Inspra film-coated tablets 25 mg blister No. 30

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

Composition

active ingredient: eplerenone;

1 tablet contains 25 mg or 50 mg of eplerenone;

excipients: lactose monohydrate; microcrystalline cellulose; croscarmellose sodium; hypromellose; sodium lauryl sulfate; talc; magnesium stearate; Opadry yellow YS-1-12524-A.

Dosage form

Film-coated tablets.

Main physicochemical properties: film-coated tablets, yellow, diamond-shaped, with stylized engraving "Pfizer" on one side of the tablet and "NSR" over "25" or "50" on the other side of the tablet for 25 mg and 50 mg tablets, respectively.

Pharmacotherapeutic group

Potassium-sparing diuretics. Aldosterone antagonists. Eplerenone. ATC 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 the EPHESUS Cardio-Nephrology Substudy (Effectiveness and Mortality Study of Eplerenone in Patients with Acute Myocardial Infarction Complicated by 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.

Eplerenone was studied in the EPHESUS study. This was a 3-year, double-blind, placebo-controlled study in 6,632 subjects with acute myocardial infarction, left ventricular dysfunction (as assessed by left ventricular ejection fraction ≤ 40%) and clinical signs of heart failure. 3–14 days after acute myocardial infarction (median 7 days), subjects received eplerenone or placebo in addition to standard care at an initial dose of 25 mg once daily. The dose was then titrated (over 4 weeks) to a target dose of 50 mg once daily, provided that serum potassium was <5 mmol/L. During the study, subjects received standard treatment, which included acetylsalicylic acid (92%), ACE inhibitors (90%), β-blockers (83%), nitrates (72%), loop diuretics (66%), or HMG-CoA reductase inhibitors (60%).

In a study of 147 healthy volunteers for ECG changes during pharmacokinetic studies, no consistent effect of eplerenone on heart rate, QRS complex duration, or PR and QT intervals was observed.

The EMPHASIS-HF study (Eplerenone Hospitalization and Mortality Study in Patients with Mild Symptomatic Heart Failure) examined the efficacy of eplerenone added to standard care on clinical outcomes in subjects with mild symptomatic systolic heart failure (NYHA functional class II).

The study enrolled subjects 55 years of age or older who had a left ventricular ejection fraction ≤ 30% or ≤ 35% with a QRS duration greater than 130 milliseconds and who had been hospitalized for cardiovascular events within the 6 months prior to the study or who had a plasma B-type natriuretic peptide (BNP) level of at least 250 pg/mL or a plasma N-terminal pro-BNP level of at least 500 pg/mL in men (750 pg/mL in women). The starting dose of eplerenone was 25 mg once daily. After 4 weeks, the dose was increased to 50 mg once daily provided that the serum potassium level was <5 mmol/L. Alternatively, if the estimated glomerular filtration rate was 30–49 mL/min/1.73 m2, the initial dose of eplerenone was 25 mg every other day and was subsequently increased to 25 mg once daily.

A total of 2737 subjects were randomized (double-blind) to eplerenone or placebo on background therapy of diuretics (85%), ACE inhibitors (78%), angiotensin II receptor blockers (19%), β-blockers (87%), antithrombotic agents (88%), lipid-lowering agents (63%), and digitalis glycosides (27%). The mean left ventricular ejection fraction was 26%, and the mean QRS duration was 122 ms. The majority of subjects (83.4%) had been hospitalized for cardiovascular events in the 6 months prior to randomization, with approximately half of these subjects being hospitalized for heart failure. Approximately 20% of subjects had implanted defibrillators or were receiving cardiac resynchronization therapy.

The primary endpoint (cardiovascular death or hospitalization for heart failure) occurred in 249 subjects (18.3%) in the eplerenone group and 356 subjects (25.9%) in the placebo group (HR 0.63; 95% CI 0.54-0.74, p < 0.001). The effect of eplerenone on the primary endpoint was consistent across all prespecified subgroups.

The secondary endpoint (all-cause mortality) occurred in 171 subjects (12.5%) in the eplerenone group and 213 subjects (15.5%) in the placebo group (HR 0.76; 95% CI 0.62-0.93, p=0.008). Cardiovascular death occurred in 147 subjects (10.8%) in the eplerenone group and 185 subjects (13.5%) in the placebo group (HR 0.76; 95% CI 0.61-0.93, p=0.01).

During the study, hyperkalemia (serum potassium > 5.5 mmol/L) occurred in 158 subjects (11.8%) in the eplerenone group and 96 subjects (7.2%) in the placebo group (p < 0.001). Hypokalemia (serum potassium < 4 mmol/L) occurred at a statistically significantly lower rate in the eplerenone group than in the placebo group (38.9% in the eplerenone group and 48.4% in the placebo group, p < 0.0001).

Children: Eplerenone has not been studied in children with heart failure.

In a 10-week study in children with hypertension (ages 4–16 years, n=304), eplerenone at doses of 25–100 mg/day, resulting in exposures similar to those in adults, did not demonstrate effective blood pressure reduction. In this study and in a 1-year safety study in 149 children aged 5–17 years, the safety profile was similar to that observed in adults. Eplerenone has not been studied in children younger than 4 years with hypertension because studies in older children have shown a lack of efficacy (see section 4.2).

No studies have been conducted on any (long-term) effects on the hormonal status of children.

Pharmacokinetics.

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

The maximum concentration of the drug in the blood plasma is reached after approximately 1.5-2 hours. The maximum concentration in the blood plasma (Cmax) and the area under the pharmacokinetic curve (AUC) change proportionally to the dose in the range of 10-100 mg and less than dose-proportionally when using doses above 100 mg. The equilibrium state is reached within 2 days from the start of treatment. Food does not affect the absorption of the drug.

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

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/h.

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 categories of subjects: elderly patients (65 years of age and older), male patients, female patients, and black patients. There were no significant differences in the pharmacokinetics of eplerenone in patients based on gender. Elderly subjects had a 22% increase in Cmax and 45% in AUC at steady state compared to younger subjects (18–45 years of age). In black subjects, 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 from 2 studies involving 51 patients aged 4 to 16 years, it was found that patient weight had 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 children with higher body weight are expected to be similar to those observed in adults with similar body weight. In patients weighing 45 kg, the volume of distribution is approximately 40% lower and peak exposure is expected to be higher than that typically observed in adults. Children were given an initial dose of eplerenone of 25 mg once daily; after 2 weeks, the dose was increased to 25 mg twice daily and, if clinically indicated, to 50 mg twice daily. At these doses, peak eplerenone concentrations in children were not significantly higher than those observed in adults at a starting dose of 50 mg once daily.

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 plasma clearance of eplerenone 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 class 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 in a subset of patients from the EPHESUS study indicated that the clearance of eplerenone in heart failure patients was not different from that in healthy elderly volunteers.

Indication

Add-on to standard β-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.

Adjunct 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%) (see section 5.1).

Contraindication

Hypersensitivity to the active substance or to any of the excipients listed in the "Composition" section.

Patients with serum potassium levels > 5 mmol/L at the time of initiation of treatment.

Patients with severe renal insufficiency (estimated glomerular filtration rate < 30 ml/min/1.73 m2).

Patients with severe hepatic insufficiency (Child-Pugh class C).

Concomitant 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).

Non-steroidal anti-inflammatory drugs (NSAIDs). Acute renal failure may occur in patients at risk (elderly, dehydrated, those taking diuretics, those with impaired renal function) due to a decrease in glomerular filtration (inhibition of vasodilator prostaglandins by non-steroidal anti-inflammatory drugs). This effect is usually reversible. In addition, a decrease in the antihypertensive effect is possible. The patient should be hydrated and renal function should be monitored at the beginning of treatment and regularly during combination therapy (see sections “Method of administration and dosage” and “Special precautions for use”).

Trimethoprim. Concomitant 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.

α1-blockers (e.g. prazosin, alfuzosin). When combining α1-blockers with eplerenone, there is a possibility of increased hypotensive effect and/or development of orthostatic hypotension. During the simultaneous use of α1-blockers, the clinical condition 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 administered concomitantly with eplerenone, there is a possibility of attenuation of the hypotensive effect due to fluid and sodium retention.

Pharmacokinetic interactions.

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

Digoxin: The systemic exposure (AUC) of digoxin 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 agents were co-administered with eplerenone.

CYP3A4 inhibitors.

Weak and moderate CYP3A4 inhibitors: Co-administration with erythromycin, saquinavir, amiodarone, diltiazem, verapamil, or fluconazole resulted in significant pharmacokinetic interactions with increases in AUC of 98-187%. Therefore, when eplerenone is co-administered with weak or moderate CYP3A4 inhibitors, the dose of eplerenone should not exceed 25 mg/day (see Dosage and Administration).

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 potent 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 potent 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 concomitant use of eplerenone and antacids.

Application features

Hyperkalemia. Due to its mechanism of action, hyperkalemia may occur during treatment with eplerenone. Serum potassium levels should be monitored in all patients at the start of treatment and during dose adjustments. Periodic monitoring is recommended thereafter, especially in patients at risk of hyperkalemia (such as the elderly, patients with renal impairment (see section 4.2) and diabetes). Potassium supplements are not recommended after initiation of eplerenone treatment due to the increased risk of hyperkalemia. It has been shown that reducing the dose of eplerenone leads to a decrease in serum potassium. In one study, the addition of hydrochlorothiazide to eplerenone therapy compensated for the increase in serum potassium.

The risk of hyperkalaemia 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 triple combination with an ACE inhibitor and an angiotensin receptor blocker (see sections 4.3 and 4.5).

Renal impairment. In patients with renal impairment (including diabetic microalbuminuria), potassium levels should be 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. Accordingly, such patients should be treated with caution. 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 were not observed. These patients require monitoring of electrolyte levels. The use of eplerenone in patients with severe renal impairment has not been studied and is therefore contraindicated in such patients (see sections 4.2 and 4.3).

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

The use of lithium, cyclosporine, tacrolimus should be avoided during treatment with eplerenone (see section "Interaction with other medicinal products and other types of interactions").

Lactose.

This medicinal product contains lactose and should not be used in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.

Sodium.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, i.e. essentially 'sodium-free'.

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

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 decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Ability to influence reaction speed when driving vehicles or other mechanisms

Studies on the effects 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 associated with treatment with the drug should be taken into account.

Method of administration and doses

Adults.

For individual dosage selection, the drug is available in doses of 25 mg and 50 mg. The maximum daily dose of the drug is 50 mg per day.

Eplerenone can be administered with or without food (see Pharmacokinetics).

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).

Eplerenone treatment is usually initiated 3–14 days after acute myocardial infarction.

Patients with NYHA class II (chronic) heart failure. Treatment of patients with NYHA class II chronic heart failure should be initiated at a dose of 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 and section 4.4).

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 during 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 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 further increase 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").

Renal impairment: Patients with mild renal impairment do not require initial dose adjustment. It is recommended to periodically monitor serum potassium levels and adjust the dose according to the table above.

Patients with moderate renal impairment (creatinine clearance

30–60 ml/min) treatment should be initiated at a dose of 25 mg every 2 days and the dose adjusted depending on the potassium concentration (see table above). Periodic monitoring of serum potassium is recommended (see section "Special instructions").

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 such 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.

Hepatic impairment: No initial dose adjustment is required in patients with mild to moderate hepatic impairment. Due to increased systemic exposure to eplerenone, frequent and regular monitoring of serum potassium is recommended in this population, especially in the elderly (see section 4.4).

Children: The safety and efficacy of eplerenone in children have not been established. Currently available information is provided in the Pharmacodynamics and Pharmacokinetics sections.

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 has been shown to bind effectively to activated charcoal. If hypotension develops, supportive treatment should be initiated. If hyperkalemia develops, treatment should be initiated according to standard guidelines.

Side effects

Two studies (EPHESUS and EMPHASIS-HF) 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 during treatment more often than during placebo, or serious adverse reactions that occurred during treatment more often than during placebo, or those that were described during post-marketing surveillance.

Adverse reactions are classified by system organ class 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 invasions.

Uncommon: pyelonephritis, infections, pharyngitis.

From the blood and lymphatic system.

Uncommon: eosinophilia.

From the endocrine system.

Uncommon: hypothyroidism.

Metabolism and digestion.

Common: hyperkalemia (see sections "Contraindications" and "Special warnings and precautions for use"), hypercholesterolemia.

Uncommon: hyponatremia, dehydration, hypertriglyceridemia.

From the psychological side.

Common: insomnia.

From the nervous system.

Common: syncope, dizziness, headache.

Uncommon: hypoesthesia.

From the heart.

Common: left ventricular failure, atrial fibrillation.

Uncommon: tachycardia.

From the side of the vessels.

Common: hypotension.

Uncommon: limb arterial thrombosis, orthostatic hypotension.

On the part of the respiratory system, chest organs and mediastinum.

Common: cough.

From the gastrointestinal tract.

Common: diarrhea, nausea, constipation, vomiting.

Uncommon: abdominal bloating.

On the part of the skin and subcutaneous tissues.

Common: rash, itching.

Uncommon: angioedema, hyperhidrosis.

On the part of the musculoskeletal system and connective tissues.

Common: muscle spasms, back pain

Uncommon: musculoskeletal pain.

From the kidneys and urinary tract.

Common: renal dysfunction (see sections "Special warnings and precautions for use" and "Interaction with other medicinal products and other types of interactions").

From the liver and biliary tract.

Uncommon: cholecystitis.

From the reproductive system and mammary glands.

Uncommon: gynecomastia.

General disorders and administration site conditions.

Common: asthenia.

Uncommon: malaise.

Laboratory studies.

Common: increased blood urea, increased creatinine.

Uncommon: decreased epidermal growth factor receptor number, increased blood glucose levels.

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.

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