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9/10/2001

Natriuretic Peptide Approved for Use in Decompensated CHF

Cheryl A. Thompson

Scios Inc. received approval to market nesiritide (Natrecor [PDF]), a brain (B)-type natriuretic peptide, for the i.v. treatment of patients with acutely decompensated congestive heart failure (CHF) who have shortness of breath at rest or with minimal activity.

Endogenous B-type natriuretic peptide is synthesized in the ventricular myocardium and indirectly causes veins and arteries to dilate. Nesiritide, containing the same 32-residue sequence of amino acids as the endogenous peptide, is produced through recombinant DNA technology.

The efficacy of nesiritide for the treatment of decompensated CHF was evaluated in five randomized, multicenter, controlled studies involving 772 patients who received a continuous i.v. infusion of the drug at a dosage of 0.01–0.03 mcg/kg/min. About half of these patients received the drug for 24–48 hours.

The largest study involved 489 patients and compared nesiritide, administered as a 2-mcg/kg bolus dose followed by a 0.01-mcg/kg/min continuous infusion, with placebo and i.v. nitroglycerin. Three hours after the start of treatment, dyspnea was rated as "improved" by a larger proportion of patients in the nesiritide group than in the other groups. Among the patients who had a pulmonary-artery catheter, nesiritide decreased the pulmonary-capillary wedge pressure within 15 minutes, achieving a mean decrease of 5.8 mm Hg at three hours. Seventy-five percent of the nesiritide-treated patients were alive at six months.

Results from several studies indicate that, within two hours of stopping nesiritide treatment, the pulmonary-capillary wedge pressure returned to within 10% of the baseline value but did not exceed that initial level.

Nesiritide leaves the plasma of patients with CHF in two phases, the first having a half-life of 2 minutes and the second a half-life of 18 minutes. This quick clearance occurs by three mechanisms: (1) cellular intake after the peptide binds to cell-surface clearance receptors, (2) cleavage of the peptide by enzymes on the surface of vascular lumens, and (3) renal filtration. The renal route of elimination is the least important mechanism of the three; according to the labeling, clinical data suggest that the dosage of nesiritide does not need to be decreased in patients with renal insufficiency.

During the clinical studies, the most commonly reported adverse effects of nesiritide therapy were hypotension, headache, back pain, and nausea. The frequencies of hypotension and nausea were notably higher at a dosage of 0.015 or 0.03 mcg/kg/min than at 0.01 mcg/kg/min. In the largest study, the serum creatinine concentration increased from baseline by at least 0.5 mg/dL in 28% of the nesiritide-treated patients .

Patients with cardiogenic shock or a systolic blood pressure of <90 mm Hg should not receive nesiritide as a primary therapy. The drug should also not be given to patients who may have a low cardiac filling pressure. Nesiritide is produced in Escherichia coli; according to the labeling, no serious allergic or anaphylactic reactions to the drug have been reported.

The recommended dosage of nesiritide is an i.v. bolus injection of 2 mcg/kg over 60 seconds followed immediately by a continuous i.v. infusion at a rate of 0.01 mcg/kg/min. Higher dosages may increase the chance that a hypotensive episode will develop and may increase the intensity and duration of that episode. There is little information available on administering nesiritide for more than 48 hours. The patient’s blood pressure should be closely monitored during nesiritide therapy.

Nesiritide is prepared for administration by adding 5 mL of fluid from a prefilled 250-mL plastic i.v. bag to the drug vial; rocking the vial gently so that the diluent comes in contact with all surfaces, including the stopper; and then transferring the entire contents of the vial to the i.v. bag. This procedure yields a 6-mcg/mL solution of nesiritide; at this concentration, a flow rate of 0.1 mL/kg/hour provides the patient with a dose of 0.01 mcg/kg/min. Before the bolus dose is given, the tubing of the i.v. administration set should be primed with 25 mL of nesiritide solution.

Correction, 11 October 2001—The above paragraph had initially stated an incorrect rate for the infusion. The correct rate now appears.

Nesiritide is incompatible with heparin, insulin, ethacrynate sodium, bumetanide, enalaprilat, hydralazine, and furosemide; sodium metabisulfite, a preservative, is also incompatible with nesiritide. Because nesiritide binds to heparin, heparin-coated catheters should not be used for nesiritide administration.

Natrecor is available in single-use vials containing 1.5 g of the lyophilized drug. The unused vials can be stored at controlled room temperature, 20–25 degrees Celsius. Treatment of a 70-kg patient for 48 hours at the recommended dosage requires two vials. A table in the product’s labeling lists the volumes that correspond to the weight-based bolus dose and subsequent infusion rate.