 24%, respectively, and in patients on hemodialysis - a decrease by 26% and 3%. No correlation was found between clearance of eplerenone from plasma and KK. Eplerenone is not removed during hemodialysis. The pharmacokinetics of eplerenone at a dose of 400 mg were compared in patients with moderate hepatic impairment (7–9 points according to Child-Pugh classification) and healthy volunteers. The equilibrium Cmax and AUC of eplerenone were increased by 3.6% and 42%, respectively. In patients with severe hepatic insufficiency, eplerenone has not been studied, so its use in this group of patients is not indicated. The pharmacokinetics of eplerenone at a dose of 50 mg were studied in patients with heart failure (II-IV FC). The equilibrium AUC and Cmax in patients with heart failure were respectively 38% and 30% higher than in healthy volunteers, selected by age, body weight and sex. The clearance of eplerenone in patients with heart failure is similar to that in healthy older people.
Indications
Myocardial infarction: in addition to standard therapy, in order to reduce the risk of cardiovascular mortality and morbidity in patients with stable left ventricular dysfunction (ejection fraction less than 40%) and clinical signs of heart failure after myocardial infarction; chronic heart failure: in addition to standard therapy, in order to reduce the risk of cardiovascular mortality and morbidity in patients with chronic heart failure of the II functional class according to the NYHA classification, with left ventricular dysfunction (ejection fraction less than 35%).
Contraindications
Clinically significant hyperkalemia; the concentration of potassium in the blood serum at the beginning of treatment is greater than 5 mmol / l; moderate or severe renal failure (QA less than 50 ml / min in patients after myocardial infarction and with chronic heart failure and QC less than 30 ml / min in patients with chronic heart failure starting from functional class II); plasma plasma creatinine levels are greater than 2 mg / dL (or greater than 177 mmol / l) in men or greater than 1.8 mg / dL (or more than 159 mmol / l) in women; severe hepatic impairment (Child-Pugh class C) simultaneous use of potassium-saving diuretics, potassium preparations or powerful CYP3A4 inhibitors, for example, itraconazole, ketoconazole, ritonavir, nelfinavir, clarithromycin, telithromycin and nefazodone; rare inherited diseases such as galactose intolerance, lapp lactase deficiency, and glucose-galactose malabsorption syndrome; there is no experience with the drug in children and adolescents under the age of 18, therefore its administration to patients of this age group is not recommended; hypersensitivity to eplerenone or other components of the drug. With caution: type 2 diabetes and microalbuminuria; simultaneous use of eplerenone, ACE inhibitors or angiotensin II receptor antagonists, drugs containing lithium, cyclosporine or tacrolimus, digoxin and warfarin in doses close to the maximum therapeutic; elderly age; renal dysfunction (CC less than 50 ml / min).
Precautionary measures
Do not exceed the recommended dose. With caution: type 2 diabetes mellitus and microalbuminuria; simultaneous use of eplerenone, ACE inhibitors or angiotensin II receptor antagonists, drugs containing lithium, cyclosporine or tacrolimus, digoxin and warfarin in doses close to the maximum therapeutic; elderly age; renal dysfunction (CC less than 50 ml / min).
Use during pregnancy and lactation
Information about the use of the drug in pregnant women do not. The drug should be prescribed with caution and only in cases where the expected benefit to the mother significantly exceeds the possible risk to the fetus / child. There is no information on the elimination of eplerenone after ingestion with breast milk.The possible undesirable effects of eplerenone on breastfed infants are unknown, so it is advisable either to stop breastfeeding or to cancel the drug, depending on its importance to the mother.
Dosage and administration
The drug is prescribed inside. Food intake does not affect the absorption of the drug Inspra. For individual dose selection, dosages of 25 and 50 mg can be applied. Myocardial Infarction Treatment should be started with a dose of 25 mg 1 time / day and increased to 50 mg 1 time / day for 4 weeks, taking into account the concentration of potassium in the blood serum (see table) . The recommended maintenance dose of the drug is 50 mg 1 time / day. Chronic heart failure, beginning with functional class II according to the NYHA classification, should also be started with a dose of 25 mg 1 time / day and increased to 50 mg 1 time / day after 4 weeks, taking into account serum potassium concentrations (see table). The maximum daily dose is 50 mg. After a temporary cessation of the drug due to an increase in serum potassium to 6 mmol / l or more, drug therapy can be resumed at a dose of 25 mg every other day when the serum potassium content is less than 5 mmol / l. General recommendations Serum potassium blood should be determined before the appointment of the drug Inspra, during the first week and 1 month after the start of therapy or when changing the dose of the drug. In the future, it is also necessary to periodically monitor the content of potassium in the serum.
Side effects
On the part of the hemopoietic system: infrequently - eosinophilia. Metabolism and nutrition disorders: often - hyperkalemia, dehydration, hypercholesterolemia, hypertriglyceridemia; infrequently - hyponatremia, hypothyroidism. Mental disorders: infrequently - insomnia. From the nervous system: often - dizziness, fainting; infrequently - headache, hypesthesia. From the side of the cardiovascular system: often - myocardial infarction, pronounced decrease in blood pressure; infrequently - atrial fibrillation, left ventricular failure, tachycardia, orthostatic hypotension, thrombosis of lower limb arteries. On the respiratory system: often - cough; infrequently - pharyngitis. From the digestive system: often - diarrhea, nausea, constipation; infrequently - flatulence,vomiting. On the side of the liver and biliary tract: infrequently - cholecystitis. On the side of the skin and subcutaneous fat: often - itching; infrequently - increased sweating, rash; frequency is unknown - angioedema. From the musculoskeletal system: often - cramps in the calf muscles of the legs, musculoskeletal pain; infrequently - back pain. From the urinary system: often - impaired kidney function. Other: infrequently - pyelonephritis, gynecomastia, asthenia, malaise. Laboratory parameters: infrequent - increase in residual urea nitrogen, creatinine, decrease in epidermal growth factor receptor expression, increase serum glucose concentrations.
Overdose
Cases of overdose of eplerenone in humans have not been described. The most likely manifestations of overdose may be a decrease in blood pressure and hyperkalemia. Treatment: if an excessive decrease in blood pressure is necessary to prescribe a supportive treatment. In the case of the development of hyperkalemia, standard therapy is indicated. Eplerenone is not removed by hemodialysis. It is established that eplerenone is actively associated with activated carbon.
Interaction with other drugs
Pharmacodynamic interactionCalis-saving diuretics and potassium drugs: given the increased risk of hyperkalemia, eplerenone should not be prescribed to patients receiving potassium-saving diuretics and potassium preparations (see Contraindications). Potassium-sparing diuretics can enhance the effects of antihypertensive drugs and other diuretics. Preparations containing lithium: the interaction of eplerenone with lithium preparations has not been studied. However, in patients who received lithium preparations in combination with diuretics and ACE inhibitors, cases of increasing the concentration and intoxication with lithium are described. If such a combination is necessary, it is advisable to control the concentration of lithium in the blood plasma (see section Special Instructions). Cyclosporin, tacrolmus: cyclosporine and tacrolimus can cause impaired renal function and increase the risk of hyperkalemia. The simultaneous use of eplerenone and cyclosporine or tacrolimus should be avoided. If during treatment with eplerenone, cyclosporine or tacrolimus is required, it is recommended to carefully monitor serum potassium and kidney function (seesection Special instructions). Non-steroidal anti-inflammatory drugs (NSAIDs): NSAID treatment can lead to acute renal failure due to direct suppression of glomerular filtration, especially in patients at risk (elderly patients and / or patients with dehydration). With the joint use of these funds before and during treatment, it is necessary to provide an adequate water regime and monitor kidney function. Trimethoprim: the simultaneous use of trimethoprim with eplerenone increases the risk of hyperkalemia. It is recommended to control serum potassium and kidney function, especially in patients with renal insufficiency and in elderly patients. ACE inhibitors and angiotensin II receptor antagonists: when using eplerenone with ACE inhibitors or angiotensin II receptor antagonists, the serum potassium should be carefully monitored. Such a combination can lead to an increased risk of hyperkalemia, especially in patients with impaired renal function, including in elderly patients. The triple combination of an ACE inhibitor and angiotensin II receptor antagonists with eplerenone should not be used. Alpha1-adrenergic blockers (prazosin, alfuzosin): while using alpha1-adrenergic blockers with eplerenone, the antihypertensive effect may increase and / or increase the risk of orthostatic hypotension in the case of an outlet or an outlet for a synergistic effect. control of blood pressure is recommended, especially when changing the position of the body. Tricyclic antidepressants, antipsychotics, amifostine, baclofen: while using these drugs with eplerenone can increase the antihypertensive effect or increase the risk of orthostatic hypotension. Glucocorticoids, tetracosactide: simultaneous use of these agents with eplerenone can lead to sodium and fluid retention. . Eplerenone is not a substrate or glycoprotein inhibitor R. Digoxin: AUC of digoxin, while used with eplerenone, is increased by 16% (90% CI: 4% -30%). Caution must be exercised if digoxin is used in doses close to the maximum therapeutic. Warfarin: there is no clinically significant pharmacokinetic interaction with warfarin.Care must be taken if warfarin is used in doses close to the maximum therapeutic ones. CYP3A4 isoenzyme substrates: In special studies, signs of the pharmacokinetic interaction of eplerenone with CYP3A4 isoenzyme substrates, for example, midazolam and cisapride, have not been identified. eplerenone with CYP3A4 isoenzyme inhibiting agents, possibly significant pharmacokinetic interaction. A strong inhibitor of the isoenzyme CYP3A4 (ketoconazole 200 mg 2 times / day) caused an increase in the AUC of eplerenone by 441%. Simultaneous use of ePlerene. , verapamil and fluconazole was accompanied by significant pharmacokinetic interaction (the degree of increase in AUC ranged from 98% to 187%). With simultaneous use of these agents with eplerenone, the dose of the latter should not exceed 25 mg (see the section Dosage and administration). CYP3A4 isoenzyme inducers Simultaneous administration of preparations containing St. John's wort (St John's Wort, a strong inducer of CYP3A4 isoenzyme) with eplerenone caused the AUC of the last thirty%. When using stronger CYP3A4 isoenzyme inducers, such as rifampicin, a more pronounced decrease in the AUC of eplerenone is possible. Given the possible reduction in eplerenone efficacy, the simultaneous use of strong inducers of the CYP3A4 isoenzyme (rifampicin, carbamazepine, phenytoin, phenobarbital, preparations containing St. John's wort) is not recommended (see section Special Instructions). Antacids: based on a pharmacokinetic clinical study of significant interaction their simultaneous use is not intended.
special instructions
Hyperkalemia When treated with Inspra, hyperkalemia may occur due to its mechanism of action. At the beginning of treatment and when changing the dose of the drug in all patients should be monitored the content of potassium in the serum.In the future, periodic monitoring of the potassium content is recommended for patients with an increased risk of hyperkalemia, for example, the elderly, patients with renal insufficiency (see the section Dosage and administration) and diabetes mellitus. Given the increased risk of hyperkalemia, the prescription of potassium drugs after the start of treatment with eplerenone is not recommended. Reducing the dose of the drug Inspra leads to a decrease in the content of potassium in the blood serum. In one study, the addition of hydrochlorothiazide to eplerenone prevented an increase in serum potassium. Renal impairment in patients with impaired renal function, incl. diabetic microalbuminuria, it is recommended to regularly monitor the content of potassium in the serum. The risk of developing hyperkalemia increases with a decrease in renal function. Although the number of patients with type 2 diabetes and microalbuminuria was limited in research, nevertheless, an increase in the frequency of hyperkalemia was noted in this small sample (see the section On Precautions). In this regard, such patients should be treated with caution. The drug Inspra is not removed during hemodialysis. Use of the drug Inspra is contraindicated in severe renal failure (see section Contraindications). Liver function impairment In patients with mild or moderate liver function disorders (5-6 and 7-9 points according to Child-Pugh), an increase in serum potassium over 5.5 mmol / l was not identified. In such patients, the concentration of electrolytes should be monitored. In patients with severely impaired liver function, eplerenone has not been studied, therefore its use is contraindicated (see section Contraindications). CYP3A4 isoenzyme inducers Simultaneous use of Inspra with strong inducers of the CYP3A4 isoenzyme is not recommended (see Interaction with other drugs). drugs containing lithium. During treatment with Inspra, the use of these agents should be avoided (see the section on Interaction with Other Drugs). Lactose Tablets Inspra contains lactose, so they should not be prescribed to patients with rare hereditary diseases such as lactose intolerance, lactase deficiency and glucose-galactose malabsorption syndrome. The effect on the ability to drive vehicles and control mechanisms The effects of Inspra on the ability to drive or use equipment have not been studied .However, given the possibility of the drug to cause dizziness and fainting, care should be taken when driving or using technology while taking the drug Inspra.