INSPRA (eplerenone)

INSPRA (eplerenone) is contraindicated in all patients with the following:

• hypersensitivity to INSPRA or any component of this medication (for a complete listing of the INSPRA components, see DOSAGE FORMS, COMPOSITION AND PACKAGING);
• 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 DRUG INTERACTIONS and DOSAGE AND ADMINISTRATION).

INSPRA (eplerenone) is also contraindicated for the treatment of hypertension in patients with:

• type 2 diabetes with microalbuminuria
• serum creatinine >132 µmol/L in males or > 115 µmol/L in females
• moderate to severe renal impairment [eGFR<50 mL/min/1.73 m²]

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 INSPRA 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 INSPRA (also incidence higher than placebo) are presented in Table 1.

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 INSPRA 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 INSPRA 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 INSPRA 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 INSPRA and 3301 placebo-treated patients. Patients were followed for an average of 16 months (see CLINICAL TRIALS). 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 INSPRA 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 INSPRA (8.4% vs. 13.1%).

Elevation of serum potassium led to appropriate dose adjustments of eplerenone (see Table 16, Dose adjustment). 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 INSPRA (also incidence higher than placebo) are presented in Table 2.

The incidences of sex hormone-related adverse events are shown in Table 3.

Hypertension:

INSPRA has been evaluated for safety in 3,299 patients as either monotherapy or co-administration therapy in the hypertension clinical trials. A total of approximately 499 patients were treated with INSPRA for over 6 months and more than 176 patients were treated for over 1 year. The most commonly reported adverse events were headache (11.2%) and upper respiratory tract infection (7.6%).

In placebo-controlled fixed-dose trials, the overall rates of adverse events were 46% with recommended doses of INSPRA and 48% % with placebo. Adverse events occurred at a similar rate regardless of age, gender, or race. Therapy was discontinued due to an adverse event in 2.5% of patients treated with INSPRA and 2.7% of patients given placebo.

The adverse events that were reported at a rate of at least 1% of patients and at a higher rate in patients treated with INSPRA versus placebo are shown in Table 4.

Gynecomastia and abnormal vaginal bleeding were reported with INSPRA (around 1%) but not with placebo. The rates increased with increasing duration of therapy.

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.

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.

EPHESUS study: Post-myocardial infarction heart failure

A summary of the incidence of hyperkalemia and hypokalemia is provided in Table 8.

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.

Creatinine: Increases of more than 44 umol/L were reported in 6.5% of patients administered INSPRA 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 INSPRA 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.

Abnormal Hematologic and Clinical Chemistry Findings in Hypertension Trials

Potassium: In the combined controlled trials, hyperkalemia rate increased with decreasing renal function, and increased with the co-administration with other antihypertensive drugs as shown in Table 11 below. It is noted that in the trial some patients were treated with higher than the maximal recommended dose of 50 mg twice daily.

Sodium: Hyponatremia (<135 mmol/L) was reported for 0% of placebo-treated patients, 0% in 25 mg daily INSPRA group, 0.7% in 50 mg daily INSPRA group and 2.1% in 100 mg daily INSPRA group.

Triglycerides: Increases in triglycerides (above 2.83 mmol/L) were reported for 6.5% in placebo group, 9.2% in 25 mg INSPRA group, 6.0% in 50 mg daily INSPRA group and 7.8% in 100 mg daily INSPRA group.

Cholesterol: Increases in serum cholesterol values greater than 5.17mmol/L were reported for 0% in placebo group, 0% in 25 mg daily INSPRA group, 1.7% in 50 mg daily INSPRA group and 1.3% in 100 mg daily INSPRA group.

Less Common Clinical Trial Adverse Events

EMPHASIS-HF study: NYHA Class II chronic heart failure

EPHESUS study: Post-myocardial infarction heart failure

Hypertension Trials: the pooled placebo-controlled, fixed-dose INSPRA hypertension studies data

Glomerular filtration rate should be estimated (eGFR) and serum potassium measured before initiating INSPRA (eplerenone) therapy since INSPRA dosing depends on these variables.

INSPRA should not be administered to heart failure patients with initial serum potassium >5.0 mmol/L, serum creatinine >221 umol/L and/or eGFR <30 mL/min/1.73 m².

Serum potassium should be measured before initiating INSPRA (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 INSPRA.

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 WARNINGS AND PRECAUTIONS - Hyperkalemia, ADVERSE REACTIONS, and DRUG INTERACTIONS). INSPRA may be administered with or without food.

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 16). Following myocardial infarction INSPRA 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 INSPRA 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 16). Following myocardial infarction INSPRA 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. INSPRA 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: INSPRA 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 WARNINGS 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 INSPRA with proper dose adjustment. The dose should be adjusted based on the serum potassium level and the dose adjustment table shown in Table 16.

Following withholding INSPRA due to serum potassium ≥ 6.0 mmol/L and the return of potassium levels within acceptable limits, INSPRA 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 INSPRA therapy should be continued or stopped.

Hypertension

INSPRA should not be administered to hypertensive patients with initial serum potassium >5.0 mmol/L, serum creatinine >132 µmol/L in males or >115 µmol/L in females, and/or eGFR <50 mL/min/1.73 m².

In patients with hypertension who have reduced eGFR, serum potassium concentrations should be closely monitored when treated with INSPRA, especially when co-administrated with other antihypertensive drugs).

For 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 the dosage of INSPRA should be increased to 50 mg twice daily. Higher dosages of INSPRA are not recommended because they have no greater effect on blood pressure and are associated with an increased risk of adverse reactions, including hyperkalemia. (See CLINICAL TRIALS)

Specific Populations

Patients with hypertension: for patients with hypertension receiving mild to moderate CYP3A4 inhibitors (e.g.erythromycin, saquinavir, verapamil, and fluconazole), the dose of INSPRA should be reduced to 25 mg once daily. (See DRUG INTERACTIONS).

Mechanism of Action

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 through both genomic and non-genomic effects.

Pharmacodynamics

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.

In dose-ranging studies of chronic heart failure (NYHA classification II-IV), the addition of eplerenone to standard therapy resulted in expected dose-dependent increases in aldosterone. Similarly, in a cardiorenal substudy of EPHESUS, therapy with eplerenone led to a significant increase in aldosterone. These results are consistent with blockade of the mineralocorticoid receptor in these populations.

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

General:  Eplerenone is cleared predominantly by cytochrome P450 (CYP) 3A4 metabolism, with an elimination half-life of 4 to 6 hours.  Steady state is reached within 2 days. Absorption is not affected by food.  Inhibitors of CYP3A4 increase blood levels of eplerenone.

Absorption and Distribution: 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 to 100 mg and less than proportional at doses above 100 mg.

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 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 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 3 to 6 hours. The apparent plasma clearance is approximately 10 L/hr.

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 WARNINGS AND PRECAUTIONS, Geriatric Use and DOSAGE AND 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 WARNINGS AND PRECAUTIONS, Hyperkalemia).

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 AND 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 DRUG 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 DRUG 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. Johns 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.

Not Applicable.