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Intravenous Dilution Guidelines

Nesiritide (Natrecor ®)

The authors make no claims of the accuracy of the information contained herein; and these suggested doses and/or guidelines are not a substitute for clinical judgment. Neither GlobalRPh Inc. nor any other party involved in the preparation of this document shall be liable for any special, consequential, or exemplary damages resulting in whole or part from any user's use of or reliance upon this material.    PLEASE READ THE DISCLAIMER CAREFULLY BEFORE ACCESSING OR USING THIS SITE. BY ACCESSING OR USING THIS SITE, YOU AGREE TO BE BOUND BY THE TERMS AND CONDITIONS SET FORTH IN THE DISCLAIMER.

Usual Diluents

D5W, NS, D5-1/2NS

Standard Dilutions   [Amount of drug] [Infusion volume] [Infusion rate]

[1.5 mg] [250 ml] [As directed]

Stability / Miscellaneous

Restrictions: Restricted to Cardiology Consult

Preparation: Reconstitute one 1.5-mg vial of Natrecor by adding 5 mL of diluent removed from a pre-filled 250-mL plastic IV bag containing the diluent of choice.
The following preservative-free diluents are recommended for reconstitution: 5% Dextrose Injection (D5W), USP; 0.9% Sodium Chloride Injection, USP; 5% Dextrose and 0.45% Sodium Chloride Injection, USP, or 5% Dextrose and 0.2% Sodium Chloride Injection, USP.

Do not shake the vial.
Rock the vial gently so that all surfaces, including the stopper, are in contact with the diluent to ensure complete reconstitution. Use only a clear, essentially colorless solution. The IV bag should be inverted several times to ensure complete mixing of the solution.

Label: Monitor BP closely.
Stability: (reconstituted vials / solutions): 24 hours RT or REF.

Dosing: IV bolus of 2 µg/kg (over 1 minute) followed by a continuous infusion of 0.01 mcg/kg/min. Withdraw bolus dose from the infusion bag. Higher initial dosages are not recommended.

Calculation: Bolus Volume (ml) = 0.33 × Patient Wt (kg).
Infusion Rate (ml/hr) = 0.1 × Patient wt (kg). There is limited experience with administering Natrecor for longer than 48 hours.

Indications: IV treatment of patients with acutely decompensated CHF who have dyspnea at rest or with minimal activity.

Actions: venous and arterial vasodilation (decreased PCWP etc), plus mild diuretic effect.



Mechanism of Action
Human BNP binds to the particulate guanylate cyclase receptor of vascular smooth muscle and endothelial cells, leading to increased intracellular concentrations of guanosine 3'5'-cyclic monophosphate (cGMP) and smooth muscle cell relaxation. Cyclic GMP serves as a second messenger to dilate veins and arteries. Nesiritide has been shown to relax isolated human arterial and venous tissue preparations that were precontracted with either endothelin-1 or the alpha-adrenergic agonist, phenylephrine.

In human studies, nesiritide produced dose-dependent reductions in pulmonary capillary wedge pressure (PCWP) and systemic arterial pressure in patients with heart failure.

In animals, nesiritide had no effects on cardiac contractility or on measures of cardiac electrophysiology such as atrial and ventricular effective refractory times or atrioventricular node conduction.

Naturally occurring atrial natriuretic peptide (ANP), a related peptide, increases vascular permeability in animals and humans and may reduce intravascular volume. The effect of nesiritide on vascular permeability has not been studied.


Pharmacokinetics
In patients with congestive heart failure (CHF), Natrecor administered intravenously by infusion or bolus exhibits biphasic disposition from the plasma. The mean terminal elimination half-life (t1/2) of Natrecor is approximately 18 minutes and was associated with approximately 2/3 of the area-under-the-curve (AUC). The mean initial elimination phase was estimated to be approximately 2 minutes. In these patients, the mean volume of distribution of the central compartment (Vc) of Natrecor was estimated to be 0.073 L/kg, the mean steady-state volume of distribution (Vss) was 0.19 L/kg, and the mean clearance (CL) was approximately 9.2 mL/min/kg. At steady state, plasma BNP levels increase from baseline endogenous levels by approximately 3-fold to 6-fold with Natrecor infusion doses ranging from 0.01 to 0.03 mcg/kg/min.


Elimination
Human BNP is cleared from the circulation via the following three independent mechanisms, in order of decreasing importance: 1) binding to cell surface clearance receptors with subsequent cellular internalization and lysosomal proteolysis; 2) proteolytic cleavage of the peptide by endopeptidases, such as neutral endopeptidase, which are present on the vascular lumenal surface; and 3) renal filtration.

INDICATIONS AND USAGE
Natrecor (nesiritide) is indicated for the intravenous treatment of patients with acutely decompensated congestive heart failure who have dyspnea at rest or with minimal activity. In this population, the use of Natrecor reduced pulmonary capillary wedge pressure and improved dyspnea.


CONTRAINDICATIONS
Natrecor is contraindicated in patients who are hypersensitive to any of its components. Natrecor should not be used as primary therapy for patients with cardiogenic shock or in patients with a systolic blood pressure < 90 mm Hg.


WARNINGS
Administration of Natrecor should be avoided in patients suspected of having, or known to have, low cardiac filling pressures.


OVERDOSAGE
No data are available with respect to overdosage in humans. The expected reaction would be excessive hypotension, which should be treated with drug discontinuation or reduction (see PRECAUTIONS) and appropriate measures.


DOSAGE AND ADMINISTRATION
The Natrecor bolus must be drawn from the prepared infusion bag.

Natrecor (nesiritide) is for intravenous use only. There is limited experience with administering Natrecor for longer than 48 hours. Blood pressure should be monitored closely during Natrecor administration.

If hypotension occurs during the administration of Natrecor, the dose should be reduced or discontinued and other measures to support blood pressure should be started (IV fluids, changes in body position). In the VMAC trial, when symptomatic hypotension occurred, Natrecor was discontinued and subsequently could be restarted at a dose that was reduced by 30% (with no bolus administration) once the patient was stabilized. Because hypotension caused by Natrecor may be prolonged (up to hours), a period of observation may be necessary before restarting the drug.


Preparation
The Natrecor bolus must be drawn from the prepared infusion bag.
  • Reconstitute one 1.5 mg vial of Natrecor by adding 5 mL of diluent removed from a pre-filled 250 mL plastic IV bag containing the diluent of choice. After reconstitution of the vial, each mL contains 0.32 mg of nesiritide. The following preservative-free diluents are recommended for reconstitution: 5% Dextrose Injection (D5W), USP; 0.9% Sodium Chloride Injection, USP; 5% Dextrose and 0.45% Sodium Chloride Injection, USP, or 5% Dextrose and 0.2% Sodium Chloride Injection, USP.
  • Do not shake the vial. Rock the vial gently so that all surfaces, including the stopper, are in contact with the diluent to ensure complete reconstitution. Use only a clear, essentially colorless solution.
  • Withdraw the entire contents of the reconstituted Natrecor vial and add to the 250 mL plastic IV bag. This will yield a solution with a concentration of Natrecor of approximately 6 mcg/mL. The IV bag should be inverted several times to ensure complete mixing of the solution.
  • Use the reconstituted solution within 24 hours, as Natrecor contains no antimicrobial preservative. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Reconstituted vials of Natrecor may be stored at 2-25°C (36-77°F) for up to 24 hours.
Dosing Instructions
The Natrecor bolus must be drawn from the prepared infusion bag.

The recommended dose of Natrecor is an IV bolus of 2 mcg/kg followed by a continuous infusion of 0.01 mcg/kg/min. Natrecor should not be initiated at a dose that is above the recommended dose.

Prime the IV tubing with 5 mL of the solution for infusion prior to connecting to the patient's vascular access port and prior to administering the bolus or starting the infusion.

The administration of the recommended dose of Natrecor is a two step process:

Step 1. Administration of the IV Bolus

After preparation of the infusion bag, as described previously, withdraw the bolus volume (see Weight-Adjusted Bolus Volume table) from the Natrecor infusion bag, and administer it over approximately 60 seconds through an IV port in the tubing.

Bolus Volume (mL) = Patient Weight (kg) / 3
Natrecor Weight-Adjusted Bolus Volume Administered Over 60 Seconds (Final Concentration = 6 mcg/mL)
Patient Weight (kg) Volume of Bolus (mL = kg/3)
60 20.0
70 23.3
80 26.7
90 30.0
100 33.3
110 36.7

Step 2. Administration of the Continuous Infusion

Immediately following the administration of the bolus, infuse Natrecor at a flow rate of 0.1 mL/kg/hr. This will deliver a Natrecor infusion dose of 0.01 mcg/kg/min.

To calculate the infusion flow rate to deliver a 0.01 mcg/kg/min dose, use the following formula (see the following Weight-Adjusted Infusion Flow Rate for Dosing table):

Infusion Flow Rate (mL/hr) = Patient Weight (kg) x 0.1

Natrecor Weight-Adjusted Infusion Flow Rate for a 0.01 mcg/kg/min Dose following Bolus (Final Concentration = 6 mcg/mL)
Patient Weight (kg) Infusion Flow Rate (mL/hr)
60 6
70 7
80 8
90 9
100 10
110 11

Dose Adjustments: The dose-limiting side effect of Natrecor is hypotension. Do not initiate Natrecor at a dose that is higher than the recommended dose of a 2 mcg/kg bolus followed by an infusion of 0.01 mcg/kg/min. In the VMAC trial there was limited experience with increasing the dose of Natrecor above the recommended dose (23 patients, all of whom had central hemodynamic monitoring). In those patients, the infusion dose of Natrecor was increased by 0.005 mcg/kg/min (preceded by a bolus of 1 mcg/kg), no more frequently than every 3 hours up to a maximum dose of 0.03 mcg/kg/min. Natrecor should not be titrated at frequent intervals as is done with other IV agents that have a shorter half-life.


Chemical/Physical Interactions
Natrecor is physically and/or chemically incompatible with injectable formulations of heparin, insulin, ethacrynate sodium, bumetanide, enalaprilat, hydralazine, and furosemide. These drugs should not be co-administered as infusions with Natrecor through the same IV catheter. The preservative sodium metabisulfite is incompatible with Natrecor. Injectable drugs that contain sodium metabisulfite should not be administered in the same infusion line as Natrecor. The catheter must be flushed between administration of Natrecor and incompatible drugs.

Natrecor binds to heparin and therefore could bind to the heparin lining of a heparin-coated catheter, decreasing the amount of Natrecor delivered to the patient for some period of time. Therefore, Natrecor must not be administered through a central heparin-coated catheter. Concomitant administration of a heparin infusion through a separate catheter is acceptable.


Storage
Store below 25°C. Do not freeze. Keep the vial in the outer carton in order to protect from light.


HOW SUPPLIED
Natrecor (nesiritide) is provided as a sterile lyophilized powder in 1.5 mg, single-use vials. Each carton contains one vial and is available in the following package:

1 vial/carton (NDC 65847-205-25)

US patent No. 5,114,923 and 5,674,710.
Distributed by Scios Inc.
Mountain View, CA 94043
Copyright 2007 Scios Inc.
20030306

Revised January 2007

Source: [package insert]
Disclaimer
The authors make no claims of the accuracy of the information contained herein; and these suggested doses are not a substitute for clinical judgment. Neither GlobalRPh Inc. nor any other party involved in the preparation of this program shall be liable for any special, consequential, or exemplary damages resulting in whole or part from any user's use of or reliance upon this material.  PLEASE READ THE DISCLAIMER CAREFULLY BEFORE ACCESSING OR USING THIS SITE. BY ACCESSING OR USING THIS SITE, YOU AGREE TO BE BOUND BY THE TERMS AND CONDITIONS SET FORTH IN THE DISCLAIMER.
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