Nesiritide uses, brand name, doses and side effects

Description of Nesiritide

Nesiritide is an intravenous recombinant purified preparation of human B-type natriuretic peptide (hBNP), a naturally-occurring hormone produced in the ventricles of the heart. The drug is produced in E. coli using recombinant DNA technology. Nesiritide is indicated for the acute treatment of decompensated congestive heart failure (CHF), and has primarily been studied in patients with elevated pulmonary capillary wedge pressure (PCWP) more than 18 to 20 mmHg. In decompensated heart failure, the use of nesiritide reduces PCWP and has been shown to improve the symptoms of heart failure, including global clinical status, dyspnea, and fatigue. The overall safety of nesiritide has been questioned based on the results of two publications which have reported an increased risk of worsening renal function and a trend toward increased mortality in nesiritide-treated patients versus placebo. A pooled analysis of three randomized controlled trials of nesiritide use in decompensated heart failure showed a nonsignificant trend toward increased deaths, when evaluated at 30 days, in the nesiritide-treated group versus a non-inotrope control group (e.g., vasodilators, diuretics). According to the manufacturer, a meta-analysis including 7 clinical trials demonstrated that administration of nesiritide did not result in increased 30-day or 180-day mortality in patients with acute decompensated heart failure. Data from the 7 studies indicate no increased mortality risk at day 30 (HR = 0.99; 95% CI: 0.8 to 1.22). Results of a pooled analysis of the 6 studies that collected 180-day data indicate no increased mortality risk with nesiritide at day 180 (HR = 0.98; 95% CI: 0.88 to 1.1). A cardiovascular expert panel consulted by the manufacturer recommended that the use of nesiritide be limited to hospitalized patients with acute decompensation of congestive heart failure who have dyspnea at rest. This patient population is similar to the VMAC trial which included 489 patients with PCWP more than 20 mmHg and required hospitalization for decompensated heart failure. The panel has also recommended evaluation of the risks and benefits of nesiritide therapy, along with consideration of other strategies to relieve dyspnea associated with acute heart failure. Nesiritide should not be used to replace diuretics for the treatment of heart failure. Since insufficient evidence is available to demonstrate benefit, the panel has recommended that the use of nesiritide be restricted in the following circumstances: use as an intermittent outpatient infusion, administration on a repetitive schedule, or use to improve renal function or enhance diuresis. The expert panel has also recommended that the manufacturer provide educational programs to inform physicians regarding the appropriate use of nesiritide.Subsequent data suggest, compared to placebo, nesiritide use is associated with an increase in worsening renal function and early death. The ASCEND-HF trial was designed to further investigate renal toxicity and mortality associated with nesiritide. Data from this trial indicate nesiritide is not associated with an increase or decrease in death and rehospitalization. Renal function was not worsened with nesiritide therapy, dyspnea was not significantly improved, and hypotension occurred more frequently with nesiritide. Based on these data, the authors concluded that nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure. Nesiritide received FDA approval for acute treatment of decompensated heart failure in August 2001.

Mechanism of Action: Nesiritide is an IV purified preparation of human B-type natriuretic peptide (hBNP). BNP is a naturally-occurring hormone produced in the ventricles of the heart. BNP should not be confused with ANP (atrial natriuretic peptide). ANP is produced in the atria while BNP is produced in the ventricles. BNP and ANP are endogenous hormones which cause natriuresis, diuresis, and vasodilation; however, the effects of BNP may be more potent and last longer.

Endogenous concentrations of hBNP are elevated in patients with heart failure; the addition of nesiritide augments the body’s normal physiologic response to heart failure. Nesiritide produces balanced arterial and venous dilation, evidenced by reductions in systemic vascular resistance, systemic arterial pressure, PCWP, right atrial pressure, and mean pulmonary arterial pressure. Nesiritide increases cardiac output and stroke volume, without increasing heart rate. It also has natriuretic actions and promotes diuresis.

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 rhBNP arterial and venous tissue preparations that were precontracted with either endothelin-1 or the alpha-adrenergic agonist, phenylephrine. Intravenous nesiritide (0.015—0.06 mcg/kg/min) produces dose-dependent reductions in pulmonary capillary wedge pressure (PCWP) and systemic blood pressure (SBP) in patients with acute decompensated heart failure. Nesiritide, at IV doses ranging from 0.015 to 0.06 mcg/kg/min for 24 hours, produces significant decreases in PCWP (27—39%), mean right atrial pressure and systemic vascular resistance (SVR); these effects are accompanied by increased cardiac index (CI) and stroke volume index (SVI), without an associated increase in heart rate. Beneficial effects are sustained throughout the infusion. Nesiritide promotes diuresis due to a direct natriuretic action, increased cardiac output, and/or decreased aldosterone levels.

Nesiritide causes potent, dose-related vasodilation that is rapid in onset and sustained for the duration of drug infusion. After initiating the recommended dosing, 60% of the 3-hour effect on PCWP reduction is achieved within 15 minutes, reaching 95% of the 3-hour effect within 1 hour. Approximately 70% of the 3-hour effect on SBP reduction is reached within 15 minutes. The pharmacodynamic half-life of the onset and offset of the hemodynamic effect of nesiritide is longer than that expected from the pharmacokinetic half-life. In patients who develop symptomatic hypotension at recommended doses, 50% recovery of SBP toward baseline is observed approximately 60 minutes following drug discontinuation or dosage reduction. When higher doses of nesiritide are infused, the duration of hypotension is sometimes prolonged for several hours.

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: Nesiritide is administered intravenously. Nesiritide exhibits biphasic elimination from the plasma in heart failure patients. The mean initial elimination phase is about 2 minutes. The mean terminal elimination half-life of nesiritide is approximately 18 minutes; however, the pharmacodynamic onset and offset of the hemodynamic effect of nesiritide is longer than what would predict from the pharmacokinetic half-life. The volume of distribution of the central compartment (Vc) is estimated to be 0.073 L/kg; the mean steady-state volume of distribution (Vss) is approximately 0.19 L/kg. The average systemic clearance is 9.2 mL/kg/minute. The mechanism of elimination of nesiritide has not been studied in humans.

Affected cytochrome P450 isoenzymes and drug transporters: none

Route-Specific Pharmacokinetics
Intravenous Route
At steady-state, plasma brain natriuretic peptide (BNP) concentrations increase from baseline endogenous concentrations by approximately 3- to 6-fold with nesiritide infusion doses ranging from 0.01 to 0.03 mcg/kg/minute. At the recommended dosing regimen, 60% of the 3-hour effect on pulmonary capillary wedge pressure (PCWP) reduction is achieved within 15 minutes after the bolus, reaching 95% of the 3-hour effect within 1 hour. Approximately 70% of the 3-hour effect on systolic blood pressure reduction is reached within 15 minutes.

Special Populations
Population pharmacokinetic analyses demonstrate that the clearance of nesiritide is proportional to body weight, supporting the weight-adjusted dosing of nesiritide (i.e., administration on a mcg/kg/minute basis).
Renal Impairment
The effects of nesiritide on PCWP, cardiac index, and systolic blood pressure are not significantly different in patients with chronic renal impairment (baseline serum creatinine 2 to 4.3 mg/dL) compared to patients with normal renal function.

Geriatric
Nesiritide clearance is not significantly influenced by age.

Gender Differences
Nesiritide clearance is not significantly influenced by gender.

Ethnic Differences
Nesiritide clearance is not significantly influenced by race or ethnicity.

• Nesiritide

• Natrecor

• Cardiovascular Agent
• Natriuretic Peptide

• Recall Info: The marketing and distribution of nesiritide powder for injection (Natrecor(R)) was discontinued in the US on 02-05-2018. (Recall Info: The marketing and distribution of nesiritide powder for injection (Natrecor(R)) was discontinued in the US on 02-05-2018.)
• Congestive heart failure, Acutely decompensated – Dyspnea: Adult

• Gastrointestinal: Nausea (3% )
• Neurologic: Dizziness (2% ), Headache (7% )

• Cardiovascular: Hypotension (4% to 17% )
• Immunologic: Hypersensitivity reaction
• Renal: Serum creatinine raised (17% to 31.4% )

• For IV use only
• Intravenous: reconstitute vial (1.5 mg) by adding 5 mL of diluent (D5W, NS, or D5-0.45% NaCl) from a pre-filled 250 mL IV plastic bag and rock vial gently, do not shake; withdraw contents and add to 250 mL IV plastic bag (6 mcg/mL)
• Intravenous: use reconstituted solutions within 24 hours
• Intravenous: prime IV tubing with an infusion of 5 mL of solution prior to connecting IV port or administering bolus or infusion
• Intravenous: bolus must be drawn from the prepared infusion bag and administered over approximately 60 seconds through IV port in the tubing
• Intravenous: following bolus, infuse at rate of 0.1 mL/kg/hr
• Intravenous: flush catheter between administration of incompatible drugs
• Intravenous: do not administer through a central heparin-coated catheter

• Important Note: The marketing and distribution of nesiritide powder for injection (Natrecor(R)) was discontinued in the US on 02-05-2018.
• Congestive heart failure, Acutely decompensated – Dyspnea: 2 mcg/kg IV bolus followed by 0.01 mcg/kg/min continuous IV infusion; bolus may not be appropriate for patients with systolic blood pressure below 110 mmHg or if recently treated with afterload reducers; reduce dose or discontinue therapy if hypotension occurs; may restart at a 30% lower dose (no bolus) after the patient is stabilized
• Congestive heart failure, Acutely decompensated – Dyspnea: Titration, may increase by 0.005 mcg/kg/min (after a bolus of 1 mcg/kg IV) no more frequently than every 3 hours up to a MAX dose of 0.03 mcg/kg/min

• Important Note: The marketing and distribution of nesiritide powder for injection (Natrecor(R)) was discontinued in the US on 02-05-2018.
• General Dosage Information: safety and effectiveness not established in children
• Congestive heart failure, Acutely decompensated – Dyspnea: 0.01 mcg/kg/minute continuous IV infusion; titration, adjust by 0.005 mcg/kg/minute every 3 hours as necessary to MAX 0.03 mcg/kg/minute ; limit increases beyond the maximum infusion rate to select patients and with hemodynamic monitoring (guideline dosage)