1 INDICATIONS AND USAGE

1.1 Patient Selection Considerations

Serum potassium levels should be measured before initiating INSPRA therapy, and INSPRA should not be prescribed if serum potassium is >5.5 mEq/L. [See CONTRAINDICATIONS (4)].

1.2 Congestive Heart Failure Post-Myocardial Infarction

INSPRA is indicated to improve survival of stable patients with left ventricular (LV) systolic dysfunction (ejection fraction ≤40%) and clinical evidence of congestive heart failure (CHF) after an acute myocardial infarction (MI).

1.3 Hypertension

INSPRA is indicated for the treatment of hypertension. INSPRA may be used alone or in combination with other antihypertensive agents.

2 DOSAGE AND ADMINISTRATION

2.1 Congestive Heart Failure Post-Myocardial Infarction

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 may be administered with or without food.

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

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 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 than 100 mg and are associated with an increased risk of hyperkalemia. [See CLINICAL STUDIES (14.2).]

2.3 Recommended Monitoring

Serum potassium should be measured before initiating INSPRA 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. [See WARNINGS AND PRECAUTIONS (5.1), ADVERSE REACTIONS (6.2).] In the EPHESUS study [See CLINICAL STUDIES (14.1)], the majority of hyperkalemia was observed within the first three months after randomization.

In all patients taking INSPRA who start taking a moderate CYP3A4 inhibitor, check serum potassium and serum creatinine in 3–7 days.

2.4 Dose Modifications for Specific Populations

For hypertensive patients receiving moderate CYP3A4 inhibitors (e.g., erythromycin, saquinavir, verapamil, and fluconazole), the starting dose of INSPRA should be reduced to 25 mg once daily. [See DRUG INTERACTIONS (7.1).]

No adjustment of the starting dose is recommended for the elderly or for patients with mild-to-moderate hepatic impairment. [See CLINICAL PHARMACOLOGY (12.3).]

3 DOSAGE FORMS AND STRENGTHS

• 25 mg tablets: yellow diamond biconvex film-coated tablets debossed with Pfizer on one side and NSR over 25 on the other
• 50 mg tablets: yellow diamond biconvex film-coated tablets debossed with Pfizer on one side and NSR over 50 on the other

4 CONTRAINDICATIONS

For All Patients

INSPRA is contraindicated in all patients with:

• serum potassium >5.5 mEq/L at initiation,
• creatinine clearance ≤30 mL/min, or
• concomitant administration of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, and nelfinavir). [See DRUG INTERACTIONS (7.1), CLINICAL PHARMACOLOGY (12.3).]

For Patients Treated for Hypertension

INSPRA is contraindicated for the treatment of hypertension in patients with:

• 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). [See WARNINGS AND PRECAUTIONS (5.1), ADVERSE REACTIONS (6.2), DRUG INTERACTIONS (7), and CLINICAL PHARMACOLOGY (12.3).]

5 WARNINGS AND PRECAUTIONS

5.1 Hyperkalemia

Minimize the risk of hyperkalemia with proper patient selection and monitoring, and avoidance of certain concomitant medications [See CONTRAINDICATIONS (4), ADVERSE REACTIONS (6.2), and DRUG INTERACTIONS (7)]. Monitor patients for the development of hyperkalemia until the effect of INSPRA is established. Patients who develop hyperkalemia (>5.5 mEq/L) may continue INSPRA therapy with proper dose adjustment. Dose reduction decreases potassium levels. [See DOSAGE AND ADMINISTRATION (2.1).]

The rates of hyperkalemia increase with declining renal function. [See ADVERSE REACTIONS (6.2).] 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. [See CONTRAINDICTIONS (4).] 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 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. [See ADVERSE REACTIONS (6.2).]

5.2 Impaired Hepatic Function

Mild-to-moderate hepatic impairment did not increase the incidence of hyperkalemia. In 16 subjects with mild-to-moderate hepatic impairment who received 400 mg of eplerenone, no elevations of serum potassium above 5.5 mEq/L were observed. The mean increase in serum potassium was 0.12 mEq/L in patients with hepatic impairment and 0.13 mEq/L in normal controls. The use of INSPRA in patients with severe hepatic impairment has not been eva luated. [See CLINICAL PHARMACOLOGY (12.3).]

5.3 Impaired Renal Function

Patients with decreased renal function are at increased risk of hyperkalemia. [See CONTRAINDICATIONS (4),WARNINGS AND PRECAUTIONS (5.1), ADVERSE REACTIONS (6.1).]

6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Hyperkalemia [See WARNINGS AND PRECAUTIONS (5.1)]

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.

6.1 Clinical Trials Experience

Congestive Heart Failure Post-Myocardial Infarction

In EPHESUS, safety was eva luated in 3307 patients treated with INSPRA and 3301 placebo-treated patients. The overall incidence of adverse events reported with INSPRA (78.9%) was similar to placebo (79.5%). Adverse events occurred at a similar rate regardless of age, gender, or race. Patients discontinued treatment due to an adverse event at similar rates in either treatment group (4.4% INSPRA vs. 4.3% placebo), with the most common reasons for discontinuation being hyperkalemia, myocardial infarction, and abnormal renal function.

Adverse reactions that occurred more frequently in patients treated with INSPRA than placebo were hyperkalemia (3.4% vs. 2.0%) and increased creatinine (2.4% vs. 1.5%). Discontinuations due to hyperkalemia or abnormal renal function were less than 1.0% in both groups. Hypokalemia occurred less frequently in patients treated with INSPRA (0.6% vs. 1.6%).

The rates of sex hormone-related adverse events are shown in Table 2.