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epleronone (Inspra)

Indications: - hypertension - post myocardial infarction* - heart failure (left ventricular systolic dysfunction)* - for use in combination with - ACE inhibitor or angiotensin receptor blocker (ARB) - other diuretic (i.e. loop diuretic) - beta-blocker * improves mortality in patients after myocardial infarction with heart failure & left ventricular ejection fraction < 40% (11.85 vs 13.6%, 12.5% vs 15.5% [6,7,8]) Contraindications: 1) renal failure a) serum creatinine > 2.5 mg/dL (men) > 2.0 mg/dL (women) [5] b) creatinine clearance < 30 mL/min 2) concurrent administration of strong CYP3A4 inhibitor (clarithromycin, ketoconazole) [4] Dosage: 1) CHF: start 25 mg PO QD; max 50 mg QD 2) hypertension: start 50 mg QD 3) max dose 50 mg BID* * Doses > 100 mg associated with increased risk of hyperkalemia without additional clinical benefit Pharmacokinetics: 1) peak plasma levels in 1.5 hours 2) may take 4 weeks for full therapeutic effect 3) volume of distribution 43-90 L 4) protein-binding 50% (primarily alpha-1 acid glycoprotein) 5) metabolized by cyt P450 3A4, metabolites inactive 6) elimination 1/2life of 4-6 hours 7) 5% eliminated unchanged in the urine Tabs: 25, 50 mg. Monitor: 1) serum K+ (one week, one month & periodically after starting or changing dose) - lower the dose if [K+] > 5.5 meq/L - withhold dose if [K+] > 6.0 meq/L 2) check serum K+ & renal function tests after starting moderate CYP3A4 inhibitor (see contraindications) [4] 3) blood pressure Adverse effects: 1) hyperkalemia 2) less likely to cause gynecomastia or impotence than spironolactone 3) hypertriglyceridemia (1-15%) dose-related 4) diarrhea (2%) 5) flu-like syndrome (2%) 6) albuminuria (1%) 7) cough (2%) Drug interactions: 1) other K+-sparing diuretics (avoid) 2) K+ supplements (avoid) 3) other drugs the increase serum K+ - ACE inhibitors, beta blockers 4) cyt P450 3A4 inhibitors -> ketoconazole, itraconazole, nefazodone, clarithromycin ritonavir Mechanism of action: 1) aldosterone antagonist 2) see spironolactone Notes: cost $99/30 tabs, 2005

Interactions

drug interactions drug adverse effects (more general classes) monitor with potassium-sparing diuretics

General

aldosterone receptor antagonist (aldosterone antagonist) K+ sparing diuretic

Properties

MISC-INFO: pregnancy-category B

Database Correlations

PUBCHEM correlations

References

  1. Prescriber's Letter 10(11):62 2003
  2. Journal Watch 23(9):72, 2003 Pitt B et al, N Engl J Med 348(Apr 3):1309, 2003 http://content.nejm.org/cgi/content/abstract/348/14/1309 Jessup M, N Engl J Med 348(14):1380, 2003 http://content.nejm.org/cgi/content/abstract/348/14/1380
  3. LexiComp, Drug Information, 2005
  4. Prescriber's Letter 17(7): 2010 Recommended Lab Monitoring for Common Medications Detail-Document#: 260704 (subscription needed) http://www.prescribersletter.com
  5. Prescriber's Letter 17(8): 2010 COMMENTARY: Eplerenone (Inspra) for Mild Systolic Heart Failure GUIDELINES: Diagnosis and Management of Heart Failure in Adults (ACC/AHA, 2009 Update) Detail-Document#: 260804 (subscription needed) http://www.prescribersletter.com
  6. Zannad F et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2010 Nov 14; [e-pub ahead of print] PMID: 21073363 http://dx.doi.org/10.1056/NEJMoa1009492 - Armstrong PW. Aldosterone antagonists - Last man standing? N Engl J Med 2010 Nov 14; [e-pub ahead of print] PMID: 21073364 http://dx.doi.org/10.1056/NEJMe101254
  7. Pitt B, Remme W, Zannad F et al Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003 Apr 3;348(14):1309-21. PMID: 12668699
  8. Medical Knowledge Self Assessment Program (MKSAP) 16, American College of Physicians, Philadelphia 2012