FDA label a0826ef2-638b-11ea-9966-442ffc2ca371

5 WARNINGS AND PRECAUTIONS Hypotension: Not recommended for patients for whom vasodilating agents are not appropriate, or other conditions in which cardiac output is dependent upon venous return, or for patients suspected to have low cardiac filling pressures. ( 5.1 ) Worsening renal impairment. Monitor serum creatinine both during and after NATRECOR administration. ( 5.2 ) Hypersensitivity: Serious hypersensitivity/allergic reactions have been reported. ( 5.3 ) 5.1 Hypotension NATRECOR may cause hypotension. In the ASCEND-HF trial, the incidence of symptomatic hypotension was 7.1% in NATRECOR-treated patients compared to 4.0% in placebo-treated patients on a background of standard care. The risk of hypotension may be increased by the concomitant use of NATRECOR with drugs affecting the renin-angiotensin system (i.e., angiotensin receptor blockers and/or angiotensin-converting enzyme inhibitors) or other afterload reducers. In the VMAC trial, in patients given the recommended dose (2 mcg/kg bolus followed by a 0.01 mcg/kg/min infusion) or the adjustable dose, the incidence of symptomatic hypotension in the first 24 hours was similar for NATRECOR (4%) and IV nitroglycerin (5%). When hypotension occurred, however, the duration of symptomatic hypotension was longer with NATRECOR ® (mean duration was 2.2 hours) than with nitroglycerin (mean duration was 0.7 hours). Administer NATRECOR only in settings where blood pressure can be monitored closely and hypotension aggressively treated. Reduce the dose of or discontinue NATRECOR in patients who develop hypotension [see Dosage and Administration (2.2) ] . Avoid administration of NATRECOR in patients suspected of having, or known to have, low cardiac filling pressures. NATRECOR is not recommended for patients for whom vasodilating agents are not appropriate, such as patients with significant valvular stenosis, restrictive or obstructive cardiomyopathy, constrictive pericarditis, pericardial tamponade, or other conditions in which cardiac output is dependent upon venous return, or for patients suspected to have low cardiac filling pressures [see Contraindications (4) ] . 5.2 Worsening of Renal Function NATRECOR may decrease renal function as judged by increases in serum creatinine. Monitor serum creatinine both during and after therapy has been completed. Monitor serum creatinine until values have stabilized. 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. When NATRECOR was initiated at doses higher than 0.01 mcg/kg/min (0.015 and 0.03 mcg/kg/min), there was an increased rate of elevated serum creatinine over baseline compared with standard therapies, although the rate of acute renal failure and need for dialysis was not increased. 5.3 Hypersensitivity Serious hypersensitivity/allergic reactions following administration of NATRECOR have been reported. These reactions are more likely to occur in individuals with a history of sensitivity to recombinant peptides. Before therapy with NATRECOR is instituted, careful inquiry should be made to determine whether the patient has had a previous hypersensitivity reaction to other recombinant peptides. If an allergic reaction to NATRECOR occurs, discontinue the drug. Some serious hypersensitivity/allergic reactions may require treatment with epinephrine, oxygen, IV fluids, antihistamines, corticosteroids, pressor amines and airway management, as clinically indicated.

6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Hypotension [see Warnings and Precautions (5.1) ] The most common adverse reactions (≥3%) are hypotension, headache, nausea, and back pain. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Scios LLC at 1-877-462-8732 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 3. Table 3: Adverse Drug Reactions Adverse drug reaction is defined as an adverse event with a frequency in the NATRECOR group ≥2% and occurred at a higher frequency than in the placebo group. Reported at ≥2% Frequency During the First 24 Hours After the Start of Infusion in Long Infusion Trials Trials in which NATRECOR was administered as a continuous infusion for ≥12 hours. of NATRECOR at the Recommended Dose excluding ASCEND-HF Results System Organ Class Adverse Reaction NATRECOR (N=331) 0.01 mcg/kg/min % (n) 704.339 [VMAC] and 704.341 [PROACTION]. Placebo (N=188) % (n) 704.311, 704.325 and 704.341 [PROACTION]. Vascular Disorders Hypotension 12 (41) 4 (7) GI Disorders Nausea 3 (11) 1 (2) Musculoskeletal Disorders Back pain 3 (11) 1 (2) Nervous System Disorders Headache 7 (24) 6 (11) Dizziness 2 (8) 2 (3) 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 Figure 1 Figure 2 6.2 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

<table width="75%"> <caption>Table 3: Adverse Drug Reactions<footnote>Adverse drug reaction is defined as an adverse event with a frequency in the NATRECOR group &#x2265;2% and occurred at a higher frequency than in the placebo group.</footnote> Reported at &#x2265;2% Frequency During the First 24 Hours After the Start of Infusion in Long Infusion Trials<footnote>Trials in which NATRECOR was administered as a continuous infusion for &#x2265;12 hours.</footnote> of NATRECOR at the Recommended Dose excluding ASCEND-HF Results</caption> <col width="34%" align="left" valign="top"/> <col width="33%" align="center" valign="top"/> <col width="33%" align="center" valign="top"/> <thead> <tr> <th>System Organ Class Adverse Reaction</th> <th>NATRECOR (N=331) 0.01 mcg/kg/min % (n)<footnote>704.339 [VMAC] and 704.341 [PROACTION].</footnote> </th> <th>Placebo (N=188) % (n)<footnote>704.311, 704.325 and 704.341 [PROACTION].</footnote> </th> </tr> </thead> <tbody> <tr> <td> <content styleCode="bold">Vascular Disorders</content> </td> <td/> <td/> </tr> <tr> <td>Hypotension</td> <td>12 (41)</td> <td>4 (7)</td> </tr> <tr> <td> <content styleCode="bold">GI Disorders</content> </td> <td/> <td/> </tr> <tr> <td>Nausea</td> <td>3 (11)</td> <td>1 (2)</td> </tr> <tr> <td> <content styleCode="bold">Musculoskeletal Disorders</content> </td> <td/> <td/> </tr> <tr> <td>Back pain</td> <td>3 (11)</td> <td>1 (2)</td> </tr> <tr> <td> <content styleCode="bold">Nervous System Disorders</content> </td> <td/> <td/> </tr> <tr> <td>Headache</td> <td>7 (24)</td> <td>6 (11)</td> </tr> <tr> <td>Dizziness</td> <td>2 (8)</td> <td>2 (3)</td> </tr> </tbody> </table>