Dekriz 50 mg tablet number 30

Dekriz (DECRIS) instructions for use

COMPOSITION

active ingredient: 1 tablet contains 25 mg or 50 mg of eplerenone;
auxiliary substances: lactose, microcrystalline cellulose, croscarmellose sodium, hypromellose, sodium lauryl sulfate, talc, magnesium stearate;
tablet shell: hypromellose, macrogol 400, polysorbate 80, titanium dioxide (E171), iron oxide yellow (E172), iron oxide red (E172).

MEDICINAL FORM

Film-coated tablets.

Basic physical and chemical properties:

dosing 25 mg round, beige, biconvex tablets with film coating, with the logo "25" on one side;
dosing 50 mg round beige, biconvex tablets with film coating, with the logo "50" on one side.

PHARMACOTHERAPEUTIC GROUP

Potassium-sparing diuretics. Antagonists of aldosterone. Eplerenone. ATC code C03D A04.

PHARMACOLOGICAL PROPERTIES

Pharmacodynamics.

Eplerenone is a relatively selective preparation for the binding of recombinant human mineralocorticoid receptors as compared to the binding of recombinant human glucocorticoid, progesterone and androgen receptors. Eplerenone prevents the binding of aldosterone, the key hormone of the renin-angiotensin-aldosterone system (RAAS), which is involved in the regulation of blood pressure and the pathophysiology of cardiovascular diseases.

Eplerenone causes a prolonged increase in the level of renin and aldosterone in the blood plasma, which is due to the regulation of renin secretion by aldosterone according to the principle of negative feedback. In this case, an increase in renin activity in the blood plasma 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.

Treatment with eplerenone 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 at a dose of 12.5 to 50 mg / day under the control of potassium level, started 3-14 days after acute MI in patients with left ventricular dysfunction (left ventricular ejection fraction ≤ 40%) and clinical signs of heart failure in addition to standard treatment (aspirin, beta-blocker, ACE inhibitor) has proven effective in reducing mortality from all causes and preventing cardiovascular complications. The clinical efficacy of eplerenone was first demonstrated in the treatment of patients under the age of 75 years. The benefits of treating patients aged 75 years have not been adequately studied. The reduction or stabilization of the NYHA functional class of heart failure in the eplerenone group was noted in a statistically significant percentage of patients than in the placebo group.

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

In the course of pharmacokinetic studies on the study of electrocardiographic changes, there was no stable effect of eplerenone on the heart rate, the duration of the QRS complex, or the PR and QT intervals.

Pharmacokinetics.

Absorption and distribution.

Absolute bioavailability of eplerenone is unknown. The maximum concentration of the drug in the plasma is reached after about 2 hours. The maximum plasma concentration (C Max) and the area under the pharmacokinetic curve (AUC) vary in proportion to the dose in the range 10-100 mg or less in a dose-proportional manner with doses above 100 mg.The equilibrium state occurs within 2 days from the start of treatment. Food does not affect the absorption of the drug.

Eplerenone binds to plasma proteins by about 50% and is mainly associated with alpha-1-acid glycoproteins. The volume of distribution of eplerenone in the equilibrium state is estimated as such, equal to 50 ± 7 liters. Eplerenone is not susceptible to binding to erythrocytes.

Metabolism and excretion.

Metabolism of eplerenone is mainly carried out due to the enzyme CYP3A4. In the human blood plasma, no active metabolites of eplerenone have been detected.

Less than 5% of the dose of eplerenone is excreted in urine and feces unchanged. After receiving a single dose of a radiolabeled drug, approximately 32% of the dose was excreted from the body with feces and about 67% was excreted in the urine. The half-life of eplerenone is about 3-5 hours. The mental clearance from the plasma is approximately 10 l / h.

Use in special patient groups.

Age, gender and race. The pharmacokinetics of eplerenone in a dose of 100 mg once a day was studied in elderly patients (aged 65 and over), men and women, as well as people of the Negroid race. The pharmacokinetics of eplerenone in men and women did not differ significantly. In elderly people, the equilibrium rates of C max (22%) and AUC (45%) were increased compared to young patients (18-45 years). The equilibrium values of C Max and AUC in the Negroid race were reduced by 19 and 26%, respectively.

Renal failure. The pharmacokinetics of eplerenone were evaluated in patients with different degrees of renal impairment and in patients who were on hemodialysis.

In patients with severe renal failure, AUC and C Max in the equilibrium state were increased by 38% and 24%, respectively, compared with the control group. In patients who were on hemodialysis, these rates were reduced by 26% and 3%, respectively, compared with the control group of patients. Correlations between the clearance of eplerenone from plasma and the clearance of creatinine are not revealed. Eplerenone is not removed by hemodialysis (see section "Features of application").

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 compared the results with the results obtained for patients without disturbing the liver function. C Max and AUC of eplerenone in the equilibrium state were increased by 3.6% and 42%, respectively (see section "Method of administration and dose"). Since studies of the use of eplerenone for the treatment of patients with severe impairment of liver function have not been performed, the appointment of eplerenone to such patients is contraindicated (see the section "Contraindications").

Heart failure. In patients with heart failure (NYHA classes II-IV), the pharmacokinetics of eplerenone administered at a dose of 50 mg were performed. The C max and AUC values in the equilibrium state in patients with heart failure were 38% and 30%, respectively, higher than in healthy patients of the corresponding age, body weight and sex. According to these results, a population analysis of the pharmacokinetics of eplerenone indicates that the eplerenone clearance in patients with heart failure does not differ from the clearance of this drug in healthy elderly volunteers.

INDICATIONS

Supplement to standard treatment with beta-blockers in order to reduce the risk of morbidity and mortality associated with cardiovascular disease in stable patients with left ventricular dysfunction (left ventricular ejection fraction ≤ 40%) and clinical signs of heart failure after a recent myocardial infarction .

Supplement 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%).

CONTRAINDICATIONS

Hypersensitivity to eplerenone or to any of the excipients.

Serum potassium level> 5 mmol / l at the time of treatment initiation.

Renal failure of severe degree (calculated glomerular filtration rate <30 ml / min / 1.73 m 2).

Severe hepatic insufficiency (class C on the Child-Pugh scale).

Simultaneous use of potassium-sparing diuretics, potassium preparations or potent inhibitors of CYP3A4 (for example, itraconazole, ketoconazole, ritonavir, nelfinavir, clarithromycin, telithromycin and nefazodone) (see "Interaction with Other Drugs and Other Interactions").

The simultaneous use of eplerenone in a triple combination, together with an ACE inhibitor and an angiotensin receptor blocker.

INTERACTION WITH OTHER DRUGS AND OTHER TYPES OF INTERACTION

Pharmacodynamic interactions.

Potassium-sparing diuretics and potassium supplements. Eplerenone should not be given to patients who receive other potassium-sparing diuretics and potassium supplements through an increased risk of developing hyperkalemia (see "Contraindications"). Under the influence of potassium-sparing diuretics, the effect of antihypertensive drugs and other diuretics can also increase.

ACE inhibitors, angiotensin receptor blockers. When using eplerenone in combination with an ACE inhibitor and / or an angiotensin receptor blocker, the risk of hyperkalemia increases. It is recommended to monitor closely the potassium level in the blood serum and the renal function, especially in patients at risk of impaired renal function, for example, in elderly patients. Eplerenone should not be used simultaneously in a triple combination with an ACE inhibitor and an angiotensin receptor blocker (see the sections "Contraindications" and "Features of Use").

Lithium. Studies of the interaction of eplerenone with lithium have not been conducted. However, patients who received lithium concomitantly with ACE inhibitors and diuretics experienced cases of toxic effects of lithium (see the section on "Features of application"). You should avoid the simultaneous use of eplerenone and lithium preparations. If it is not possible to avoid the use of this combination, you should monitor the level of lithium in the blood plasma (see section "Features of application").

Ciclosporin, tacrolimus. Cyclosporine and tacrolimus can cause renal dysfunction and increase the risk of hyperkalemia.You should avoid the simultaneous use of eplerenone and cyclosporine or tacrolimus. If it is necessary to administer cyclosporin and tacrolimus in the treatment of eplerenone, it is recommended that the serum potassium level be carefully monitored (see section "Application features").

Non-steroidal anti-inflammatory drugs (NSAIDs). Due to the direct effect on the glomerular filtration of treatment, NSAIDs can lead to acute renal failure, especially in patients at high risk (elderly and / or dehydrated). Patients who receive eplerenone and NSAIDs need adequate water management and control of their kidney function prior to treatment.

Trimethoprim. Simultaneous 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 impaired renal function.

Alpha-1-blockers (eg prazosin, alfuzosin). The combination of alpha-1-adrenergic receptors and eplerenone can enhance hypotensive action and / or cause orthostatic hypotension.

With the simultaneous use of alpha-1-adrenergic receptors, the clinical status of patients with orthostatic hypotension should be monitored.

Tricyclic antidepressants, neuroleptics, amifostine, baclofen. The simultaneous administration of these drugs and eplerenone can enhance hypotensive action and increase the risk of orthostatic hypotension.

Glucocorticoids, tetracosactide. With the simultaneous administration of these drugs and eplerenone, the hypotensive effect may be weakened due to fluid and sodium retention.

Pharmacokinetic interaction.

In vitro studies indicate that eplerenone is not an inhibitor of the isoenzymes CYP1A2, CYP2C19, CYP2C9, CYP2D6 or CYP3A4. Eplerenone is not a substrate or an inhibitor of P-glycoprotein.

Digoxin. The level of systemic exposure (AUC) of digoxin with simultaneous use with eplerenone increases by 16% (90% CI: 4-30%). It should be used with caution in appointing digoxin at doses close to the upper limit of the therapeutic range.

Warfarin. Clinically important pharmacokinetic interactions with warfarin have not been described. It should be cautious to prescribe warfarin in doses close to the upper limit of the therapeutic range.

Substrates CYP3A4. Pharmacokinetic studies with substrate samples of CYP3A4 (eg, midazolam and cisapride) showed no evidence of marked pharmacokinetic interactions with the simultaneous use of these drugs and eplerenone.

Inhibitors of CYP3A4. Powerful inhibitors of CYP3A4: with the simultaneous use of eplerenone and drugs that suppress the activity of the enzyme CYP3A4, it is possible to develop pronounced pharmacokinetic interactions. Under the influence of a potent inhibitor of CYP3A4 (ketoconazole 200 mg twice daily), the eplerenone AUC increased by 441% (see the section "Contraindications.") The simultaneous use of eplerenone and potent CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin, telithromycin and nefazadone ) (see the section "Contraindications").

Weak and moderate inhibitors of CYP3A4. Application simultaneously with erythromycin, saquinavir, amiodarone, diltiazem, verapamil and fluconazole led to pronounced pharmacokinetic interactions with an increase in AUC levels of 98-187%. Thus, with the simultaneous administration of eplerenone and mild or moderate CYP3A4 inhibitors, the dose of eplerenone should not exceed 25 mg (see section "Method of administration and dose").

Inductors CYP3A4. Simultaneous use of eplerenone and St. John's wort (powerful inducer CYP3A4) led to a decrease in AUC of eplerenone by 30%. The use of more powerful CYP3A4 inducers (such as rifampicin) can lead to a more pronounced decrease in AUC eplerenone. It is not recommended to use powerful inducers CYP3A4 (rifampicin, carbamazepine, phenytoin, phenobarbital, St. John's wort) at the same time as the risk of a decrease in the effectiveness of eplerenone (see section "Application features").

Antacids. Based on the results of a clinical pharmacokinetic study, simultaneous use of eplerenone and antacid preparations is not expected to have significant interactions.

FEATURES OF APPLICATION

Hyperkalemia. During treatment with eplerenone, according to its mechanism of action, it is possible to develop hyperkalemia. In all patients at the beginning of treatment and when changing the dose of the drug should monitor the potassium level in the serum. In the future, periodic monitoring is recommended, especially in patients at risk of hyperkalemia (such as elderly patients, patients with renal insufficiency (see the "Application and dose" section), and diabetes). After starting treatment with eplerenone It is not recommended to use potassium supplements through an increased risk of developing hyperkalemia. It has been demonstrated that a reduction in the dose of eplerenone leads to a decrease in potassium concentration in the blood serum. In one study, it was demonstrated that the additional administration of hydrochlorothiazide in the treatment of eplerenone compensated for an increase in serum potassium concentration.

When using eplerenone in combination with an ACE inhibitor and / or an angiotensin receptor blocker, the risk of hyperkalemia increases.

Eplerenone should not be used simultaneously in a triple combination with an ACE inhibitor and an angiotensin receptor blocker (see the sections "Contraindications" and "Interaction with other drugs and other interactions").

Impaired renal function. In patients with impaired renal function (including diabetic microalbuminuria), the level of potassium should be monitored regularly. Decreased kidney function is accompanied by an increased risk of hyperkalemia. In patients with type 2 diabetes and microalbuminuria, an increased incidence of hyperkalemia was observed. Therefore, the treatment of such patients should be done with caution. Eplerenone is not removed by hemodialysis.

Violation of the function of the liver. In patients with mild and moderate impairment of liver function (classes A and B according to the Child-Pugh classification), there was no increase in the serum potassium level of more than 5.5 mmol / l. Such patients need to control the levels of electrolytes. The use of eplerenone for the treatment of patients with severe renal impairment have not studied therefore eplerenone contraindicated in these patients (see "Dosing and Administration" and "Contra ').

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

Lithium, cyclosporin, tacrolimus should not be administered in the treatment of eplerenone (see "Interaction with other drugs and other types of interactions" section).

Lactose: the drug includes lactose, so it should not be given to patients with the rare genetic disorders (galactose intolerance, congenital lactase deficiency syndrome lappa or malabsorption of glucose and galactose).

Use during pregnancy or lactation

Pregnancy.There are no adequate data on the use of eplerenone to pregnant women there. Information obtained in the course of animal studies do not indicate direct or indirect adverse effects on pregnancy, embryo-fetal development, childbirth and post-natal development. Appoint eplerenone to pregnant women with caution.

Lactation. Unknown eplerenone penetrates into breast milk after oral primeneniya.Odnovremenno preclinical data suggest the presence of eplerenone and / or its metabolites in milk and rats of normal development of pups exposed eplerenone follows. Since the potential of side effects in infants who are breastfed are not investigated, it should be a clinical decision on the termination of breastfeeding or withdrawal of the drug, depending on the importance of the drug to the mother.

Ability to influence the reaction rate when driving or operating other machines:

Studies eplerenone effect on the ability to drive vehicles or other mechanisms not performed. Eplerenone does not cause drowsiness or impairment of cognitive function but when driving or operating other mechanisms should consider the possibility of dizziness during treatment.

METHOD OF USE AND DOSES

Tablets contain the drug dose of 25 mg or 50 mg. The maximum daily dose of 50 mg per day.

Eplerenone can be taken with food or without food (see "Pharmacokinetics" section).

Patients with heart failure after myocardial infarction. The recommended maintenance dose of eplerenone 50 mg 1 time per day. Treatment should start with a dose of 25 mg 1 time per day and gradually increased up to the target dose of 50 mg 1 time per day. It is desirable to achieve the target dose for 4 weeks, taking into account the level of potassium in the blood serum (Table). eplerenone treatment is usually necessary to begin after 3-14 days after an acute myocardial infarction.

Patients with heart failure class II (chronic) in NYHA classification.

Treatment of patients with chronic heart failure according to NYHA class II classification should begin with a dose of 25 mg 1 time per day and gradually increased up to the target dose of 50 mg 1 time per sutki.Zhelatelno achieve this dose level for four weeks, given the level of potassium in the blood serum ( see table below and "application Features" section).

Patients whose serum potassium level greater than 5 mmol / l, should not begin treatment eplerenone (see "Contraindications").

serum potassium should be determined before treatment eplerenone, during the first week of treatment and one month after the start of treatment or dose adjustment. If necessary periodically to determine the level of potassium in the serum during the treatment.

After initiation of treatment dose should be adjusted to the concentration of potassium in blood serum, as indicated in the table below.

No dose adjustment after starting treatment.

The concentration of potassium in the serum (mmol / L)	Act	correction dose
<5.0	Increase	25 mg 1 time in 2 days to 25 mg 1 time per day From 25 mg 1 time per day to 50 mg 1 time per day
5.0-5.4	Without changes	Dose is not changed
5,5-5,9	decrease	From 1 to 50 mg once daily to 25 mg 1 time per day 25 mg 1 time per day to 25 mg 1 time in 2 days From 25 mg of 1 every 2 days to temporary suspension
³ 6,0	abeyance	-

After the temporary cancel eplerenone through increasing potassium levels in ³ 6 mmol / l resumption of treatment is possible at a dose of 25 mg of 1 every 2 days after lowering the potassium concentration below 5 mmol / l.

Elderly patients.

For elderly patients is not necessary to correct the initial dose. Due to age-related decrease in renal function intensity risk of hyperkalemia in elderly patients increases. The risk is also increased in case of concomitant disease accompanied by increased systemic exposure of the drug, in particular violation of mild to moderate severity of liver functions. It is recommended to carry out periodic monitoring of the level of potassium in the blood serum (see "Application Features" section).

Impaired renal function.

Patients with mild impairment of renal function is not required the initial dose adjustment. It is recommended to carry out periodic monitoring of the level of potassium in the blood serum (see section "Properties application") and adjust the dose in accordance with the table above.

Patients with impaired renal function moderate severity (creatinine clearance of 30-60 mg / ml) should begin with a dose of 25 mg of 1 every 2 days and the dose adjusted, depending on the concentration of potassium (see table above). It is recommended to carry out periodic monitoring of the level of potassium in the blood serum (see "Application Features" section).

The experience of the drug in patients with creatinine clearance <50 mL / min and heart failure after myocardial infarction offline. For the treatment of these patients, eplerenone should be used with caution.

The use doses greater than 25 mg per day to patients with creatinine clearance <50 mL / min was not investigated.

Eplerenone is contraindicated in patients with severe renal impairment (creatinine clearance <30 mL / min) (see "Contraindications"). Eplerenone is not excreted via dialysis.

Abnormal liver functions.

Patients with mild to moderate hepatic impairment does not need initial dose correction function, however, due to increasing levels of systemic exposure eplerenone this category of patients, particularly elderly patients recommended for frequent and regular monitoring of the concentration of potassium in blood serum (see "Application Features" section).

Combined use.

In the case of simultaneous application with weak or moderate inhibitors of CYP3A4 (e.g. amiodarone, diltiazem and verapamil) can begin treatment eplerenone with an initial dose of 25 mg 1 time per day The dose should not exceed 25 mg 1 time per day (see "Interaction section with other medicaments products and other forms of interaction ").

Children

Information that would enable to recommend the use of eplerenone in the treatment of children who do not. Therefore the use in this age group of patients is not recommended.

OVERDOSE

Reported adverse reactions associated with overdose of eplerenone in humans, produced no bylo.Ozhidaetsya that the most likely manifestations of overdose of the drug in humans will be hypotension or hyperkalemia. Eplerenone is not possible to deduce from the body by hemodialysis. It has been demonstrated that eplerenone effectively binds to the activated carbon. With the development of arterial hypotension should start maintenance treatment. With the development of hyperkalemia treatment should be started according to the standards.

ADVERSE REACTIONS

Below are side reactions which may involve the use of eplerenone and which occurred during treatment more frequently than with placebo or serious adverse events that occurred during treatment more frequently than with placebo, or those that have been described in during post-marketing surveillance.

Adverse events categorized by organ systems and absolute frequency.

The frequency is defined as: often (> 1/100 and <1/10); uncommon (> 1/1000 and <1/100).

Infections and infestations: common - infection; infrequently - pyelonephritis, pharyngitis.

On the part of the blood: rare - eosinophilia.

From endocrine system: rarely - hypothyroidism.

Metabolic disorders: often - hyperkalemia (see "Contraindications" and "application Features"); infrequently - hyponatremia, dehydration, hypercholesterolemia, hypertriglyceridemia.

On the part of the psyche: rarely - insomnia.

From the nervous system: often - dizziness, fainting; rarely - headache, hypoesthesia.

With the cardiovascular system: often - myocardial infarction, hypotension, rarely - left ventricular failure, atrial fibrillation, tachycardia, thrombosis of arteries, orthostatic hypotension.

The respiratory system: often - cough.

On the part of the digestive tract: often - diarrhea, nausea, constipation; rarely - vomiting, abdominal distension.

Skin: often - a rash, itching; rarely - rash; frequency is unknown - angioedema.

On the part of the musculoskeletal system: often - muscle cramps, pain in the musculoskeletal system, not often - back pain.

From the urinary system: often - impaired renal function (see "Features of the application" and "Interaction with other medicinal products and other forms of interaction").

From the digestive system: rarely - cholecystitis.

Reproductive system: Infrequent - gynecomastia.

General disorders and administration site at: often - fatigue, malaise.

Laboratory parameters: often - increase of urea; Infrequent - increased creatinine levels, reduced amounts of epidermal growth factor receptors, increase blood glucose levels.

In the EPHESUS study noted an increase in the number of cases of stroke in elderly patients (≥ 75 years). However, a statistically significant difference was between the incidence of stroke in the eplerenone group and in the placebo group.

SHELF LIFE

3 years.

STORAGE CONDITIONS

Store in the original packaging at a temperature not higher than 25 ° С. Keep out of the reach of children.

PACKAGING

10 tablets in a blister, 3 blisters in a cardboard package.

CATEGORY RELEASE

On prescription.