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2005 Safety Alert: Natrecor (nesiritide) |
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The following information is from Scios. Contact the company for a copy of any referenced enclosures. Dear Healthcare Provider: We are writing to provide you with information about the recommendations of an expert panel of cardiology and heart failure clinicians with regard to NATRECOR® (nesiritide). We recently asked Dr. Eugene Braunwald, Distinguished Hersey Professor of Medicine, Harvard Medical School, to convene such a panel to review and assess important data associated with this medicine. The panel also provided advice on the ongoing and planned clinical development program for NATRECOR® as well as recommendations for use. With respect to recent questions raised about worsened renal function and mortality, the panel
provided a consensus statement on each after review of the available data (see attached panel
recommendations), including review of the original 2001 product labeling that has described these
risks.1 They endorsed our plan to add substantially to the current knowledge base about
NATRECOR® by conducting several clinical trials, including a large trial of clinical outcomes to
further assess the benefits and risks of NATRECOR®. The panel also strongly encouraged Scios and
investigators to continue enrollment of patients in current NATRECOR® trials (e.g., FUSION II) and The Panel also made recommendations about the appropriate use of NATRECOR® and encouraged us to engage in an educational campaign to ensure that clinicians understand when the use of NATRECOR® is appropriate and when it is not appropriate. The panel made the following specific, verbatim recommendations: 1) The use of Natrecor should be strictly limited to patients presenting to the hospital with acutely decompensated congestive heart failure who have dyspnea at rest, as were the patients in the largest trial that led to approval of the drug (VMAC). Physicians considering the use of nesiritide should consider its efficacy in reducing dyspnea, the possible risks of the drug summarized above, and the availability of alternate therapies to relieve the symptoms of congestive heart failure. 2) Nesiritide should not be used to replace diuretics. Furthermore, because sufficient evidence is not currently available to demonstrate benefit for the applications listed below, nesiritide should not be used:
3) Scios should immediately undertake a pro-active educational program to inform physicians regarding the conditions and circumstances in which nesiritide should and should not be used, as described above. Sponsor supported communications, including review articles of nesiritide, should reflect the above recommendations. Scios should ensure that current and future marketing and sales activities related to nesiritide are consistent with this educational program. With patient care as our highest priority, we write today to help you understand the data supporting the use of NATRECOR® so that you can make the best medical decisions for your patients. NATRECOR® for Acutely Decompensated Heart Failure NATRECOR® 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. The recommended dose of NATRECOR® is an IV bolus of 2 mcg/kg followed by a continuous infusion of 0.01 mcg/kg/min. Consistent with the clinical trials supporting its approval, the commercial use of NATRECOR® in clinical practice (non-investigational) should be strictly limited to patients with acutely decompensated heart failure with a clinical presentation severe enough to warrant hospitalization (whether presenting to an Emergency Department, Observation Unit, or direct admission to a Hospital Ward or Intensive Care Unit). NATRECOR® should be administered in a clinical setting where blood pressure can be closely monitored. NATRECOR® should not be initiated at a dose that is above the recommended dose. The prescribing information for NATRECOR® reflects data from 10 clinical trials including
941 patients with CHF (chronic CHF NYHA class II-III 61%, class IV 36%; mean age 60 years,
women 28%). There were five randomized, multi-center, placebo- or active-controlled studies in
which 772 patients with decompensated CHF received continuous infusions of NATRECOR® at
doses ranging from 0.01 to 0.03 mcg/kg/min. Of these patients, the majority (70%) received the
NATRECOR® infusion for at least 24 hours; 48% received NATRECOR® for 24–48 hours, and
22% received NATRECOR® for greater than 48 hours. The VMAC trial, the largest relied upon for the approval of the drug, was a randomized, double-blind
study of 489 patients who required hospitalization for management of shortness of breath at rest or
with minimal activity (such as talking, eating, or bathing) due to acutely decompensated CHF.
Patients with acute coronary syndrome, preserved systolic function, arrhythmia, and renal
insufficiency were not excluded. The study compared the effects of NATRECOR®, placebo, and
IV nitroglycerin when added to background therapy (IV and oral diuretics, non-IV cardiac
medications, dobutamine, and dopamine). VMAC was designed to show primary efficacy
comparisons between NATRECOR® and placebo. The nitroglycerin arm was included to show the
relative safety and tolerability of NATRECOR® in comparison to a commonly used IV vasodilator. Unsupported Uses of NATRECOR® We understand that NATRECOR® is also being administered as intermittent and scheduled infusions to treat severely ill congestive heart failure patients, particularly in the outpatient setting. Although a clinical development program is currently underway in this setting (FUSION II trial), Scios does not recommend NATRECOR® for this use at this time. To our knowledge, the only controlled clinical trial to assess the use of NATRECOR® for serial infusions in the outpatient setting is FUSION I (Follow-up Serial Infusion of Nesiritide). FUSION I was a pilot study (n=210) and was not powered to adequately assess the effectiveness or safety of serial infusions of NATRECOR®. The size of the study, its design, and its findings provide an inadequate basis to recommend the routine use of intermittent, serial, or scheduled repetitive infusions of NATRECOR®. We also understand that in certain instances NATRECOR® is being used to replace diuretics, to
improve renal function and/or to enhance diuresis. To date, adequate clinical data that demonstrate
clinically relevant diuretic properties or positive renal effects of NATRECOR® does not exist.
Scios does not recommend such use. Moreover, it is important to understand that clinical trial data
show that the use of NATRECOR® was associated with a dose-dependent increase in serum
creatinine. In VMAC, the serum creatinine rose by more than 0.5 mg/dL above baseline in at least
one blood draw in 7% of patients in the control groups and 8% in the nesiritide groups by 5 days, and Additional Safety Information NATRECOR® may cause hypotension. If hypotension occurs during administration of NATRECOR®, the dose should be reduced or discontinued, and blood pressure should be monitored closely. At the recommended dose of NATRECOR®, the incidence of symptomatic hypotension (4%) was similar to that of IV nitroglycerin (5%). Asymptomatic hypotension occurred in 8% of patients treated with either drug. The mean duration of symptomatic hypotension was longer with NATRECOR® than IV nitroglycerin (2.2 versus 0.7 hours, respectively). Higher doses of NATRECOR® increased the risk of hypotension and elevated creatinine. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with NATRECOR® may be associated with azotemia. Other adverse events reported at a rate of at least 5% during the first 24 hours of infusion with either NATRECOR® plus standard care or IV nitroglycerin plus standard care therapy, included, respectively: ventricular tachycardia (3%, 5%), nonsustained ventricular tachycardia (3%, 5%), headache (8%, 20%), abdominal pain (1%, 5%), and nausea (4%, 6%). NATRECOR® should not be used in patients with systolic blood pressure <90 mm Hg or as primary therapy in patients with cardiogenic shock. NATRECOR® is not recommended for patients for whom vasodilating agents are not appropriate and should be avoided in patients with low cardiac filling pressures. In the seven NATRECOR® clinical trials that collected mortality data through 30 days, 5.3% in the NATRECOR® treatment group died as compared with 4.3% in the group treated with other standard medications. In the four clinical trials in which mortality was collected through 180 days, 21.7% in the NATRECOR® treatment group died as compared with 21.5% in the group treated with other standard medications. There are insufficient numbers of deaths to identify or exclude, with confidence, a moderate excess of risk to survival after treatment with NATRECOR®. We are committed to keeping you informed about those uses of NATRECOR® that have been proven to be effective and safe. If you have any questions about the use of NATRECOR® or need additional information, please call our Medical Information department at 877-4-NATRECOR (877-462-8732). Conclusion We remain confident that NATRECOR® is safe and effective when used as recommended to treat the
patients described in the prescribing information. Although questions have been raised about the
safety of NATRECOR®, it is important to note that more information from controlled clinical trials
exists about NATRECOR® than for any other therapy available to treat these patients. Through a
robust clinical development program, Scios remains committed to providing patients and the clinical
community with additional efficacy and safety information about NATRECOR® in the hospital
setting as well as for other potential indications. As with any medication, health care providers Sincerely, Darlene P. Horton, MD
BELOW IS THE PANEL’S REPORT, ISSUED ON JUNE 13, 2005: Nesiritide (Natrecor ®) is the first member of a new drug class, human B-type natriuretic peptide (hBNP) and is manufactured from E coli using recombinant DNA technology. The approval of the drug was based on the evaluation of 10 completed clinical trials involving 1456 patients with congestive heart failure. These trials showed that the drug reduced dyspnea and produced dosedependent reductions in pulmonary capillary wedge pressure and systolic arterial pressure when added to standard care. Since approval, 2 additional trials involving 447 patients have been completed. Nesiritide was approved in 2001 “for the intravenous treatment of patients with acutely decompensated congestive heart failure who have dyspnea at rest or with minimal activity” and it has been widely used. Two recent publications have raised questions about the safety of nesiritide with respect to worsening renal function and death. The data on which these analyses were based were available to and known by the FDA. Scios expanded these analyses to include data from all available trials, and convened this panel with the following objectives: 1) To review and discuss nesiritide efficacy and safety data; 2) To provide guidance on proposed clinical development strategies for nesiritide; and 3) To review the current package insert and to provide recommendations on the use of nesiritide. The Nesiritide Advisory Panel met in Boston, MA on June 8, 2005. Prior to the meeting, the panel members reviewed substantial material provided by Scios, including the original (August 2001) and the current (April 2005) package inserts, communications sent to physicians by Scios, the recent papers by Sackner-Bernstein et al, as well as nesiritide publications, including a submitted paper. At the meeting, in depth presentations of substantial additional analyses of existing data were made, plans for future trials were reviewed and extensive discussions were held with Scios scientific staff. The panel also held two closed-door executive sessions which were independent of the sponsor and during which the recommendations were prepared. Our conclusions and recommendations are based on the data supplied by Scios. Eugene Braunwald, MD (Chairman) John C. Burnett, Jr., MD Wilson S. Colucci, MD Barry M. Massie, MD John J.V. McMurray, M.D. Christopher M. O’Connor, MD Milton Packer, MD Ileana Piña, MD, FACC Bertram Pitt, MD James Young, MD RENAL DYSFUNCTION The panel noted that the use of nesiritide was associated with a dose-dependent increase in serum creatinine indicating renal dysfunction at doses described in the package insert (0.01 to 0.03 ug/kg/min), including the dose recommended for initiation of treatment (0.01 ug/kg/min). In the largest trial that led to the approval of the drug (VMAC), which used a dose of 0.01 ug/kg/min, the serum creatinine rose by more than 0.5 mg/dL above baseline in at least one blood draw in 7% of patients in the control groups and 8% in the nesiritide groups by 5 days, and by 21% and 28% respectively, by 30 days. 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. These should examine renal function in a more systematic and comprehensive way and relate changes in renal function to clinical outcomes. Additional analyses of existing data to identify the characteristics of patients who experience creatinine elevation should be conducted. MORTALITY The panel noted that 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. However, the confidence intervals around this ratio are wide and the number of deaths
in a pooled analysis of all six of the controlled clinical trials (84) is insufficient to identify or exclude,
with confidence, a moderate excess of risk to survival. Also, there are potentially important
imbalances in baseline characteristics and in other treatments received concomitantly, and the trials
differ with respect to the treatments with which nesiritide was compared. No increased hazard is CLINICAL TRIALS 1) The panel strongly recommends continued enrollment in ongoing trials of nesiritide, as well as enrollment in trials that are soon to commence. The panel notes that these trials have been or will be reviewed by regulatory agencies and that the safety of patients in all of these trials is carefully monitored by appropriately constituted and independent Data Safety and Monitoring Committees. 2) The panel endorses Scios’ plan to conduct, in a timely manner, a large (several thousand
subjects) trial of clinical outcomes to assess further the benefits and risks of nesiritide
compared to standard therapy. This trial should be initiated without delay.
The panel recommends that this trial should include patients presenting to a hospital with 3) Additional mechanistic studies, including an examination of the effect of doses lower than those approved should be considered. Further exploration of the data from the completed trials should be carried out to examine the effects of nesiritide in subgroups of patients. FINAL RECOMMENDATIONS 1) The use of nesiritide should be strictly limited to patients presenting to the hospital with acutely decompensated congestive heart failure who have dyspnea at rest, as were the patients in the largest trial that led to approval of the drug (VMAC). Physicians considering the use of nesiritide should consider its efficacy in reducing dyspnea, the possible risks of the drug summarized above, and the availability of alternate therapies to relieve the symptoms of congestive heart failure. 2) Nesiritide should not be used to replace diuretics. Furthermore, because sufficient evidence is not currently available to demonstrate benefit for the applications listed below, nesiritide should not be used:
3) Scios should immediately undertake a pro-active educational program to inform physicians regarding the conditions and circumstances in which nesiritide should and should not be used, as described above. Sponsor supported communications, including review articles of nesiritide, should reflect the above recommendations. Scios should ensure that current and future marketing and sales activities related to nesiritide are consistent with this educational program. Natrecor Label April 2005
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