Inspra

Generic Name: Eplerenone
Class: Mineralocorticoid (Aldosterone) Receptor Antagonists
VA Class: CV704
Chemical Name: 9,11α-Epoxy-17-hydroxy-3-oxo-17α-pregn-4-ene-7α,21-dicarboxylic acid, γ-lactone, methyl ester
Molecular Formula: C₂₄H₃₀O₆
CAS Number: 107724-20-9

Introduction

Relatively selective mineralocorticoid (aldosterone) receptor antagonist.^{1 2 3 10 11}

Uses for Inspra

CHF after AMI

Used to reduce the risk of mortality following AMI in clinically stable patients with left ventricular systolic dysfunction (i.e., left ventricular ejection fraction [LVEF] ≤40%) and CHF.^{1 17 21}

Hypertension

Management of hypertension.^{1 2 3 4 10 11 24}

Used as monotherapy or in combination with other classes of antihypertensive agents (e.g., ACE inhibitors, angiotensin II receptor antagonists, calcium-channel blocking agents, β-adrenergic blocking agents, thiazide diuretics).^{1 2 4 10 11 22}

Inspra Dosage and Administration

General

• 
  

  Serum potassium concentrations should be measured prior to initiation of therapy, within the first week, and at 1 month after initiation of therapy or dosage adjustment.¹

  
  


• 
  

  Serum potassium concentrations should be monitored periodically thereafter during therapy, and dosage of the drug should be modified according to serum potassium concentrations.¹ (See Table: Dosage Modification in CHF for Serum Potassium Concentrations under Dosage.)

  
  

Administration

Oral Administration

Administer orally^{1 2 3 11 22} without regard to meals.¹

Dosage

Adults

CHF after AMI

Oral

Initially, 25 mg once daily.¹ Titrate dosage as tolerated to a target dosage of 50 mg once daily, preferably within 4 weeks of initiation of therapy in patients without hyperkalemia (defined as serum potassium concentrations ≥5.5 mEq/L).¹

Dosage Modification in CHF for Serum Potassium Concentrations1

Serum Potassium (mEq/L)	Dosage Adjustment
<5	In those receiving 25 mg every other day, increase to 25 mg daily In those receiving 25 mg daily, increase to 50 mg daily
5–5.4	None
5.5–5.9	In those receiving 50 mg daily, decrease to 25 mg daily In those receiving 25 mg daily, decrease to 25 mg every other day In those receiving 25 mg every other day, withhold therapy
≥6	Withhold

Hypertension

Oral

Dosage must be individualized and adjusted according to the BP response.^{1 2}

Initially, 50 mg once daily.^{1 3 8} If BP is not adequately controlled after 4 weeks, increase dosage to 50 mg twice daily.¹

In hypertensive patients currently receiving therapy with weak inhibitors of the CYP3A4 isoenzyme (e.g., erythromycin, saquinavir, verapamil, fluconazole), reduce the initial dosage to 25 mg once daily.^{1 3 8}

Prescribing Limits

Adults

Hypertension

Oral

50 mg twice daily.¹ No additional benefit from higher dosages (>100 mg daily) and such dosages have been associated with increased risk of hyperkalemia.¹

Special Populations

Hepatic Impairment

No adjustment in the initial dosage is necessary in those with mild-to-moderate hepatic impairment.^{1 21} (See Hepatic Impairment under Cautions.)

Geriatric Patients

No adjustment in the initial dosage is necessary.^{1 21}

Cautions for Inspra

Contraindications

• 
  

  Serum potassium concentrations >5.5 mEq/L at initiation of therapy.¹

  
  


• 
  

  Cl_cr ≤ 30 mL/minute.¹

  
  


• 
  

  Concomitant therapy with potent CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir) or any agent described as a potent CYP3A4 inhibitor in its prescribing information.^{1 4}

  
  


• 
  

  In hypertensive patients having type 2 diabetes mellitus with microalbuminuria.¹

  
  


• 
  

  In hypertensive patients with S_cr >2 or 1.8 mg/dL in males or females, respectively.¹

  
  


• 
  

  In hypertensive patients with Cl_cr <50 mL/minute.¹

  
  


• 
  

  In hypertensive patients receiving potassium supplements or potassium-sparing diuretics (e.g., amiloride, spironolactone, triamterene).^{1 4 8}

  
  

Warnings/Precautions

Warnings

Hyperkalemia

Most serious risk associated with therapy is hyperkalemia (serum potassium >5.5 mEq/L).¹ Hyperkalemia may cause serious, sometimes fatal, cardiac arrhythmias.^{1 11} Increased risk of hyperkalemia in patients with impaired renal function or diabetes mellitus and in patients receiving concurrent agents affecting the renin-angiotensin-aldosterone system (e.g., ACE inhibitors, angiotensin II receptor antagonists).^{1 2 4 8 11 13 21} Monitor serum potassium concentrations periodically.^{1 21} (See Table: Dosage Modification in CHF for Serum Potassium Concentrations under Dosage.)¹

Specific Populations

Pregnancy

Category B.

Lactation

Distributed into milk in animals.¹ Discontinue nursing or the drug.¹

Pediatric Use

Safety and efficacy not established in children <18 years of age.^{1 21}

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults.¹ Geriatric patients ≥75 years of age with CHF following an AMI did not benefit from the addition of eplerenone to standard medical therapy.¹ Because of the greater frequency of decreased renal function, the incidence of hyperkalemia may be increased in the elderly.¹ (See Renal Impairment under Cautions.)

Hepatic Impairment

Safety and efficacy not established in patients with severe hepatic impairment.¹ Serum potassium concentrations not affected in patients with mild-to-moderate hepatic impairment.¹

Renal Impairment

Use with caution in patients with CHF following an AMI, who have renal impairment (i.e., S_cr >2 or 1.8 mg/dL in males or females, respectively, or Cl_cr ≤50 mL/minute) or those with diabetes mellitus (including those with proteinuria).¹

Drug contraindicated in hypertensive patients with S_cr >2 or 1.8 mg/dL in males or females, respectively, and in those hypertensive patients with Cl_cr <50 mL/minute.¹

Blacks

Initial BP reduction may be smaller in black patients compared with nonblack patients;¹ such difference does not appear to occur during continued therapy.²

Common Adverse Effects

In patients with CHF following AMI: hyperkalemia,^{1 17} increased S_cr,¹ urinary tract disorders,¹⁷ adverse CNS effects,¹⁷ adverse GI effects.¹⁷

In patients with hypertension: dizziness, fatigue, flu-like symptoms, cough, diarrhea, abdominal pain, hyperkalemia, decreased serum sodium concentrations, abnormal vaginal bleeding, gynecomastia, hypercholesterolemia, hypertriglyceridemia, mastodynia, albuminuria.¹

Interactions for Inspra

Metabolized by CYP3A4 isoenzyme.¹

Drugs Affecting Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction (altered plasma eplerenone concentrations) with drugs that induce or inhibit CYP3A4.¹

Does not inhibit or induce the CYP isoenzymes 1A2, 3A4, 2C19, 2C9, or 2D6, suggesting that the drug is unlikely to alter the pharmacokinetics of drugs metabolized by these enzymes.^{1 21}

Specific Drugs and Food¹

Drug or Food	Interaction	Comments
ACE inhibitors	Potential pharmacodynamic interaction (increased serum potassium concentrations, hyperkalemia)
Amiloride	Increased risk for hyperkalemia	Concomitant use contraindicated in patients with hypertension
Amiodarone	Pharmacokinetic interaction unlikely
Amlodipine	Pharmacokinetic interaction unlikely
Angiotensin II receptor antagonists	Potential pharmacodynamic interaction (increased serum potassium concentrations, hyperkalemia)
Antacids (e.g., aluminum- and magnesium-containing)	Pharmacokinetic interaction unlikely
Astemizole	Pharmacokinetic interaction unlikely
Chlorzoxazone	Pharmacokinetic interaction unlikely
Cisapride	Pharmacokinetic interaction unlikely
Clarithromycin	Increased plasma concentrations of eplerenone	Concomitant use contraindicated
Cyclosporine	Pharmacokinetic interaction unlikely
Dexamethasone	Pharmacokinetic interaction unlikely
Dextromethorphan	Pharmacokinetic interaction unlikely
Diclofenac	Pharmacokinetic interaction unlikely
Digoxin	Pharmacokinetic interaction unlikely
Erythromycin	Increased plasma concentrations of eplerenone	Reduce eplerenone dosage (See Hypertension under Dosage and Administration)
Ethinyl estradiol	Pharmacokinetic interaction unlikely
Fluconazole	Increased plasma concentrations of eplerenone	Reduce eplerenone dosage (See Hypertension under Dosage and Administration)
Fluoxetine	Pharmacokinetic interaction unlikely
Glyburide	Pharmacokinetic interaction unlikely
Grapefruit juice	Increased eplerenone exposure
Hormonal contraceptives (norethindrone/ethinyl estradiol)	Pharmacokinetic interaction unlikely
Itraconazole	Increased plasma concentrations of eplerenone	Concomitant use contraindicated
Ketoconazole	Increased plasma concentrations of eplerenone	Concomitant use contraindicated
Lithium	Potential pharmacokinetic and pharmacologic interaction (increased serum lithium concentrations resulting in lithium toxicity).1 Such interaction observed with concomitant administration of diuretics and/or ACE inhibitors and lithium.1 5 7 14 15	If used concomitantly, frequently monitor serum lithium concentrations.1
Losartan	Pharmacokinetic interaction unlikely
Midazolam	Pharmacokinetic interaction unlikely
Mephobarbital	Pharmacokinetic interaction unlikely
Methylphenidate	Pharmacokinetic interaction unlikely
Methylprednisolone	Pharmacokinetic interaction unlikely
Nefazodone	Increased plasma concentrations of eplerenone	Concomitant use contraindicated
Nelfinavir	Increased plasma concentrations of eplerenone	Concomitant use contraindicated
Nifedipine	Pharmacokinetic interaction unlikely
NSAIAs	Potential pharmacologic effects (decreased antihypertensive effect and/or severe hyperkalemia in patients with impaired renal function)
Phenacetin	Pharmacokinetic interaction unlikely
Phenytoin	Pharmacokinetic interaction unlikely
Potassium-sparing agents or potassium supplements	Potential pharmacodynamic interaction (increased risk of hyperkalemia) 1 4 21
Ritonavir	Increased plasma concentrations of eplerenone	Concomitant use contraindicated
Saquinavir	Increased plasma concentrations of eplerenone	Reduce eplerenone dosage (See Hypertension under Dosage and Administration)
St. John's wort	Decreased eplerenone AUC
Simvastatin	Pharmacokinetic interaction unlikely
Spironolactone	Increased risk for hyperkalemia	Concomitant use contraindicated in patients with hypertension
Tolbutamide	Pharmacokinetic interaction unlikely
Triamterene	Increased risk for hyperkalemia	Concomitant use contraindicated in patients with hypertension
Triazolam	Pharmacokinetic interaction unlikely
Troleandomycin	Increased plasma concentrations of eplerenone	Concomitant use contraindicated
Verapamil	Increased plasma concentrations of eplerenone	Reduce eplerenone dosage (See Hypertension under Dosage and Administration)
Warfarin	Pharmacokinetic interaction unlikely

Inspra Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations usually attained within 1.5 hours.¹

Onset

During chronic therapy, hypotensive effect apparent within 2 weeks and maximum antihypertensive effect generally achieved after 4 weeks.¹

Duration

In patients not receiving other antihypertensive drugs, BP may return to pretreatment levels within 1 week following discontinuance.^{1 21}

Food

Food does not appear to affect absorption.¹

Special Populations

In geriatric patients ≥65 years of age at steady state, peak plasma concentrations and AUC increased by 22 and 45%, respectively, compared with younger adults (18–45 years old).¹

In geriatric black patients at steady state, peak plasma concentrations and AUC were 19 and 26% lower, respectively, than in geriatric white patients.^{1 25}

In patients with severe renal impairment at steady state, peak plasma concentration and AUC were increased by 24 and 38%, respectively,¹ while in those undergoing hemodialysis, peak plasma concentrations and AUC were decreased by 3 and 26%, respectively.¹

In patients with moderate (Child-Pugh class B) hepatic impairment at steady state, peak plasma concentrations and AUC were increased by 3.6 and 42%, respectively, compared with healthy individuals.¹

In patients with heart failure (NYHA class II–IV) at steady state, peak plasma concentrations and AUC increased by 30 and 38%, respectively, compared with healthy individuals.¹

Distribution

Extent

Apparent volume of distribution at steady state is 43–90 L.¹

Plasma Protein Binding

50% (mainly α₁-acid glycoproteins).¹

Distributed into milk in rats; not known whether distributed into human milk.¹

Elimination

Metabolism

Metabolized to inactive metabolites principally by CYP3A4 isoenzyme.^{1 2}

Elimination Route

Approximately 67 and 32% of a dose is excreted in urine and feces, respectively, principally as metabolites.^{1 2}

Half-life

4–6 hours.¹

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).¹

ActionsActions

• 
  

  Inhibits physiologic effects of aldosterone.^{1 2 3 4 10}

  
  


• 
  

  Produces sustained increases in plasma renin and serum aldosterone concentrations, reflecting the inhibition of the negative feedback of aldosterone on renin secretion.^{1 2 3 10 11}

  
  


• 
  

  Some of the antihypertensive effects may be related to restoration of endothelial function by increasing the release of nitric oxide, which results in vasodilation.^{2 9 12}

  
  


• 
  

  Reduces coronary vascular inflammation,^{17 18} the risk of subsequent development of interstitial myocardial and coronary perivascular fibrosis,^{2 17 18 19 20} cardiac hypertrophy,^{2 20} and/or ventricular remodeling.^{2 17 20}

  
  

Advice to Patients

• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.¹

  
  


• 
  

  Importance of not using concomitant potassium supplements, salt substitutes containing potassium, potassium-sparing diuretics (amiloride, triamterene, spironolactone), or potent inhibitors of liver enzymes without consulting a clinician.¹

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹

  
  


• 
  

  Importance of informing patients of other important precautionary information.¹ (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Eplerenone

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	25 mg	Inspra	Pfizer
		50 mg	Inspra	Pfizer

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Eplerenone 25MG Tablets (GREENSTONE): 30/$99.99 or 90/$275.99

Eplerenone 50MG Tablets (GREENSTONE): 30/$99.99 or 90/$275.99

Inspra 25MG Tablets (PFIZER U.S.): 30/$139.88 or 90/$404.73

Inspra 50MG Tablets (PFIZER U.S.): 30/$141.94 or 90/$405.09

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions July 2005. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. G. D. Searle. Inspra (eplerenone) tablets prescribing information. Chicago, IL; 2003 Oct.

2. Zillich AJ, Carter BL. Eplerenone—a novel selective aldosterone blocker. Ann Pharmacother. 2002; 36:1567-76. [IDIS 487932] [PubMed 12243608]

3. Weinberger MH, Roniker B, Krause SL et al.. Eplerenone, a selective aldosterone blocker, in mild-to-moderate hypertension. Am J Hypertens. 2002; 15:709-16. [PubMed 12160194]

4. Sica DA. Current concepts of pharmacotherapy in hypertension. Eplerenone: a new aldosterone receptor antagonist— are the FDAs restrictions appropriate? J Clin Hypertens (Greenwich). 2002; 4:441-5.

5. Mignat C, Unger T. ACE inhibitors: drug interactions of clinical significance. Drug Saf. 1995; 12:334-47. [PubMed 7669262]

6. Johnson AG, Seideman P. Ray RO. Adverse drug interactions with nonsteroidal anti-inflammatory drugs (NSAIDS): Recognition, management and avoidance. Drug Saf. 1993; 8:99-127. [PubMed 8452660]

7. Vipond AJ, Bakewell S, Telford R et al. Lithium toxicity. Anesthesia. 1996; 12:1156-8.

8. Schepkens H, Vanholder R, Billiouw JM et al. Life-threatening hyperkalemia during combined therapy with angiotensin-converting enzyme inhibitors and spironolactone: an analysis of 25 cases. Am J Med. 2001; 110:438-41. [IDIS 464149] [PubMed 11331054]

9. Quaschning T, Ruschitzka F, Shaw S et al. Aldosterone receptor antagonism normalizes vascular function in liquorice-induced hypertension. Hypertension. 2001; 37(pt. 2):801-5. [PubMed 11230376]

10. Liew D, Krum H. The role of aldosterone recptor blockade in the management of cardiovascular disease. Curr Opin Investig Drugs. 2002; 3:1468-73. [PubMed 12431020]

11. Krum H, Nolly H, Workman D et al. Efficacy of eplerenone added to renin-angiotensin blockade in hypertensive patients. Hypertension. 2002; 40:117-23. [PubMed 12154100]

12. Leclercq B, Jaimes EA, Raij L. Nitric oxide synthase and hypertension. Curr Opin Nephrol Hypertens. 2002; 11:185-9. [PubMed 11856911]

13. Epstein M, Buckalew V, Altamirano J et al. Eplerenone reduces proteinuria in type II diabetes mellitus: implications for aldosterone involvement in the pathogenesis of renal dysfunction. J Am Coll Cardiol. 2002; 39(Suppl. A):249A.

14. Douste-Blazy PH, Rostin M, Livarek B et al. Angiotensin converting enzyme inhibitors and lithium treatment. Lancet. 1986; 1:1448. [IDIS 218599] [PubMed 2872554]

15. .Merck. Vasotec tablets (enalapril maleate) prescribing information (dated 2002 Jan). In: Physicians’ desk reference. 57th ed. Montvale, NJ: Medical Economics Company Inc; 2003:2116-20.

16. Gómez Sánchez EP. Hypertension and the mineralcorticoid receptor in the brain. Ann NY Acad Sci. 1994; 746:415-7. [PubMed 7825903]

17. 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; 348:1309-21. [IDIS 496790] [PubMed 12668699]

18. Brown NJ. Eplerenone: cardiovascular protection. Circulation. 2003; 107:2512-8. [IDIS 501047] [PubMed 12756192]

19. Delyani JA, Robinson EL, Rudolph AE. Effect of a selective aldosterone receptor antagonist in myocardial infarction. Am J Physiol Heart Circ Physiol. 2001; 50:H647-54.

20. Suzuki G, Morita H, Mishima T et al. Effects of long-term monotherapy with eplerenone, a novel aldosterone blocker, on progression of left ventricular dysfunction and remodeling in dogs with heart failure. Circulation. 2002; 106:2967-72. [PubMed 12460880]

21. Pfizer, New York, NY: Personal communication.

22. National Heart, Lung, and Blood Institute National High Blood Pressure Education Program. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII) Express. Bethesda, MD: May 14 2003. From NIH website. (). (Also published in JAMA. 2003; 289.)

23. Vasan RS, Evans JC, Larson MG et al. Serum aldosterone and the incidence of hypertension in nonhypertensive persons. N Engl J Med. 2004; 351:33-41. [PubMed 15229305]

24. White WB, Carr AA, Krause S et al. Assessment of the novel selective aldosterone blocker eplerenone using ambulatory and clinical blood pressure in patients with systemic hypertension. Am J Cardiol. 2003; 92:38-42. [IDIS 502001] [PubMed 12842242]

25. Office of Clincial Pharmacology and Biopharmaceutics, Food and Drug Administration. Clinical pharmacology and biopharmaceutics review section of FDA approval package for eplerenone. Rockville, MD: Food and Drug Administration; 2002 Sep 27.

More Inspra resources

• Inspra Side Effects (in more detail)
• Inspra Dosage
• Inspra Use in Pregnancy & Breastfeeding
• Drug Images
• Inspra Drug Interactions
• Inspra Support Group
• 0 Reviews for Inspra - Add your own review/rating

• Inspra Prescribing Information (FDA)


• Inspra MedFacts Consumer Leaflet (Wolters Kluwer)


• Inspra Concise Consumer Information (Cerner Multum)


• Inspra Advanced Consumer (Micromedex) - Includes Dosage Information


• Eplerenone Prescribing Information (FDA)


• Eplerenone Professional Patient Advice (Wolters Kluwer)

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