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Active ingredients
Eplerenone
Release form
Pills
Composition
eplerenone 50 mg. Adjuvants: lactose monohydrate - 77.34 mg, microcrystalline cellulose - 30.76 mg, hypromellose 15cP - 2.5 mg, sodium lauryl sulfate - 1.7 mg, croscarmellose sodium - 6 mg, magnesium stearate - 1.7 mg. The composition of the shell: - 8 mg (hypromellose 6cP (E464) - 3.2 mg, titanium dioxide (E171) - 1.82 mg, lactose monohydrate - 1.68 mg, macrogol 3350 - 0.64 mg, triacetin - 0.48 mg, iron dye yellow oxide (E172) - 0.18 mg) .
Pharmacological effect
Absorption and distribution After taking eplerenone orally at a dose of 100 mg, the absolute bioavailability is 69%. Cmax in the blood plasma is reached approximately 2 hours after ingestion. Cmax and AUC linearly depend on the dose in the range from 10 to 100 mg and nonlinearly in a dose of more than 100 mg. Css 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 CYP3A4. 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 eliminated 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. The pharmacokinetics of eplerenone at a dose of 100 mg 1 time / day were studied in elderly patients (over 65) in men and women. The parameters of the pharmacokinetics of eplerenone in men and women were not significantly different. In equilibrium in elderly patients, Cmax and AUC were 22% and 45% higher, respectively, than in 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 failure showed an increase in the 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 by hemodialysis. The pharmacokinetics of eplerenone at a dose of 400 mg were compared in patients with moderate liver dysfunction (7–9 on the Child-Pugh scale) and healthy volunteers. The equilibrium Cmax and AUC of eplerenone were increased by 3.6% and 42%, respectively. In patients with severe liver failure, eplerenone has not been studied, therefore its use in this group of patients is contraindicated. The pharmacokinetics of eplerenone at a dose of 50 mg were studied in patients with heart failure (NYHA classification II-IV). 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.
Pharmacokinetics
Potassium-sparing diuretic. Eplerenone has a high selectivity for mineralocorticoid receptors in humans, unlike glucocorticoid, progesterone and androgen receptors, and prevents the binding of mineralocorticoid receptors to aldosterone, the key hormone PAAC, which is involved in the regulation of blood pressure and the pathogenesis of cardiovascular diseases. blood plasma and aldosterone in serum. Subsequently, renin secretion is suppressed by aldosterone via a feedback mechanism. However, an increase in renin activity or concentration of circulating aldosterone does not affect the effects of eplerenone. No significant effect of eplerenone on heart rate, duration of QRS, PR, or QT intervals was found in healthy volunteers.
Indications
- myocardial infarction: in addition to standard therapy 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 to reduce cardiovascular mortality and morbidity in patients with chronic heart failure of the second functional class according to the NYHA classification with a reduced ejection fraction of the left ventricle (less than 35%).
Contraindications
- clinically significant hyperkalemia; - serum potassium concentration at the beginning of treatment more than 5 mmol / l; - moderate or severe renal failure (CC less than 30 ml / min in patients with chronic heart failure, functional class IIHA, NYHA classification); - severe liver failure degree (more than 9 points on the Child-Pugh scale) - simultaneous use of potassium-saving diuretics, potassium preparations or powerful CYP3A4 inhibitors, for example, itraconazole, ketoconazole, ritonavir, nelfinavir, clarithromycin, telithromycin and nefazodone; - plasma creatinine concentration is more than 2 mg / dL (or more than 177 mmol / l) in men or more than 1.8 mg / dL (or more than 159 mmol / l) in women; - lactase deficiency, lactose intolerance, glucose malabsorption syndrome- galactose; - children and adolescents under 18 years of age (there is no experience with the drug in this age group); - hypersensitivity to eplerenone or other components of the drug. The drug should be used with caution in 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 at doses close to the maximum therapeutic; with impaired renal function (CC less than 50 ml / min); elderly patients.
Precautionary measures
During treatment, psoriasis may worsen. During pheochromocytoma, propranolol can only be used after taking an alpha blocker. After a long course of treatment, propranolol should be discontinued gradually, under the supervision of a physician. during anesthesia, you must stop taking propranolol or find a remedy for anesthesia with minimal negative inotropic effects. The impact on the ability to drive vehicles and control mechanisms of patients whose activities require increased attention, the question of the use of propranolol on an outpatient basis should be addressed only after evaluating the individual response of the patient.
Use during pregnancy and lactation
Information about the use of the drug in pregnant women do not.When pregnancy drug Espiro should be prescribed with caution and only in cases where the expected benefit to the mother significantly exceeds the potential risk to the fetus / child. There is no information on the release of eplerenone in breast milk after oral administration. 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 administered orally, regardless of the meal. Myocardial Infarction Treatment should 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 the concentration of potassium in the blood serum (see table 1). The recommended maintenance dose of Espiro is 50 mg 1 time / day. After a temporary cessation of Espiro, due to an increase in serum potassium to 6 mmol / l or more, therapy with Espiro can be resumed at a dose of 25 mg every other day when the concentration potassium in the serum will be less than 5 mmol / l. The concentration of potassium in the serum should be determined before the appointment of the drug Espiro, 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 concentration of potassium in the blood serum. Correction of the initial dose in elderly patients is not required. Due to the age-related decline in kidney function in elderly patients, the risk of hyperkalemia increases, especially in the presence of comorbidities that increase serum levels of eplerenone, in particular, in violation of liver function from mild to moderate severity. It is recommended to periodically determine the concentration of potassium in the serum (see table 1). Correction of the initial dose in patients with impaired mild renal function is not required. The degree of hyperkalemia increases with the deterioration of renal function. It is recommended to periodically determine the concentration of potassium in the serum (see table 1). Eplerenone is not removed by hemodialysis. In patients with severe renal impairment (CC less than 30 ml / min), use of the drug is contraindicated. In patients with chronic heart failure IIfunctional class according to the NYHA classification and moderate renal dysfunction (CC 30-60 ml / min) should begin therapy with a dose of 25 mg every other day, followed by dose adjustment depending on the serum potassium concentration (see table 1). use of the drug Espiro in patients with heart failure after myocardial infarction and CC is less than 50 ml / min. It is necessary to use Espiro with caution in such patients. In patients with QA less than 50 ml / min, the use of Espiro in a dose of 25 mg 1 time / day has not been studied. Correction of the initial dose in patients with impaired liver function from mild to moderate severity is not required. Given the increasing concentration of eplerenone in these patients, it is recommended to regularly monitor the concentration of potassium in the blood serum, especially in elderly patients. The use of espiro in patients with severely impaired liver function is contraindicated. Concomitant therapy In the simultaneous use of drugs that have a weak or moderately pronounced inhibitory effect on CYP3A4, for example, erythromycin, saquinavir, amiodarone, diltiazem, verapamil and fluconazole, treatment with Espiro can begin 25 mg 1 time / day.
Side effects
The following undesirable effects are given in accordance with the following gradation of the frequency of their occurrence according to the classification of the World Health Organization: very often (≥10%); often (≥1%, less than 10%); infrequently (≥0.1%, less than 1%); rarely (≥0.01%, less than 0.1%); very rarely (less than 0.01%, including individual messages); frequency is unknown (according to available data, it is impossible to establish the frequency of occurrence). From the hematopoietic system: infrequently - eosinophilia. From the endocrine system: infrequently - hypothyroidism. From metabolism and nutrition: often - hyperkalemia, hypercholesterolemia, hypertriglyceridemia, dehydration; infrequently - hyponatremia. Mental disorders: infrequently - insomnia. On the nervous system: often - dizziness, fainting; infrequently - headache, hypesthesia. From the side of the cardiovascular system: frequent - marked reduction of blood pressure, myocardial infarction; infrequently - atrial fibrillation, left ventricular failure, tachycardia, orthostatic hypotension,thrombosis of the arteries of the lower extremities. On the part of the respiratory system: often - cough; infrequently - pharyngitis. From the digestive system: often - diarrhea, nausea, constipation; rarely - flatulence, vomiting, cholecystitis. On the side of the skin and subcutaneous tissues: often - pruritus; infrequently - increased sweating. From the musculoskeletal system: often - calf muscles, muscle and skeletal pain; infrequently - back pain. From the urinary system: often - impaired kidney function; infrequently - pyelonephritis. Allergic reactions: infrequently - skin rash; frequency is unknown - angioedema. Other: infrequently - asthenia, malaise, gynecomastia. Laboratory parameters: infrequently - increased concentration of residual urea nitrogen, creatinine, decreased expression of the epidermal growth factor receptor, increase in serum glucose concentration.
Overdose
Cases of overdose of eplerenone in humans have not been described. The most likely manifestations of overdose can be excessive blood pressure reduction and hyperkalemia. Treatment: If blood pressure drops too much, supportive treatment should be prescribed. 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 given to patients receiving potassium-saving diuretics and potassium preparations. 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 increased concentration and intoxication with lithium have been described. If such a combination is necessary, it is advisable to control the concentration of lithium in the blood plasma. Cyclosporine, tacrolimus: 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 cyclosporine or tacrolimus is required during eplerenone treatment, it is recommended to regularly monitor serum potassium concentration and kidney function. NSAIDs: NSAID treatment can lead to acute renal failure due to direct suppression of glomerular filtration, especially in at-risk patients (elderly patients and / or dehydrated patients). 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 monitor serum potassium concentration 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, serum potassium should be regularly 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 APAII with eplerenone should not be used. Alfa1-adrenergic blockers (prazosin, alfuzosin): while using alpha1-adrenergic blockers with eplerenone, the antihypertensive effect may increase and / or the risk of orthostatic hypotension may be increased, and therefore it is recommended to control blood pressure body position changes. Tricyclic antidepressants, neuroleptics, amifostine, baclofen: while using these agents with eplerenone, the antihypertensive effect of silt can be enhanced increase the risk of developing orthostatic gipotenzii.Glyukokortikoidy, tetracosactide: the simultaneous use of these means with eplerenone can lead to sodium retention and zhidkosti.Farmakokineticheskoe vzaimodeystvieIssledovaniya in vitro indicates that eplerenone does not inhibit isozymes CYP1A2, CYP2C19, CYP2C9, CYP2D6 and CYP3A4. 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 substrates: in special studies, there were no signs of pharmacokinetic interaction of eplerenone with CYP3A4 substrates, for example, midazolam and cisapride. with CYP3A4 inhibiting agents, significant pharmacokinetic interaction is possible. A potent CYP3A4 inhibitor (ketoconazole 200 mg 2 times / day) caused an increase in the AUC of eplerenone by 441%. Simultaneous use of ePeroneum 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. Inducers of CYP3A4: simultaneous administration of preparations containing St. John's wort (a powerful inducer of CYP3A4), with eplerenone, caused the AUC of the latter to decrease by 30%. When using more potent inducers of CYP3A4, such as rifampicin, a more pronounced decrease in the AUC of eplerenone is possible. Given the possible decrease in eplerenone efficacy, the simultaneous use of powerful inducers of CYP3A4 (rifampicin, carbamazepine, phenytoin, phenobarbital, preparations containing St. John's wort) is not recommended.
special instructions
Hyperkalemia When treated with Espiro, 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 monitor the concentration of potassium in the serum.In the future, periodic monitoring of the potassium content is recommended in patients with an increased risk of hyperkalemia, for example, in elderly patients, patients with renal insufficiency and diabetes. Given the increased risk of hyperkalemia, the prescription of potassium drugs after starting treatment with Espiro is not recommended. Reducing the dose of the drug Espiro leads to a decrease in the concentration of potassium in the serum. In one study, the addition of hydrochlorothiazide to eplerenone prevented an increase in serum potassium concentration. Renal impairment in patients with impaired renal function, including diabetic microalbuminuria, it is recommended to regularly monitor the concentration 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. Therefore, in such patients, treatment should be carried out with caution. Eplerenone is not removed by hemodialysis. Use of the drug Espiro is contraindicated in severe renal failure. Liver function impairment In patients with mild or moderate liver function impairment (5-6 and 7-9 grades on the Child-Pugh scale), an increase in serum potassium levels greater than 5.5 mmol / l was not detected . In such patients, the electrolyte content should be monitored. In patients with severely impaired liver function, eplerenone has not been studied, therefore its use is contraindicated. CYP3A4 inducers Simultaneous use of Espiro with powerful CYP3A4 inducers is not recommended. Cyclosporin, tacrolimus, preparations containing lithium. During treatment with Espiro, avoid taking these agents. therefore, they should not be prescribed to patients with rare hereditary diseases, such as lactose intolerance, lactase deficiency and malabsorb syndrome ii glucose-galaktozy.Vliyanie on ability to drive vehicles and management mehanizmamiVliyanie Espirit drug on the ability to drive vehicles or use sophisticated technology has not been studied.However, given the possibility of the drug to cause dizziness and fainting, care should be taken when driving vehicles or using sophisticated equipment while taking Espiro.