Natrecor

Dosage Forms And Strengths

NATRECOR® (nesiritide) is provided in a sterile, single-use vial. Each 1.5 mg vial contains a white- to off-white lyophilized powder for intravenous (IV) administration after reconstitution.

Storage And Handling

NATRECOR® (nesiritide) is provided as a sterile lyophilized powder in 1.5 mg, single-use vials. Each carton contains one vial and is available in the following package:

1 vial/carton (NDC 65847-205-25)

Store below 25°C. Do not freeze. Keep the vial in the outer carton in order to protect from light.

Manufactured for Scios Inc. Titusville, NJ 08560. Revised: 07/2012

NATRECOR® (nesiritide) is indicated for the treatment of patients with acutely decompensated 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 short term (3 hours) symptoms of dyspnea.

NATRECOR® (nesiritide) is for intravenous (IV) use only. There is limited experience with administering NATRECOR® for longer than 96 hours. Monitor blood pressure closely during NATRECOR® administration.

Recommended Dosage

The recommended dose of NATRECOR® is an IV bolus of 2 mcg/kg followed by a continuous infusion of 0.01 mcg/kg/min. Do not initiate NATRECOR® at a dose that is above the recommended dose.

The loading dose may not be appropriate for those with low systolic blood pressure (SBP) < 110 mm Hg or for patients recently treated with afterload reducers.

The administration of the recommended dose of NATRECOR® is a two step process:

Step 1. Administration of the IV Bolus

After preparation of the infusion bag, withdraw the bolus volume (see Table 1) from the NATRECOR® infusion bag, and administer it over approximately 60 seconds through an IV port in the tubing.

Bolus Volume (mL) = Patient Weight (kg) / 3

Table 1: NATRECOR® Weight-Adjusted Bolus Volume Administered Over 60 Seconds (Final Concentration = 6 mcg/mL)

Step 2. Administration of the Continuous Infusion

Immediately following the administration of the bolus, infuse NATRECOR® at a flow rate of 0.1 mL/kg/hr. This will deliver a NATRECOR® infusion dose of 0.01 mcg/kg/min.

To calculate the infusion flow rate to deliver a 0.01 mcg/kg/min dose, use the following formula (see Table 2):

Infusion Flow Rate (mL/hr) = Patient Weight (kg) x 0.1

Table 2: NATRECOR® Weight-Adjusted Infusion Flow Rate for a 0.01 mcg/kg/min Dose Following Bolus (Final Concentration = 6 mcg/mL)

Dose Adjustments

The dose-limiting side effect of NATRECOR® is hypotension. If hypotension occurs during the administration of NATRECOR®, reduce the dose of or discontinue NATRECOR® and initiate other measures to support blood pressure (IV fluids, changes in body position). When symptomatic hypotension occurs, discontinue NATRECOR®. Because hypotension caused by NATRECOR® may be prolonged (up to hours), a period of observation may be necessary before restarting the drug. NATRECOR® may be subsequently restarted at a dose that is reduced by 30% (with no bolus administration) once the patient has stabilized.

Do not up-titrate NATRECOR® more frequently than every 3 hours. Use central hemodynamic monitoring and do not exceed 0.03 mg/kg/min.

Preparation and Administration Instructions

The NATRECOR® bolus must be drawn from the prepared infusion bag. Prime the IV tubing with 5 mL of the solution for infusion prior to connecting to the patient's vascular access port and prior to administering the bolus or starting the infusion.

1. Reconstitute one 1.5 mg vial of NATRECOR® by adding 5 mL of diluent removed from a pre-filled 250 mL plastic IV bag containing the diluent of choice. After reconstitution of the vial, each mL contains 0.32 mg of nesiritide. The following preservative-free diluents are recommended for reconstitution: 5% Dextrose Injection (D5W), USP; 0.9% Sodium Chloride Injection, USP; 5% Dextrose and 0.45% Sodium Chloride Injection, USP, or 5% Dextrose and 0.2% Sodium Chloride Injection, USP.
2. Do not shake the vial. Rock the vial gently so that all surfaces, including the stopper, are in contact with the diluent to ensure complete reconstitution. Use only a clear, essentially colorless solution.
3. Withdraw the entire contents of the reconstituted NATRECOR® vial and add to the 250 mL plastic IV bag. This will yield a solution with a concentration of NATRECOR® of approximately 6 mcg/mL. Invert the IV bag several times to ensure complete mixing of the solution.
4. Use the reconstituted solution within 24 hours, as NATRECOR® contains no antimicrobial preservative. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Reconstituted vials of NATRECOR® may be stored at 2 to 25°C (36 to 77°F) for up to 24 hours.

Chemical/Physical Interactions

NATRECOR® is physically and/or chemically incompatible with injectable formulations of heparin, insulin, ethacrynate sodium, bumetanide, enalaprilat, hydralazine, and furosemide. Do not co-administer these drugs with NATRECOR® through the same IV catheter. The preservative sodium metabisulfite is incompatible with NATRECOR®. Do not administer injectable drugs that contain sodium metabisulfite in the same infusion line as NATRECOR®. Flush the catheter between administration of NATRECOR® and incompatible drugs.

NATRECOR® binds to heparin and therefore could bind to the heparin lining of a heparin-coated catheter, decreasing the amount of NATRECOR® delivered to the patient for some period of time. Therefore, do not administer NATRECOR® through a central heparin-coated catheter. Concomitant administration of a heparin infusion through a separate catheter is acceptable.

NATRECOR® is contraindicated in patients with:

• Persistent systolic blood pressure < 100 mm Hg prior to therapy because of an increased risk of symptomatic hypotension
• Known hypersensitivity to any of its components
• Cardiogenic shock

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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 reninangiotensin 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.

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.

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.

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.

Non-Clinical Toxicology

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Long-term studies in animals have not been performed to evaluate the carcinogenic potential or the effect on fertility of nesiritide. Nesiritide did not increase the frequency of mutations when used in an in vitro bacterial cell assay (Ames test). No other genotoxicity studies were performed.

Use In Specific Populations

Pregnancy

Pregnancy Category C.

It is not known whether NATRECOR® can cause fetal harm when administered to pregnant women or if it can affect reproductive capacity. A developmental reproductive toxicology study was conducted in pregnant rabbits using doses up to 1440 mcg/kg/day given by constant infusion for 13 days. At this level of exposure (based on AUC, approximately 70 x human exposure at the recommended dose) no adverse effects on live births or fetal development were observed. 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.

Pediatric Use

The safety and effectiveness of NATRECOR® in pediatric patients have not been established.

Geriatric Use

Of the total number of patients in clinical trials treated with NATRECOR® (n=4505), 52% were 65 years or older and 27% were 75 years or older. No overall differences in effectiveness were observed between these patients and younger patients, 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.

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 3.

Table 3: 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 180day data were collected (Studies 325, 326, 329, 339, 341 and A093 [ASCEND-HF]). The results indicate that with the addition of the ASCEND-HF data, 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

DRUG INTERACTIONS

No trials specifically examining potential drug interactions with NATRECOR® were conducted, although many concomitant drugs (including IV nitroglycerin) were used in clinical trials. No drug interactions were detected except for an increase in symptomatic hypotension in patients receiving afterload reducers or affecting the renin-angiotensin system (i.e., ARBs and/or ACE inhibitors).

The co-administration of NATRECOR® with nitroprusside, milrinone, or IV ACE inhibitors has not been evaluated.

Pregnancy Category C.

It is not known whether NATRECOR® can cause fetal harm when administered to pregnant women or if it can affect reproductive capacity. A developmental reproductive toxicology study was conducted in pregnant rabbits using doses up to 1440 mcg/kg/day given by constant infusion for 13 days. At this level of exposure (based on AUC, approximately 70 x human exposure at the recommended dose) no adverse effects on live births or fetal development were observed. NATRECOR® should be used during pregnancy only if the potential benefit justifies any possible risk to the fetus.

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 3.

Table 3: 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 180day data were collected (Studies 325, 326, 329, 339, 341 and A093 [ASCEND-HF]). The results indicate that with the addition of the ASCEND-HF data, 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

Overdose with NATRECOR® therapy has been reported and is primarily the result of either a miscalculated NATRECOR® dose or a mechanical error such as an infusion-pump malfunction or an infusion-pump programming error. The most frequently reported adverse event reported with NATRECOR® overdose is hypotension, which may be symptomatic and may persist for several hours. Asymptomatic hypotensive events may resolve with drug stoppage. In some cases hypotension may persist for several hours beyond discontinuation. In the event of an overdose, discontinue NATRECOR® and support blood pressure.

With a dosing regimen of NATRECOR® of 2 mcg/kg IV bolus followed by an intravenous infusion dose of 0.01 mcg/kg/min, Table 4 and Figure 3 summarize the changes in the VMAC trial in PCWP and other measures during the first 3 hours.

Table 4: Mean Hemodynamic Change from Baseline in the VMAC study

Figure 3: PCWP through 3 Hours in VMAC

With this dosing regimen, 60% of the 3-hour effect on PCWP reduction is achieved within 15 minutes after the bolus, reaching 95% of the 3-hour effect within 1 hour. Approximately 70% of the 3-hour effect on SBP reduction is reached within 15 minutes. The pharmacodynamic (PD) half-life of the onset and offset of the hemodynamic effect of NATRECOR® is longer than what the PK half-life of 18 minutes would predict. Longer infusions may exaggerate the discrepancy from onset and offset effects. For example, in patients who developed symptomatic hypotension in the VMAC (Vasodilation in the Management of Acute Congestive Heart Failure) trial, half of the recovery of SBP toward the baseline value after discontinuation or reduction of the dose of NATRECOR® was observed in about 60 minutes. When higher doses of NATRECOR® were infused, the duration of hypotension was sometimes several hours.

No rebound increase to levels above baseline state was observed. There was also no evidence of tachyphylaxis to the hemodynamic effects of NATRECOR® in the clinical trials.

In the VMAC trial, in which the use of diuretics was not restricted, the mean change in volume status (output minus input) during the first 24 hours in the nitroglycerin and NATRECOR® groups was similar: 1279 ± 1455 mL and 1257 ± 1657 mL, respectively.

Distribution

In patients with heart failure (HF), NATRECOR® administered intravenously by infusion or bolus exhibits biphasic disposition from the plasma. The mean terminal elimination half-life (t1/2) of nesiritide is approximately 18 minutes and was associated with approximately 2/3 of the area-under-the-curve (AUC). The mean initial elimination phase was estimated to be approximately 2 minutes. In these patients, the mean volume of distribution of the central compartment (Vc) of nesiritide was estimated to be 0.073 L/kg, the mean steady-state volume of distribution (Vss) was 0.19 L/kg, and the mean clearance (CL) was approximately 9.2 mL/min/kg. At steady state, plasma BNP levels increase from baseline endogenous levels by approximately 3-fold to 6-fold with NATRECOR® infusion doses ranging from 0.01 to 0.03 mcg/kg/min.

Metabolism and Excretion

The mechanism of elimination of nesiritide has not been studied specifically in humans.