ELERAX

contains eplerenone, a blocker of aldosterone binding at the mineralocorticoid receptor.

Eplerenone is chemically described as

Pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy-17-hydroxy-3-oxo-, γ-lactone, methyl ester, (7α,11α,17α)-.

Its empirical formula is

C 24 H 30 O and it has a molecular weight of 414.50.

The structural formula of eplerenone is represented below: Eplerenone is an odorless, white to off-white crystalline powder.

It is very slightly soluble in water, with its solubility essentially pH-independent.

The octanol/water partition coefficient of eplerenone is approximately 7.1 at pH 7.0.

INSPRA tablets for oral administration contain 25 mg or 50 mg of eplerenone and the following inactive ingredients: croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, red iron oxide, sodium lauryl sulfate, talc, titanium dioxide, and yellow iron oxide. structural formula of eplerenone.

• Improving survival of stable adult patients with symptomatic heart failure with reduced ejection fraction (HFrEF) after an acute myocardial infarction.

• The treatment of hypertension in adults, to lower blood pressure.

Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. 1.1 Heart Failure Post-Myocardial Infarction INSPRA is indicated to improve survival of stable adult patients with symptomatic heart failure with reduced ejection fraction (≤40%) (HFrEF) after an acute myocardial infarction (MI). 1.2 Hypertension INSPRA is indicated for the treatment of hypertension in adults, to lower blood pressure.

Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular (CV) events, primarily strokes and MI.

These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes.

Control of high blood pressure should be part of comprehensive CV risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake.

Many patients will require more than one drug to achieve blood pressure goals.

For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce CV morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits.

The largest and most consistent

CV outcome benefit has been a reduction in the risk of stroke, but reductions in MI and CV mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased CV risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit.

Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease).

These considerations may guide selection of therapy.

INSPRA may be used alone or in combination with other antihypertensive agents.

Lactation Diabetes Pregnancy Primary hyperaldosteronism

Mild to moderate hepatic impairment Mild to moderate renal impairment Diabetic nephropathy Sports Elderly Subject at risk of hyperkalaemia Subject under 18.

Eplerenone binds to the mineralocorticoid receptor and blocks the binding of aldosterone, a component of the renin-angiotensin-aldosterone-system (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.

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 aldosterone circulating levels do not overcome the effects of eplerenone.

Eplerenone selectively binds to human mineralocorticoid receptors relative to its binding to recombinant human glucocorticoid, progesterone, and androgen receptors. 12.2 Pharmacodynamics There was no significant change in average heart rate among patients treated with INSPRA in the combined clinical studies.

No consistent effects of

INSPRA on heart rate, QRS duration, or PR or QT interval were observed in 147 normal subjects evaluated for electrocardiographic changes during pharmacokinetic studies. 12.3 Pharmacokinetics Eplerenone is cleared predominantly by cytochrome P450 (CYP) 3A4 metabolism, with an elimination half-life of 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.

Mean peak plasma concentrations of eplerenone are reached approximately 1.5 to 2 hours following oral administration.

The absolute bioavailability of eplerenone is 69% following administration of a 100 mg oral tablet.

Both peak plasma levels (C max ) and area under the curve (AUC) are dose proportional for 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% and it is primarily bound to alpha 1-acid glycoproteins.

The apparent volume of distribution at steady state ranged from to 90 L. Eplerenone does not preferentially bind to red blood cells.

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 to 6 hours.

The apparent plasma clearance is approximately 10 L/hr. 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.

At steady state, elderly subjects had increases in C max (22%) and AUC (45%) compared with younger subjects (18 to 45 years).

The pharmacokinetics of eplerenone did not differ significantly between males and females.

At steady state, C max was 19% lower and AUC was 26% lower in Blacks.

The pharmacokinetics of eplerenone was evaluated in patients with varying degrees of renal impairment 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.

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.

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 Eplerenone is metabolized primarily by CYP3A4.

CYP3A cause increased exposure.

Drug-drug interaction studies were conducted with a 100 mg dose of eplerenone.

Following a single dose of

INSPRA 100 mg and CYP3A inhibitor ketoconazole 200 mg twice a day, eplerenone’s C max was 1.7-fold and AUC was 5.4-fold compared with eplerenone alone.

Administration of eplerenone with moderate

CYP3A inhibitors (e.g., erythromycin 500 mg BID, verapamil 240 mg once daily, saquinavir 1200 mg three times a day, fluconazole 200 mg once daily) resulted in increases in C max of eplerenone ranging from 40% to 60% and AUC from 100% to 190%.

Grapefruit juice caused a 25% increase in exposure.

Eplerenone is not an inhibitor of

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, or 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.

John’s wort (a CYP3A 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.

eplerenone: Mechanism of action Plerenone has a relative selectivity in its binding to recombinant human mineralocorticoids compared to its binding to recombinant human glucocorticoids, progesterone receptors and androgens.

Plerenone prevents the binding of aldosterone, an essential hormone in the renin-angiotensin-aldosterone (SRAA) system, which is involved in the regulation of blood pressure and the physiopathology of cardiovascular disease. eplerenone induced prolonged elevations of plasma renin and serum aldosterone, corresponding to the inhibition of the negative back control of aldosterone on renin secretion.

Increased plasma renin activity and circulating aldosterone levels did not compensate for the effects of plerenone.

• Hyperkalaemia (Common)
• Increased blood glucose (Uncommon)
• Eosinophilia (Uncommon)
• Epidermal growth factor receptor (decrease) (Uncommon)
• Hyponatremia (Uncommon)
• Uremia (increase) (Common)
• Hypertriglyceridaemia (Uncommon)
• Blood creatinine (increase) (Common)
• Hypercholesterolaemia (Common)
• Pruritus (Common)
• Rash (Common)
• Hyperhidrosis (Uncommon)
• Asthenia (Common)
• Hypothyroidism (Uncommon)
• Gynecomastia (Uncommon)
• Cholecystitis (Uncommon)
• Oedema of Quincke (Uncommon)
• Infection (Uncommon)
• Dehydration (Uncommon)
• Feeling dizzy (Common)
• Pharyngitis (Uncommon)
• Insomnia (Common)
• Left heart failure (Common)
• Orthostatic hypotension (Uncommon)
• Blood thrombosis of a limb (Uncommon)
• Myocardial infarction (Common)
• Malaise (Uncommon)
• Left ventricular failure (Common)
• Syncope (Common)
• Tachycardia (Uncommon)
• Atrial fibrillation (Common)
• Hypotension (Common)
• Diarrhoea (Common)
• Nausea (Common)
• Flatulence (Uncommon)
• Constipation (Common)
• Vomiting (Common)
• Muscle spasm (Common)
• Musculoskeletal pain (Uncommon)
• Sleeping (Common)
• Headache (Common)
• Hypoesthesia (Uncommon)
• Stroke Cough (Common)
• Renal impairment (Common)
• Pyelonephritis (Uncommon).

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 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 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.

• serum potassium >5.5 mEq/L at initiation,.

• creatinine clearance ≤30 mL/min, or.

• concomitant administration of strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, and nelfinavir) .

• type 2 diabetes with microalbuminuria,.

• serum creatinine >2.0 mg/dL in males or >1.8 mg/dL in females,.

• creatinine clearance <50 mL/min, or.

• concomitant administration of potassium supplements or potassium-sparing diuretics (e.g., amiloride, spironolactone, or triamterene) .

• Serum potassium >5.5 mEq/L at initiation.

• Creatinine clearance ≤30 mL/min.

• Type 2 diabetes with microalbuminuria.

• Serum creatinine >2.0 mg/dL in males, >1.8 mg/dL in females.

• Creatinine clearance <50 mL/min.

• Concomitant use of potassium supplements or potassium-sparing diuretics.

Initiate treatment with 25 mg once daily.

Titrate to maximum of 50 mg once daily within 4 weeks, as tolerated.

Dose adjustments may be required based on potassium levels.

Hypertension: 50 mg once daily, alone or combined with other antihypertensive agents.

For inadequate response, increase to 50 mg twice daily.

Higher dosages are not recommended.

For all patients

Measure serum potassium before starting INSPRA and periodically thereafter. 2.1 Heart Failure Post-Myocardial Infarction Initiate treatment at 25 mg once daily and titrate to the recommended dose of 50 mg once daily, preferably within 4 weeks as tolerated by the patient.

Once treatment with

INSPRA has begun, adjust the dose based on the serum potassium level as shown in Table 1.

Table 1.

Dose Adjustment in Heart Failure Post-MI Serum Potassium (mEq/L) Dose Adjustment <5.0 25 mg every other day to 25 mg once daily 25 mg once daily to 50 mg once daily 5.0-5.4 No adjustment 5.5-5.9 50 mg once daily to 25 mg once daily 25 mg once daily to 25 mg every other day 25 mg every other day to withhold ≥6.0 Withhold and restart at 25 mg every other day when potassium levels fall to <5.5 mEq/L 2.2 Hypertension The recommended starting dose of INSPRA is 50 mg administered once daily.

The full therapeutic effect of

INSPRA is apparent within 4 weeks.

For patients with an inadequate blood pressure response to 50 mg once daily increase the dosage of INSPRA to 50 mg twice daily.

Higher dosages of

INSPRA are not recommended because they have no greater effect on blood pressure than 100 mg and are associated with an increased risk of hyperkalemia. 2.3 Recommended Monitoring Measure serum potassium before initiating INSPRA therapy, within the first week, and at one month after the start of treatment or dose adjustment.

Assess serum potassium periodically thereafter.

Check serum potassium and serum creatinine within 3-7 days of a patient initiating a moderate CYP3A inhibitor ACE inhibitors, angiotensin II blockers or nonsteroidal anti-inflammatories. 2.4 Dose Modification for Use with Moderate CYP3A Inhibitors In post-MI HFrEF patients receiving a moderate CYP3A inhibitor (e.g., erythromycin, saquinavir, verapamil, and fluconazole), do not exceed 25 mg once daily.

In patients with hypertension receiving a moderate CYP3A inhibitor, initiate at 25 mg once daily.

For inadequate blood pressure response, dosing may be increased to a maximum of 25 mg twice daily.

Tablets are yellow, diamond biconvex, and film-coated.

They are debossed with “VLE” on one side.

They are supplied as follows

Dose Deboss Side 2 NDC 58151-xxx-xx Bottle/30 25 mg NSR 25 142-93 50 mg NSR 50 143-93 Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) .

The available data from published case reports on eplerenone use during pregnancy are insufficient to establish a drug-associated risk of major birth defects, miscarriage, adverse maternal or fetal outcomes.

In animal studies, no adverse developmental effects were observed when eplerenone was administered to pregnant rats and rabbits during organogenesis at exposures and 31 times, respectively the human exposure at the 100 mg/day therapeutic dose.

The estimated background risk of major birth defects and miscarriage for the indicated population are unknown.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Maternal and/or Embryo/Fetal Risk Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage).

Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death.

Pregnant women with hypertension should be carefully monitored and managed accordingly.

Pregnant women with heart failure are at increased risk for preterm birth.

Stroke volume and heart rate increase during pregnancy, increasing cardiac output, especially during the first trimester.

Clinical classification of heart disease may worsen with pregnancy and lead to maternal death.

Closely monitor pregnant patients for destabilization of their heart failure.

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 and 31 times the human AUC for the 100 mg/day therapeutic dose, respectively) administered during organogenesis.

No teratogenic effects were seen in rats or rabbits, although decreased rat fetal weights were observed, and decreased body weight in maternal rabbits and increased rabbit fetal resorptions and post-implantation loss were observed at the highest administered dosages.

In a pre.

• and postnatal development study, pregnant rats were administered eplerenone at doses up to 1000 mg/kg/day from Gestation Day 6 through Lactation Day 20.

Decreased pup weights were observed beginning at birth at 1000 mg/kg/day.

The safety and effectiveness of

INSPRA for treatment of hypertension have not been established in pediatric patients.

In a 10-week study of 304 hypertensive pediatric patients ages to 16 years treated with INSPRA up to 100 mg per day, doses that produced exposure similar to that in adults, INSPRA did not lower blood pressure effectively.

In this study and in a 1-year pediatric safety study in 149 patients (age range to 17 years), the incidence of reported adverse events was similar to that of adults.

INSPRA was not studied for treatment of hypertension in pediatric patients younger than 4 years of age because the study in older pediatric patients did not demonstrate effectiveness.

INSPRA have not been established in pediatric patients with heart failure.

Of the total number of patients in EPHESUS, 3340 (50%) were and over, while 1326 (20%) were and over.

Patients greater than 75 years did not appear to benefit from the use of INSPRA.

No differences in 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 and older.

Of the total number of subjects in clinical hypertension studies of INSPRA, 1123 (23%) were and over, while 212 (4%) were and over.

No overall differences in safety or effectiveness were observed between elderly subjects and younger subjects, however due to age-related decreases in creatine clearance, the risk of hyperkalemia may be increased.