Eplerenona Pentafarma

Eplerenone.

Excipients/Inactive Ingredients: Core excipients: Lactose Monohydrate, Microcrystalline Cellulose, Croscarmellose Sodium, Hypromellose, Sodium Lauryl Sulfate, Talc, Magnesium Stearate.
Film coating excipients: OPADRY YELLOW YS-1-12524-A: Hypromellose, Titanium dioxide, Macrogol, Polysorbate 80, Iron oxide yellow, Iron oxide red.

Pharmacology: Pharmacokinetics: Special Populations and Conditions: Age, Gender, and Race: The pharmacokinetics of eplerenone at a dose of 100 mg once daily has 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 C_max (22%) and AUC (45%) compared with younger subjects (18 to 45 years). At steady state, C_max was 19% lower and AUC was 26% lower in Blacks (see Use in the Elderly under Precautions and Dosage & Administration).
Renal Insufficiency: The pharmacokinetics of eplerenone was evaluated in patients with varying degrees of renal insufficiency and in patients undergoing hemodialysis. Compared with control subjects, steady-state AUC and C_max 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 Hyperkalemia under Precautions).
Hepatic Insufficiency: The pharmacokinetics of eplerenone 400 mg has been investigated in patients with moderate (Child-Pugh Class B) hepatic impairment and compared with normal subjects. Steady-state C_max and AUC of eplerenone were increased by 3.6% and 42%, respectively (see Dosage & Administration).
Heart Failure: The pharmacokinetics of eplerenone 50 mg was evaluated in 8 patients with heart failure (NYHA classification II-IV) and 8 matched (gender, age, weight) healthy controls. Compared with the controls, steady state AUC and C_max in patients with stable heart failure were 38% and 30% higher, respectively.
Drug-Drug Interactions (see Interactions): Drug-drug interaction studies were conducted with a 100 mg dose of eplerenone.
Eplerenone is metabolized primarily by CYP3A4. A potent inhibitor of CYP3A4 (ketoconazole) caused increased exposure of 5.4 fold; while less potent CYP3A4 inhibitors (erythromycin, saquinavir, verapamil, and fluconazole) resulted in increases ranging from 2.0-2.9 fold.
Grapefruit juice caused only a small increase (about 25%) in exposure (see Interactions).
Eplerenone is not an inhibitor of CYP1A2, CYP3A4, CYP2C19, CYP2C9, or CYP2D6. Eplerenone did not inhibit the metabolism of amiodarone, amlodipine, astemizole, chlorzoxazone, cisapride, dexamethasone, dextromethorphan, diclofenac, 17α-ethinyl estradiol, fluoxetine, losartan, lovastatin, mephobarbital, methylphenidate, methylprednisolone, metoprolol, midazolam, nifedipine, phenacetin, phenytoin, simvastatin, tolbutamide, triazolam, verapamil, and warfarin in vitro. Eplerenone is not a substrate or an inhibitor of P-Glycoprotein at clinically relevant doses.
No clinically significant drug-drug pharmacokinetic interactions were observed when eplerenone was administered with cisapride, cyclosporine, digoxin, glyburide, midazolam, oral contraceptives (norethindrone/ethinyl estradiol), simvastatin, or warfarin. St. John's Wort (a CYP3A4 inducer) caused a small (about 30%) decrease in eplerenone AUC.
No significant changes in eplerenone pharmacokinetics were observed when eplerenone was administered with aluminum and magnesium-containing antacids.

EPLERENONA PENTAFARMA TABLETS (eplerenone) is indicated as an adjunct to standard therapy to reduce the risk of cardiovascular mortality and hospitalization for heart failure in patients with NYHA class II systolic chronic heart failure and left ventricular systolic dysfunction. In patients 75 years and older a reduction in cardiovascular mortality was not observed with EPLERENONA PENTAFARMA TABLETS (see Use in the Elderly under Precautions).
EPLERENONA PENTAFARMA TABLETS (eplerenone) is indicated as an adjunct to standard therapy to reduce the risk of mortality and hospitalization for heart failure following myocardial infarction in clinically stable adult patients who have evidence of heart failure and left ventricular systolic dysfunction (ejection fraction ≤40%). In patients 75 years and older a reduction in mortality was not observed with EPLERENONA PENTAFARMA TABLETS (see Use in the Elderly under Precautions).
Serum potassium level should be measured and glomerular filtration rate should be estimated before starting EPLERENONA PENTAFARMA TABLETS therapy and EPLERENONA PENTAFARMA TABLETS should not be administered if initial serum potassium is >5.0 mmol/L or if estimated glomerular filtration rate is <30 mL/min/1.73 m² (see Contraindications, Precautions, and Dosage & Administration).

Glomerular filtration rate should be estimated (eGFR) and serum potassium measured before initiating EPLERENONA PENTAFARMA TABLETS (eplerenone) therapy since EPLERENONA PENTAFARMA TABLETS dosing depends on these variables.
EPLERENONA PENTAFARMA TABLETS should not be administered to heart failure patients with initial serum potassium >5.0 mmol/L, serum creatinine >221 μmol/L and/or eGFR <30 mL/min/1.73 m².
Serum potassium should be measured before initiating EPLERENONA PENTAFARMA TABLETS (eplerenone) therapy, within the first week and at one month after the start of treatment or after a dose adjustment. Serum potassium should be measured periodically thereafter, as clinically warranted.
Hyperkalemia can be expected at any time during treatment with EPLERENONA PENTAFARMA TABLETS.
Efforts should be made to decrease the dietary potassium intake. Patients should be asked about their use of potassium containing salt substitutes and dietary supplements. Factors, such as patient characteristics, serum potassium levels and concomitant medications, may indicate that additional monitoring of serum potassium is appropriate (see Hyperkalemia under Precautions, Adverse Reactions, and Interactions).
Recommended Dose and Dosage Adjustment: Heart failure: Renal Impairment: Patients with eGFR of ≥50 mL/min/1.73 m²: For chronic heart failure NYHA Class II and post-myocardial infarction heart failure patients with serum potassium ≤5 mmol/L, 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). Following myocardial infarction EPLERENONA PENTAFARMA TABLETS should be initiated 3-14 days after MI.
The maximum daily dose in patients with eGFR of ≥50 mL/min/1.73 m² is 50 mg daily. In patients using a mild to moderate CYP3A4 inhibitor, the maximum daily dose of EPLERENONA PENTAFARMA TABLETS is 25 mg.
Patients with eGFR of 30-49 mL/min/1.73 m²: For chronic heart failure NYHA Class II and post-myocardial infarction heart failure patients with serum potassium ≤5 mmol/L, treatment should be initiated at a dose of 25 mg once every other day and titrated to the target dose of 25 mg once daily preferably within 4 weeks, taking into account the serum potassium level (see Table 1). Following myocardial infarction EPLERENONA PENTAFARMA TABLETS should be initiated 3-14 days after MI.
The maximum dose in patients with an eGFR 30-49 mL/min/1.73 m² is 25 mg once daily. EPLERENONA PENTAFARMA TABLETS should not be given to patients on a mild to moderate CYP3A4 inhibitor because a lower dose than 25 mg once daily has not been studied.
Patients with eGFR of <30 mL/min/1.73 m²: EPLERENONA PENTAFARMA TABLETS is contraindicated in patients with severe renal impairment.
Hepatic Impairment: Mild-to-Moderate Hepatic Impairment: No initial dosage adjustment is necessary.
Severe Hepatic Impairment: See Contraindications and Precautions.
Dose adjustment based on serum potassium levels for heart failure patients: Patients who develop hyperkalemia (>5.5 mmol/L) may still benefit from EPLERENONA PENTAFARMA TABLETS with proper dose adjustment. The dose should be adjusted based on the serum potassium level and the dose adjustment table shown in Table 1. (See Table 1.)

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Following withholding EPLERENONA PENTAFARMA TABLETS due to serum potassium ≥6.0 mmol/L and the return of potassium levels within acceptable limits, EPLERENONA PENTAFARMA TABLETS can be restarted at a test dose of 25 mg every other day. There are no data to demonstrate that 25 mg every other day is effective and such dosing should be considered to be only a temporary situation. After a test period of one week on 25 mg every other day, serum potassium levels should be measured. If potassium levels return within acceptable limits, the dose can be increased to 25 mg every day and serum potassium should be measured after one week. It could then be determined if EPLERENONA PENTAFARMA TABLETS therapy should be continued or stopped.

For the management of a suspected drug overdose, contact the regional Poison Control Centre.
No cases of adverse events associated with overdose of EPLERENONA PENTAFARMA TABLETS (eplerenone) in humans have been reported. Lethality was not observed in mice, rats, or dogs after single oral doses that provided C_max exposures at least 25 times higher than in humans receiving eplerenone 100 mg/day. Dogs showed emesis, salivation, and tremors at a C_max 41 times the human therapeutic C_max, progressing to sedation and convulsions at higher exposures.
The most likely manifestation of human overdosage would be anticipated to be hypotension and/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.

EPLERENONA PENTAFARMA TABLETS (eplerenone) is contraindicated in all patients with the following: hypersensitivity to EPLERENONA PENTAFARMA TABLETS; patients with clinically significant hyperkalemia; severe hepatic impairment (Child-Pugh Class C); serum potassium >5.0 mmol/L at initiation; severe renal impairment [eGFR <30 mL/min/1.73 m²]; concomitant use with potassium-sparing diuretics, potassium supplements or strong CYP3A4 inhibitors such as ketoconazole, itraconazole, nefazodone, telithromycin, clarithromycin, ritonavir, and nelfinavir (see Interactions and Dosage & Administration).

Hyperkalemia: The principal risk of EPLERENONA PENTAFARMA TABLETS (eplerenone) is hyperkalemia. Hyperkalemia, if not recognized in a timely manner, can cause serious, sometimes fatal, arrhythmias. All patients prescribed EPLERENONA PENTAFARMA TABLETS must have their serum potassium level measured before initiating EPLERENONA PENTAFARMA TABLETS therapy, within one week and at one month after the first dose or after a dose adjustment, and measured periodically thereafter, as clinically warranted (see Dosage & Administration).
Hyperkalemia can be minimized by appropriate patient selection, avoidance of certain concomitant treatments, thoroughly informing the patient and periodic monitoring until the effect of EPLERENONA PENTAFARMA TABLETS has been established.
For patient selection and medications which should not be prescribed concomitantly with EPLERENONA PENTAFARMA TABLETS or prescribed with caution, see Contraindications, Interactions, and Adverse Reactions.
EPLERENONA PENTAFARMA TABLETS should not be administered to heart failure patients with initial serum potassium >5.0 mmol/L, and/or eGFR <30 mL/min/1.73 m². The incidence of hyperkalemia increases with declining renal function (see Tables 6 and 9 in Adverse Reactions).
Diabetic patients with heart failure (HF) who are treated with EPLERENONA PENTAFARMA TABLETS, especially those with proteinuria or renal impairment, should also be treated with caution as they have an increased risk of hyperkalemia. Patients with either diabetes or renal impairment/proteinuria also have an increased risk of hyperkalemia, however the incidence remains lower than in patients with both of these comorbidities (see Tables 7 and 10 in Adverse Reactions).
Impaired Hepatic Function: In 16 subjects with mild-to-moderate hepatic impairment (Child-Pugh Class B) who received 400 mg of eplerenone, no elevations of serum potassium above 5.5 mmol/L were observed. C_max was not significantly changed but AUC was increased by 42% and eplerenone clearance 30% lower compared to matched controls. The dose recommended is 8 times smaller and, therefore, no dose adjustment is necessary in patients with mild to moderate hepatic impairment.
The use of EPLERENONA PENTAFARMA TABLETS in patients with severe hepatic impairment has not been evaluated and therefore, EPLERENONA PENTAFARMA TABLETS is contraindicated in these patients (see Contraindications, Dosage & Administration, and Pharmacology: Pharmacokinetics: Special Populations and Conditions under Actions).
Impaired Renal Function: See Hyperkalemia as previously mentioned, Contraindications, and Adverse Reactions.
Carcinogenesis, Mutagenesis: Preclinical studies of safety pharmacology, genotoxicity, carcinogenic potential and toxicity to reproduction revealed no special hazard for humans.
In repeat 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.
Use in Pregnancy: See Pregnant Women under Use in Pregnancy & Lactation.
Use in Lactation: See Nursing Women under Use in Pregnancy & Lactation.
Use in Children: The safety and effectiveness of EPLERENONA PENTAFARMA TABLETS have not been established in pediatric patients and EPLERENONA PENTAFARMA TABLETS is not recommended in this patient population.
Use in the Elderly: There were 1641 (46%) patients treated with eplerenone who were 65 and over, while 616 (18.6%) were 75 and over. Patients greater than 75 years did not appear to benefit from the use of eplerenone.
There were 1854 (68%) patients treated with eplerenone in EMPHASIS-HF who were 65 years and over, while 657 (24%) were 75 years and over. Both subgroups of patients appeared to benefit from the use of eplerenone compared to placebo-treated patients, based on the results from the primary endpoint (composite endpoint CV mortality or hospitalization for heart failure) but these results were driven by a significant reduction of hospitalization for heart failure. While hospitalization for heart failure was reduced in all age groups, the study did not show a reduction in cardiovascular mortality with eplerenone in patients 75 years and older.
No initial dose adjustment is required in the elderly. Due to an age-related decline in renal function, the risk of hyperkalemia is increased in elderly patients. This risk may be further increased when co-morbidity associated with increased systemic exposure is also present, in particular mild-to-moderate hepatic impairment. Periodic monitoring of serum potassium is recommended.

Pregnant Women: There are no EPLERENONA PENTAFARMA TABLETS studies in pregnant women. Eplerenone did not impair fertility and was not teratogenic in animals but the risk to the fetus of pregnant women is not known. Therefore, EPLERENONA PENTAFARMA TABLETS should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
Nursing Women: It has not been determined if EPLERENONA PENTAFARMA TABLETS is present in human breast milk, however it was present in rat breast milk at a milk to plasma ratio of 0.85. 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.

Clinical Trial Adverse Events: Because clinical trials are conducted under very specific conditions the adverse drug reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
NYHA Class II Chronic Heart Failure: EMPHASIS-HF study: NYHA Class II chronic heart failure: In the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF), safety was evaluated in 1364 patients treated with eplerenone and followed-up for a median duration of 675 days, and 1372 placebo-treated patients, followed-up for a median of 615 days during the double-blind phase of the trial. All causality adverse events that occurred in ≥2% of subjects treated with eplerenone (also incidence higher than placebo) are presented in Table 2. (See Table 2.)

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The overall incidence of treatment-related adverse events reported with eplerenone versus placebo was 21.3% and 17.1%, respectively. The only treatment-related AE that occurred in ≥2% of subjects in either treatment group was hyperkalemia (7.0% in the eplerenone group vs 2.9% in the placebo group). A total of 1272 subjects reported serious adverse events (SAE); 586 subjects (43.0%) in the eplerenone group and 686 subjects (50.0%) in the placebo group.
A total of 472 subjects discontinued from the study due to adverse events; 215 subjects (15.8%) in the eplerenone group and 257 subjects (18.7%) in the placebo group. A total of 32 subjects discontinued due to hyperkalemia; 19 subjects (1.4%) in the eplerenone group and 13 subjects (0.9%) in the placebo group.
A summary of the incidence of hyperkalemia and hypokalemia is provided in Table 5.
Heart Failure following Myocardial Infarction: EPHESUS study: Post-myocardial infarction heart failure: In the eplerenone post-acute myocardial infarction heart failure efficacy and survival study (EPHESUS), safety was evaluated in 3307 patients treated with eplerenone and 3301 placebo-treated patients. Patients were followed for an average of 16 months. Vital status was confirmed for 99.7% of patients.
The most serious adverse events in EPHESUS were endpoint events (e.g., death, cardiac failure) and these were significantly more frequent in the placebo treatment group. Serious adverse events that were significantly associated with eplerenone treatment included dehydration, arterial leg thrombosis, increased creatinine, and pyelonephritis; the incidence of these was low (≤0.5%).
Headache was the most frequent adverse reaction among eplerenone subjects in single- and multiple-dose trials. Adverse events that occurred more frequently in patients treated with eplerenone than placebo were hyperkalemia (summarized in Table 7). Eplerenone-treated patients also experienced more postural hypotension (0.7% vs 0.3% on placebo). Other adverse events more frequent during eplerenone treatment were increased blood urea nitrogen (BUN), increased creatinine, hypothyroidism, gastroesophageal reflux, pancreatitis, ketosis, arterial leg thrombosis, sepsis, and varicose veins. Hypokalemia (<3.5 mmol/l) occurred less frequently in patients treated with eplerenone (8.4% vs. 13.1%).
Elevation of serum potassium led to appropriate dose adjustments of eplerenone (see Table 1 in Dosage & Administration). Permanent discontinuations of eplerenone treatment due to hyperkalemia were infrequent (0.7% eplerenone vs 0.3% placebo); no eplerenone patient died from hyperkalemia. Sepsis led to permanent discontinuation of study medication in 2 eplerenone patients. No patients permanently discontinued study medication due to postural hypotension.
Adverse events experienced by ≥2.0% of subjects treated with eplerenone (also incidence higher than placebo) are presented in Table 3. (See Table 3.)

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The incidences of sex hormone-related adverse events are shown in Table 4. (See Table 4.)

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Clinical Chemistry Findings: EMPHASIS-HF study: NYHA Class II chronic heart failure: A summary of the incidence of hyperkalemia and hypokalemia is provided in Table 5. (See Table 5.)

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The higher risk of hyperkalemia in patients with renal impairment and, low estimated glomerular filtration rate (eGFR) and history of diabetes mellitus (EMPHASIS-HF study) are shown in Table 6 and Table 7 respectively. (See Tables 6 and 7.)

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EPHESUS study: Post-myocardial infarction heart failure: A summary of the incidence of hyperkalemia and hypokalemia is provided in Table 8. (See Table 8.)

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The higher risk of hyperkalemia in patients with renal impairment and, proteinuria and history of diabetes mellitus (EPHESUS study) are shown in Table 9 and Table 10 respectively. (See Tables 9 and 10.)

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Creatinine: Increases of more than 44 μmol/L were reported in 6.5% of patients administered eplerenone and in 4.9% of placebo-treated patients.
Blood Urea Nitrogen: In EPHESUS, a mean increase of 0.17 mmol/L in blood urea nitrogen (BUN) was reported in patients treated with eplerenone and a mean 0.31 mmol/L decrease for placebo-treated patients. BUN increased in 1.6% and 1.0% of subjects, respectively. The incidence of patients with a value of 1.3xULN for BUN is 36.0% for the eplerenone group compared to 30.5% for placebo.
Less Common Clinical Trial Adverse Events: EMPHASIS-HF study: NYHA Class II chronic heart failure: See Table 11.

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EPHESUS study: Post-myocardial infarction heart failure: See Table 12.

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Overview: Inhibitors of CYP3A4: EPLERENONA PENTAFARMA TABLETS (eplerenone) metabolism is predominantly mediated via CYP3A4 and therefore, EPLERENONA PENTAFARMA TABLETS should not be used with drugs described as strong inhibitors of CYP3A4 in their labeling (see Table 13 as follows, Contraindications, and Dosage & Administration).
Caution should be used in patients treated with mild to moderate CYP3A4 inhibitors; dosing should not exceed 25 mg QD in patients with an eGFR ≥50 mL/min/1.73 m². For patients with moderate renal impairment (eGFR 30-49 mL/min/1.73 m²), EPLERENONA PENTAFARMA TABLETS is not recommended because a lower dose than 25 mg once daily has not been studied.
Inducers of CYP3A4: St. John's Wort was found to decrease exposure and to increase clearance of EPLERENONA PENTAFARMA TABLETS significantly indicating that concomitant use of strong inducers of CYP3A4 such as phenobarbital, phenytoin, rifampicin, carbamazepine should be avoided.
ACE Inhibitors and Angiotensin II Receptor Antagonists: In EPHESUS and EMPHASIS-HF, 3020 (91%) and 1282 (94%) patients, respectively, 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 mmol/L were similar regardless of the use of ACEI/ARB. However, as ACEI/ARB can also increase serum potassium levels in some patients, concomitant use with EPLERENONA PENTAFARMA TABLETS dictates that greater caution should be exercised.
Lithium: A drug interaction study of EPLERENONA PENTAFARMA TABLETS with lithium has not been conducted. However, lithium toxicity has been reported in patients receiving lithium concomitantly with diuretics and ACE inhibitors and concomitant administration of EPLERENONA PENTAFARMA TABLETS may worsen lithium toxicity. Serum lithium levels should be monitored frequently if EPLERENONA PENTAFARMA TABLETS is administered concomitantly with lithium, as excretion may be altered as a result of modifications in sodium balance induced by the aldosterone antagonist. Lithium has also been reported to increase plasma renin activity and aldosterone levels.
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): A drug interaction study of EPLERENONA PENTAFARMA TABLETS with an NSAID has not been conducted. The administration of potassium-sparing antihypertensive drugs 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 EPLERENONA PENTAFARMA TABLETS and NSAIDs including COX-2 Inhibitors, are used concomitantly, blood pressure, renal function and serum potassium should be closely monitored.
Herbal Preparations and Salt Substitutes: The full consequence of using EPLERENONA PENTAFARMA TABLETS in patients taking herbal preparations and/or salt substitutes has not been established, and caution should be exercised. Theoretically, patients who are taking herbal preparations that affect blood pressure or contain high levels of potassium may be at risk of hypotension/hypertension or hyperkalemia (see Precautions). Clinicians should consider discontinuing the herbal preparation or salt substitute or closely monitoring patients using such a combination. Such preparations may include (but not limited to): dandelion, potassium iodine, laminaria, morinda, oleander, phosphate salts and potassium preparations, cat's claw, cod liver oil, and licorice.
Drug-Drug Interactions: Drug-drug interaction studies were conducted with a 100 mg dose of eplerenone and the outcomes are summarized in Table 13. (See Table 13.)

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Drug-Food Interactions: EPLERENONA PENTAFARMA TABLETS may be administered with or without food.

Store below 25°C.
Protect from light and moisture.

Diuretics

C03DA04 - eplerenone ; Belongs to the class of aldosterone antagonists. Used as potassium-sparing diuretics.

P₁S₁S₃