Renial film-coated tablets 25 mg blister No. 30

Instructions Renial film-coated tablets 25 mg blister No. 30

Composition

active ingredient: eplerenone;

1 tablet contains eplerenone in terms of 100% substance 25 mg;

excipients: lactose monohydrate; microcrystalline cellulose; croscarmellose sodium; hypromellose; sodium lauryl sulfate; talc; magnesium stearate;

film coating: hypromellose, macrogol 400; polysorbate 80; titanium dioxide (E 171); iron oxide yellow (E 172); iron oxide red (E 172).

Dosage form

Film-coated tablets.

Main physicochemical properties: beige tablets, round in shape with a biconvex surface, with the inscription "25" on one side of the tablet.

Pharmacotherapeutic group

Potassium-sparing diuretics. Aldosterone antagonists. Eplerenone.

ATX code C03D A04.

Pharmacological properties

Pharmacodynamics

Mechanism of action. Eplerenone has a relative selectivity for binding to recombinant human mineralocorticoid receptors compared to its interaction with recombinant human glucocorticoid, progesterone, and androgen receptors. Eplerenone inhibits the binding of receptors to aldosterone, an important hormone of the renin-angiotensin-aldosterone system, which is involved in the regulation of blood pressure and is involved in the pathophysiological mechanisms of cardiovascular disease.

Pharmacodynamic effects: Eplerenone has been shown to cause sustained increases in plasma renin and serum aldosterone levels, consistent with inhibition of the negative feedback pathway of aldosterone on renin secretion. However, increases in plasma renin activity and serum aldosterone levels do not inhibit the action of eplerenone.

In a dose-ranging study in chronic heart failure (New York Heart Association (NYHA) class II-IV), the addition of eplerenone to standard therapy resulted in the expected dose-related increase in aldosterone levels. Similarly, in one cardio-nephrology study (an efficacy and mortality study of eplerenone in patients with acute myocardial infarction, complicated left ventricular dysfunction, and heart failure), treatment with eplerenone resulted in a significant increase in aldosterone levels. These results support mineralocorticoid receptor blockade in this population.

Long-term treatment with eplerenone at a dose of 25 to 50 mg per day under potassium monitoring, initiated 3 to 14 days after acute myocardial infarction (MI) in patients with left ventricular dysfunction (left ventricular ejection fraction ≤ 40%) and clinical signs of heart failure in addition to standard treatment (acetylsalicylic acid, beta-blocker, ACE inhibitor, loop diuretics, or HMG-CoA reductase inhibitors) has been shown to be effective in preventing cardiovascular complications and reducing mortality. The clinical efficacy of eplerenone has primarily been demonstrated in patients under 75 years of age. The benefit of treatment in patients over 75 years of age has not been well studied. Improvement or stabilization of NYHA functional class of heart failure in the eplerenone group was observed in a greater percentage of patients than in the placebo group.

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

In pharmacokinetic studies examining electrocardiographic changes, no consistent effect of eplerenone on heart rate, QRS complex duration, or PR and QT intervals was observed.

In patients with systolic heart failure (aged 55 years and older with left ventricular ejection fraction ≤ 30% or ≤ 35% combined with QRS duration greater than 130 ms) and mild symptoms (NYHA functional class II), adding eplerenone (initial dose 25 mg/day, increased after 4 weeks to 50 mg/day if serum potassium is less than 5.0 mmol/L) to standard therapy that included diuretics, ACE inhibitors, angiotensin II receptor blockers, beta-blockers, antithrombotic agents, lipid-lowering agents, and digitalis glycosides was found to be statistically significantly lower than baseline in the incidence or occurrence of hospitalization for heart failure or cardiovascular death, as well as death from any cause. therapy (without eplerenone).

Pharmacokinetics

Absorption: The absolute bioavailability of eplerenone following a 100 mg oral dose is 69%.

Distribution: Eplerenone is approximately 50% bound to plasma proteins and is primarily bound to alpha-1-acid glycoprotein. The apparent volume of distribution of eplerenone at steady state is estimated to be 42-90 L. Eplerenone does not bind to erythrocytes.

Biotransformation: Eplerenone is metabolized primarily by the enzyme CYP3A4. No active metabolites of eplerenone have been identified in human plasma.

Elimination: Less than 5% of an eplerenone dose is excreted in the urine and feces as unchanged drug. Following a single oral dose of radiolabeled drug, approximately 32% of the dose was excreted in the feces and approximately 67% was excreted in the urine. The elimination half-life of eplerenone is approximately 3-6 hours. The apparent plasma clearance is approximately 10 L/hour.

Use in specific populations.

Age, gender, and race. Pharmacokinetics of eplerenone administered at a dose of 100 mg once daily have been studied in the following patient populations: elderly (65 years and older), male, female, and black patients. There were no significant differences in the pharmacokinetics of eplerenone between patients based on gender. Elderly patients had a 22% increase in Cmax and 45% in AUC at steady state compared to younger patients (18-45 years). In black patients, Cmax was 19% lower and AUC was 26% lower at steady state (see Dosage and Administration).

Children. Using a population pharmacokinetic model for eplerenone concentrations, patient weight was found to have a statistically significant effect on the volume of distribution of eplerenone, but not on its elimination. The volume of distribution of eplerenone and peak exposure in patients with higher body weight are expected to be similar to those observed in adults of similar body weight. In patients weighing 45 kg, the volume of distribution is approximately 40% lower; peak exposure is expected to be higher than that typically observed in adults.

Renal impairment. The pharmacokinetics of eplerenone have been evaluated in patients with varying degrees of renal impairment and in patients undergoing hemodialysis. In patients with severe renal impairment, steady-state AUC and Cmax were increased by 38% and 24%, respectively, compared to controls. In patients undergoing hemodialysis, these values were decreased by 26% and 3%, respectively, compared to controls. There was no correlation between eplerenone plasma clearance and creatinine clearance. Eplerenone is not removed by hemodialysis (see section 4.4).

Hepatic impairment. The pharmacokinetics of eplerenone at a dose of 400 mg were studied in patients with moderate hepatic impairment (Child-Pugh B) and compared with those in patients without hepatic impairment. The steady-state Cmax and AUC of eplerenone were increased by 3.6% and 42%, respectively (see section 4.2). Since eplerenone has not been studied in patients with severe hepatic impairment, eplerenone is contraindicated in such patients (see section 4.3).

Heart Failure: A pharmacokinetic study of eplerenone administered at a dose of 50 mg was conducted in patients with heart failure (NYHA class II-IV). The steady-state Cmax and AUC values in heart failure patients were 38% and 30% higher, respectively, than in age-, weight-, and sex-matched healthy volunteers. Consistent with these results, a population pharmacokinetic analysis of eplerenone suggests that the clearance of eplerenone in heart failure patients is not different from that in healthy elderly volunteers.

Indication

Add-on to standard beta-blocker therapy to reduce the risk of cardiovascular morbidity and mortality in stable patients with left ventricular dysfunction (left ventricular ejection fraction ≤ 40%) and clinical signs of heart failure after a recent myocardial infarction.

Addition to standard optimal therapy to reduce the risk of cardiovascular morbidity and mortality in adult patients with NYHA class II (chronic) heart failure and left ventricular dysfunction (left ventricular ejection fraction ≤ 30%).

Contraindication

Hypersensitivity to eplerenone or to any of the excipients of the medicinal product; serum potassium level > 5 mmol/l at the time of initiation of treatment; severe renal insufficiency (estimated glomerular filtration rate < 30 ml/min/1.73 m2); severe hepatic insufficiency (Child-Pugh class C);

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

Interaction with other medicinal products and other types of interactions

Pharmacodynamic interactions.

Potassium-sparing diuretics and potassium supplements: Eplerenone should not be administered to patients receiving other potassium-sparing diuretics and potassium supplements due to the increased risk of hyperkalemia (see section 4.3). Potassium-sparing diuretics may also potentiate the effects of antihypertensive drugs and other diuretics.

ACE inhibitors, angiotensin receptor blockers. The risk of hyperkalemia may be increased when eplerenone is used in combination with an ACE inhibitor and/or angiotensin receptor blocker. Close monitoring of serum potassium and renal function is recommended, especially in patients at risk of renal impairment, such as the elderly. Eplerenone should not be used concomitantly in triple combination with an ACE inhibitor and an angiotensin receptor blocker (see sections 4.3 and 4.4).

Lithium: No interaction studies have been conducted with eplerenone and lithium. However, lithium toxicity has been reported in patients receiving lithium concomitantly with ACE inhibitors and diuretics (see section 4.4). The concomitant use of eplerenone and lithium should be avoided. If this combination cannot be avoided, plasma lithium levels should be monitored (see section 4.4).

Cyclosporine, tacrolimus. Cyclosporine and tacrolimus may cause renal dysfunction and increase the risk of hyperkalemia. The concomitant use of eplerenone and cyclosporine or tacrolimus should be avoided. If cyclosporine and tacrolimus are necessary during treatment with eplerenone, careful monitoring of serum potassium is recommended (see section 4.4).

Nonsteroidal anti-inflammatory drugs (NSAIDs). Due to their direct effect on glomerular filtration, treatment with NSAIDs may lead to acute renal failure, especially in patients at high risk (elderly and/or dehydrated). Patients receiving eplerenone and NSAIDs should be adequately hydrated and their renal function monitored prior to initiation of treatment.

Trimethoprim. Concomitant use of trimethoprim and eplerenone increases the risk of hyperkalemia. Serum potassium and renal function should be monitored, especially in elderly patients and patients with impaired renal function.

Alpha-1 blockers (e.g. prazosin, alfuzosin). When alpha-1 blockers are combined with eplerenone, there is a possibility of increased hypotensive effects and/or orthostatic hypotension. In case of concomitant use of alpha-1 blockers, the clinical status of patients should be monitored for orthostatic hypotension.

Tricyclic antidepressants, neuroleptics, amifostine, baclofen. Concomitant use of these drugs and eplerenone may potentially potentiate the hypotensive effect and increase the risk of orthostatic hypotension.

Glucocorticoids, tetracosactide. When these drugs are used simultaneously with eplerenone, there is a possibility of weakening the hypotensive effect due to fluid and sodium retention.

Pharmacokinetic interactions.

Eplerenone is not an inhibitor of CYP1A2, CYP2C19, CYP2C9, CYP2D6, or CYP3A4 isoenzymes, nor is it a substrate or inhibitor of P-glycoprotein.

Digoxin: Digoxin AUC increased by 16% (90% CI: 4-30%) when co-administered with eplerenone. Caution should be exercised when administering digoxin at doses near the upper end of the therapeutic range.

Warfarin: No clinically significant pharmacokinetic interactions with warfarin have been described. Caution should be exercised when prescribing warfarin at doses near the upper end of the therapeutic range.

CYP3A4 Substrates: Pharmacokinetic studies with CYP3A4 substrate samples (i.e., midazolam and cisapride) did not reveal any evidence of significant pharmacokinetic interactions when these drugs were co-administered with eplerenone.

CYP3A4 inhibitors.

Potent CYP3A4 inhibitors. With the simultaneous use of eplerenone and drugs that inhibit the activity of the CYP3A4 enzyme, the development of pronounced pharmacokinetic interactions is possible. Under the influence of a potent CYP3A4 inhibitor (ketoconazole 200 mg 2 times a day), the AUC of eplerenone increases by 441% (see section "Contraindications"). The simultaneous use of eplerenone and potent CYP3A4 inhibitors, such as ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin, telithromycin and nefazodone, is contraindicated (see section "Contraindications").

CYP3A4 inducers. Concomitant use of eplerenone and St. John's wort (a strong CYP3A4 inducer) resulted in a 30% decrease in eplerenone AUC. Use of more strong CYP3A4 inducers (such as rifampicin) may result in a more pronounced decrease in eplerenone AUC. Due to the risk of decreased efficacy of eplerenone, concomitant use of strong CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, phenobarbital, St. John's wort) is not recommended (see section 4.4).

Antacids: Based on the results of a clinical pharmacokinetic study, no significant interactions are expected with the simultaneous use of eplerenone and antacids.

Application features

Hyperkalemia. During treatment with eplerenone, in accordance with its mechanism of action, hyperkalemia may develop. Serum potassium levels should be monitored in all patients at the beginning of treatment and during dose changes. Periodic monitoring is recommended thereafter, especially in patients at risk of hyperkalemia, such as the elderly, patients with renal insufficiency (see section 4.2) and patients with diabetes. After starting treatment with eplerenone, potassium supplements are not recommended due to the increased risk of hyperkalemia. Reducing the dose of eplerenone leads to a decrease in serum potassium. There is evidence that the additional use of hydrochlorothiazide during treatment with eplerenone compensates for the increase in serum potassium.

The risk of hyperkalemia may be increased when eplerenone is used in combination with an ACE inhibitor and/or an angiotensin receptor blocker.

Eplerenone should not be used concomitantly in a triple combination with an ACE inhibitor and an angiotensin receptor blocker (see sections 4.3 and 4.5).

Renal impairment: Patients with renal impairment (including diabetic microalbuminuria) should have their potassium levels monitored regularly. Decreased renal function is associated with an increased risk of hyperkalemia. Although the results of the EPHESUS study in patients with type 2 diabetes and microalbuminuria are limited, an increased incidence of hyperkalemia was observed in this small group of patients. Eplerenone is not removed by hemodialysis.

Hepatic impairment. In patients with mild to moderate hepatic impairment (Child-Pugh class A and B), serum potassium levels above 5.5 mmol/L are not expected to increase. These patients should be monitored for electrolytes. Eplerenone has not been studied in patients with severe renal impairment and is therefore contraindicated in these patients (see sections 4.3 and 4.4).

CYP3A4 inducers: Concomitant use of eplerenone and strong CYP3A4 inducers is not recommended (see section 4.5).

Lithium, cyclosporine, tacrolimus should not be administered during treatment with eplerenone (see section “Interaction with other medicinal products and other types of interactions”).

Fertility: There is no information on the effect on human fertility.

Lactose. The drug contains lactose, so it should not be prescribed to patients with rare hereditary disorders (galactose intolerance, congenital Lapp lactase deficiency or glucose-galactose malabsorption syndrome).

Ability to influence reaction speed when driving vehicles or other mechanisms

Studies on the effect of eplerenone on the ability to drive or use machines have not been conducted. Eplerenone does not cause drowsiness or cognitive impairment, but when driving or operating machinery, the possibility of dizziness should be taken into account.

Use during pregnancy or breastfeeding

Pregnancy: There are no adequate data from the use of eplerenone in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition, or postnatal development. Eplerenone should be administered with caution to pregnant women.

Breastfeeding. It is not known whether eplerenone is excreted in human milk after oral administration. However, nonclinical data indicate that eplerenone and/or its metabolites are present in the milk of rats and that the offspring exposed to eplerenone in this manner developed normally. Since the potential for adverse reactions in breastfed infants has not been studied, a clinical decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Method of administration and doses

The drug is available in doses of 25 mg and 50 mg. The maximum daily dose of the drug is 50 mg.

Patients with heart failure after myocardial infarction. The recommended maintenance dose of eplerenone is 50 mg once daily. Treatment should be initiated at 25 mg once daily and titrated to a target dose of 50 mg once daily. This dose level should be achieved within 4 weeks, taking into account serum potassium levels (see table below). Treatment with eplerenone is usually initiated 3 to 14 days after acute myocardial infarction.

Patients with NYHA class II (chronic) heart failure.

Treatment of patients with chronic heart failure class II according to the NYHA classification should be initiated at a dose of 25 mg once daily and gradually increased to a target dose of 50 mg once daily. It is advisable to reach this dose level within 4 weeks, taking into account the level of potassium in the blood serum (see table below and section "Special instructions").

Patients with serum potassium levels greater than 5 mmol/L should not initiate treatment with eplerenone (see section 4.3).

Serum potassium levels should be measured before initiating treatment with eplerenone, during the first week of treatment, and one month after initiation of treatment or dose adjustment. Serum potassium levels should be measured periodically later in treatment as necessary.

After initiation of treatment, the dose should be adjusted based on serum potassium levels as shown in the table below.

Dose adjustment after initiation of treatment.

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

Elderly patients.

There is no need to adjust the initial dose of the drug for elderly patients. Due to age-related decline in renal function, the risk of developing hyperkalemia in elderly patients increases. The risk may be further increased in the presence of concomitant diseases accompanied by increased systemic exposure to the drug, in particular mild to moderate liver dysfunction. It is recommended to periodically monitor the level of potassium in the blood serum (see section "Special instructions").

Kidney dysfunction.

Patients with mild renal impairment do not require adjustment of the initial dose. It is recommended to periodically monitor serum potassium levels (see section "Special warnings and precautions for use") and adjust the dose of the drug according to the table above.

Patients with moderate renal impairment (creatinine clearance 30-60 mg/ml) should start treatment with 25 mg every other day and adjust the dose depending on the potassium concentration (see table above). Periodic monitoring of serum potassium is recommended (see section 4.4).

There is no experience in patients with creatinine clearance < 50 ml/min and heart failure after myocardial infarction. Eplerenone should be used with caution in these patients.

Doses greater than 25 mg/day have not been studied in patients with creatinine clearance < 50 mL/min.

Eplerenone is contraindicated in patients with severe renal impairment (creatinine clearance < 30 ml/min) (see section 4.3). Eplerenone is not dialysable.

Liver dysfunction.

Patients with mild or moderate hepatic impairment do not require adjustment of the initial dose, however, due to increased systemic exposure to eplerenone, frequent and regular monitoring of serum potassium is recommended in this category of patients, and especially in elderly patients (see section "Special warnings and precautions for use").

Combined use.

In case of concomitant use with weak or moderate CYP3A4 inhibitors (e.g. amiodarone, diltiazem and verapamil), eplerenone treatment can be initiated at a starting dose of 25 mg once daily. The dose should not exceed 25 mg once daily (see section 4.5).

Children

There are no data on the use of eplerenone in children, therefore the use of the drug in this group of patients is not recommended.

Overdose

There have been no reports of adverse reactions associated with eplerenone overdose in humans. The most likely manifestations of overdose in humans are expected to be hypotension or hyperkalemia. Eplerenone is not removed by hemodialysis. Eplerenone is effectively bound to activated charcoal. If hypotension develops, supportive treatment should be initiated. If hyperkalemia develops, treatment should be initiated according to standards.

Adverse reactions

In two studies (EPHESUS and EMPHASIS-HF), it was demonstrated that the overall incidence of adverse reactions with eplerenone and placebo was similar.

The following are adverse reactions that are possibly related to the use of eplerenone and that occurred with eplerenone treatment more often than with placebo, or serious adverse reactions that occurred with eplerenone treatment more often than with placebo, or those that were described during post-marketing surveillance.

Adverse reactions are classified by organ system and absolute frequency: very common (≥ 1/10), common (≥ 1/100 - < 1/10), uncommon (≥ 1/1000 - < 1/100), rare (≥ 1/10000 - < 1/1000), very rare (< 1/10000), frequency unknown (cannot be estimated from the available information).

Infections and infestations: uncommon: infection, pyelonephritis, pharyngitis.

From the blood and lymphatic system: infrequently - eosinophilia.

On the part of the endocrine system: infrequently - hypothyroidism.

Metabolism and digestion: often - hyperkalemia (see sections "Contraindications" and "Features of use"), hypertriglyceridemia; infrequently - hyponatremia, dehydration, hypercholesterolemia.

On the part of the psyche: infrequently - insomnia.

From the nervous system: often - dizziness, syncope, headache; infrequently - hypoesthesia.

Cardiac disorders: often – left ventricular failure, atrial fibrillation; infrequently – tachycardia.

From the vascular system: often - hypotension; infrequently - thrombosis of the arteries of the extremities, orthostatic hypotension.

Respiratory, thoracic and mediastinal disorders: often - cough.

From the gastrointestinal tract: often - diarrhea, nausea, constipation, vomiting; infrequently - bloating.

Skin and subcutaneous tissue disorders: common: rash, itching; uncommon: hyperhidrosis, angioedema.

Musculoskeletal and connective tissue disorders: common: muscle spasms, back pain; uncommon: musculoskeletal pain.

On the part of the kidneys and urinary tract: often - impaired renal function (see sections "Interaction with other medicinal products and other types of interactions" and "Special instructions for use").

Liver and biliary tract disorders: infrequently - cholecystitis.

Reproductive system and breast disorders: uncommon – gynecomastia.

General disorders and administration site conditions: uncommon – asthenia, malaise.

Laboratory tests: often - increased blood urea; increased creatinine; infrequently - decreased epidermal growth factor receptor number, increased blood glucose level.

In the EPHESUS study, a numerically higher number of strokes were reported in patients ≥ 75 years of age. However, there was no statistically significant difference in the incidence of strokes between the eplerenone (30) and placebo (22) groups. In the EMPHASIS-HF study, the number of strokes in patients ≥ 75 years of age was 9 in the eplerenone group and 8 in the placebo group.

Reporting of suspected adverse reactions.

Reporting of suspected adverse reactions after the marketing authorisation of a medicinal product is important. This allows for continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions in accordance with local requirements.

Expiration date

3 years.

Storage conditions

Store in the original packaging at a temperature not exceeding 25°C.

Keep out of reach of children.

Packaging

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

Vacation category

According to the recipe.

Producer

PJSC "Kyivmedpreparat".

Location of the manufacturer and its business address

Ukraine, 01032, Kyiv, Saksaganskoho St. 139.