Renal 25 mg tablets No. 30

RENIAL instructions for use

Composition:

active ingredient: eplerenone; 1 tablet contains eplerenone in terms of 100% substance 25 mg or 50 mg; auxiliary substances: lactose, monohydrate; microcrystalline cellulose; sodium croscarmellose; hypromellose; sodium lauryl sulfate; talc; magnesium stearate; film membrane: hypromellose, macrogol 400; polysorbate 80; titanium dioxide (E 171); iron oxide yellow (E172); iron oxide red (E 172).

Dosage form

Film-coated tablets.

Basic physical and chemical properties:

tablets beige, round with a biconvex surface, with the inscription "25" or "50" on one side of the tablet.

Pharmacotherapeutic group

Potassium-sparing diuretics. Antagonists of aldosterone. Epleenon.Cod ATX C03D A04.

Pharmacological properties

Pharmacodynamics. Eplerenone has a relative selectivity in binding to recombinant human receptors to mineralocorticoids in comparison to its interaction with recombinant human receptors to glucocorticoids, progesterone and androgens. Eplerenone prevents the binding of receptors to aldosterone, an important hormone of the renin-angiotensin-aldosterone system, which is involved in the regulation of arterial pressure and is involved in the pathophysiological mechanisms of the development of cardiovascular diseases.

The use of eplerenone leads to a steady increase in the level of renin in the blood plasma and aldosterone in the blood serum, which testifies to the inhibition of the negative reverse effect of aldosterone on the secretion of renin. An increase in renin activity in plasma and the levels of aldosterone in the blood resulting from it does not lead to inhibition of the action of eplerenone.

There is evidence that the addition of eplerenone to a standard treatment regimen in patients with chronic cardiac insufficiency (NYHA class GG-PG) leads to the expected dose-dependent increase in aldosterone levels. Similarly, other data confirm an increase in the level of aldosterone and blockage of receptors for mineralocorticoids.

There is information that eplerenone reduces the risk of death due mainly to a reduction in mortality due to cardiovascular abnormalities. There are no data on the 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 blood plasma is achieved after 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 of 10-100 mg and less in proportion with doses over 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 imaginary volume of the distribution of eplerenone in the equilibrium state is estimated as equal to 50 ± 7 liters. Eplerenone is not prone 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 oral administration of a single dose of a radiolabeled drug, approximately 32% of the dose is excreted from the body with feces and about 67% in the urine. The half-life of eplerenone is about 3-5 hours. Imaginary clearance from the blood plasma is approximately 10 liters / hour.

Use in special patient groups.

Age, gender and race. There were no significant differences in the pharmacokinetics of eplerenone when taken in a dose of 100 mg in men and women. In elderly patients, an increase in the C _max (22%) and AUC (45%) levels was observed in the equilibrium state compared with younger patients (18-45 years). In patients of the Negroid race in the equilibrium state, C _max was lower by 19%, and AUC by 26% (see the section "Method of administration and dose").Renal failure. In patients with severe renal failure, AUC and C _max in the equilibrium state increase by 38% and 24%, respectively. In patients who are on hemodialysis, these rates are lower by 26% and 3%, respectively. Correlation between the eplerenone clearance in plasma and the creatinine clearance is not established. Eplerenone is not excreted in hemodialysis (see "Features of application"). Liver failure. When using 400 mg eplerenone in patients with moderate liver damage (class B according to the Child-Pugh classification), _Cmax and AUC of eplerenone in the equilibrium state increase by 3.6% and 42%, respectively (see the section "Dosing and Administration" ).

Heart failure. In patients with heart failure (classes II-IV according to the NYHA classification), the C _max and AUC values in equilibrium are 38% and 30% higher than in healthy volunteers of the appropriate age, body weight and sex. There is evidence that the clearance of eplerenone in patients with heart failure does not differ from the clearance of this drug in healthy elderly volunteers.

Clinical characteristics

Indications. Supplement to standard treatment with beta-blockers to reduce the risk of morbidity and mortality associated with cardiovascular disease in stable patients with left ventricular dysfunction (LVEF <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 grade II chronic heart failure (NYHA) and left ventricular dysfunction (left ventricular ejection fraction <30%).

Contraindications

• Hypersensitivity to eplerenone or any other of the excipients;
• serum potassium level> 5 mmol / l at the time of treatment initiation;
• severe renal insufficiency (calculated glomerular filtration rate <30 ml / min / 1.73 m ² );
• hepatic failure of severe degree (class C according to Child-Pugh classification). Treatment with potassium-sparing diuretics, potassium supplements or potent inhibitors of CYP3A4 (eg itraconazole, ketoconazole,
• ritonavir, nelfinavir, clarithromycin, telithromycin and nefazodone) (see "Interaction with Other Drugs and Other Interactions");
• simultaneous application of eplerenone in a triple combination together with an ACE inhibitor and an angiotensin receptor blocker.

Interaction with other drugs and other interactions

Pharmacodynamic interactions.

Potassium-sparing diuretics and potassium supplements. Eplerenone should not be given to patients who receive other potassium-sparing diuretics and potassium supplements because of the increased risk of developing hyperkalemia (see section "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 may increase. It is recommended that careful monitoring of serum potassium levels and renal function be performed, especially in patients at risk of renal dysfunction, 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, there is evidence that patients receiving lithium concurrently with ACE inhibitors and diuretics, there are cases of toxic effects of lithium (see "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 impaired renal function and increase the risk of hyperkalemia. You should avoid the simultaneous use of eplerenone and cyclosporine or tacrolimus.If it is necessary to administer cyclosporine and tacrolimus in the treatment of eplerenone, it is recommended that the serum potassium level be carefully monitored (see section "Features of application"). 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 (old age and / or dehydration). Patients who receive eplerenone and NSAIDs should be provided with adequate water regimen 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). When combining alpha-1-blockers and eplerenone, it is possible to intensify the hypotensive effect and / or the occurrence of orthostatic hypotension. With the simultaneous use of alpha-1-blockers should monitor the clinical condition of patients for orthostatic hypotension.

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

Glucocorticoids, tetracosactide. With the simultaneous administration of these drugs and eplerenone, there is the possibility of weakening the hypotensive effect due to fluid and sodium retention.

Pharmacokinetic interaction.

Eplerenone is not an inhibitor of isoenzymes CYP1A2, CYP2C19, CYP2C9, CYP2D6 or CYP3A4, as well as substrate or 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 significant pharmacokinetic interactions with warfarin have not been described. Caution should be given to warfarin in doses close to the upper limit of the therapeutic range.

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

Inhibitors of CYP3A4. Powerful inhibitors of CYP3A4: with 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 powerful inhibitor of CYP3A4 (ketoconazole 200 mg twice a day), the eplerenone AUC increases by 441% (see the section "Contraindications"). Contraindicated simultaneous use of eplerenone and potent inhibitors of CYP3A4 (ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin, telithromycin and nefazadone) (see section "Contraindications").

Weak and moderate inhibitors of CYP3A4. Application simultaneously with erythromycin, saquinavir, amiodarone, diltiazem, verapamil and fluconazole leads to pronounced pharmacokinetic interactions with an increase in AUC levels by 98187%. Accordingly, with the simultaneous administration of eplerenone and mild or moderate CYP3A4 inhibitors, the dose of eplerenone should not exceed 25 mg (see the section "Dosing and Administration").

Inductors CYP3A4. Simultaneous use of eplerenone and St. John's wort (powerful inducer CYP3A4) leads to a decrease in AUC eplerenone by 30%. The use of more powerful CYP3A4 inducers (such as rifampicin) can lead to a more pronounced decrease in AUC eplerenone. Because of the risk of decreased eplerenone effectiveness, powerful CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, phenobarbital, St. John's wort) are not recommended to be used concomitantly with this drug (see section "Application features").

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

Application features

Hyperkalemia. During treatment with eplerenone, according to its mechanisms 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 section "Method of administration and dose") and patients with diabetes mellitus). After starting treatment with eplerenone, it is not recommended to use potassium supplements because of the increased risk of developing hyperkalemia. Reducing the dose of eplerenone leads to a decrease in the concentration of potassium in the blood serum. There is evidence that the additional administration of hydrochlorothiazide in the treatment of eplerenone compensates for the increase in potassium concentration in the blood serum.

When using eplerenone in combination with an ACE inhibitor and / or an angiotensin receptor blocker, the risk of hyperkalemia may increase. Eplerenone should not be used simultaneously in a triple combination, together 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. Eplerenone is not excreted 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), an increase in the serum potassium level of more than 5.5 mmol / l is not observed. Such patients need to control the level of electrolytes. The use of eplerenone for the treatment of patients with severe renal dysfunction has not been studied, and therefore eplerenone is contraindicated in the use of such patients (see the section on "Dosing and Administration" and "Contraindications"). Inductors CYP3A4. Simultaneous administration of eplerenone and powerful inducers of CYP3A4 is not recommended (see the section "Interaction with Other Drugs and Other Interactions").

Lithium, cyclosporine, tacrolimus should not be prescribed in the treatment of eplerenone (see section "Interaction with other drugs and other interactions"). Lactose. The composition of the drug includes lactose, so it should not be prescribed to patients with rare hereditary disorders (intolerance to galactose, congenital insufficiency of Lapp's lactase or a syndrome of impaired glucose and galactose absorption).

Use during pregnancy or lactation

Pregnancy. Adequate data on the use of eplerenone in pregnant women do not. Prescribe eplerenone to pregnant women with caution.

Lactation. It is not known whether eplerenone penetrates human milk after oral administration. Since the potential for side effects in infants who are breastfed is not investigated, a clinical decision should be made to stop breastfeeding or discontinue the drug, depending on the importance of the drug to the mother.

The ability to influence the reaction rate when driving vehicles or other mechanisms

Studies of the effect of eplerenone on the ability to drive motor vehicles or other mechanisms have not been conducted.Eplerenone does not cause drowsiness or cognitive impairment, but when driving or working with other mechanisms, the possibility of developing dizziness during drug treatment should be considered.

Dosing and Administration

The drug exists in doses of 25 mg and 50 mg. The maximum daily dose is 50 mg. Eplerenone can be taken with or without food (see section "Pharmacokinetics").

Patients with heart failure after a previous myocardial infarction. The recommended maintenance dose of eplerenone is 50 mg once a day. Treatment 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 desirable to achieve this dose level for 4 weeks, given the serum potassium level (see table below). Treatment with eplerenone usually needs to start 3-14 days after an acute myocardial infarction.

Patients with heart failure class II (chronic) according to the classification of NYHA.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 day. It is desirable to achieve the target dose for 4 weeks, taking into account the level of potassium in the blood serum (see. The table below and "Application Properties").

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 determine the potassium level in serum during treatment later.

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 blood syrovotke (mmol / l)	Act	correction dose
<5.0	Increase	From 25 mg of 1 to 2 times of the day 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 not change
5,5-5,9	decrease	From 1 to 50 mg once daily to 25 mg 1 time per day. From 25 mg 1 time per day to 25 mg of 1 every 2 days. From 25 mg of 1 every 2 days to temporary suspension.
> 6.0	abeyance	-

After the temporary cancel eplerenone because of higher levels of potassium to> 6 mmol / l resumption of treatment is possible at a dose of 25 mg of 1 every 2 days after reducing the concentration of potassium to less than 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 may be further increased in the case of concomitant disease which is accompanied by increased systemic exposure of the drug, in particular disorders of the liver of mild to moderate degree. 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 renal dysfunction require correction initial dose. It is recommended to carry out periodic monitoring of the level of potassium in the blood serum (see. See "Properties application") and adjust the dose in accordance with the table above.

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

Experience with the drug to 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, not investigated.

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

Abnormal liver functions.

Patients with mild to moderate hepatic impairment require correction starting dose function, however, due to increasing levels of systemic exposure eplerenone these patients and the elderly especially, patients are advised to conduct frequent and regular monitoring of serum potassium concentration (cm. "Application Features" section) .

Combined use.

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

Children

No data on the use of eplerenone children, so the use of a drug of this group of patients is not recommended.

Overdose

Reported adverse reactions associated with overdose of eplerenone in humans has not been received. It is expected that the most likely manifestations of overdose in humans will be hypotension or hyperkalemia. Eplerenone is not possible to deduce from the body by hemodialysis. 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

Adverse reactions classified by system organ and frequency of occurrence. Infections and infestations: common - infection; infrequently - pyelonephritis, pharyngitis.

Disorders of the blood system and lymphatic system: Infrequent - eosinophilia. Disorders of the endocrine system: rarely - hypothyroidism.

Disorders of metabolism and digestive system: often - hyperkalemia (see section "Contraindications" and "Features of the application."); Infrequently - hyponatremia, dehydration, hypercholesterolemia, hypertriglyceridemia.

Disorders of the psyche: rarely - insomnia.

Nervous system disorders: often - dizziness, fainting; rarely - headache, hypoesthesia.

Disorders of the heart: often - myocardial infarction; infrequently - left ventricular failure, atrial fibrillation, tachycardia.

Disorders of the cardiovascular system: often - hypotension; rarely - thrombosis of arteries, orthostatic hypotension.

Disorders of the respiratory system, organs, thoracic and mediastinal disorders: often - cough.

Disorders of the gastrointestinal tract: often - diarrhea, nausea, constipation; rarely - vomiting, abdominal distension.

Disorders of the skin and subcutaneous tissue disorders: often - a rash, itching; rarely - rash; frequency is unknown - angioedema.

Disorders of the musculoskeletal system and connective tissue disorders: often - muscle cramps, pain in the musculoskeletal system; infrequently - back pain.

Disorders of the kidneys and urinary tract: often - renal dysfunction (see sections "Features of application" and "interaction with other drugs and other types of interactions.").

Disorders of the liver and biliary tract: infrequent - cholecystitis. Disorders of the reproductive system and mammary glands: rarely - gynecomastia.

General disorders and disorders in the injection site: rarely - fatigue, malaise.

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

Shelf life

3 years from date of manufacture in bulk.

Storage conditions

Stored in original package at a temperature not higher than 25 ° S.Hranit the reach of children.

Packaging

10 tablets in a blister pack. 3 blisters in a pack.

Category tempered

On prescription.