Adverse events that occurred with at least a 3% frequency during the first 24 hours of Natrecor infusion are shown in the following table.

Adverse Event	VMAC Trial		Other Long Infusion Trials
	Nitroglycerin(n = 216)	Natrecor Recommended Dose (n = 273)	Control* (n = 256)	Natrecor mcg/kg/min
				0.015 (n = 253)	0.03 (n = 246)
Cardiovascular
Hypotension	25 (12%)	31 (11%)	20 (8%)	56 (22%)	87 (35%)
Symptomatic Hypotension	10 (5%)	12 (4%)	8 (3%)	28 (11%)	42 (17%)
Asymptomatic Hypotension	17 (8%)	23 (8%)	13 (5%)	31 (12%)	49 (20%)
Ventricular Tachycardia (VT)	11 (5%)	9 (3%)	25 (10%)	25 (10%)	10 (4%)
Non-sustained VT	11 (5%)	9 (3%)	23 (9%)	24 (9%)	9 (4%)
Ventricular Extrasystoles	2 (1%)	7 (3%)	15 (6%)	10 (4%)	9 (4%)
Angina Pectoris	5 (2%)	5 (2%)	6 (2%)	14 (6%)	6 (2%)
Bradycardia	1 (< 1%)	3 (1%)	1 (< 1%)	8 (3%)	13 (5%)
Body as a Whole
Headache	44 (20%)	21 (8%)	23 (9%)	23 (9%)	17 (7%)
Abdominal Pain	11 (5%)	4 (1%)	10 (4%)	6 (2%)	8 (3%)
Back Pain	7 (3%)	10 (4%)	4 (2%)	5 (2%)	3 (1%)
Nervous
Insomnia	9 (4%)	6 (2%)	7 (3%)	15 (6%)	15 (6%)
Dizziness	4 (2%)	7 (3%)	7 (3%)	16 (6%)	12 (5%)
Anxiety	6 (3%)	8 (3%)	2 (1%)	8 (3%)	4 (2%)
Digestive
Nausea	13 (6%)	10 (4%)	12 (5%)	24 (9%)	33 (13%)
Vomiting	4 (2%)	4 (1%)	2 (1%)	6 (2%)	10 (4%)

* Includes dobutamine, milrinone, nitroglycerin, placebo, dopamine, nitroprusside, or amrinone.

Adverse events that are not listed in the above table that occurred in at least 1% of patients who received any of the above Natrecor doses included: Tachycardia, atrial fibrillation, AV node conduction abnormalities, catheter pain, fever, injection site reaction, confusion, paresthesia, somnolence, tremor, increased cough, hemoptysis, apnea, increased creatinine, sweating, pruritus, rash, leg cramps, amblyopia, anemia. All reported events (at least 1%) are included except those already listed, those too general to be informative, and those not reasonably associated with the use of the drug because they were associated with the condition being treated or are very common in the treated population.

In placebo and active-controlled clinical trials, Natrecor has not been associated with an increase in atrial or ventricular tachyarrhythmias. In placebo-controlled trials, the incidence of VT in both Natrecor and placebo patients was 2%. In the PRECEDENT (Prospective Randomized Evaluation of Cardiac Ectopy with Dobutamine or Natrecor Therapy) trial, the effects of Natrecor (n = 163) and dobutamine (n = 83) on the provocation or aggravation of existing ventricular arrhythmias in patients with decompensated CHF was compared using Holter monitoring. Treatment with Natrecor (0.015 and 0.03 mcg/kg/min without an initial bolus) for 24 hours did not aggravate pre-existing VT or the frequency of premature ventricular beats, compared to a baseline 24-hour Holter tape.

Clinical Laboratory

In the PRECEDENT trial, the incidence of elevations in serum creatinine to > 0.5 mg/dL above baseline through day 14 was higher in the Natrecor 0.015-mcg/kg/min group (17%) and the Natrecor 0.03-mcg/kg/min group (19%) than with standard therapy (11%). In the VMAC trial, through day 30, the incidence of elevations in creatinine to > 0.5 mg/dL above baseline was 28% and 21% in the Natrecor (2 mcg/kg bolus followed by 0.010 mcg/kg/min) and nitroglycerin groups, respectively.

Effect on Mortality

Data from all seven studies in which 30-day data were collected are presented in the chart below. The data depict hazard ratios and confidence intervals of mortality data for randomized and treated patients with Natrecor® relative to active controls through day 30 for each of the 7 individual studies (Studies 311, 325, 326, 329 [PRECEDENT], 339 [VMAC], 341 [PROACTION], and 348 [FUSION I]).

The figure (on logarithmic scale) also contains a plot for the six studies involving hospitalized or Emergency Department patients combined (n = 1507), and for all 7 studies combined (n = 1717). The percentage is the Kaplan-Meier estimate.

The figure below represents 180-day mortality hazard ratios for randomized and treated patients from all four individual studies where 180-day data were collected, 16 week hazard ratios for Study 348 (180-day data were not collected), and the four studies with 180-day data pooled (n = 1167).

There were few deaths in these studies, so the confidence limits around the hazard ratios for mortality are wide. The studies are also small, so some potentially important baseline imbalances exist among the treatment groups, the effects of which cannot be ascertained.

:No trials specifically examining potential drug interactions with Natrecor were conducted, although many concomitant drugs were used in clinical trials. No drug interactions were detected except for an increase in symptomatic hypotension in patients receiving oral ACE inhibitors (see PRECAUTIONS, Cardiovascular).

The co-administration of Natrecor with IV vasodilators such as nitroglycerin, nitroprusside, milrinone, or IV ACE inhibitors has not been evaluated (these drugs were not co-administered with Natrecor in clinical trials).

Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals have not been performed to evaluate the carcinogenic potential or the effect on fertility of

Natrecor. Natrecor did not increase the frequency of mutations when used in an in vitro bacterial cell assay (Ames test). No other genotoxicity studies were performed.

Pregnancy: Category C: Animal reproductive studies have not been conducted with Natrecor. It is also not known whether Natrecor can cause fetal harm when administered to pregnant women or can affect reproductive capacity. Natrecor should be used during pregnancy only if the potential benefit justifies any possible risk to the fetus.

Nursing Mothers: It is not known whether this drug is excreted in human milk. Therefore, caution should be exercised when Natrecor is administered to a nursing woman.

Pediatric Use: The safety and effectiveness of Natrecor in pediatric patients has not been established.

Geriatric Use: Of the total number of subjects in clinical trials treated with Natrecor (n = 941), 38% were 65 years or older and 16% were 75 years or older. No overall differences in effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. Some older individuals may be more sensitive to the effect of Natrecor than younger individuals.