United States of America - The Food and Drug Administration has posted the recommendations of an expert panel of cardiology and heart failure clinicians with regard to nesiritide (Natrecor®), the first member of a new drug class, human B-type natriuretic peptide (hBNP) manufactured from E coli using recombinant DNA technology.

Nesiritide was approved in 2001 for the intravenous treatment of patients with acutely decompensated congestive heart failure who have dyspnoea at rest or with minimal activity. Two recent publications have raised questions about the safety of nesiritide with respect to worsening renal function and death. A Nesiritide Advisory Panel was convened and has published a report with the following observations.

Renal dysfunction

The use of nesiritide has been associated with a dose-dependent increase in serum creatinine indicating renal dysfunction at doses described in the package insert, including the dose recommended for initiation of treatment. Most of these increases occurred days after discontinuation of the drug. The mechanism of these creatinine changes, their duration, implications for survival, longer term renal function and other clinical consequences is not clear. There is no evidence, however, that nesiritide results in improvement in renal function.

Studies to clarify the mechanism and reversibility of the observed changes in creatinine should be undertaken. Additional analyses of existing data to identify the characteristics of patients who experience creatinine elevation should be conducted.

Mortality

Completed trials show that the use of nesiritide was associated with a trend toward an increase in mortality rate at 30 days, with a hazard ratio of approximately 1.3, a 30% increase. No increased hazard is observed at 180 days. Because of the small numbers of events in the current database and the inconclusive nature of these findings, the panel recommends that additional studies be conducted to assess the effect of nesiritide on survival.

Clinical trials

The panel strongly recommended continued enrolment in ongoing trials of nesiritide, as well as enrolment in trials that are soon to commence. This includes a plan to conduct a large (several thousand subjects) trial of clinical outcomes to assess further the benefits and risks of nesiritide compared to standard therapy.

Further exploration of the data from the completed trials should be carried out to examine the effects of nesiritide in subgroups of patients.

Recommendations

The use of nesiritide should be strictly limited to patients presenting to the hospital with acutely decompensated congestive heart failure who have dyspnoea at rest.

Nesiritide should not be used to replace diuretics. Furthermore, nesiritide should not be used:

• for intermittent outpatient infusion
• for scheduled repetitive use
• to improve renal function, or
• to enhance diuresis.

The sponsor should immediately undertake a proactive educational program to inform physicians regarding the conditions and circumstances in which nesiritide should and should not be used.

Reference: 2005 Safety Alert and The Panel's report, 13 July 2005 on http://www.fda.gov/medwatch