Inspra

Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat and moisture (not in the bathroom).

Unneeded medications should be disposed of in special ways to ensure that pets, children, and other people cannot consume them. However, you should not flush this medication down the toilet. Instead, the best way to dispose of your medication is through a medicine take-back program. Talk to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in your community. See the FDA's Safe Disposal of Medicines website (http://goo.gl/c4Rm4p) for more information if you do not have access to a take-back program.

It is important to keep all medication out of sight and reach of children as many containers (such as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child-resistant and young children can open them easily. To protect young children from poisoning, always lock safety caps and immediately place the medication in a safe location – one that is up and away and out of their sight and reach. http://www.upandaway.org

INSPRA 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-3oxo-, γ-lactone, methyl ester, (7α,11α,17α)-. Its empirical formula is C24H30O6 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: lactose, microcrystalline cellulose, croscarmellose sodium, hypromellose, sodium lauryl sulfate, talc, magnesium stearate, titanium dioxide, polyethylene glycol, polysorbate 80, and iron oxide yellow and iron oxide red.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Relatively selective mineralocorticoid (aldosterone) receptor antagonist.1 2 3 10 11

Heart Failure after Acute MI

Used to reduce the risk of mortality following acute MI in clinically stable patients with left ventricular systolic dysfunction (i.e., left ventricular ejection fraction [LVEF] ≤40%) and heart failure.1 17 21 524

Therapy with an aldosterone antagonist (i.e., eplerenone or spironolactone) recommended by ACCF and AHA to reduce morbidity and mortality following acute MI in patients with reduced LVEF (≤40%) who develop symptoms of heart failure or who have a history of diabetes mellitus, unless contraindicated.524

Hypertension

Management of hypertension.1 2 3 4 10 11 24

Used as monotherapy or in combination with other classes of antihypertensive agents.1 2 4 10 11

Not considered a preferred agent for initial management of hypertension, but may be used as add-on therapy if BP not adequately controlled with the recommended antihypertensive drug classes (i.e., ACE inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, thiazide diuretics).501 502 503 504

Chronic Heart Failure

Has been used in the management of chronic heart failure† (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.524 700 721

ACCF and AHA recommend the addition of an aldosterone antagonist (i.e., eplerenone or spironolactone) in selected patients with heart failure and reduced LVEF who are already receiving an agent to inhibit the renin-angiotensin-aldosterone (RAA) system (e.g., ACE inhibitor, angiotensin II receptor antagonist, angiotensin receptor-neprilysin inhibitor [ARNI]) and a β-blocker; careful patient selection required to minimize the risk of hyperkalemia and renal insufficiency.524 700

General

• Measure serum potassium concentrations prior to initiation of therapy, within the first week, and at 1 month after initiation of therapy or dosage adjustment.1

• Monitor serum potassium concentrations periodically thereafter, and modify drug dosage accordingly.1 (See Table: Dosage Modification in Heart Failure for Serum Potassium Concentrations under Dosage and Administration.)

Hypertension

• Carefully monitor BP during initial titration or subsequent upward dosage adjustment.500 501

• Goal is to achieve and maintain optimal control of BP; individualize specific target BP based on consideration of multiple factors, including patient age and comorbidities, and currently available evidence from clinical studies.500 501

Administration

Oral Administration

Administer orally1 2 3 11 without regard to meals.1

Dosage

Adults

Initially, 25 mg once daily.1 Titrate dosage 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 ≥5.5 mEq/L).1

ACCF/AHA recommendation: Hold eplerenone therapy if serum potassium >5.5 mEq/L or renal function worsens; consider resuming therapy at reduced dosage after resolution (for ≥72 hours) of hyperkalemia (serum potassium <5 mEq/L) and renal insufficiency.524

Initially, 50 mg once daily.1 3 8 If BP is not adequately controlled after 4 weeks, increase dosage to 50 mg twice daily.1

In hypertensive patients currently receiving therapy with weak inhibitors of CYP3A4 (e.g., erythromycin, saquinavir, verapamil, fluconazole), reduce the initial dosage to 25 mg once daily.1 3 8

Has been administered at an initial dosage of 25 mg once daily and increased after 4 weeks of therapy to 50 mg once daily in patients with serum potassium ≤5 mEq/L and adequate renal function.524 721

Hold eplerenone therapy if serum potassium >5.5 mEq/L or renal function worsens; consider resuming therapy at reduced dosage after resolution (for ≥72 hours) of hyperkalemia (serum potassium <5 mEq/L) and renal insufficiency.524

Prescribing Limits

Adults

50 mg twice daily.1 No additional benefit from higher dosages (>100 mg daily) and such dosages have been associated with increased risk of hyperkalemia.1

Special Populations

Hepatic Impairment

No adjustment in the initial dosage is necessary in those with mild-to-moderate hepatic impairment.1 21 (See Hepatic Impairment under Cautions.)

Renal Impairment

Heart failure patients with eGFR 30–49 mL/minute per 1.73 m2: Initially, 25 mg once every other day; maintenance dosage of 25 mg once daily (after 4 weeks of therapy and if serum potassium ≤5 mEq/L).524

Heart failure patients with eGFR <30 mL/minute per 1.73 m2: Use is potentially harmful.524

Geriatric Patients

No adjustment in the initial dosage is necessary.1 21

Storage

Oral

25°C (may be exposed to 15–30°C).1

• Inhibits physiologic effects of aldosterone.1 2 3 4 10

• Produces sustained increases in plasma renin and serum aldosterone concentrations, reflecting the inhibition of the negative feedback of aldosterone on renin secretion.1 2 3 10 11

• Some of the antihypertensive effects may be related to restoration of endothelial function by increasing the release of nitric oxide, which results in vasodilation.2 9 12

• Reduces coronary vascular inflammation,17 18 the risk of subsequent development of interstitial myocardial and coronary perivascular fibrosis,2 17 18 19 20 cardiac hypertrophy,2 20 and/or ventricular remodeling.2 17 20

• If you have an allergy to eplerenone or any other part of Inspra (eplerenone).
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have any of these health problems: High blood sugar (diabetes) with protein in urine, high potassium levels, or kidney disease.
• If you are taking any of these drugs: Clarithromycin, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, or troleandomycin.
• If you are taking any of these drugs: Amiloride, potassium, spironolactone, or triamterene.
• If you are breast-feeding or plan to breast-feed.

This is not a list of all drugs or health problems that interact with this medicine.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take Inspra with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

Pregnancy

Pregnancy Category B

There are no adequate and well-controlled studies in pregnant women. Inspra 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, Inspra 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 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, decide whether to discontinue nursing or discontinue the drug.

Pediatric Use

In a 10-week study of 304 hypertensive pediatric patients age 4 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 5 to 17 years), the incidence of reported adverse events was similar to that of adults.

Inspra has not been studied in hypertensive patients less than 4 years old because the study in older pediatric patients did not demonstrate effectiveness.

Inspra 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 Inspra [see Clinical Studies (14.1)].

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 65 and older [see Warnings and Precautions (5.1)].

Hypertension

Of the total number of subjects in clinical hypertension studies of Inspra, 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, however due to age-related decreases in creatine clearance, the risk of hyperkalemia may be increased [see Warnings and Precautions (5.1)].

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.