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APOTEX CORP
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60505265203

eplerenone 50 mg tablet (generic inspra)

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Uses

Heart Failure

Heart Failure After Myocardial Infarction

Eplerenone is used to improve survival following acute myocardial infarction in clinically stable patients with left ventricular dysfunction (i.e., left ventricular ejection fraction [LVEF] 40% or less) who have demonstrated clinical evidence of heart failure. The American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) recommend therapy with an aldosterone antagonist (i.e., spironolactone, eplerenone) to reduce morbidity and mortality following acute myocardial infarction in patients with reduced LVEF (40% or less) who develop symptoms of heart failure or who have a history of diabetes mellitus, unless contraindicated. Efficacy of eplerenone for improving survival has been evaluated in a multicenter, randomized, double-blind, placebo-controlled study (the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study; EPHESUS) involving 6632 patients with acute myocardial infarction complicated by congestive heart failure and left-ventricular dysfunction. Results of this study indicate that the addition of eplerenone (25-50 mg daily; mean dosage: 43 mg daily) to standard therapy (e.g., aspirin, nitrates, angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, β-adrenergic blocking agents (β-blockers), hydroxymethylglutaryl-coenzyme A [HMG-CoA] reductase inhibitors, loop diuretics) 3-14 days (mean: 7 days) after acute myocardial infarction reduced the risk of mortality from any cause, and of hospitalization or mortality from cardiovascular causes by 15 and 13%, respectively, compared with standard therapy and placebo. In addition, eplerenone reduced the risk of mortality or hospitalization from any cause by 8% and mortality from cardiovascular causes by 17%. Eplerenone did not appear to affect the rates of re-infarction.

Chronic Heart Failure

Eplerenone has been used in the management of chronic heart failure (New York Heart Association [NYHA] class II-IV) with reduced ejection fraction in conjunction with standard therapy for heart failure to increase survival and reduce heart failure-related hospitalizations.

Current guidelines for the management of heart failure in adults generally recommend a combination of drug therapies to reduce morbidity and mortality, including neurohormonal antagonists (e.g., ACE inhibitors, angiotensin II receptor antagonists, angiotensin receptor-neprilysin inhibitors [ARNIs], β-blockers, aldosterone receptor antagonists) that inhibit the detrimental compensatory mechanisms in heart failure. ACCF and AHA recommend the addition of an aldosterone antagonist (i.e., spironolactone or eplerenone) in selected patients with heart failure and reduced LVEF who are already receiving a β-blocker and an agent to inhibit the renin-angiotensin-aldosterone (RAA) system (e.g., ACE inhibitor, angiotensin II receptor antagonist, ARNI); careful patient selection is required to minimize the risk of hyperkalemia and renal insufficiency.

Aldosterone receptor antagonists are also recommended, unless contraindicated, in conjunction with standard heart failure therapy to reduce morbidity and mortality following acute myocardial infarction in patients with reduced LVEF who develop symptoms of heart failure or who have a history of diabetes mellitus. ACCF and AHA state that there are limited data to support or refute whether spironolactone and eplerenone are interchangeable. The perceived difference between eplerenone and spironolactone is attributed to the selectivity of aldosterone receptor antagonism and not the effectiveness of mineralocorticoid-blocking activity.(See Description.)

In a randomized, double-blind study (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure [EMPHASIS-HF]), in patients with mild heart failure symptoms (NYHA class II), eplerenone (in addition to therapy with an ACE inhibitor and/or angiotensin II receptor antagonist and β-blocker) reduced the risk of death and heart failure-related hospitalization compared with placebo. Patients enrolled in the study were at least 55 years of age, had an ejection fraction of 30% or less (mean: 26%), and were receiving treatment with a β-blocker and an ACE inhibitor and/or an angiotensin II receptor antagonist at the recommended or maximally tolerated dosage. Approximately 50% of patients had been previously hospitalized for heart failure and had a history of myocardial infarction. In patients with serum potassium concentration of 5 mEq/L or less, eplerenone was administered in a dosage of 25 mg once daily, which was increased after 4 weeks of therapy to 50 mg once daily; patients with decreased renal function (estimated glomerular filtration rate [eGFR] 30-49 mL/minute per 1.73 m) received an initial eplerenone dosage of 25 mg once every other day with an increase to 25 mg once daily after 4 weeks. Eplerenone substantially reduced the primary composite end point of death from cardiovascular causes or hospitalization for heart failure compared with placebo (18.3 versus 25.9%, respectively). Hyperkalemia (serum potassium exceeding 5.5 mEq/L) developed in approximately 12% of patients receiving eplerenone.

Hypertension

Eplerenone is used orally in the management of hypertension. The drug may be used as monotherapy or in combination with other classes of antihypertensive agents.

Because of established clinical benefits (e.g., reductions in overall mortality and in adverse cardiovascular, cerebrovascular, and renal outcomes), ACE inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics generally are considered the preferred drugs for the initial management of hypertension in adults; however, aldosterone antagonists (e.g., eplerenone, spironolactone) may be considered as add-on therapy if goal blood pressure cannot be achieved with the recommended drugs. Aldosterone antagonists may be particularly useful in selected patients with heart failure or following myocardial infarction. For information on antihypertensive therapy for patients with heart failure or following myocardial infarction,

Safety and efficacy of eplerenone, given alone or in combination with other antihypertensive agents, in the treatment of hypertension have been evaluated in several placebo-controlled studies. In 2 studies of 8-12 weeks' duration, patients with baseline diastolic pressure of 95-114 mm Hg were randomized to receive eplerenone (25-400 mg daily, administered as a single dose or in 2 divided doses) monotherapy (611 patients) or placebo (140 patients). In these patients, eplerenone (50-400 mg daily) decreased placebo-corrected seated and standing trough systolic blood pressure (determined 4 hours before morning dose) by about 5-13 mm Hg and diastolic blood pressure by about 3-7 mm Hg. Antihypertensive effect of eplerenone was maintained through 8-24 weeks. Results of other studies indicate that in patients not receiving other antihypertensive drugs, blood pressure may return to pretreatment levels within 1 week following discontinuance of eplerenone. Although eplerenone has lowered blood pressure in all races studied, monotherapy with the drug has produced a smaller reduction in blood pressure during the initial dosage titration period in black hypertensive patients, a population associated with low-renin hypertension; however, this population difference in response does not appear to occur during continued therapy.

Eplerenone may be used in combination with other antihypertensive agents (e.g., ACE inhibitors, angiotensin II receptor antagonists, calcium-channel blocking agents, β-blockers, thiazide diuretics).

For information on overall principles and expert recommendations for the management of hypertension,

Dosage and Administration

General

Eplerenone is administered orally and may be given without regard to meals.

Heart Failure

Heart Failure after Myocardial Infarction

When used following myocardial infarction in adults with clinical evidence of heart failure, an initial eplerenone dosage of 25 mg once daily is recommended. Therapy is then titrated upward in one increment of 25 mg as tolerated to a target dosage of 50 mg once daily, preferably within 4 weeks of initiation of therapy, in patients without hyperkalemia (defined as serum potassium concentrations of 5.5 mEq/L or greater).

The manufacturer states that serum potassium concentrations should be measured prior to initiation of therapy, within the first week, and at 1 month after initiation of therapy or dosage adjustment. Serum potassium concentrations should be monitored periodically thereafter during eplerenone therapy and dosage of the drug should be modified according to serum potassium concentrations. Some experts recommend that serum potassium concentrations and renal function be checked within 2-3 days and again 7 days after initiation of an aldosterone antagonist. Subsequent monitoring should be performed as needed based upon the stability of renal function and fluid status but should occur at least monthly for the first 3 months and then every 3 months thereafter. The manufacturer recommends that in patients in whom serum potassium concentrations increase to 5.5-5.9 mEq/L, eplerenone dosage should be decreased to 25 mg daily in patients receiving 50 mg daily and to 25 mg every other day in those receiving eplerenone 25 mg daily; the drug should be withheld in patients with such serum potassium concentration increases who are receiving eplerenone 25 mg every other day. In patients in whom serum potassium concentrations increase to 6 mEq/L or more, eplerenone therapy should be withheld until serum potassium concentrations decrease to less than 5.5 mEq/L. Therapy with eplerenone may then be reinitiated at a dosage of 25 mg every other day. If serum potassium concentrations decrease to less than 5 mEq/L, dosage should be increased gradually (in 25-mg increments) to the maximum tolerated therapeutic dosage (up to 50 mg daily). Alternatively, the American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) recommend withholding eplerenone if the patient's serum potassium concentration exceeds 5.5 mEq/L or if renal function worsens; therapy may be resumed at a reduced dosage after confirming resolution (for at least 72 hours) of hyperkalemia (serum potassium decreases to less than 5 mEq/L) and of renal insufficiency. ACCF and AHA state that patients should also be specifically instructed to stop taking an aldosterone receptor antagonist if they have diarrhea or are dehydrated or if therapy with a concomitant loop diuretic is interrupted.

Chronic Heart Failure

When used in patients with chronic heart failure and reduced LVEF in conjunction with standard heart failure therapy, eplerenone has been administered at an initial dosage of 25 mg once daily, which may be increased after 4 weeks of therapy to 50 mg once daily in patients with a serum potassium concentration of 5 mEq/L or less and adequate renal function (estimated glomerular filtration rate [eGFR] at least 50 mL/minute per 1.73 m). ACCF and AHA recommend that serum potassium concentrations and renal function be checked within 2-3 days and again at 7 days after initiation of an aldosterone antagonist. Subsequent monitoring should be performed as needed based upon the stability of renal function and fluid status, but should occur at least monthly for the first 3 months and every 3 months thereafter. ACCF and AHA recommend withholding eplerenone if the patient's serum potassium concentration exceeds 5.5 mEq/L or if renal function worsens; therapy may be resumed at a reduced dosage after confirming resolution (for at least 72 hours) of hyperkalemia (i.e., serum potassium decreases to less than 5 mEq/L) and of renal insufficiency. ACCF and AHA state that patients should also be specifically instructed to stop taking an aldosterone receptor antagonist if they have diarrhea or are dehydrated or if therapy with a concomitant loop diuretic is interrupted.

Hypertension

Dosage of eplerenone must be individualized and adjusted according to the blood pressure response. The usual initial dosage of eplerenone in adults is 50 mg once daily. Following oral administration of eplerenone, the hypotensive effect is usually apparent within 2 weeks with full hypotensive effect occurring within 4 weeks. If blood pressure response is inadequate with the initial dosage, dosage may be increased to 50 mg twice daily. Administration of higher than recommended dosages (i.e., exceeding 100 mg daily) does not appear to provide added benefit, and has been associated with an increased risk of hyperkalemia.

In hypertensive patients currently receiving therapy with moderate inhibitors of the cytochrome P-450 (CYP) 3A4 isoenzyme (e.g., erythromycin, saquinavir, verapamil, fluconazole), the initial dosage of eplerenone should be reduced to 25 mg once daily.

Blood Pressure Monitoring and Treatment Goals

Careful monitoring of blood pressure during initial titration or subsequent upward adjustment in dosage of eplerenone is recommended.

The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure; specific target levels of blood pressure should be individualized based on consideration of multiple factors, including patient age and comorbidities, and the currently available evidence from clinical studies.

For additional information on initiating and adjusting eplerenone dosage in the management of hypertension,

Special Populations

Renal Impairment

ACCF and AHA state that the dosage of eplerenone should be reduced in heart failure patients with marginal renal function (eGFR 30-49 mL/minute per 1.73 m); an initial dosage of 25 mg once every other day and a maintenance dosage of 25 mg once daily (after 4 weeks of therapy and if serum potassium is 5 mEq/L or less) has been recommended. These experts state that use of an aldosterone antagonist is potentially harmful in patients with an eGFR less than 30 mL/minute per 1.73 m because of the potential for life-threatening hyperkalemia or renal insufficiency.(See Endocrine, Electrolyte, and Metabolic Effects under Warnings/Precautions: Warnings, in Cautions.)

Cautions

Contraindications

Eplerenone is contraindicated in patients with serum potassium concentrations exceeding 5.5 mEq/L at initiation of therapy, in those with creatinine clearance of 30 mL/minute or less, and in those receiving concomitant therapy with potent inhibitors of cytochrome P-450 (CYP) isoenzyme 3A4 (e.g., ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir) or any agent described as a potent CYP3A4 inhibitor in its prescribing information.

In addition, when used for hypertension, the drug is contraindicated in patients with type 2 diabetes mellitus with microalbuminuria; serum creatinine concentrations exceeding 2 or 1.8 mg/dL in males or females, respectively; creatinine clearance less than 50 mL/minute; and in those receiving potassium supplements or potassium-sparing diuretics (e.g., amiloride, spironolactone, triamterene).

Warnings/Precautions

Warnings

Endocrine, Electrolyte, and Metabolic Effects

The most serious risk associated with eplerenone therapy is hyperkalemia (serum potassium exceeding 5.5 mEq/L), which may cause serious, sometimes fatal, cardiac arrhythmias. Patients with impaired renal function or diabetes mellitus and patients receiving concurrent agents affecting the renin-angiotensin-aldosterone system (e.g., angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists) are at an increased risk for developing hyperkalemia. Eplerenone should be used with caution in patients with heart failure following an acute myocardial infarction, who have renal impairment (i.e., serum creatinine concentrations exceeding 2 or 1.8 mg/dL in males or females, respectively, or creatinine clearance of 50 mL/minute or less) or those with diabetes mellitus (including those with proteinuria). Serum potassium concentrations should be monitored periodically in patients receiving eplerenone.(See Heart Failure after Myocardial Infarction under Dosage and Administration: Dosage.) Dosage reduction has been shown to decrease serum potassium concentrations.

Specific Populations

Pregnancy

Category B.

Lactation

Eplerenone is distributed into milk in rats; a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Pediatric Use

Safety and efficacy have not been established in children younger than 18 years of age. For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, .

Geriatric Use

No substantial differences in safety and efficacy have been observed in geriatric patients relative to younger adults. Geriatric patients 75 years of age and older with congestive heart failure following an acute myocardial infarction did not benefit from the addition of eplerenone to standard medical therapy. Because geriatric patients may have decreased renal function (reduced creatinine clearance), the incidence of hyperkalemia may be increased in geriatric patients (65 years of age and older).(See Endocrine, Electrolyte, and Metabolic Effects under Warnings/Precautions: Warnings, in Cautions.)

Hepatic Impairment

Safety and efficacy have not been established in patients with severe hepatic impairment. Serum potassium concentrations were not affected in patients with mild-to-moderate hepatic impairment.

Renal Impairment

Patients with renal impairment are at an increased risk for developing hyperkalemia. For precautionary information about use of eplerenone in patients with renal impairment, see Cautions: Contraindications and see Endocrine, Electrolyte, and Metabolic Effects under Warnings/Precautions: Warnings in Cautions.

Common Adverse Effects

Adverse effects occurring in 2% or more of patients receiving eplerenone for the management of congestive heart failure following acute myocardial infarction, but occurring at greater incidence in patients receiving the drug than in those receiving placebo, include hyperkalemia, increased serum creatinine concentrations, urinary tract disorders, adverse CNS effects, and adverse GI effects.

Adverse effects reported in 1% or more of patients receiving eplerenone for the management of hypertension are dizziness, fatigue, flu-like symptoms, cough, diarrhea, abdominal pain, hyperkalemia, decreased serum sodium concentrations, abnormal vaginal bleeding, gynecomastia, hypercholesterolemia, hypertriglyceridemia, mastodynia, or albuminuria.

Drug Interactions

Drugs Affecting Hepatic Microsomal Enzymes

Since eplerenone is primarily metabolized in the liver by the cytochrome P-450 (CYP) 3A4 isoenzyme, concomitant use of drugs that affect CYP3A4 hepatic microsomal enzymes may alter the metabolism of eplerenone. Following administration of a single 100-mg dose of eplerenone in individuals receiving ketoconazole 200 mg twice daily, peak plasma concentrations and area under the concentration-time curve (AUC) of eplerenone were increased by 1.7-fold and 5.4-fold, respectively, compared with administration of eplerenone alone. Concomitant administration of eplerenone and moderate CYP3A inhibitors (e.g., erythromycin 500 mg twice daily, verapamil hydrochloride 240 mg once daily, saquinavir 1.2 g three times daily, fluconazole 200 mg once daily) resulted in increases of 40-60 % in peak plasma eplerenone concentrations and 100-190% increases in AUC. For further precautionary information about concurrent use of eplerenone with inhibitors of the CYP3A4 isoenzyme, see Cautions: Contraindications and see Hypertension under Dosage and Administration: Dosage.

Concomitant use of eplerenone and grapefruit juice may result in a small (about 25%) increase in eplerenone exposure.

Coadministration of eplerenone and St. John's wort (Hypericum perforatum), a CYP3A4 isoenzyme inducer, resulted in a 30% decrease in AUC of eplerenone.

Eplerenone is not an inhibitor or inducer of the CYP isoenzymes 1A2, 3A4, 2C19, 2C9, or 2D6, suggesting that the drug is unlikely to alter the pharmacokinetics of drugs metabolized by these enzymes. In in vitro pharmacokinetic studies, eplerenone did not inhibit the metabolism of amiodarone, amlodipine, astemizole, chlorzoxazone, cisapride, dexamethasone, dextromethorphan, diclofenac, ethinyl estradiol, fluoxetine, losartan, lovastatin, mephobarbital, methylphenidate, methylprednisolone, metoprolol, midazolam, nifedipine, phenacetin (no longer commercially available in the US), phenytoin, simvastatin, tolbutamide, triazolam, verapamil, or warfarin.

Drugs Affecting or Affected by P-glycoprotein Transport

Eplerenone is not a substrate or an inhibitor of P-glycoprotein at clinically relevant dosages.

Drugs that Block the Renin-Angiotensin System

Potential pharmacodynamic interaction (increased serum potassium concentrations, hyperkalemia) when eplerenone is used concomitantly with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor antagonist for the treatment of hypertension. In patients with heart failure following myocardial infarction, who were receiving eplerenone, the rates of developing hyperkalemia were similar regardless of treatment with an ACE inhibitor or angiotensin II receptor antagonist.

Lithium

Potential pharmacokinetic and pharmacologic interaction (increased serum lithium concentrations resulting in lithium toxicity). No formal drug interaction studies have been performed. However, concomitant administration of diuretics and/or ACE inhibitors with lithium resulted in lithium toxicity. The manufacturer of eplerenone recommends that serum lithium concentrations be monitored frequently when eplerenone and lithium are administered concurrently.

Nonsteroidal Anti-inflammatory Agents

Potential pharmacologic effects (decreased antihypertensive effect and/or severe hyperkalemia in patients with impaired renal function). No formal drug interaction studies have been performed. However, concomitant administration of other potassium-sparing antihypertensive agents with nonsteroidal anti-inflammatory agents (NSAIAs) resulted in the mentioned effects. Patients should be monitored to determine whether the desired therapeutic response is achieved.

Drugs Increasing Serum Potassium Concentrations

Potential pharmacodynamic interaction (increased risk of hyperkalemia) when the drug is used concurrently with other potassium-sparing agents or potassium supplements. For further precautionary information about concurrent use of eplerenone with other potassium-sparing agents, see Cautions: Contraindications.

Other Drugs

Pharmacokinetic interactions are unlikely with aluminum or magnesium-containing antacids, digoxin, warfarin, midazolam, cisapride, cyclosporine, simvastatin, glyburide, or oral contraceptives containing ethinyl estradiol and norethindrone.

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