Eplerenone

Eplerenone is an antihypertensive agent belonging to Potassium Sparing Diuretics.

Eplerenone is a potassium-sparing diuretic that is used to treat the symptoms of High Blood Pressure (Hypertension) and Heart Failure post-Myocardial Infarction.

Mean peak plasma concentrations of eplerenone are reached approximately 1.5 hours to 2 hours following oral administration. The absolute bioavailability of eplerenone is 69%. Both peak plasma levels (Cmax) and area under the curve (AUC) are doses proportional at doses of 25 mg to 100 mg and less than proportional at doses above 100 mg. Upon repeat dosing, steady-state levels are reached within 2 days. The plasma protein binding of eplerenone is about 50%. The apparent volume of distribution at a steady state ranged from 42 to 90 L. Eplerenone metabolism is primarily mediated via CYP3A4. 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.

Eplerenone shows common side effects Headache, dizziness, diarrhea, stomach pain, cough, excessive tiredness, flu-like symptoms, breast enlargement or tenderness, abnormal vaginal bleeding, etc.

Eplerenone is available in the form of Oral Tablets.

Eplerenone is available in India, the US, the UK, Japan, Austria, Canada, Europe, and Netherland.

Eplerenone belonging to the Potassium Sparing Diuretics acts as an antihypertensive agent.

Eplerenone binds to the mineralocorticoid receptor and thereby blocks the binding of aldosterone (a component of the renin-angiotensin-aldosterone-system, or RAAS). Aldosterone synthesis, which occurs primarily in the adrenal gland, is modulated by multiple factors, including angiotensin II and non-RAAS mediators such as adrenocorticotropic hormone (ACTH) and potassium. Aldosterone binds to mineralocorticoid receptors in both epithelial (e.g., kidney) and nonepithelial (e.g., heart, blood vessels, and brain) tissues and increases blood pressure through induction of sodium reabsorption and possibly other mechanisms.

The onset of action of Eplerenone is not clinically established.

The Duration of Action for Eplerenone in the body is not clinically established.

The Tmax was found within 1.5- 2 hours.

Eplerenone is available in the form of an Oral Tablet.

Eplerenone Tablets are taken orally, and it is usually taken once a day.

Eplerenone is a potassium-sparing diuretic that is used to treat the symptoms of High Blood Pressure (Hypertension) and Heart Failure post-Myocardial Infarction. Eplerenone may be used alone or with other medications.

Eplerenone is an antihypertensive agent belonging to Potassium Sparing Diuretics.

Eplerenone selectively blocks mineralocorticoid receptors reducing blood pressure in a dose-dependent manner and appears to prevent myocardial and vascular fibrosis.

Eplerenone is approved for use in the following clinical indications

• Congestive Heart Failure Post-Myocardial Infarction

Eplerenone is indicated to improve the survival of stable patients with left ventricular (LV) systolic dysfunction (ejection fraction ≤40%) and clinical evidence of congestive heart failure (CHF) after an acute myocardial infarction (MI).

• Hypertension

Eplerenone is indicated for the treatment of hypertension. Eplerenone may be used alone or in combination with other antihypertensive agents.

• Congestive Heart Failure Post-Myocardial Infarction

Oral: Initial: 25 mg once daily; may double the dose after 4 weeks if serum potassium remains <5 mEq/L and renal function is stable, to a maximum target dose of 50 mg once daily.

• Hypertension

Oral: Initial: 50 mg once daily; evaluate response after ~2 to 4 weeks and titrate the dose, as needed, to a maximum of 50 mg twice daily. Twice daily dosing is usually required for adequate BP lowering. Patients with severe asymptomatic hypertension and no signs of acute end organ damage should be evaluated for medication titration within 1 week.

Eplerenone is available in various strengths as 25mg and 50mg.

Eplerenone is available in the form of an Oral Tablet.

Do not use salt substitutes containing potassium such as Bananas, oranges, potatoes, peas, mushrooms, cantaloupe, honeydew, apricots, grapefruit, raisins, and dates.

Eplerenone is contraindicated in patients with

• Types 2 diabetes with microalbuminuria
• Serum creatinine over 2.0 mg/dL in males and 1.8 mg/dL in females or a CrCl below 50mL/min
• Concomitant use of potassium supplementation or potassium-sparing diuretics
• Since Addison's disease characteristically demonstrates an aldosterone deficiency, eplerenone is also contraindicated in these patients.

• Hyperkalemia

Minimize the risk of hyperkalemia with proper patient selection and monitoring, and avoidance of certain concomitant medications. Monitor patients for the development of hyperkalemia until the effect of Eplerenone is established. Patients who develop hyperkalemia (>5.5 mEq/L) may continue Eplerenone therapy with proper dose adjustment. Dose reduction decreases potassium levels. The rates of hyperkalemia increase with declining renal function. Patients with hypertension who have serum creatinine levels >2.0 mg/dL (males) or >1.8 mg/dL (females) or creatinine clearance ≤50 mL/min should not be treated with Eplerenone. Patients with CHF post-MI who have serum creatinine levels >2.0 mg/dL (males) or >1.8 mg/dL (females) or creatinine clearance ≤50mL/min should be treated with Eplerenone with caution. Diabetic patients with CHF post-MI should also be treated with caution, especially those with proteinuria. The subset of patients in the EPHESUS study with both diabetes and proteinuria on the baseline urinalysis had increased rates of hyperkalemia compared to patients with either diabetes or proteinuria.

• Impaired Hepatic Function

Mild-to-moderate hepatic impairment did not increase the incidence of hyperkalemia. In 16 subjects with mild-to-moderate hepatic impairment who received 400 mg of eplerenone, no elevations of serum potassium above 5.5 mEq/L were observed. The mean increase in serum potassium was 0.12 mEq/L in patients with hepatic impairment and 0.13 mEq/L in normal controls. The use of Eplerenone in patients with severe hepatic impairment has not been evaluated.

• Impaired Renal Function

Patients with decreased renal function are at increased risk of hyperkalemia.

Consumption of alcohol is not recommended during treatment with Eplerenone due to the increased risk of hypotension (low blood pressure), lightheadedness, fainting, dizziness, etc.

The concentration of eplerenone in human breast milk after oral administration is unknown. However, preclinical data show that eplerenone and/or metabolites are present in rat breast milk (0.85:1 [milk: plasma] AUC ratio) obtained after a single oral dose. Peak concentrations in plasma and milk were obtained from 0.5 to 1 hour after dosing. Rat pups exposed to 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.

Pregnancy Category B

There are no adequate and well-controlled studies on pregnant women. Eplerenone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Do not use salt substitutes containing potassium such as Bananas, oranges, potatoes, peas, mushrooms, cantaloupe, honeydew, apricots, grapefruit, raisins, and dates.

• Common Adverse effects

Hyperkalemia, Increased serum creatinine, Acute myocardial infarction, angina pectoris, increased gamma-glutamyl transferase, Dizziness, headache, and Renal insufficiency.

• Rare Adverse effects

• CYP3A4 Inhibitors

Because Eplerenone metabolism is predominantly mediated via CYP3A4, do not use Eplerenone with drugs that are strong inhibitors of CYP3A4. In patients with hypertension taking moderate CYP3A4 inhibitors, reduce the starting dose of Eplerenone to 25 mg once daily.

• ACE Inhibitors and Angiotensin II Receptor Antagonists

Congestive Heart Failure Post-Myocardial Infarction In EPHESUS, (91%) patients receiving Eplerenone 25 to 50 mg also received ACE inhibitors or angiotensin II receptor antagonists (ACEI/ARB). Rates of patients with maximum potassium levels >5.5 mEq/L were similar regardless of the use of ACEI/ARB. In clinical studies of patients with hypertension, the addition of Eplerenone 50 to 100 mg to ACE inhibitors and angiotensin II receptor antagonists increased mean serum potassium slightly (about 0.09–0.13 mEq/L). In a study in diabetics with microalbuminuria, Eplerenone 200 mg combined with the ACE inhibitor enalapril 10 mg increased the frequency of hyperkalemia (serum potassium >5.5 mEq/L) from 17% on enalapril alone to 38%.

• Lithium

A drug interaction study of eplerenone with lithium has not been conducted. Lithium toxicity has been reported in patients receiving lithium concomitantly with diuretics and ACE inhibitors. Serum lithium levels should be monitored frequently if Eplerenone is administered concomitantly with lithium.

• Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

A drug interaction study of eplerenone with an NSAID has not been conducted. The administration of other potassium-sparing antihypertensives with NSAIDs has been shown to reduce the antihypertensive effect in some patients and result in severe hyperkalemia in patients with impaired renal function. Therefore, when Eplerenone and NSAIDs are used concomitantly, patients should be observed to determine whether the desired effect on blood pressure is obtained and monitored for changes in serum potassium levels.

The common side effects of Eplerenone include the following

• Common
  

Headache, dizziness, diarrhea, stomach pain, cough, excessive tiredness, flu-like symptoms, breast enlargement or tenderness, and abnormal vaginal bleeding.

• Rare

Chest pain, tingling in arms and legs, loss of muscle tone, weakness or heaviness in legs, confusion, lack of energy, cold, gray skin, and irregular heartbeat.

• Pregnancy

Pregnancy Category B

There are no adequate and well-controlled studies on pregnant women. Eplerenone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Teratogenic Effects Embryo-fetal development studies were conducted with doses up to 1000 mg/kg/day in rats and 300 mg/kg/day in rabbits (exposures up to 32 and 31 times the human AUC for the 100 mg/day therapeutic dose, respectively). No teratogenic effects were seen in rats or rabbits, although decreased body weight in maternal rabbits and increased rabbit fetal resorptions and post-implantation loss were observed at the highest administered dosage. Because animal reproduction studies are not always predictive of human response, Eplerenone should be used during pregnancy only if clearly needed.

• Nursing Mothers

The concentration of eplerenone in human breast milk after oral administration is unknown. However, preclinical data show that eplerenone and/or metabolites are present in rat breast milk (0.85:1 [milk: plasma] AUC ratio) obtained after a single oral dose. Peak concentrations in plasma and milk were obtained from 0.5 to 1 hour after dosing. Rat pups exposed to 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.

• Pediatric Use

In a 10-week study of 304 hypertensive pediatric patients aged, 4 to 17 years treated with Eplerenone up to 100 mg per day, doses that produced exposure similar to that in adults, Eplerenone did not lower blood pressure effectively. In this study and in a 1-year pediatric safety study in 149 patients, the incidence of reported adverse events 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 did not demonstrate effectiveness. Eplerenone has not been studied in pediatric patients with heart failure.

• Geriatric Use

Congestive Heart Failure Post-Myocardial Infarction

Of the total number of patients in EPHESUS, 3340 (50%) were 65 and over, while 1326 (20%) were 75 and over. Patients greater than 75 years did not appear to benefit from the use of Eplerenone. No differences in the overall incidence of adverse events were observed between elderly and younger patients. However, due to age-related decreases in creatinine clearance, the incidence of laboratory-documented hyperkalemia was increased in patients 65 and older.

Hypertension

Of the total number of subjects in clinical hypertension studies of Eplerenone, 1123 (23%) were 65 and over, while 212 (4%) were 75 and over. No overall differences in safety or effectiveness were observed between elderly subjects and younger subjects.

• No cases of human overdosage with eplerenone have been reported. Lethality was not observed in mice, rats, or dogs after single oral doses that provided Cmax exposures at least 25 times higher than in humans receiving eplerenone 100 mg/day. Dogs showed emesis, salivation, and tremors at a Cmax 41 times the human therapeutic Cmax, progressing to sedation and convulsions at higher exposures.
• The most likely manifestation of human overdosage would be anticipated to be hypotension or hyperkalemia. Eplerenone cannot be removed by hemodialysis. Eplerenone has been shown to bind extensively to charcoal. If symptomatic hypotension should occur, supportive treatment should be instituted. If hyperkalemia develops, standard treatment should be initiated.

Pharmacodynamic

There was no significant change in average heart rate among patients treated with Eplerenone in the combined clinical studies. 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

Eplerenone is cleared predominantly by cytochrome P450 (CYP) 3A4 metabolism, with an elimination half-life of 3 to 6 hours. Steady-state is reached within 2 days. Absorption is not affected by food. Inhibitors of CYP3A (e.g., ketoconazole, saquinavir) increase blood levels of Eplerenone.

• Absorption

Mean peak plasma concentrations of eplerenone are reached approximately 1.5 to 2 hours following oral administration. Absorption is not affected by food. The absolute bioavailability of eplerenone is 69% following administration of a 100 mg oral tablet. Both peak plasma levels (Cmax) and area under the curve (AUC) are doses proportional at doses of 25 mg to 100 mg and less than proportional at doses above 100 mg. Upon repeat dosing, steady-state levels are reached within 2 days.

• Distribution

The plasma protein binding of eplerenone is about 50% and it is primarily bound to alpha 1-acid glycoproteins. The apparent volume of distribution at a steady state ranged from 42 to 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 an unchanged drug in the urine and feces. Following a single oral dose of the radio-labeled 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.

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