Inspra Information
Inspra (Eplerenone) Dosage And Administration
Treatment should be initiated at 25 mg once daily and titrated to the recommended dose of 50 mg once daily, preferably within 4 weeks as tolerated by the patient. Inspra (Eplerenone) may be administered with or without food.
Once treatment with Inspra (Eplerenone) has begun, adjust the dose based on the serum potassium level as shown in Table 1.
Serum potassium should be measured before initiating Inspra (Eplerenone) therapy, within the first week, and at one month after the start of treatment or dose adjustment. Serum potassium should be assessed periodically thereafter. Patient characteristics and serum potassium levels may indicate that additional monitoring is appropriate. In the EPHESUS study , the majority of hyperkalemia was observed within the first three months after randomization.
In all patients taking Inspra (Eplerenone) who start taking a moderate CYP3A4 inhibitor, check serum potassium and serum creatinine in 3–7 days.
For hypertensive patients receiving moderate CYP3A4 inhibitors (e.g., erythromycin, saquinavir, verapamil, and fluconazole), the starting dose of Inspra (Eplerenone) should be reduced to 25 mg once daily.
No adjustment of the starting dose is recommended for the elderly or for patients with mild-to-moderate hepatic impairment.
Inspra (Eplerenone) Contraindications
Inspra (Eplerenone) is contraindicated in all patients with:
Inspra (Eplerenone) is contraindicated for the treatment of hypertension in patients with:
Inspra (Eplerenone) Warnings And Precautions
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 Inspra (Eplerenone) is established. Patients who develop hyperkalemia (>5.5 mEq/L) may continue Inspra (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 Inspra (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 Inspra (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.
Inspra (Eplerenone) Adverse Reactions
The following adverse reactions are discussed in greater detail in other sections of the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice.
Inspra (Eplerenone) Drug Interactions
Because eplerenone metabolism is predominantly mediated via CYP3A4, do not use Inspra (Eplerenone) with drugs that are strong inhibitors of CYP3A4.
In patients with hypertension taking moderate CYP3A4 inhibitors, reduce the starting dose of Inspra (Eplerenone) to 25 mg once daily.
In EPHESUS , 3020 (91%) patients receiving Inspra (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 Inspra (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, Inspra (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%.
Inspra (Eplerenone) Use In Specific Populations
In a 10-week study of 304 hypertensive pediatric patients age 4 to 17 years treated with Inspra (Eplerenone) up to 100 mg per day, doses that produced exposure similar to that in adults, Inspra (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.
Inspra (Eplerenone) has not been studied in hypertensive patients less than 4 years old because the study in older pediatric patients did not demonstrate effectiveness.
Inspra (Eplerenone) has not been studied in pediatric patients with heart failure.
Inspra (Eplerenone) Overdosage
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 exposures at least 25 times higher than in humans receiving eplerenone 100 mg/day. Dogs showed emesis, salivation, and tremors at a C 41 times the human therapeutic C, 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.
Inspra (Eplerenone) Description
Inspra (Eplerenone) 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 CHOand 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 (Eplerenone) for oral administration contains 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.
Inspra (Eplerenone) Clinical Pharmacology
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 recombinant human mineralocorticoid receptors relative to its binding to recombinant human glucocorticoid, progesterone, and androgen receptors.
Inspra (Eplerenone) Clinical Studies
The eplerenone post-acute myocardial infarction heart failure efficacy and survival study (EPHESUS) was a multinational, multicenter, double-blind, randomized, placebo-controlled study in patients clinically stable 3–14 days after an acute myocardial infarction (MI) with left ventricular dysfunction (as measured by left ventricular ejection fraction [LVEF] ≤40%) and either diabetes or clinical evidence of congestive heart failure (CHF) (pulmonary congestion by exam or chest x-ray or S). Patients with CHF of valvular or congenital etiology, patients with unstable post-infarct angina, and patients with serum potassium >5.0 mEq/L or serum creatinine >2.5 mg/dL were to be excluded. Patients were allowed to receive standard post-MI drug therapy and to undergo revascularization by angioplasty or coronary artery bypass graft surgery.
Patients randomized to Inspra (Eplerenone) were given an initial dose of 25 mg once daily and titrated to the target dose of 50 mg once daily after 4 weeks if serum potassium was
EPHESUS randomized 6,632 patients (9.3% U.S.) at 671 centers in 27 countries. The study population was primarily white (90%, with 1% Black, 1% Asian, 6% Hispanic, 2% other) and male (71%). The mean age was 64 years (range, 22–94 years). The majority of patients had pulmonary congestion (75%) by exam or x-ray and were Killip Class II (64%). The mean ejection fraction was 33%. The average time to enrollment was 7 days post-MI. Medical histories prior to the index MI included hypertension (60%), coronary artery disease (62%), dyslipidemia (48%), angina (41%), type 2 diabetes (30%), previous MI (27%), and CHF (15%).
The mean dose of Inspra (Eplerenone) was 43 mg/day. Patients also received standard care including aspirin (92%), ACE inhibitors (90%), ß-blockers (83%), nitrates (72%), loop diuretics (66%), or HMG-CoA reductase inhibitors (60%).
Patients were followed for an average of 16 months (range, 0–33 months). The ascertainment rate for vital status was 99.7%.
The co-primary endpoints for EPHESUS were (1) the time to death from any cause, and (2) the time to first occurrence of either cardiovascular (CV) mortality [defined as sudden cardiac death or death due to progression of congestive heart failure (CHF), stroke, or other CV causes] or CV hospitalization (defined as hospitalization for progression of CHF, ventricular arrhythmias, acute myocardial infarction, or stroke).
For the co-primary endpoint for death from any cause, there were 478 deaths in the Inspra (Eplerenone) group (14.4%) and 554 deaths in the placebo group (16.7%). The risk of death with Inspra (Eplerenone) was reduced by 15% [hazard ratio equal to 0.85 (95% confidence interval 0.75 to 0.96; p = 0.008 by log rank test)]. Kaplan-Meier estimates of all-cause mortality are shown in Figure 1 and the components of mortality are provided in Table 9.
Figure 1. Kaplan-Meier Estimates of All-Cause Mortality
Most CV deaths were attributed to sudden death, acute MI, and CHF.
The time to first event for the co-primary endpoint of CV death or hospitalization, as defined above, was longer in the Inspra (Eplerenone) group (hazard ratio 0.87, 95% confidence interval 0.79 to 0.95, p = 0.002). An analysis that included the time to first occurrence of CV mortality and all CV hospitalizations (atrial arrhythmia, angina, CV procedures, progression of CHF, MI, stroke, ventricular arrhythmia, or other CV causes) showed a smaller effect with a hazard ratio of 0.92 (95% confidence interval 0.86 to 0.99; p = 0.028). The combined endpoints, including combined all-cause hospitalization and mortality were driven primarily by CV mortality. The combined endpoints in EPHESUS, including all-cause hospitalization and all-cause mortality, are presented in Table 10.
Mortality hazard ratios varied for some subgroups as shown in Figure 2. Mortality hazard ratios appeared favorable for Inspra (Eplerenone) for both genders and for all races or ethnic groups, although the numbers of non-Caucasians were low (648, 10%). Patients with diabetes without clinical evidence of CHF and patients greater than 75 years did not appear to benefit from the use of Inspra (Eplerenone) . Such subgroup analyses must be interpreted cautiously.
The safety and efficacy of Inspra (Eplerenone) have been evaluated alone and in combination with other antihypertensive agents in clinical studies of 3091 hypertensive patients. The studies included 46% women, 14% Blacks, and 22% elderly (age ≥65). The studies excluded patients with elevated baseline serum potassium (>5.0 mEq/L) and elevated baseline serum creatinine (generally >1.5 mg/dL in males and >1.3 mg/dL in females).
Two fixed-dose, placebo-controlled, 8- to 12-week monotherapy studies in patients with baseline diastolic blood pressures of 95 to 114 mm Hg were conducted to assess the antihypertensive effect of Inspra (Eplerenone) . In these two studies, 611 patients were randomized to Inspra (Eplerenone) and 140 patients to placebo. Patients received Inspra (Eplerenone) in doses of 25 to 400 mg daily as either a single daily dose or divided into two daily doses. The mean placebo-subtracted reductions in trough cuff blood pressure achieved by Inspra (Eplerenone) in these studies at doses up to 200 mg are shown in Figures 3 and 4.
Patients treated with Inspra (Eplerenone) 50 to 200 mg daily experienced significant decreases in sitting systolic and diastolic blood pressure at trough with differences from placebo of 6–13 mm Hg (systolic) and 3–7 mm Hg (diastolic). These effects were confirmed by assessments with 24-hour ambulatory blood pressure monitoring (ABPM). In these studies, assessments of 24-hour ABPM data demonstrated that Inspra (Eplerenone) , administered once or twice daily, maintained antihypertensive efficacy over the entire dosing interval. However, at a total daily dose of 100 mg, Inspra (Eplerenone) administered as 50 mg twice per day produced greater trough cuff (4/3 mm Hg) and ABPM (2/1 mm Hg) blood pressure reductions than 100 mg given once daily.
Blood pressure lowering was apparent within 2 weeks from the start of therapy with Inspra (Eplerenone) , with maximal antihypertensive effects achieved within 4 weeks. Stopping Inspra (Eplerenone) following treatment for 8 to 24 weeks in six studies did not lead to adverse event rates in the week following withdrawal of Inspra (Eplerenone) greater than following placebo or active control withdrawal. Blood pressures in patients not taking other antihypertensives rose 1 week after withdrawal of Inspra (Eplerenone) by about 6/3 mm Hg, suggesting that the antihypertensive effect of Inspra (Eplerenone) was maintained through 8 to 24 weeks.
Blood pressure reductions with Inspra (Eplerenone) in the two fixed-dose monotherapy studies and other studies using titrated doses, as well as concomitant treatments, were not significantly different when analyzed by age, gender, or race with one exception. In a study in patients with low renin hypertension, blood pressure reductions in Blacks were smaller than those in whites during the initial titration period with Inspra (Eplerenone) .
Inspra (Eplerenone) has been studied concomitantly with treatment with ACE inhibitors, angiotensin II receptor antagonists, calcium channel blockers, beta blockers, and hydrochlorothiazide. When administered concomitantly with one of these drugs Inspra (Eplerenone) usually produced its expected antihypertensive effects.
There was no significant change in average heart rate among patients treated with Inspra (Eplerenone) in the combined clinical studies. No consistent effects of Inspra (Eplerenone) on heart rate, QRS duration, or PR or QT interval were observed in 147 normal subjects evaluated for electrocardiographic changes during pharmacokinetic studies.
Inspra (Eplerenone) How Supplied/storage And Handling
Inspra (Eplerenone) Tablets, 25 mg, are yellow diamond biconvex film-coated tablets. They are debossed with on one side and over on the other. They are supplied as follows:
Inspra (Eplerenone) Patient Counseling Information
Patients receiving Inspra (Eplerenone) should be informed:
Inspra (Eplerenone)
Inspra (Eplerenone) Principal Display Panel
