Professional Drug Information > Natrecor, Nesiritide

Nesiritide (Systemic)

VA CLASSIFICATION
Primary: CV900

Commonly used brand name(s): Natrecor.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Cardiotonic—

Indications

Accepted

Heart failure, congestive (treatment)—Nesiritide is indicated for the intravenous treatment of patients with acutely decompensated congestive heart failure who have dyspnea at rest or with minimal activity.^{01}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Nesiritide is a sterile, purified preparation of human B-type natriuretic peptide (hBNP) manufactured from Escherichia coli using recombinant DNA technology.^{01} It has the same 32–amino acid sequence as the endogenous peptide, which is produced by the ventricular myocardium.^{01}
Molecular weight—
     3464 grams per mole^{01}

Mechanism of action/Effect:

Human BNP increases intracellular concentrations of guanosine 3'5'-cyclic monophosphate (cGMP) and smooth muscle cell relaxation by binding to the particulate guanylate cyclase receptor of vascular smooth muscle and endothelial cells. Cyclic GMP serves as a second messenger to dilate veins and arteries.^{01} In human studies in patients with heart failure, nesiritide has been shown to reduce pulmonary capillary wedge pressure (in a dose-dependent manner) and systemic arterial pressure.^{01}

Absorption:

Administration of nesiritide exhibits biphasic disposition from the plasma.^{01}


Distribution:

Volume of distribution of the central compartment (V_C): 0.073 L per kg.^{01}

Volume of distribution at steady state (V_SS): 0.19 L per kg.^{01}

Half-life:

Mean terminal elimination half-life is approximately 18 minutes.^{01}

Elimination:
    Nesiritide is cleared via three independent mechanisms. They are:
   • Cellular internalization and lysosomal proteolysis after binding to cell surface clearance receptors.^{01}
   • Proteolytic cleavage by endopeptidases, such as neutral endopeptidase, which are present on the vascular lumenal surface.^{01}
   • Renal filtration.^{01}


Precautions to Consider

Carcinogenicity and Tumorigenicity

Long-term studies in animals have not been performed.^{01}

Mutagenicity

Nesiritide did not increase the frequency of mutations when used in an in vitro bacterial cell assay, the Ames test. No other genotoxicity studies were performed.^{01}

Pregnancy/Reproduction
Fertility—
Long-term studies in animals have not been performed to evaluate the effect on fertility.^{01}

Pregnancy—
Studies have not been done in humans.^{01}

Studies have not been done in animals.^{01}

FDA Pregnancy Category C.^{01}

Breast-feeding

It is not known whether nesiritide is distributed into human breast milk.^{01}

Pediatrics

No information is available on the relationship of age to the effects of nesiritide in the pediatric population.^{01} Safety and efficacy have not been established.^{01}


Geriatrics


Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of nesiritide in the elderly. In clinical studies, no overall differences in effectiveness or response were observed. However, some elderly patients may be more sensitive to the effects of nesiritide than younger patients.^{01}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Angiotensin-converting enzyme (ACE) inhibitors, oral    (concomitant use may cause an increase in symptomatic hypotension)

^{01}

Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Creatinine, serum    ( values may be increased to 0.5 mg per dL above baseline or higher)

^{01}
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Cardiomyopathy, restrictive or obstructive or
» Conditions in which cardiac output is dependent upon venous return or
» Low cardiac filling pressure or
» Pericardial tamponade or
» Pericarditis, constrictive or
» Systolic blood pressure less than 90 mm Hg or
» Valvular stenosis, significant    (use of nesiritide is not recommended)

^{01}
» Hypersensitivity to nesiritide^{01}
» Shock, cardiogenic    (nesiritide should not be used as primary therapy for these patients)

^{01}
Risk-benefit should be considered when the following medical problems exist
Heart failure, severe    (patients with renal function dependent on the activity of the renin-angiotensin-aldosterone system who are also in severe heart failure may develop azotemia if treated with nesiritide^{01})


» Systolic blood pressure between 90 and 100 mm Hg    (risk of symptomatic hypotension may be increased;^{01} nesiritide should be used with caution^{01})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Allergic reaction or
Untoward reaction    (patients should always be monitored following the parenteral administration of protein pharmaceuticals or E. coli–derived products)

^{01}
Blood pressure    (nesiritide should only be administered in settings where blood pressure can be monitored closely; the dose should be reduced or the medication may be discontinued in patients who develop hypotension)

^{01}


Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Hypotension, asymptomatic ^{01}

Incidence less frequent
    
Angina pectoris (chest pain or discomfort; chest tightness; shortness of breath)^{01}
    
apnea (bluish lips or skin; difficulty in breathing)^{01}
    
atrial fibrillation (fast or irregular heartbeat; dizziness; fainting)^{01}
    
AV node conduction abnormalities ^{01}
    
bradycardia (slow or irregular heartbeat ; lightheadedness ; dizziness or fainting; unusual tiredness or weakness)^{01}
    
hypotension, symptomatic (cool, clammy skin; dizziness ; lightheadedness; weakness)^{01}
    
ventricular extrasystoles ( fast or irregular heartbeat)^{01}
    
ventricular tachycardia (fast heartbeat)<sup>{01}

{01}</sup>

Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Headache ^{01}
{01}
Incidence less frequent
    
Abdominal pain ^{01}
    
amblyopia (blurred, or impaired vision )^{01}
    
anemia (pale skin; troubled breathing; unusual bleeding or bruising; unusual tiredness or weakness )^{01}
    
anxiety ^{01}
    
back pain ^{01}
    
catheter pain ^{01}
    
confusion ^{01}
    
cough, increased ^{01}
    
cramps of the leg ^{01}
    
dizziness ^{01}
    
fever ^{01}
    
hemoptysis ( coughing or spitting up blood)^{01}
    
injection site reaction ^{01}
    
insomnia ( sleeplessness)^{01}
    
nausea ^{01}
    
paresthesia (burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings on the skin)^{01}
    
pruritus (itching skin)^{01}
    
rash ^{01}
    
somnolence (sleepiness or unusual drowsiness)^{01}
    
sweating ^{01}
    
tremor ^{01}
    
vomiting ^{01}





Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

No data are available with respect to overdosage in humans. The expected reaction would be excessive hypotension.^{01}

Treatment of overdose
Treatment should be symptomatic and supportive.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Nesiritide (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to nesiritide
Other medications, especially oral angiotensin-converting enzyme (ACE) inhibitors
Other medical problems, especially cardiogenic shock, conditions in which cardiac output is dependent upon venous return, constrictive pericarditis, low cardiac filling pressure, pericardial tamponade, restrictive or obstructive cardiomyopathy, significant valvular stenosis, or systolic blood pressure less than 100 mm Hg

Proper use of this medication

» Proper dosing


Side/adverse effects
Signs of potential side effects, especially asymptomatic hypotension, angina pectoris, apnea, atrial fibrillation, AV node conduction abnormalities, bradycardia, symptomatic hypotension, ventricular extrasystoles, and ventricular tachycardia


General Dosing Information

For treatment of adverse effects
If hypotension should occur, the dose of nesiritide should be reduced or the medication may be discontinued.^{01} Administration of intravenous fluids, changes in body position, or other measures to increase blood pressure may be instituted, as needed.^{01} Hypotension may last for up to several hours, therefore, the patient should be closely observed before restarting the medication.^{01}


Parenteral Dosage Forms

NESIRITIDE FOR INJECTION

Usual Adult Dose
Cardiotonic
Intravenous, 2 mcg per kg of body weight administered as a bolus over approximately sixty seconds followed by a continuous infusion at a dose of 0.01 mcg per kg of body weight per minute.^{01}

Note: Nesiritide should not be initiated at a dose that is above the recommended dose^{01}



Usual pediatric dose
Safety and efficacy have not been established.^{01}

Usual Geriatric Dose
See Usual adult dose.

Size(s) usually available:
U.S.—


1.5 mg (Rx) [Natrecor (citric acid monohydrate 2.1 mg) (mannitol 20 mg) (sodium citrate dihydrate 2.94 mg)^{01}]

Packaging and storage:
Store between 20 and 25 °C ( 68 and 77 °F), excursions permitted to 15 to 30 °C (59 to 86 °F), or refrigerated between 2 and 8 °C (36 and 46 °F). Keep in carton until time of use.^{01}

Preparation of dosage form:
Add 5 mL of diluent removed from a pre-filled 250-mL plastic IV bag to one 1.5-mg vial of nesiritide. Gently rock the contents of the vial to ensure complete reconstitution. Add the reconstituted nesiritide to the 250-mL plastic IV bag and invert the bag several times to ensure complete mixing.^{01} The resulting solution will have a concentration of approximately 6 mcg per mL.^{01} Five percent dextrose injection, 0.9% sodium chloride injection, 5% dextrose and 0.45% sodium chloride injection, or 5% dextrose and 0.2% sodium chloride injection may be used as a diluent.^{01}

Stability:
The reconstituted solution should be used within 24 hours.^{01}

Incompatibilities:
Nesiritide is chemically and/or physically incompatible with injectable formulations of bumetanide, enalaprilat, ethacrynate sodium, furosemide, heparin, hydralazine, and insulin.^{01} These drugs should not be administered with nesiritide through the same intravenous catheter.^{01}

The preservative, sodium metabisulfite, also is incompatible with nesiritide.^{01} Injectable drugs that contain this preservative should not be administered with nesiritide through the same infusion line.^{01}

Nesiritide binds to heparin.^{01} Therefore, heparin-coated catheters should not be used for administration because the amount of nesiritide delivered to the patient may be decreased.^{01} Heparin infusions should be administered through a separate catheter.^{01}

Developed: 10/09/2001
Revised: 12/03/2001

References

1. Product Information: Natrecor®, nesiritide. Scios Inc., Sunnyvale, CA. (PI written 08/2001) reviewed 09/2001.
   

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