HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use INSPRA safely and effectively. See full prescribing information for INSPRA. INSPRA (eplerenone) tablet for oral use ...
These highlights do not include all the information needed to use INSPRA safely and effectively. See full prescribing information for INSPRA.
INSPRA (eplerenone) tablet for oral use
Initial U.S. Approval: 2002
INDICATIONS AND USAGE
INSPRA is an aldosterone antagonist indicated for:
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Improving survival of stable patients with LV systolic dysfunction (LVEF ≤40%) and CHF after an acute myocardial infarction. (1.2)
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Hypertension, alone or combined with other agents. (1.3)
DOSAGE AND ADMINISTRATION
CHF Post-MI: 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. (2.1)
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. (2.2)
For all patients:
Measure serum potassium before starting INSPRA and periodically thereafter. (2.3)
DOSAGE FORMS AND STRENGTHS
Tablets: 25 mg, 50 mg (3)
CONTRAINDICATIONS
For all patients:
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Serum potassium >5.5 mEq/L at initiation (4)
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Creatinine clearance ≤30 mL/min (4)
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Concomitant use with strong CYP3A4 inhibitors (4, 7.1)
For the treatment of hypertension:
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Type 2 diabetes with microalbuminuria (4)
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Serum creatinine >2.0 mg/dL in males, >1.8 mg/dL in females (4)
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Creatinine clearance <50 mL/min (4)
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Concomitant use of potassium supplements or potassium-sparing diuretics (4)
WARNINGS AND PRECAUTIONS
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Hyperkalemia: Patients with decreased renal function and diabetics with proteinuria are at increased risk. Proper patient selection and monitoring and avoiding certain concomitant medications can minimize the risk. (5.1)
ADVERSE REACTIONS
CHF Post-MI: Most common adverse reactions (>2% and more frequent than with placebo): hyperkalemia and increased creatinine. (6.1)
Hypertension: Most common adverse reactions (≥2% and more frequent than with placebo): dizziness, diarrhea, coughing, fatigue and flu-like symptoms. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
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CYP3A4 Inhibitors: Reduce the starting dose for hypertension to 25 mg once daily when used with moderate CYP3A4 inhibitors (e.g., verapamil, erythromycin, saquinavir, fluconazole). (2.4, 7.1, 12.3)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 8/2009
FULL PRESCRIBING INFORMATION: CONTENTS*
Table of Contents
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 ...
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 ...
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 ...
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25 mg tablets: yellow diamond biconvex film-coated tablets debossed with Pfizer on one side and NSR over 25 on the other
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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 ...
For All Patients
INSPRA is contraindicated in all patients with:
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serum potassium >5.5 mEq/L at initiation,
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creatinine clearance ≤30 mL/min, or
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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:
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 ...
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).]
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 ...
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.
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.
Hypertension
INSPRA has been eva luated for safety in 3091 patients treated for hypertension. A total of 690 patients were treated for over 6 months and 106 patients were treated for over 1 year.
In placebo-controlled studies, the overall rates of adverse events were 47% with INSPRA and 45% with placebo. Adverse events occurred at a similar rate regardless of age, gender, or race. Therapy was discontinued due to an adverse event in 3% of patients treated with INSPRA and 3% of patients given placebo. The most common reasons for discontinuation of INSPRA were headache, dizziness, angina pectoris/myocardial infarction, and increased GGT. 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 in daily doses of 25 to 400 mg versus placebo are shown in Table 3.
Gynecomastia and abnormal vaginal bleeding were reported with INSPRA but not with placebo. The rates of these sex hormone-related adverse events are shown in Table 4. The rates increased slightly with increasing duration of therapy. In females, abnormal vaginal bleeding was also reported in 0.8% of patients on antihypertensive medications (other than spironolactone) in active control arms of the studies with INSPRA.
6.2 Clinical Laboratory Test Findings
Congestive Heart Failure Post-Myocardial Infarction
Creatinine: Increases of more than 0.5 mg/dL were reported for 6.5% of patients administered INSPRA and for 4.9% of placebo-treated patients.
Potassium: In EPHESUS [see CLINICAL STUDIES (14.1)], the frequencies of patients with changes in potassium (<3.5 mEq/L or >5.5 mEq/L or ≥6.0 mEq/L) receiving INSPRA compared with placebo are displayed in Table 5.
Table 6 shows the rates of hyperkalemia in EPHESUS as assessed by baseline renal function (creatinine clearance).
Table 7 shows the rates of hyperkalemia in EPHESUS as assessed by two baseline characteristics: presence/absence of proteinuria from baseline urinalysis and presence/absence of diabetes. [See WARNINGS AND PRECAUTIONS (5.1).]
Hypertension
Potassium: In placebo-controlled fixed-dose studies, the mean increases in serum potassium were dose-related and are shown in Table 8 along with the frequencies of values >5.5 mEq/L.
