Pharmacology Update

Eplerenone Tablets (Inspra Searle)—A New Aldosterone Antagonist

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD

A new aldosterone receptor antagonist has been approved by the FDA. Eplereone, a selective aldosterone receptor antagonist (SARA), is the first approval in this class since the introduction of spironolactone close to 3 decades earlier. It is chemically similar to canrnone, an active metabolite of spironolactone. Eplerenone will be marketed as Inspra by Searle.

Indications

Eplerenone is indicated for the treatment of hypertension and may be used as monotherapy or in combination with other antihypertensive drugs.1

Dosage

The recommended starting dose is 50 mg once daily and may be increased to 50 mg twice daily if adequate blood pressure reduction is not achieved within 4 weeks. No dose adjustment is recommended for patients with mild-to-moderate hepatic impairment.1

The drug is contraindicated in patients with serum potassium > 5.5 meq/L, serum creatinine > 2.0 mg/dL in males or > 1.8 mg/dL in females, creatinine clearance < 50 mg/min, and type 2 diabetes with microalbuminuria. Patients should not use potassium supplements or potassium containing salt substitutes.

Eplerenone is available as 50 mg and 100 mg tablets.

Potential Advantages

Eplerenone has greater selectivity for the aldosterone receptor and minimal affinity for other steroid receptors. Potential progestational and antiandrogenic side effects appeared to be less common than with spironolactone.2 Eplerenone appears to be more effective in African- American patients and patients with low-renin hypertension than losartan.4,5

Potential Disadvantages

Eplerenone is less effective than spironolactone in the reduction of blood pressure. A 100 mg daily dose (50 mg twice daily) of eplerenone produces about 75% of the blood pressure reduction compared to 100 mg of spironolactone.3 Eplerenone is metabolized by the cytochrome P450 3A4 isoenzyme. Concomitant use with strong inhibitors of this isoenzyme (ie, itraconazole, ketoconazole) is contraindicated.1

Comments

Eplerenone is the first competitive aldosterone receptor antagonist to be approved since spironolactone was introduced in the 1970s. Comparative trials suggest that eplerenone is somewhat less effective than spironolactone at equal milligram doses. In an 8-week study in patients with mild-to-moderate hypertension, the reduction in systolic and diastolic blood pressure for 50 mg of eplerenone twice daily (n = 54) and 100 mg daily (n = 49) was approximately 50-75% of that achieved with spironolactone 50 mg twice daily (n = 48).3 Changes in SBP and DBP from baseline were -16.7 mm Hg and -9.5 mm Hg, respectively, for spironolactone. For eplerenone it was -11.9 mm Hg and -7.8 mm Hg with twice daily dosing and -7.9 mm Hg and -4.4 mm Hg with once daily dosing. A similar trend was reported for 24-hour ambulatory blood pressure monitoring. Eplerenone appears to be equally effective in African-American patients as well as patients with low-renin hypertension.7 The antihypertensive effect of eplerenone was assessed when added to existing angiotensin converting enzyme inhibitors or angiotensin II receptor antagonist.6 The frequency of gynecomastia or abnormal vaginal bleeding was 1% and 2.1% in the long-term study.1

Eplerenone is currently being evaluated in patients with heart failure as a complication of acute myocardial infarction. The 6200-patient randomized EPlerenone’s neurolHormonal Efficacy and Survival Study (EPHESUS) is expected soon. The primary end points are all-cause mortality and cardiovascular mortality or cardiovascular hospitalization.9 Secondary end points include time to first event, health status assessment, and economic outcomes. Cost for eplerenone was not available at the time of this review.

Clinical Implications

Nepherenone provides an alternative to spironolactone with possibly a lower frequency of progestational and antiandrogenic side effect. Aldosterone has been reported to have an important role in the cardiovascular pathophysiology as demonstrated by the benefit of spironolactone in severe heart failure.8 The findings of EPHESUS and other studies involving nepherenone, such as diabetic nephropathy, will define the future role of this new selective aldosterone antagonist.

Dr. Elliott is Northern California Kaiser Permanente; Asst. Clinical Professor of Medicine, University of California-San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Both are Associate Editors of Internal Medicine Alert.

References

1. Inspra Product Information. September 2002. G.D. Searle, LLC.

2. Delyani JA, et al. Cardiovasc Drug Rev. 2001;19(3): 185-200.

3. Weinberger M, et al. Am J Hypertens. 2002;15(8): 709-716.

4. Pratt JH, et al. Am J Hypertens. 2002;15(part 2):213A.

5. Weinberger M, et al. Am J Hypertens. 2002;15 (part 2):24A.

6. Krum H, et al. Hypertension. 2002;40(2):117-123.

7. Zillich AJ, Carter, BL. Ann Pharmacother. 2002;36: 1567-1576.

8. Pitt B, et al. N Engl J Med. 1999;341(10):709-717.

9. Spertus JA, et al. Am Heart J. 2002;143(4):636-642.