INSPRA Eplerenone 50mg Film-Coated Tablet 1's
RXDRUG-DR-XY30975-1pc
Discreet Packaging
FDA-registered Products
FDA-licensed Pharmacies
Indications/Uses
Hypertension: Eplerenone is indicated for the treatment of hypertension. In these patients, eplerenone may be used alone or in combination with other antihypertensive agents.
Heart Failure - Post Myocardial Infarction (MI): Eplerenone is indicated, in addition to standard therapy, to reduce the risk of cardiovascular mortality and morbidity in stable patients with left ventricular dysfunction (left ventricular ejection fraction [LVEF] ≤40%) and clinical evidence of heart failure after recent MI.
New York Heart Association (NYHA) Class II (Chronic) Heart Failure: Eplerenone is indicated in addition to standard optimal therapy to reduce the risk of cardiovascular mortality and morbidity in adult patients with NYHA class II (chronic) heart failure and left ventricular systolic dysfunction (LVEF ≤35%).
Heart Failure - Post Myocardial Infarction (MI): Eplerenone is indicated, in addition to standard therapy, to reduce the risk of cardiovascular mortality and morbidity in stable patients with left ventricular dysfunction (left ventricular ejection fraction [LVEF] ≤40%) and clinical evidence of heart failure after recent MI.
New York Heart Association (NYHA) Class II (Chronic) Heart Failure: Eplerenone is indicated in addition to standard optimal therapy to reduce the risk of cardiovascular mortality and morbidity in adult patients with NYHA class II (chronic) heart failure and left ventricular systolic dysfunction (LVEF ≤35%).
Dosage/Direction for Use
The maximum dose regimen is 50 mg daily for heart failure and 100 mg daily for hypertension.
Hypertension: Eplerenone may be used alone or in combination with other antihypertensive agents. The recommended starting dose of eplerenone is 50 mg administered once daily. If blood pressure is not adequately controlled, the dose of eplerenone can be increased to 100 mg daily.
Heart Failure - Post MI: The recommended maintenance dose of eplerenone is 50 mg once daily. Treatment should be initiated at 25 mg once daily and titrated in one step to the target dose of 50 mg once daily preferably within 4 weeks, taking into account the serum potassium level (see Table 1 Dose Adjustment Table in Heart Failure - Post MI). After initiation, the dose should be adjusted based on the serum potassium level as shown in Table 1 Dose Adjustment Table in Heart Failure - Post MI.
NYHA Class II (Chronic) Heart Failure: For chronic heart failure NYHA class II patients, treatment should be initiated at a dose of 25 mg once daily and titrated to the target dose of 50 mg once daily preferably within 4 weeks, taking into account the serum potassium level (see Table 1 Dose Adjustment Table in Heart Failure - Post MI and Precautions).
Hypertension: Eplerenone may be used alone or in combination with other antihypertensive agents. The recommended starting dose of eplerenone is 50 mg administered once daily. If blood pressure is not adequately controlled, the dose of eplerenone can be increased to 100 mg daily.
Heart Failure - Post MI: The recommended maintenance dose of eplerenone is 50 mg once daily. Treatment should be initiated at 25 mg once daily and titrated in one step to the target dose of 50 mg once daily preferably within 4 weeks, taking into account the serum potassium level (see Table 1 Dose Adjustment Table in Heart Failure - Post MI). After initiation, the dose should be adjusted based on the serum potassium level as shown in Table 1 Dose Adjustment Table in Heart Failure - Post MI.
NYHA Class II (Chronic) Heart Failure: For chronic heart failure NYHA class II patients, treatment should be initiated at a dose of 25 mg once daily and titrated to the target dose of 50 mg once daily preferably within 4 weeks, taking into account the serum potassium level (see Table 1 Dose Adjustment Table in Heart Failure - Post MI and Precautions).
Following withholding eplerenone due to serum potassium ≥6.0 mmol/L (or ≥6.0 mEq/L), eplerenone can be re-started at a dose of 25 mg every other day when potassium levels have fallen below 5.0 mmol/L (or 5.0 mEq/L).
General Considerations: Potassium: Serum potassium should be measured before initiating eplerenone therapy, within the first week and at one month after the start of treatment or dose adjustment. Serum potassium should be assessed periodically thereafter.
Food: Eplerenone may be administered with or without food.
Concomitant CYP3A4 Medications: Patients receiving mild to moderate CYP3A4 inhibitors, such as erythromycin, saquinavir, verapamil, and fluconazole should receive the dose of 25 mg once daily. (See Interactions.)
Special Populations and Special Considerations for Dosing: Use in Hepatic Impairment: Mild-to-Moderate Hepatic Impairment: No initial dose adjustment is necessary. (See Contraindications and Precautions.)
Use in Renal Impairment: No initial dose adjustment is required in patients with mild renal impairment. The rates of hyperkalemia increase with declining renal function. Periodic monitoring of serum potassium with dose adjustment according to Table 1 Dose Adjustment Table in Heart Failure - Post MI is recommended (see Precautions).
Patients with NYHA Class II (Chronic) Heart Failure and moderate renal impairment (CrCl 30-60 mL/min) should be started at 25 mg every other day, and dose should be adjusted based on the potassium level (see Table 1 Dose Adjustment Table in Heart Failure - Post MI). Periodic monitoring of serum potassium is recommended (see Precautions).
There is no experience in Post MI heart failure patients with CrCl <50 mL/min. The use of eplerenone in these patients should be done cautiously. Doses above 25 mg daily have not been studied in patients with CrCl <50 mL/min.
Use in patients with severe renal impairment (CrCl ˂30 mL/min) is contraindicated (see Contraindications). Eplerenone is not dialyzable.
For hypertensive patients with moderate-to-severe renal impairment or Type 2 diabetes with microalbuminuria, see Contraindications and Precautions.
Use in the Elderly: No initial adjustment of the dose is required in elderly patients (see Precautions).
Use in Children: Eplerenone has not been studied in hypertensive patients less than 4 years old because the study in older pediatric patients did not demonstrate efficacy. Currently available data are described in Pharmacology: Pharmacodynamics and Pharmacokinetics under Actions.
Safety and efficacy of eplerenone have not been studied in pediatric patients with heart failure.
General Considerations: Potassium: Serum potassium should be measured before initiating eplerenone therapy, within the first week and at one month after the start of treatment or dose adjustment. Serum potassium should be assessed periodically thereafter.
Food: Eplerenone may be administered with or without food.
Concomitant CYP3A4 Medications: Patients receiving mild to moderate CYP3A4 inhibitors, such as erythromycin, saquinavir, verapamil, and fluconazole should receive the dose of 25 mg once daily. (See Interactions.)
Special Populations and Special Considerations for Dosing: Use in Hepatic Impairment: Mild-to-Moderate Hepatic Impairment: No initial dose adjustment is necessary. (See Contraindications and Precautions.)
Use in Renal Impairment: No initial dose adjustment is required in patients with mild renal impairment. The rates of hyperkalemia increase with declining renal function. Periodic monitoring of serum potassium with dose adjustment according to Table 1 Dose Adjustment Table in Heart Failure - Post MI is recommended (see Precautions).
Patients with NYHA Class II (Chronic) Heart Failure and moderate renal impairment (CrCl 30-60 mL/min) should be started at 25 mg every other day, and dose should be adjusted based on the potassium level (see Table 1 Dose Adjustment Table in Heart Failure - Post MI). Periodic monitoring of serum potassium is recommended (see Precautions).
There is no experience in Post MI heart failure patients with CrCl <50 mL/min. The use of eplerenone in these patients should be done cautiously. Doses above 25 mg daily have not been studied in patients with CrCl <50 mL/min.
Use in patients with severe renal impairment (CrCl ˂30 mL/min) is contraindicated (see Contraindications). Eplerenone is not dialyzable.
For hypertensive patients with moderate-to-severe renal impairment or Type 2 diabetes with microalbuminuria, see Contraindications and Precautions.
Use in the Elderly: No initial adjustment of the dose is required in elderly patients (see Precautions).
Use in Children: Eplerenone has not been studied in hypertensive patients less than 4 years old because the study in older pediatric patients did not demonstrate efficacy. Currently available data are described in Pharmacology: Pharmacodynamics and Pharmacokinetics under Actions.
Safety and efficacy of eplerenone have not been studied in pediatric patients with heart failure.
Overdosage
No cases of adverse events associated with overdose of eplerenone in humans have been reported. The most likely manifestation of human overdose would be hypotension and/or hyperkalemia, consequently patients should be treated symptomatically and supportive measures instituted, as required. Eplerenone cannot be removed by hemodialysis. Eplerenone has been shown to bind extensively to charcoal.
Administration
May be taken with or without food.
Contraindications
Eplerenone is contraindicated in all patients with the following: hypersensitivity to eplerenone or any component of this medication; clinically significant hyperkalemia or with conditions associated with hyperkalemia; serum potassium level >5.0 mmol/L (mEq/L) at initiation; moderate to severe renal impairment (creatinine clearance <50 mL/min) in post MI heart failure (Eplerenone Post-acute Myocardial Infarction Heart failure Efficacy and Survival Study [EPHESUS]) or creatinine clearance of ˂30 mL/min in NYHA Class II (chronic) heart failure (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure [EMPHASIS-HF]); severe hepatic impairment (Child-Pugh Class C); concomitant use with potassium-sparing diuretics, or potent inhibitors of CYP450 3A4 such as ketoconazole, itraconazole, and ritonavir, (see Interactions).
Eplerenone is also contraindicated in hypertensive patients with the following conditions: type 2 diabetes with microalbuminuria; serum creatinine >2.0 mg/dL (or >177 µmol/L) in males or >1.8 mg/dL (or >159 µmol/L) in females; concomitant use with potassium supplements.
Eplerenone is also contraindicated in hypertensive patients with the following conditions: type 2 diabetes with microalbuminuria; serum creatinine >2.0 mg/dL (or >177 µmol/L) in males or >1.8 mg/dL (or >159 µmol/L) in females; concomitant use with potassium supplements.
Special Precautions
Hyperkalemia: Eplerenone is associated with an increased risk of hyperkalemia. This risk can be minimized by patient selection, avoidance of certain concomitant treatments, and monitoring. Eplerenone should generally not be administered to patients who are receiving potassium supplements (see Contraindications). Potassium levels should be monitored regularly in patients with impaired renal function, including diabetic microalbuminuria (see as follows). Dose reduction of eplerenone has been shown to decrease serum potassium levels (see Dosage & Administration).
The risk of hyperkalemia may increase when eplerenone is used in combination with an Angiotensin-converting enzyme (ACE) inhibitor and/or an angiotensin receptor blocker (ARB).
Impaired Hepatic Function: Due to increased systemic exposure to eplerenone in patients with mild-to-moderate hepatic impairment, frequent and regular monitoring of serum potassium is recommended in these patients, especially when elderly. The use of eplerenone in patients with severe hepatic impairment (Child-Pugh Class C) has not been evaluated and is therefore contraindicated (see Dosage & Administration and Contraindications).
Impaired Renal Function: See Hyperkalemia as previously mentioned and Contraindications.
CYP 3A4 Inducers: Co-administration of eplerenone with potent CYP 3A4 inducers is not recommended (see Interactions).
Information for Patients: Patients receiving eplerenone should be informed not to use potassium supplements, salt substitutes containing potassium, or contraindicated medications without consulting the prescribing healthcare professional.
Effects on Ability to Drive and Use Machines: Dizziness and syncope have been reported to occur in some patients. Caution is advised when driving or operating machinery until the response to initial treatment has been determined.
Use in the Elderly: Due to age-related decline in renal function, the risk of hyperkalemia is increased in elderly patients. Periodic monitoring of serum potassium is recommended.
The risk of hyperkalemia may increase when eplerenone is used in combination with an Angiotensin-converting enzyme (ACE) inhibitor and/or an angiotensin receptor blocker (ARB).
Impaired Hepatic Function: Due to increased systemic exposure to eplerenone in patients with mild-to-moderate hepatic impairment, frequent and regular monitoring of serum potassium is recommended in these patients, especially when elderly. The use of eplerenone in patients with severe hepatic impairment (Child-Pugh Class C) has not been evaluated and is therefore contraindicated (see Dosage & Administration and Contraindications).
Impaired Renal Function: See Hyperkalemia as previously mentioned and Contraindications.
CYP 3A4 Inducers: Co-administration of eplerenone with potent CYP 3A4 inducers is not recommended (see Interactions).
Information for Patients: Patients receiving eplerenone should be informed not to use potassium supplements, salt substitutes containing potassium, or contraindicated medications without consulting the prescribing healthcare professional.
Effects on Ability to Drive and Use Machines: Dizziness and syncope have been reported to occur in some patients. Caution is advised when driving or operating machinery until the response to initial treatment has been determined.
Use in the Elderly: Due to age-related decline in renal function, the risk of hyperkalemia is increased in elderly patients. Periodic monitoring of serum potassium is recommended.
Use In Pregnancy & Lactation
Fertility/Pregnancy: Eplerenone has not been studied in pregnant women. Animal studies did not indicate direct or indirect adverse effects with respect to pregnancy; embryofetal development, parturition and post-natal development (see Pharmacology: Toxicology: Preclinical Safety Data under Actions). Caution should be exercised when prescribing eplerenone to pregnant women.
Lactation: It is unknown if eplerenone is excreted in human breast milk after oral administration. However, preclinical data show that eplerenone and/or metabolites are present in rat breast milk and that rat pups exposed by this route developed normally. Because many drugs are excreted in human milk and because of the unknown potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Lactation: It is unknown if eplerenone is excreted in human breast milk after oral administration. However, preclinical data show that eplerenone and/or metabolites are present in rat breast milk and that rat pups exposed by this route developed normally. Because many drugs are excreted in human milk and because of the unknown potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Adverse Reactions
Hypertension: The following adverse events are those with suspected relationship to the treatment and are from the monotherapy arms of four placebo-controlled trials in subjects with hypertension who received eplerenone 25 mg to 400 mg. Events with incidence greater than 1% and greater than placebo are provided as follows.
Note: Adverse events that are too general to be informative or are very common in the treated population are excluded. (See Table 2.)
Note: Adverse events that are too general to be informative or are very common in the treated population are excluded. (See Table 2.)
Heart Failure Post MI and NYHA Class II (Chronic) Heart Failure: In two studies (EPHESUS and EMPHASIS-HF), the overall incidence of adverse events and the discontinuation rate due to adverse events reported with eplerenone was similar to placebo.
The most frequent adverse event reported in EPHESUS and EMPHASIS-HF studies was hyperkalemia with an incidence rate of 3.4% and 8.7% for eplerenone, respectively.
Adverse events reported as follows are those with suspected relationship to treatment. Adverse events are listed by body system and absolute frequency. (See Table 3.)
The most frequent adverse event reported in EPHESUS and EMPHASIS-HF studies was hyperkalemia with an incidence rate of 3.4% and 8.7% for eplerenone, respectively.
Adverse events reported as follows are those with suspected relationship to treatment. Adverse events are listed by body system and absolute frequency. (See Table 3.)
Drug Interactions
Potassium-sparing diuretics: Eplerenone should not be administered to patients receiving potassium-sparing diuretics (see Contraindications and Hyperkalemia under Precautions).
ACE inhibitors, ARBs: The risk of hyperkalemia may increase when eplerenone is used in combination with an ACE inhibitor and/or an ARB. Close monitoring of serum potassium and renal function is recommended, especially in patients at risk for impaired renal function, e.g., the elderly.
Digoxin: No clinically significant drug-drug pharmacokinetic interactions have been found with digoxin. While a statistically significant 16% increase in AUC0-24 was observed with digoxin 200 mcg and eplerenone 100 mg once daily in a pharmacokinetic study in healthy volunteers, this increase was not accompanied by clinical evidence of digoxin toxicity.
Warfarin: No clinically significant drug-drug pharmacodynamic interactions have been found with warfarin.
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Drug interaction studies of eplerenone have not been conducted with NSAIDs. NSAIDs administered with potassium-sparing antihypertensives have been shown to result in hyperkalemia in patients with impaired renal function.
Lithium: Drug interaction studies of eplerenone have not been conducted with lithium. Lithium toxicity has been reported in patients receiving lithium concomitantly with diuretics and ACE inhibitors.
In vitro studies indicate that eplerenone is not an inhibitor of CYP1A2, CYP2C19, CYP2C9, CYP2D6 or CYP3A4 isozymes. Eplerenone is not a substrate or an inhibitor of P-glycoprotein.
CYP3A4 substrates: Results of pharmacokinetic studies with CYP3A4 probe-substrates, i.e. midazolam and cisapride, showed no significant pharmacokinetic interactions when these drugs were co-administered with eplerenone.
CYP3A4 inhibitors: Potent CYP3A4 inhibitors: Significant pharmacokinetic interactions may occur when eplerenone is co-administered with drugs that inhibit the CYP3A4 enzyme. A potent inhibitor of CYP3A4 (ketoconazole 200 mg twice daily) led to a 441% increase in AUC of eplerenone (see Contraindications). The concomitant use of eplerenone with potent CYP3A4 inhibitors such as ketoconazole, itraconazole, and ritonavir is contraindicated (see Contraindications).
Mild to moderate CYP3A4 inhibitors: Co-administration with erythromycin, saquinavir, verapamil, or fluconazole has led to significant pharmacokinetic interactions with rank order increases in AUC ranging from 98% to 187%. Eplerenone dosing should therefore not exceed 25 mg daily when mild to moderate inhibitors of CYP3A4 are co-administered with eplerenone (see Dosage & Administration).
CYP3A4 inducers: Co-administration of St. John's Wort (a potent CYP3A4 inducer) with eplerenone caused a 30% decrease in eplerenone AUC. A more pronounced decrease in eplerenone AUC may occur with more potent CYP3A4 inducers and the concomitant use of potent CYP3A4 inducers with eplerenone is not recommended (see Precautions).
ACE inhibitors, ARBs: The risk of hyperkalemia may increase when eplerenone is used in combination with an ACE inhibitor and/or an ARB. Close monitoring of serum potassium and renal function is recommended, especially in patients at risk for impaired renal function, e.g., the elderly.
Digoxin: No clinically significant drug-drug pharmacokinetic interactions have been found with digoxin. While a statistically significant 16% increase in AUC0-24 was observed with digoxin 200 mcg and eplerenone 100 mg once daily in a pharmacokinetic study in healthy volunteers, this increase was not accompanied by clinical evidence of digoxin toxicity.
Warfarin: No clinically significant drug-drug pharmacodynamic interactions have been found with warfarin.
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Drug interaction studies of eplerenone have not been conducted with NSAIDs. NSAIDs administered with potassium-sparing antihypertensives have been shown to result in hyperkalemia in patients with impaired renal function.
Lithium: Drug interaction studies of eplerenone have not been conducted with lithium. Lithium toxicity has been reported in patients receiving lithium concomitantly with diuretics and ACE inhibitors.
In vitro studies indicate that eplerenone is not an inhibitor of CYP1A2, CYP2C19, CYP2C9, CYP2D6 or CYP3A4 isozymes. Eplerenone is not a substrate or an inhibitor of P-glycoprotein.
CYP3A4 substrates: Results of pharmacokinetic studies with CYP3A4 probe-substrates, i.e. midazolam and cisapride, showed no significant pharmacokinetic interactions when these drugs were co-administered with eplerenone.
CYP3A4 inhibitors: Potent CYP3A4 inhibitors: Significant pharmacokinetic interactions may occur when eplerenone is co-administered with drugs that inhibit the CYP3A4 enzyme. A potent inhibitor of CYP3A4 (ketoconazole 200 mg twice daily) led to a 441% increase in AUC of eplerenone (see Contraindications). The concomitant use of eplerenone with potent CYP3A4 inhibitors such as ketoconazole, itraconazole, and ritonavir is contraindicated (see Contraindications).
Mild to moderate CYP3A4 inhibitors: Co-administration with erythromycin, saquinavir, verapamil, or fluconazole has led to significant pharmacokinetic interactions with rank order increases in AUC ranging from 98% to 187%. Eplerenone dosing should therefore not exceed 25 mg daily when mild to moderate inhibitors of CYP3A4 are co-administered with eplerenone (see Dosage & Administration).
CYP3A4 inducers: Co-administration of St. John's Wort (a potent CYP3A4 inducer) with eplerenone caused a 30% decrease in eplerenone AUC. A more pronounced decrease in eplerenone AUC may occur with more potent CYP3A4 inducers and the concomitant use of potent CYP3A4 inducers with eplerenone is not recommended (see Precautions).
Storage
Store at temperatures not exceeding 30°C.
Action
Pharmacologic Category: Aldosterone Antagonist.
Pharmacology: Pharmacodynamics: Mechanism of Action of Eplerenone: Eplerenone has relative selectivity in binding to recombinant human mineralocorticoid receptors compared to its binding to recombinant human glucocorticoid, progesterone and androgen receptors. Eplerenone prevents the binding of aldosterone, a key hormone in the renin-angiotensin-aldosterone-system (RAAS), which is involved in the regulation of blood pressure and the pathophysiology of cardiovascular disease.
Eplerenone has been shown to produce sustained increases in plasma renin and serum aldosterone, consistent with inhibition of the negative regulatory feedback of aldosterone on renin secretion. The resulting increased plasma renin activity and circulating aldosterone levels do not overcome the effects of eplerenone.
Hypertension: Eplerenone was studied in 3091 hypertensive patients, comprising 46% women, 14% blacks and 22% ≥65 years. Patients were excluded if they had elevated baseline serum potassium (>5.0 mmol/L) or creatinine >133 μmol/L for men and >115 μmol/L for women. Two fixed-dose, placebo-controlled 8 to 12 week monotherapy studies in hypertensive patients randomized 611 patients to eplerenone (doses ranging from 25 mg to 400 mg daily as either a single daily dose or two daily doses) and 140 subjects to placebo. Patients treated with 50 mg to 200 mg daily experienced significant decreases in sitting blood pressure at trough with differences from placebo of 6-13 mmHg (systolic) and 3-7 mmHg (diastolic), effects confirmed with 24-hour ambulatory measurements.
Blood pressure lowering was apparent by 2 weeks and the maximal effect by 4 weeks of treatment. In 6 studies, after 8 to 24 weeks of therapy the discontinuation of eplerenone, placebo or active control resulted in similar adverse event rates in the week following withdrawal. In eplerenone-treated patients blood pressure rose in patients not taking other antihypertensives, suggesting that eplerenone's effect was maintained through 8 to 24 weeks. Overall, eplerenone's effects are unaffected by age, gender or race with the exception of patients with low renin hypertension where a single study showed smaller blood pressure reductions with eplerenone in black than white patients during the initial titration period.
Eplerenone has been studied concomitantly with treatment with ACE inhibitors, angiotensin II receptor antagonists, calcium channel blockers, beta blockers, and hydrochlorothiazide. When administered concomitantly with one of these drugs eplerenone usually produced its expected antihypertensive effects.
Pediatric Population: In a 10-week study of pediatric patients with hypertension (age range 4 to 16 years, n=304), eplerenone, at doses (from 25 mg up to 100 mg per day) that produced exposure similar to that in adults, did not lower blood pressure effectively. In this study and in a 1-year pediatric safety study in 149 patients (age range 5 to 17 years), the safety profile was similar to that of adults. Eplerenone has not been studied in hypertensive patients less than 4 years old because the study in older pediatric patients showed a lack of efficacy (see Dosage & Administration).
Heart Failure Post MI: In dose-ranging studies of chronic heart failure (NYHA classification II-IV), the addition of eplerenone to standard therapy resulted in expected dose-dependent increases in aldosterone.
Eplerenone was studied in EPHESUS, (a double-blind, placebo-controlled study in 6632 subjects with acute MI, left ventricular dysfunction (as measured by LVEF ≤40%), and clinical signs of heart failure. Within 3 to 14 days (median 7 days) after an acute MI, patients received eplerenone or placebo in addition to standard therapies at an initial dose of 25 mg once daily and titrated to the target dose of 50 mg once daily after 4 weeks if serum potassium was <5.0 mmol/L. During the study patients received standard care including acetylsalicylic acid (92%), ACE inhibitors (90%), beta blockers (83%), nitrates (72%), loop diuretics (66%), or HMG CoA reductase inhibitors (60%).
In EPHESUS, the co-primary endpoints were all-cause mortality and the combined endpoint of cardiovascular (CV) death or CV hospitalization; 14.4% of patients assigned to eplerenone and 16.7% of subjects assigned to placebo died (all causes), while 26.7% of patients assigned to eplerenone and 30.0% assigned to placebo met the combined endpoint of CV death or hospitalization. Thus, in EPHESUS, eplerenone reduced the risk of death from any cause by 15% (RR 0.85; 95% CI, 0.75-0.96; p = 0.008) compared to placebo, primarily by reducing CV mortality. The combined risk of CV death or CV hospitalization was reduced by 13% with eplerenone (RR 0.87; 95% CI, 0.79-0.95; p = 0.002). The absolute risk reductions for the endpoints all-cause mortality and combined CV mortality/hospitalization were 2.3% and 3.3%, respectively. Clinical efficacy was primarily demonstrated when eplerenone therapy was initiated in patients aged <75 years old. The benefits of therapy in those patients over the age of 75 are unclear. NYHA functional classification improved or remained stable for a statistically significant greater proportion of patients receiving eplerenone compared to placebo. The incidence of hyperkalemia was 3.4% in the eplerenone group vs. 2.0% in the placebo group (p < 0.001). The incidence of hypokalemia was 0.5% in the eplerenone group vs. 1.5% in the placebo group (p <0.001).
NYHA Class II (chronic) Heart Failure: In the EMPHASI-HF trial the effect of eplerenone when added to standard therapy was investigated on clinical outcomes in patients with systolic heart failure and mild symptoms (NYHA functional class II).
Patients were included if they were at least 55 years old, had a LVEF ≤30%, or LVEF ≤35% in addition to QRS duration of ˃130 msec, and were either hospitalized for CV reasons 6 months prior to inclusion or had a plasma level of B-type natriuretic peptide (BNP) of at least 250 pg/mL or a plasma level of N-terminal pro-BNP of at least 500 pg/mL in men (750 pg/mL in women). Eplerenone was started at a dose of 25 mg once daily and was increased after 4 weeks to 50 mg once daily if the serum potassium level was ˂5.0 mmol/L. Alternatively, if the estimated glomerular filtration rate (GFR) was 30-49 mL/min/1.73 m2, eplerenone was started at 25 mg on alternate days, and increased to 25 mg once daily.
In total, 2737 patients were randomized (double-blind) to treatment with eplerenone or placebo including baseline therapy of diuretics (85%), ACE inhibitors (78%), angiotensin II receptor blockers (19%), beta blockers (87%), anti thrombotic drugs (88%), lipid-lowering agents (63%), and digitalis glycosides (27%). The mean LVEF was ~26% and the mean QRS duration was ~122 msec. Most of the patients (83.4%) were previously hospitalized for CV reasons within 6 months of randomization, with around 50% of them due to heart failure. Around 20% of the patients had implantable defibrillators or cardiac resynchronization therapy.
The primary endpoint, death from cardiovascular causes or hospitalization for heart failure occurred in 249 (18.3%) patients in the eplerenone group and 356 (25.9%) patients in the placebo group (RR 0.63, 95% CI, 0.54-0.74; p˂0.001). The effect of eplerenone on the primary endpoint outcomes was consistent across all pre-specified subgroups.
The secondary endpoint of all-cause mortality was met by 171 (12.5%) patients in the eplerenone group and 213 (15.5%) patients in the placebo group (RR 0.76; 95% CI, 0.62-0.93; p = 0.008). Death from CV causes was reported in 147 (10.8%) patients in the eplerenone group and 185 (13.5%) subjects in the placebo group (RR 0.76; 95% CI, 0.61-0.94; p = 0.01).
During the study, hyperkalemia (serum potassium level ˃5.5 mmol/L) was reported in 158 (11.8%) patients in the eplerenone group and 96 (7.2%) subjects in the placebo group (p ˂ 0.001). Hypokalemia, defined as serum potassium level ˂4.0 mmol/L, was statistically lower with eplerenone when compared to placebo (38.9% for eplerenone compared to 48.4% for placebo, p ˂0.0001).
Electrocardiography: No consistent effects of eplerenone on heart rate, QRS duration, or PR or QT interval were observed in 147 normal subjects evaluated for electrocardiographic changes during pharmacokinetic studies.
Pharmacokinetics: Absorption and Distribution: The absolute bioavailability of eplerenone is 69% following administration of a 100 mg oral tablet. Maximum plasma concentrations are reached after approximately 1.5 to 2 hours. Both peak plasma levels (Cmax) and area under the curve (AUC) are dose proportional for doses of 10 mg to 100 mg and less than proportional at doses above 100 mg. Steady-state is reached within 2 days. Absorption is not affected by food.
The plasma protein binding of eplerenone is about 50% and is primarily bound to alpha 1-acid glycoproteins. The apparent volume of distribution at steady-state is estimated to be 42-90 L. Eplerenone does not preferentially bind to red blood cells.
Metabolism and Excretion: Eplerenone metabolism is primarily mediated via CYP3A4. No active metabolites of eplerenone have been identified in human plasma.
Less than 5% of an eplerenone dose is recovered as unchanged drug in the urine and feces. 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 to 6 hours. The apparent plasma clearance is approximately 10 L/hr.
Special Populations: Age, Gender, and Race: The pharmacokinetics of eplerenone at a dose of 100 mg once daily have been investigated in the elderly (≥65 years), in males and females, and in blacks. The pharmacokinetics of eplerenone did not differ significantly between males and females. At steady-state, elderly subjects had increases in Cmax (22%) and AUC (45%) compared with younger subjects (18 to 45 years). At steady-state, Cmax was 19% lower and AUC was 26% lower in blacks (see Dosage & Administration).
Renal Insufficiency: The pharmacokinetics of eplerenone were evaluated in patients with varying degrees of renal insufficiency and in patients undergoing hemodialysis. Compared with control subjects, steady-state AUC and Cmax were increased by 38% and 24%, respectively, in patients with severe renal impairment and were decreased by 26% and 3%, respectively, in patients undergoing hemodialysis. No correlation was observed between plasma clearance of eplerenone and creatinine clearance. Eplerenone is not removed by hemodialysis (see Overdosage).
Hepatic Insufficiency: The pharmacokinetics of eplerenone 400 mg have been investigated in patients with moderate (Child-Pugh Class B) hepatic impairment and compared with normal subjects. Steady-state Cmax and AUC of eplerenone were increased by 3.6% and 42%, respectively (see Dosage & Administration). Since the use of eplerenone has not been investigated in patients with severe hepatic impairment, eplerenone is contraindicated in this patient group (see Contraindications).
Heart Failure: The pharmacokinetics of eplerenone 50 mg were evaluated in patients with heart failure (NYHA classification II-IV). Compared with healthy subjects matched according to age, weight and gender, steady-state AUC and Cmax in heart failure patients were 38% and 30% higher, respectively. Consistent with these results, a population pharmacokinetic analysis of eplerenone based on a subset of patients from EPHESUS indicates that apparent clearance of eplerenone in patients with heart failure was similar to that in healthy elderly subjects.
Pediatric Population: A population pharmacokinetic model for eplerenone concentrations from two studies in 51 pediatric hypertensive patients of ages 4 to 16 years identified that patient body weight had a statistically significant effect on eplerenone volume of distribution but not on its clearance. Eplerenone volume of distribution and peak exposure in a heavier pediatric patient are predicted to be similar to that in an adult of similar body weight; in a lighter 45-kg patient, the volume of distribution is about 40% lower and the peak exposure is predicted to be higher than typical adults. Eplerenone treatment was initiated at 25 mg once daily in pediatric patients and increased to 25 mg twice daily after 2 weeks and eventually 50 mg twice daily, if clinically indicated; at these doses, the highest observed eplerenone concentration in pediatric subjects were not substantially higher than those in adults initiated at 50 mg once daily.
Toxicology: Preclinical Safety Data: Carcinogenesis, Mutagenesis, Impairment of Fertility: Pre-clinical studies of safety pharmacology, genotoxicity, carcinogenic potential and toxicity to reproduction revealed no special hazard for humans.
In repeated dose toxicity studies, prostate atrophy was observed in rats and dogs at exposure levels several-fold above clinical exposure levels. The prostatic changes were not associated with adverse functional consequences. The clinical relevance of these findings is unknown.
Studies in rats and rabbits showed no teratogenic effects, although decreased body weight in maternal rabbits and increased rabbit fetal resorptions and post-implantation loss were observed at the highest administered dosage.
Pharmacology: Pharmacodynamics: Mechanism of Action of Eplerenone: Eplerenone has relative selectivity in binding to recombinant human mineralocorticoid receptors compared to its binding to recombinant human glucocorticoid, progesterone and androgen receptors. Eplerenone prevents the binding of aldosterone, a key hormone in the renin-angiotensin-aldosterone-system (RAAS), which is involved in the regulation of blood pressure and the pathophysiology of cardiovascular disease.
Eplerenone has been shown to produce sustained increases in plasma renin and serum aldosterone, consistent with inhibition of the negative regulatory feedback of aldosterone on renin secretion. The resulting increased plasma renin activity and circulating aldosterone levels do not overcome the effects of eplerenone.
Hypertension: Eplerenone was studied in 3091 hypertensive patients, comprising 46% women, 14% blacks and 22% ≥65 years. Patients were excluded if they had elevated baseline serum potassium (>5.0 mmol/L) or creatinine >133 μmol/L for men and >115 μmol/L for women. Two fixed-dose, placebo-controlled 8 to 12 week monotherapy studies in hypertensive patients randomized 611 patients to eplerenone (doses ranging from 25 mg to 400 mg daily as either a single daily dose or two daily doses) and 140 subjects to placebo. Patients treated with 50 mg to 200 mg daily experienced significant decreases in sitting blood pressure at trough with differences from placebo of 6-13 mmHg (systolic) and 3-7 mmHg (diastolic), effects confirmed with 24-hour ambulatory measurements.
Blood pressure lowering was apparent by 2 weeks and the maximal effect by 4 weeks of treatment. In 6 studies, after 8 to 24 weeks of therapy the discontinuation of eplerenone, placebo or active control resulted in similar adverse event rates in the week following withdrawal. In eplerenone-treated patients blood pressure rose in patients not taking other antihypertensives, suggesting that eplerenone's effect was maintained through 8 to 24 weeks. Overall, eplerenone's effects are unaffected by age, gender or race with the exception of patients with low renin hypertension where a single study showed smaller blood pressure reductions with eplerenone in black than white patients during the initial titration period.
Eplerenone has been studied concomitantly with treatment with ACE inhibitors, angiotensin II receptor antagonists, calcium channel blockers, beta blockers, and hydrochlorothiazide. When administered concomitantly with one of these drugs eplerenone usually produced its expected antihypertensive effects.
Pediatric Population: In a 10-week study of pediatric patients with hypertension (age range 4 to 16 years, n=304), eplerenone, at doses (from 25 mg up to 100 mg per day) that produced exposure similar to that in adults, did not lower blood pressure effectively. In this study and in a 1-year pediatric safety study in 149 patients (age range 5 to 17 years), the safety profile was similar to that of adults. Eplerenone has not been studied in hypertensive patients less than 4 years old because the study in older pediatric patients showed a lack of efficacy (see Dosage & Administration).
Heart Failure Post MI: In dose-ranging studies of chronic heart failure (NYHA classification II-IV), the addition of eplerenone to standard therapy resulted in expected dose-dependent increases in aldosterone.
Eplerenone was studied in EPHESUS, (a double-blind, placebo-controlled study in 6632 subjects with acute MI, left ventricular dysfunction (as measured by LVEF ≤40%), and clinical signs of heart failure. Within 3 to 14 days (median 7 days) after an acute MI, patients received eplerenone or placebo in addition to standard therapies at an initial dose of 25 mg once daily and titrated to the target dose of 50 mg once daily after 4 weeks if serum potassium was <5.0 mmol/L. During the study patients received standard care including acetylsalicylic acid (92%), ACE inhibitors (90%), beta blockers (83%), nitrates (72%), loop diuretics (66%), or HMG CoA reductase inhibitors (60%).
In EPHESUS, the co-primary endpoints were all-cause mortality and the combined endpoint of cardiovascular (CV) death or CV hospitalization; 14.4% of patients assigned to eplerenone and 16.7% of subjects assigned to placebo died (all causes), while 26.7% of patients assigned to eplerenone and 30.0% assigned to placebo met the combined endpoint of CV death or hospitalization. Thus, in EPHESUS, eplerenone reduced the risk of death from any cause by 15% (RR 0.85; 95% CI, 0.75-0.96; p = 0.008) compared to placebo, primarily by reducing CV mortality. The combined risk of CV death or CV hospitalization was reduced by 13% with eplerenone (RR 0.87; 95% CI, 0.79-0.95; p = 0.002). The absolute risk reductions for the endpoints all-cause mortality and combined CV mortality/hospitalization were 2.3% and 3.3%, respectively. Clinical efficacy was primarily demonstrated when eplerenone therapy was initiated in patients aged <75 years old. The benefits of therapy in those patients over the age of 75 are unclear. NYHA functional classification improved or remained stable for a statistically significant greater proportion of patients receiving eplerenone compared to placebo. The incidence of hyperkalemia was 3.4% in the eplerenone group vs. 2.0% in the placebo group (p < 0.001). The incidence of hypokalemia was 0.5% in the eplerenone group vs. 1.5% in the placebo group (p <0.001).
NYHA Class II (chronic) Heart Failure: In the EMPHASI-HF trial the effect of eplerenone when added to standard therapy was investigated on clinical outcomes in patients with systolic heart failure and mild symptoms (NYHA functional class II).
Patients were included if they were at least 55 years old, had a LVEF ≤30%, or LVEF ≤35% in addition to QRS duration of ˃130 msec, and were either hospitalized for CV reasons 6 months prior to inclusion or had a plasma level of B-type natriuretic peptide (BNP) of at least 250 pg/mL or a plasma level of N-terminal pro-BNP of at least 500 pg/mL in men (750 pg/mL in women). Eplerenone was started at a dose of 25 mg once daily and was increased after 4 weeks to 50 mg once daily if the serum potassium level was ˂5.0 mmol/L. Alternatively, if the estimated glomerular filtration rate (GFR) was 30-49 mL/min/1.73 m2, eplerenone was started at 25 mg on alternate days, and increased to 25 mg once daily.
In total, 2737 patients were randomized (double-blind) to treatment with eplerenone or placebo including baseline therapy of diuretics (85%), ACE inhibitors (78%), angiotensin II receptor blockers (19%), beta blockers (87%), anti thrombotic drugs (88%), lipid-lowering agents (63%), and digitalis glycosides (27%). The mean LVEF was ~26% and the mean QRS duration was ~122 msec. Most of the patients (83.4%) were previously hospitalized for CV reasons within 6 months of randomization, with around 50% of them due to heart failure. Around 20% of the patients had implantable defibrillators or cardiac resynchronization therapy.
The primary endpoint, death from cardiovascular causes or hospitalization for heart failure occurred in 249 (18.3%) patients in the eplerenone group and 356 (25.9%) patients in the placebo group (RR 0.63, 95% CI, 0.54-0.74; p˂0.001). The effect of eplerenone on the primary endpoint outcomes was consistent across all pre-specified subgroups.
The secondary endpoint of all-cause mortality was met by 171 (12.5%) patients in the eplerenone group and 213 (15.5%) patients in the placebo group (RR 0.76; 95% CI, 0.62-0.93; p = 0.008). Death from CV causes was reported in 147 (10.8%) patients in the eplerenone group and 185 (13.5%) subjects in the placebo group (RR 0.76; 95% CI, 0.61-0.94; p = 0.01).
During the study, hyperkalemia (serum potassium level ˃5.5 mmol/L) was reported in 158 (11.8%) patients in the eplerenone group and 96 (7.2%) subjects in the placebo group (p ˂ 0.001). Hypokalemia, defined as serum potassium level ˂4.0 mmol/L, was statistically lower with eplerenone when compared to placebo (38.9% for eplerenone compared to 48.4% for placebo, p ˂0.0001).
Electrocardiography: No consistent effects of eplerenone on heart rate, QRS duration, or PR or QT interval were observed in 147 normal subjects evaluated for electrocardiographic changes during pharmacokinetic studies.
Pharmacokinetics: Absorption and Distribution: The absolute bioavailability of eplerenone is 69% following administration of a 100 mg oral tablet. Maximum plasma concentrations are reached after approximately 1.5 to 2 hours. Both peak plasma levels (Cmax) and area under the curve (AUC) are dose proportional for doses of 10 mg to 100 mg and less than proportional at doses above 100 mg. Steady-state is reached within 2 days. Absorption is not affected by food.
The plasma protein binding of eplerenone is about 50% and is primarily bound to alpha 1-acid glycoproteins. The apparent volume of distribution at steady-state is estimated to be 42-90 L. Eplerenone does not preferentially bind to red blood cells.
Metabolism and Excretion: Eplerenone metabolism is primarily mediated via CYP3A4. No active metabolites of eplerenone have been identified in human plasma.
Less than 5% of an eplerenone dose is recovered as unchanged drug in the urine and feces. 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 to 6 hours. The apparent plasma clearance is approximately 10 L/hr.
Special Populations: Age, Gender, and Race: The pharmacokinetics of eplerenone at a dose of 100 mg once daily have been investigated in the elderly (≥65 years), in males and females, and in blacks. The pharmacokinetics of eplerenone did not differ significantly between males and females. At steady-state, elderly subjects had increases in Cmax (22%) and AUC (45%) compared with younger subjects (18 to 45 years). At steady-state, Cmax was 19% lower and AUC was 26% lower in blacks (see Dosage & Administration).
Renal Insufficiency: The pharmacokinetics of eplerenone were evaluated in patients with varying degrees of renal insufficiency and in patients undergoing hemodialysis. Compared with control subjects, steady-state AUC and Cmax were increased by 38% and 24%, respectively, in patients with severe renal impairment and were decreased by 26% and 3%, respectively, in patients undergoing hemodialysis. No correlation was observed between plasma clearance of eplerenone and creatinine clearance. Eplerenone is not removed by hemodialysis (see Overdosage).
Hepatic Insufficiency: The pharmacokinetics of eplerenone 400 mg have been investigated in patients with moderate (Child-Pugh Class B) hepatic impairment and compared with normal subjects. Steady-state Cmax and AUC of eplerenone were increased by 3.6% and 42%, respectively (see Dosage & Administration). Since the use of eplerenone has not been investigated in patients with severe hepatic impairment, eplerenone is contraindicated in this patient group (see Contraindications).
Heart Failure: The pharmacokinetics of eplerenone 50 mg were evaluated in patients with heart failure (NYHA classification II-IV). Compared with healthy subjects matched according to age, weight and gender, steady-state AUC and Cmax in heart failure patients were 38% and 30% higher, respectively. Consistent with these results, a population pharmacokinetic analysis of eplerenone based on a subset of patients from EPHESUS indicates that apparent clearance of eplerenone in patients with heart failure was similar to that in healthy elderly subjects.
Pediatric Population: A population pharmacokinetic model for eplerenone concentrations from two studies in 51 pediatric hypertensive patients of ages 4 to 16 years identified that patient body weight had a statistically significant effect on eplerenone volume of distribution but not on its clearance. Eplerenone volume of distribution and peak exposure in a heavier pediatric patient are predicted to be similar to that in an adult of similar body weight; in a lighter 45-kg patient, the volume of distribution is about 40% lower and the peak exposure is predicted to be higher than typical adults. Eplerenone treatment was initiated at 25 mg once daily in pediatric patients and increased to 25 mg twice daily after 2 weeks and eventually 50 mg twice daily, if clinically indicated; at these doses, the highest observed eplerenone concentration in pediatric subjects were not substantially higher than those in adults initiated at 50 mg once daily.
Toxicology: Preclinical Safety Data: Carcinogenesis, Mutagenesis, Impairment of Fertility: Pre-clinical studies of safety pharmacology, genotoxicity, carcinogenic potential and toxicity to reproduction revealed no special hazard for humans.
In repeated dose toxicity studies, prostate atrophy was observed in rats and dogs at exposure levels several-fold above clinical exposure levels. The prostatic changes were not associated with adverse functional consequences. The clinical relevance of these findings is unknown.
Studies in rats and rabbits showed no teratogenic effects, although decreased body weight in maternal rabbits and increased rabbit fetal resorptions and post-implantation loss were observed at the highest administered dosage.
MedsGo Class
Diuretics
Features
Brand
Inspra
Full Details
Dosage Strength
50 mg
Drug Ingredients
- Eplerenone
Drug Packaging
Film-Coated Tablet 1's
Generic Name
Eplerenone
Dosage Form
Film-Coated Tablet
Registration Number
DRP-9762
Drug Classification
Prescription Drug (RX)
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