NATRECOR SIDE EFFECTS

SIDE EFFECTS

The following are discussed in more detail in other sections of the labeling:

• Hypotension

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. A causal relationship for NATRECOR cannot be reliably established in individual cases. Adverse drug reactions that occurred at least ≥2% more frequently on NATRECOR® than on placebo during the first 24 hours of infusion (excluding the ASCEND-HF study) are shown in Table 1.

Table 1: Adverse Drug Reactions* Reported at ≥2% Frequency During the First 24 Hours After the Start of Infusion in Long Infusion Trials† of NATRECOR at the Recommended Dose excluding ASCEND-HF Results

Laboratory adverse drug reactions that occurred in ≥2% of patients and collected during the first 14 days after the start of NATRECOR infusion included: hypoglycemia.

Worsening Renal Function

In the ASCEND-HF trial, through Day 30, the incidence of renal impairment as measured by a >25% decrease in glomerular filtration rate (calculated based on serum creatinine) was observed in 31.4% and 29.5% in the NATRECOR and placebo groups, respectively. Other metrics of decompensated renal function such as an increase in creatinine of > 0.5 mg/dl, a 50% increase in creatinine or a value of ≥ 2 or 100% increase in creatinine were more frequent in the NATRECOR group. At 30 days post enrollment, more subjects in the NATRECOR group had elevated levels of creatinine of 50% greater than baseline compared to placebo 4.6% versus 3.3%. In the ASCEND-HF study there were relatively few subjects requiring either hemofiltration or dialysis.

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 0.01 mcg/kg/min) and nitroglycerin groups, respectively.

Neutral Effect on Mortality

A meta-analysis performed of seven clinical trials demonstrated NATRECOR did not increase mortality in patients with acute decompensated heart failure (ADHF) at Day 30 or Day 180 (see Figures 1 and 2). Data from seven studies in which 30-day data were collected are presented in Figure 1. The data depict hazard ratios (HR) and confidence intervals (CI) of mortality data for randomized and treated patients with NATRECOR relative to active or placebo controls through Day 30 for each of the seven individual studies along with the overall combined estimate (Studies 311, 325, 326, 329 [PRECEDENT], 339 [VMAC], 341 [PROACTION], and A093 [ASCEND-HF]).

Figure 1 (on logarithmic scale) also contains an estimate for the seven studies combined (n=8514). The results indicate that there is no increased mortality risk for NATRECOR at Day 30 (seven studies pooled: HR=0.99; 95% CI: 0.80, 1.22). The percentages are the Kaplan-Meier estimates.

Figure 1: 30-Day All-Cause Mortality Hazard Ratios

*Studies 704.311, 704.325, 704.326, 704.329, 704.339, 704.341 and ASCEND-HF

Figure 2 presents 180-day mortality hazard ratios from all six individual studies where 180-day data were collected (Studies 325, 326, 329, 339, 341 and A093 [ASCEND-HF]). The results indicate that, there is no increased mortality risk for NATRECOR at Day 180 (six studies pooled: HR=0.98; 95% CI: 0.88, 1.10).

Figure 2: 180-Day All-Cause Mortality Hazard Ratios

*Studies 704.325, 704.326, 704.329, 704.339, 704.341 and ASCEND-HF

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of NATRECOR. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to estimate their frequency reliably or to establish a causal relationship to drug exposure.

• Hypersensitivity reactions
• Infusion site extravasation
• Pruritus
• Rash