Natrecor

Generic Name: Nesiritide
Class: Vasodilating Agents, Miscellaneous
VA Class: CV900
Chemical Name: Natriuretic factor-32 (human brain clone λhBNP57)
Molecular Formula: C₁₄₃H₂₄₄N₅₀O₄₂S₄
CAS Number: 124584-08-3

Introduction

Vasodilator; a biosynthetic (recombinant DNA origin) form of human B-type natriuretic peptide (BNP).^{1 4 7 8}

Uses for Natrecor

Decompensated Congestive Heart Failure

Used alone or in conjunction with other standard therapies (e.g., diuretics, cardiac glycosides) for treatment of patients with acutely decompensated CHF who have dyspnea at rest or with minimal activity (i.e., NYHA class IV symptoms).^{1 2 5 7 8 9}

Ability to improve overall clinical status and symptoms of decompensated CHF (e.g., dyspnea, fatigue) may be comparable to that of standard IV therapy (principally dobutamine, milrinone, or nitroglycerin).^{2 7 9} However, until more data are available, some clinicians suggest reserving nesiritide for use in patients who do not respond to nitroglycerin or who cannot be treated with sodium nitroprusside.⁹

Manufacturer recommends strictly limiting use to patients with acutely decompensated CHF whose manifestations warrant hospitalization or management in emergency department.¹⁴

Manufacturer does not recommend use of intermittent, serial, or scheduled repetitive infusions in an outpatient setting for treatment of severe CHF.¹⁴ Clinical studies are ongoing.^{14 15}

Manufacturer does not recommend use as replacement therapy for diuretics, to improve renal function, and/or to enhance diuresis.¹⁴ Use is associated with dose-dependent elevations in S_cr.^{1 10 12 13 14} (See Renal Effects under Cautions.)

Natrecor Dosage and Administration

General

• 
  

  Administer only in settings where BP can be closely monitored; no specific need for arterial catheters, pulmonary artery catheters, or telemetry.^{1 7 14}

  
  

Administration

Administer IV loading dose followed by continuous IV infusion.^{1 7}

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Reconstituted solutions contain no preservatives; solutions preferably should be prepared immediately before use.⁷

Prime IV tubing with 5 mL of diluted nesiritide solution prior to connecting the tubing to the patient’s vascular access port and prior to administering the loading dose or starting the infusion.^{1 7}

Withdraw loading dose from the infusion bag containing diluted nesiritide solution and administer through port in IV infusion set; continuous infusion should follow immediately.^{1 7}

Do not administer through a central catheter coated with heparin, since nesiritide binds to heparin.¹

Reconstitution

Remove 5 mL of a preservative-free diluent (see Solution Compatibility under Stability) from a prefilled 250-mL infusion bag and add the 5 mL of diluent to a vial labeled as containing 1.5 mg of nesiritide.^{1 7} Swirl vial gently to ensure dissolution; do not shake.^{1 7}

Dilution

Following reconstitution, add entire contents of the vial to the original 250-mL infusion bag, to yield a final nesiritide concentration of approximately 6 mcg/mL; invert bag several times to ensure complete mixing.^{1 7}

Rate of Administration

Administer loading dose over approximately 60 seconds followed immediately by continuous IV infusion of nesiritide (6 mcg/mL) at a rate of 0.1 mL/kg per hour (approximately 0.01 mcg/kg per minute).^{1 7}

The volume of diluted (6 mcg/mL) solution needed to administer a 2-mcg/kg loading dose can be calculated by using the following formula or can be obtained from the following table:^{1 7}

Loading dose volume (in mL) = patient weight (in kg) / 3

Patient Weight (kg)	Loading Dose Volume (mL)
60	20
70	23.3
80	26.7
90	30
100	33.3
110	36.7

The rate (in mL/hr) at which the diluted (6 mcg/mL) solution must be infused to deliver a dosage of 0.01 mcg/kg per minute can be calculated by using the following formula or can be obtained from the following table:^{1 7}

Continuous infusion rate (in mL/hr) = patient weight (in kg) × 0.1

Patient Weight (kg)	Continuous Infusion Rate (mL/hr)
60	6
70	7
80	8
90	9
100	10
110	11

Dosage

Because of the possibility of dose-related episodes of severe and/or protracted hypotension, do not initiate nesiritide at higher than recommended dosages.^{1 7}

Do not titrate at frequent intervals.^{1 7 10}

Adults

Decompensated Congestive Heart Failure

IV

Loading dose of 2 mcg/kg over approximately 60 seconds, followed immediately by continuous infusion of 0.01 mcg/kg per minute.^{1 7}

In VMAC study, infusion rate was increased in increments of 0.005 mcg/kg per minute, no more frequently than every 3 hours up to a maximum dosage of 0.03 mcg/kg per minute, in a limited number of patients receiving invasive hemodynamic monitoring.^{1 7}

If hypotension occurs, reduce dosage or discontinue drug and institute supportive measures (e.g., IV fluids, changes in body position).^{1 7 10} In VMAC study, nesiritide could be reinitiated without a loading dose and with a 30% reduction in infusion rate following observation and stabilization of patient.^{1 7}

Prescribing Limits

Adults

IV

Maximum 0.03 mcg/kg per minute.^{1 7}

Limited experience with infusions lasting >48 hours.¹ In clinical studies, 48% of patients received nesiritide for 24–48 hours.¹

Cautions for Natrecor

Contraindications

• 
  

  Known hypersensitivity to nesiritide or any ingredient in the formulation.¹

  
  


• 
  

  Should not be used as primary therapy for patients with cardiogenic shock or in those with SBP of <90 mm Hg.^{1 7 10}

  
  

Warnings/Precautions

Warnings

Concomitant Cardiac Disorders

Use not recommended in patients with known or suspected low cardiac filling pressures or in those for whom vasodilating agents are not appropriate (e.g., patients with substantial valvular stenosis, restrictive or obstructive cardiomyopathy, constrictive pericarditis, pericardial tamponade, or other conditions in which cardiac output depends on venous return).^{1 10}

Sensitivity Reactions

Hypersensitivity Reactions

Risk of allergic reaction with parenteral administration of proteins or Escherichia coli-derived products; however, no serious allergic or anaphylactic reactions reported to date with nesiritide.^{1 10}

General Precautions

Risk of Mortality

Pooled analyses of data from controlled clinical trials indicate numerical, but not statistically significant, increases in 30-day mortality with nesiritide compared with other therapies (generally nitroglycerin and diuretics).^{1 10 11 14} Mortality rates of 5.3 versus 4.3%^{1 10 14} and of 7.2 versus 4%¹¹ have been reported for nesiritide compared with other therapies, depending on study-selection criteria.^{1 10 11 14}

Mortality rates at 180 days: Pooled analyses of data from controlled clinical trials indicate mortality rates of 21.7% (nesiritide) or 21.5% (other therapies).^{1 10 14}

Current analyses are limited by potential confounding factors (e.g., baseline differences between treatment groups), study size (e.g., small studies with few patient deaths), and other limitations inherent in pooled analyses of existing trials.^{1 10 11 14} Adequate, prospective clinical studies are needed to determine whether nesiritide is associated with an increased risk of death in patients with acutely decompensated CHF.^{1 10 11 14}

Hypotensive Effects

Incidence of symptomatic hypotension in initial 24 hours of therapy similar with nesiritide or IV nitroglycerin (4 or 5%, respectively), but more prolonged with nesiritide (mean duration: 2.2 hours) than with nitroglycerin (mean duration: 0.7 hour).^{1 7 9 10}

Higher dosages have been associated with increased risk of hypotension.^{1 7 10 14}

If hypotension occurs, institute supportive measures (e.g., IV fluids).¹ Dosage reduction or drug discontinuance may be required.^{1 7 10}

Use with caution in patients with baseline SBP of <100 mm Hg and in those receiving other hypotensive agents concomitantly.^{1 7} (See Specific Drugs under Interactions.)

Renal Effects

Possible worsening of renal function in susceptible patients.^{1 10 12 13 14} Not known whether worsening renal function reflects hemodynamic effects or renal injury; further study is needed.^{10 12 13 14}

Possible azotemia in patients with severe CHF whose renal function depends on activity of the renin-angiotensin-aldosterone system.^{1 10 12 13 14}

Higher dosages have been associated with increased risk of elevated S_cr.^{7 10 14}

Specific Populations

Pregnancy

Category C.¹

Lactation

Not known whether nesiritide is distributed into milk;¹ use with caution in nursing women.¹

Pediatric Use

Safety and efficacy not established in children <18 years of age.^{1 7}

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.¹

Common Adverse Effects

Hypotension,^{1 7 10} ventricular tachycardia,^{1 7 10} ventricular extrasystoles,^{1 7} angina pectoris,¹ bradycardia,¹ headache,^{1 7 10} insomnia,¹ abdominal pain,^{1 14} back pain,^{1 7} dizziness,^{1 7} anxiety,^{1 7} nausea,^{1 7 10} vomiting.¹

Interactions for Natrecor

No formal drug interaction studies to date.^{1 7} However, concomitant use of other cardiovascular agents (except IV vasodilators [e.g., nitroglycerin, sodium nitroprusside, milrinone] and IV ACE inhibitors) was allowed in clinical studies.^{1 7}

Specific Drugs

Drug	Interaction
ACE inhibitors	Increased incidence of symptomatic hypotension1 Pharmacokinetic interaction unlikely1
Angiotensin II receptor antagonists	May increase risk of hypotension1
Antiarrhythmic agents (class III)	Pharmacokinetic interaction unlikely1
Anticoagulants	Pharmacokinetic interaction unlikely1
β-Adrenergic blocking agents	May increase risk of hypotension1
Calcium-channel blocking agents	May increase risk of hypotension1
Digoxin	Pharmacokinetic interaction unlikely1
Diuretics	May increase risk of hypotension1
Dobutamine	Pharmacokinetic interaction unlikely1
HMG-CoA reductase inhibitor [statin] antilipemic agents	Pharmacokinetic interaction unlikely1
Hypotensive agents	May increase risk of hypotension1
Nitrates (oral)	Pharmacokinetic interaction unlikely1

Natrecor Pharmacokinetics

Elimination

Elimination Route

Binding to cell surface clearance receptors with subsequent cellular internalization and lysosomal proteolysis; proteolytic cleavage of the peptide by endopeptidases (e.g., neutral endopeptidase) on the vascular lumenal surface; and renal filtration.¹

Half-life

Biphasic; mean initial-phase and terminal-phase half-lives of approximately 2 and 18 minutes, respectively.¹

Stability

Storage

Parenteral

Powder for Injection

20–25°C (may be exposed to temperatures ranging from 15–30°C).¹

Store reconstituted solution at 20–25°C or refrigerate at 2–8°C; use up to 24 hours after reconstitution.^{1 7}

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Compatible1
Dextrose 5% in water
Dextrose 5% and 0.2 or 0.45% sodium chloride
Sodium chloride 0.9%

Drug Compatibility

Incompatible with drugs that contain the preservative sodium metabisulfite.¹

Y-site Compatibility1

Incompatible
Bumetanide
Enalaprilat
Ethacrynate sodium
Furosemide
Heparin
Hydralazine hydrochloride
Insulin

ActionsActions

• 
  

  A vasodilator that is structurally and pharmacologically identical to endogenous BNP,^{1 4 7 8} the principal natriuretic peptide responsible for maintaining normal fluid and sodium homeostasis in patients with CHF.⁸

  
  


• 
  

  Produces dose-dependent reductions in pulmonary capillary wedge pressure and systemic arterial pressure and has modest diuretic and natriuretic effects in patients with CHF.^{1 4 7 8 9}

  
  


• 
  

  Proarrhythmic effects have not been observed in patients with decompensated CHF receiving nesiritide.^{3 4 7}

  
  

Advice to Patients

• 
  

  Risk of symptomatic hypotension.^{1 7}

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.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.

Nesiritide

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection, for IV infusion	1.5 mg	Natrecor	Scios

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 May 2006. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Scios Inc. Natrecor (nesiritide) for injection prescribing information. Fremont, CA; 2005 Apr.

2. Colucci WS, Elkayam U, Horton DP et al. Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure. N Engl J Med. 2000; 343:246-53. [IDIS 450037] [PubMed 10911006]

3. Burger AJ, Dennish G III, Dinerman J et al. Nesiritide therapy for decompensated CHF is not proarrhythmic. PRECEDENT study. Paper presented at 3rd scientific meeting of the Heart Failure Society of America. San Francisco, CA: 1999; Sept 22-25. (Abstract revision 1, 2000 Jul 27).

4. Colucci WS. Nesiritide for the treatment of decompensated heart failure. J Card Fail. 2001; 7:92-100. [PubMed 11264555]

5. Young, J. Vasodilation in the management of acute congestive heart failure (VMAC). Paper presented at 10th American Heart Association AHA) scientific sessions. New Orleans, LA: 2000; Nov 12-15. From the Medscape web site.

6. Silver MA, Ghali JK, Horton DP et al. Effect of nesiritide versus dobutamine on short-term outcomes in the treatment of acutely decompensated heart failure. J Card Fail. 1998; 4(Suppl 1):40. Abstract.

7. Scios, Sunnyvale, CA: Personal communication.

8. Hobbs RE, Mills RM, Young JB. An update on nesiritide for treatment of decompensated heart failure. Exp Opin Invest Drugs. 2001; 10:935-42.

9. Anon. Nesiritide for decompensated congestive heart failure. Med Lett Drugs Ther. 2001; 43:100-1.

10. Horton DP. Dear healthcare professional letter regarding important drug warning on Natrecor and possible adverse effects on survival and kidney function compared to control agents (e.g., nitroglycerin and diuretics). Scios Inc: Fremont, CA; 2005 May 6. From FDA web site. Accessed May 20, 2005.

11. Sackner-Bernstein JD, Kowalski M, Fox M et al. Short-term risk of death after treatment with nesiritide for decompensated heart failure: a pooled analysis of randomized controlled trials. JAMA. 2005; 293:1900-5.

12. Sackner-Bernstein JD, Skopicki HA, Aaronson KD. Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation. 2005; 111:1487-91.

13. Teerlink JR, Massie BM. Nesiritide and worsening of renal function: the emperor’s new clothes? Circulation. 2005; 111:1459-61.

14. Horton DP. Dear healthcare professional letter regarding recommendations of an expert panel of cardiology and heart failure clinicians on the appropriate use of Natrecor (nesiritide) and the drug's effect on mortality and kidney function. Scios Inc: Fremont, CA; 2005 July 13. From FDA web site. Accessed Oct. 20, 2005.

15. Yancy CW. Treatment with B-type natriuretic peptide for chronic decompensated heart failure: insights learned from the follow-up serial infusion of nesiritide (FUSION) trial.Heart Fail Rev. 2004;9:209-16.

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• Natrecor Side Effects (in more detail)
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• Natrecor Drug Interactions
• Natrecor Support Group
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• Natrecor Prescribing Information (FDA)


• Natrecor Consumer Overview


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