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Noratak

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Noratak uses


1 INDICATIONS AND USAGE

Noratak® (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 Noratak® reduced pulmonary capillary wedge pressure and improved short term (3 hours) symptoms of dyspnea.

Noratak® is a natriuretic peptide 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 Noratak® reduced pulmonary capillary wedge pressure and improved symptomatic dyspnea when measured at 3 hours of infusion. (1)

2 DOSAGE AND ADMINISTRATION

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

Monitor blood pressure closely during Noratak® administration. (2)

The recommended dose of Noratak® is an IV bolus of 2 mcg/kg followed by a continuous infusion of 0.01 mcg/kg/min. Do not initiate Noratak® at a dose that is above the recommended dose. The bolus dose may not be appropriate for those with low SBP <110 mm Hg or those recently treated with afterload reducers such as nitroglycerin. (2.1)

2.1 Recommended Dosage

The recommended dose of Noratak® is an IV bolus of 2 mcg/kg followed by a continuous infusion of 0.01 mcg/kg/min. Do not initiate Noratak® 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 Noratak® is a two step process:

Step 1. Administration of the IV Bolus

After preparation of the infusion bag , withdraw the bolus volume from the Noratak® infusion bag, and administer it over approximately 60 seconds through an IV port in the tubing.

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

Patient Weight (kg) Volume of Bolus (mL=kg/3)
60 20.0
70 23.3
80 26.7
90 30.0
100 33.3
110 36.7

Step 2. Administration of the Continuous Infusion

Immediately following the administration of the bolus, infuse Noratak® at a flow rate of 0.1 mL/kg/hr. This will deliver a Noratak® 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 :

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

Patient Weight (kg) Infusion Flow Rate (mL/hr)
60 6
70 7
80 8
90 9
100 10
110 11

2.2 Dose Adjustments

The dose-limiting side effect of Noratak® is hypotension. If hypotension occurs during the administration of Noratak®, reduce the dose of or discontinue Noratak® and initiate other measures to support blood pressure. When symptomatic hypotension occurs, discontinue Noratak®. Because hypotension caused by Noratak® may be prolonged (up to hours), a period of observation may be necessary before restarting the drug. Noratak® 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 Noratak® more frequently than every 3 hours. Use central hemodynamic monitoring and do not exceed 0.03 mcg/kg/min.

2.3 Preparation and Administration Instructions

The Noratak® 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.

2.4 Chemical/Physical Interactions

Noratak® 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 Noratak® through the same IV catheter. The preservative sodium metabisulfite is incompatible with Noratak®. Do not administer injectable drugs that contain sodium metabisulfite in the same infusion line as Noratak®. Flush the catheter between administration of Noratak® and incompatible drugs.

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

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3 DOSAGE FORMS AND STRENGTHS

Noratak® (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.

Single-use vial: 1.5 mg vial (3)

4 CONTRAINDICATIONS

Noratak® is contraindicated in patients with:

5 WARNINGS AND PRECAUTIONS

5.1 Hypotension

Noratak® may cause hypotension. In the ASCEND-HF trial, the incidence of symptomatic hypotension was 7.1% in Noratak®-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 Noratak® 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 Noratak® (4%) and IV nitroglycerin (5%). When hypotension occurred, however, the duration of symptomatic hypotension was longer with Noratak® (mean duration was 2.2 hours) than with nitroglycerin (mean duration was 0.7 hours).

Administer Noratak® only in settings where blood pressure can be monitored closely and hypotension aggressively treated. Reduce the dose of or discontinue Noratak® in patients who develop hypotension .

Avoid administration of Noratak® in patients suspected of having, or known to have, low cardiac filling pressures.

Noratak® 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 .

5.2 Worsening of Renal Function

Noratak® 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 Noratak® may be associated with azotemia. When Noratak® was initiated at doses higher than 0.01 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 Noratak® have been reported.

These reactions are more likely to occur in individuals with a history of sensitivity to recombinant peptides. Before therapy with Noratak® 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 Noratak® 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.

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6 ADVERSE REACTIONS

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


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 Noratak® cannot be reliably established in individual cases.

Adverse drug reactions that occurred at least ≥2% more frequently on Noratak® than on placebo during the first 24 hours of infusion (excluding the ASCEND-HF study) are shown in Table 3.

System Organ Class

Adverse Reaction

 Noratak® (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 Noratak® 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 Noratak® 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 Noratak® group. At 30 days post enrollment, more subjects in the Noratak® 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 Noratak® 0.015 mcg/kg/min group (17%) and the Noratak® 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 Noratak® (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 Noratak® did not increase mortality in patients with acute decompensated heart failure (ADHF) at Day 30 or Day 180. 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 Noratak® 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 Noratak® at Day 30 (seven studies pooled: HR=0.99; 95% CI: 0.80, 1.22). The percentages are the Kaplan-Meier estimates.

*Studies 704.311, 704.325, 704.326, 704.329, 704.339, 704.341 and ASCEND-HF
Figure 1: 30-Day All-Cause Mortality Hazard Ratios

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 with the addition of the ASCEND-HF data, there is no increased mortality risk for Noratak® at Day 180 (six studies pooled: HR=0.98; 95% CI: 0.88, 1.10).

*Studies 704.325, 704.326, 704.329, 704.339, 704.341 and ASCEND-HF
Figure 2: 180-Day All-Cause Mortality Hazard Ratios
Figure 1 Figure 2

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Noratak®. 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.

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7 DRUG INTERACTIONS

No trials specifically examining potential drug interactions with Noratak® 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 Noratak® with nitroprusside, milrinone, or IV ACE inhibitors has not been evaluated.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

It is not known whether Noratak® 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 × human exposure at the recommended dose) no adverse effects on live births or fetal development were observed. Noratak® should be used during pregnancy only if the potential benefit justifies any possible risk to the fetus.

8.3 Nursing Mothers

It is not known whether this drug is excreted in human milk.

8.4 Pediatric Use

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

8.5 Geriatric Use

Of the total number of patients in clinical trials treated with Noratak® (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 Noratak® than younger individuals.

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10 OVERDOSAGE

Overdose with Noratak® therapy has been reported and is primarily the result of either a miscalculated Noratak® 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 Noratak® 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 Noratak® and support blood pressure .

11 DESCRIPTION

Noratak® (nesiritide) is a sterile, purified preparation of human B-type natriuretic peptide (hBNP), and is manufactured from E. coli using recombinant DNA technology. Noratak has a molecular weight of 3464 g/mol and an empirical formula of C143H244N50O42S4. Noratak has the same 32 amino acid sequence as the endogenous peptide, which is produced by the ventricular myocardium.

Noratak® is formulated as the citrate salt of rhBNP, and 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. The quantitative composition of the lyophilized drug per vial is: Noratak 1.58 mg, citric acid monohydrate 2.1 mg, mannitol 20.0 mg, and sodium citrate dihydrate 2.94 mg.

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Human BNP is secreted by the ventricular myocardium in response to stretch and exists in several isoforms in the human body. Elevated levels of BNP have been associated with advanced heart failure and are considered to be a compensatory mechanism in this disease. Human BNP binds to the particulate guanylate cyclase receptor of vascular smooth muscle and endothelial cells, leading to increased intracellular concentrations of guanosine 3'5'-cyclic monophosphate (cGMP) and smooth muscle cell relaxation. Cyclic GMP serves as a second messenger to dilate veins and arteries. Noratak has been shown to relax isolated human arterial and venous tissue preparations that were precontracted with either endothelin-1 or the alpha-adrenergic agonist, phenylephrine.

In animals, Noratak had no effects on cardiac contractility or on measures of cardiac electrophysiology such as atrial and ventricular effective refractory times or atrioventricular node conduction.

12.2 Pharmacodynamics

With a dosing regimen of Noratak® 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.

Effects at 3 Hours Placebo

(n=62)

 Nitroglycerin

(n=60)

 Noratak®

(n=124)
Pulmonary capillary wedge pressure (mm Hg) -2.0 -3.8 -5.8
Right atrial pressure (mm Hg) 0.0 -2.6 -3.1
Cardiac index (L/min/M2) 0.0 0.2 0.1
Mean pulmonary artery pressure (mm Hg) -1.1 -2.5 -5.4
Systemic vascular resistance (dynes∙sec∙cm-5) -44 -105 -144
Systolic blood pressureBased on all treated patients: placebo n=142, nitroglycerin n=143, Noratak® n=204 (mm Hg) -2.5 -5.7 -5.6p <0.05 compared to placebo

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 Noratak® 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 Noratak® was observed in about 60 minutes. When higher doses of Noratak® 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 Noratak® 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 Noratak® groups was similar: 1279 ± 1455 mL and 1257 ± 1657 mL, respectively.

Figure 3

12.3 Pharmacokinetics

Distribution

In patients with heart failure (HF), Noratak® administered intravenously by infusion or bolus exhibits biphasic disposition from the plasma. The mean terminal elimination half-life (t1/2) of Noratak 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 Noratak 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 Noratak® infusion doses ranging from 0.01 to 0.03 mcg/kg/min.

Metabolism and Excretion

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

Special Populations

Renal Impairment

Clinical data suggest that dose adjustment is not required in patients with renal impairment. The effects of Noratak on PCWP, cardiac index (CI), and systolic blood pressure (SBP) were not significantly different in patients with chronic renal impairment (baseline serum creatinine ranging from 2 mg/dL to 4.3 mg/dL), and patients with normal renal function.

Body Weight

The population pharmacokinetic (PK) analyses carried out to determine the effects of demographics and clinical variables on PK parameters showed that clearance of Noratak is proportional to body weight, supporting the administration of weight-adjusted dosing of Noratak (i.e., administration on a mcg/kg/min basis).

Age, Gender, Race/Ethnicity

Noratak clearance was not influenced significantly by age, gender, or race/ethnicity.

Severity of HF

Noratak clearance was not influenced significantly by baseline endogenous hBNP concentration, severity of HF (as indicated by baseline PCWP, baseline CI, or New York Heart Association [NYHA] classification).

Effects of Concomitant Medications

The co-administration of Noratak® with enalapril did not have significant effects on the PK of Noratak®. The PK effect of co-administration of Noratak® with other IV vasodilators such as nitroglycerin, nitroprusside, milrinone, or IV ACE inhibitors has not been evaluated. During clinical studies, Noratak® was administered concomitantly with other medications, including: diuretics, digoxin, oral ACE inhibitors, anticoagulants, oral nitrates, statins, class III antiarrhythmic agents, beta-blockers, dobutamine, calcium channel blockers, angiotensin II receptor antagonists, and dopamine. Although no PK interactions were specifically assessed, there did not appear to be evidence suggesting any clinically significant PK interaction.

13 NON-CLINICAL TOXICOLOGY

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

14 CLINICAL STUDIES

Noratak® has been studied in 11 clinical trials including 4505 patients with HF (NYHA class II–III 56%, NYHA class IV 27%; mean age 64 years, women 32%). There were six randomized, multi-center, placebo- or active-controlled studies (comparative agents included nitroglycerin, dobutamine, milrinone, nitroprusside, or dopamine) in which 4269 patients with decompensated HF received continuous infusions of Noratak® at doses ranging from 0.01 to 0.03 mcg/kg/min. Of these patients, the majority (n=3358, 79%) received the Noratak® infusion for at least 24 hours; 2182 (51%) received Noratak® for 24 to 48 hours, and 1176 (28%) received Noratak® for greater than 48 hours.

In the initial five of these six controlled trials, Noratak® was used alone or in conjunction with other standard therapies, including diuretics (79%), digoxin (62%), oral ACE inhibitors (55%), anticoagulants (38%), oral nitrates (32%), statins (18%), class III antiarrhythmic agents (16%), beta-blockers (15%), dobutamine (15%), calcium channel blockers (11%), angiotensin II receptor antagonists (6%), and dopamine (4%).

In the ASCEND-HF trial (Acute Study of Clinical Effectiveness of Nesiritide in patients with Decompensated Heart Failure), Noratak® was used alone or in conjunction with other standard therapies. Most patients (99.4%) received diuretic medications in conjunction with Noratak®, with the most commonly used diuretic being furosemide (55%). The following standard therapies were used in ≥2% of patients: beta-blockers (72%), aspirin (64%); oral ACE inhibitors (60%), statins (50%), aldosterone antagonists (48%), digoxin/digitalis glycoside (39%), oral or topical nitrates (30%), oral anticoagulants (29%), clopidogrel/thienopyridine (21%), angiotensin receptor antagonists (19%), antiarrhythmic agents (16%), IV nitroglycerin (16%); calcium channel blockers (13%), hydralazine (11%), dobutamine (8%), dopamine (5%), alpha blockers (4%), IV opiates (5%), and NSAIDs (4%). The following standard therapies were used in <2% of patients: COX2 inhibitors, milrinone, epinephrine, levosimendan, nitroprusside, norepinephrine, phenylephrine, and vasopressin.

Noratak® has been studied in a broad range of patients, including the elderly (53% >65 years of age), women (33%), minorities (17% black), and patients with a history of significant morbidities such as hypertension (71%), previous myocardial infarction (38%), diabetes (43%), atrial fibrillation/flutter (37%), ventricular tachycardia/fibrillation (10%), and preserved systolic function (20%). In trials other than the ASCEND-HF trial, Noratak® was also studied in patients with nonsustained ventricular tachycardia (25%) and patients with acute coronary syndromes less than 7 days before the start of Noratak® (4%).

The VMAC (Vasodilation in the Management of Acute Congestive Heart Failure) trial was a randomized, double-blind study of 489 patients (246 patients requiring a right heart catheter, 243 patients without a right heart catheter) who required hospitalization for management of shortness of breath at rest due to acutely decompensated HF. The study compared the effects of Noratak®, placebo, and IV nitroglycerin when added to background therapy (IV and oral diuretics, non-IV cardiac medications, dobutamine, and dopamine). Patients with acute coronary syndrome, preserved systolic function, arrhythmia, and renal impairment were not excluded. The primary endpoints of the study were the change from baseline in PCWP and the change from baseline in patients' dyspnea, evaluated after three hours. Close attention was also paid to the occurrence and persistence of hypotension, given nesiritide's relatively long (compared to nitroglycerin) PK and PD half-life.

Noratak® was administered as a 2 mcg/kg bolus over approximately 60 seconds, followed by a continuous fixed dose infusion of 0.01 mcg/kg/min. After the 3-hour placebo-controlled period, patients receiving placebo crossed over to double-blinded active therapy with either Noratak® or nitroglycerin. The nitroglycerin dose was titrated at the physician's discretion. A subset of patients in the VMAC trial with central hemodynamic monitoring who were treated with Noratak® (62 of 124 patients) were allowed dose increases of Noratak® after the first 3 hours of treatment if the PCWP was ≥20 mm Hg and the SBP was ≥100 mm Hg. Dose increases of a 1 mcg/kg bolus followed by an increase of the infusion dose by 0.005 mcg/kg/min were allowed every 3 hours, up to a maximum dose of 0.03 mcg/kg/min. Overall, 23 patients in this subset had the dose of Noratak® increased in the VMAC trial.

In the VMAC study, patients receiving Noratak® reported greater improvement in their dyspnea at 3 hours than patients receiving placebo (p=0.034).

In the dose-response study, patients receiving both doses of Noratak® reported greater improvement in dyspnea at 6 hours than patients receiving placebo.

Noratak® was also studied in a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial evaluating the efficacy and safety of Noratak® compared with placebo the ASCEND-HF Study, which was a trial where both arms were administered in addition to standard care, in patients with ADHF. The study was divided into a screening phase, a double-blind treatment phase, and a follow-up phase, including a Day 30 visit and a telephone contact at Day 180. Patients who qualified for the study were ≥18 years of age, hospitalized for the management of ADHF or diagnosed with ADHF within 48 hours after being hospitalized for another reason. They were randomized to receive either Noratak® as a continuous IV infusion at 0.010 mcg/kg/min with or without an initial 2 mcg/kg bolus (at the discretion of the physician) or a matching placebo bolus and infusion.

The primary objective of ASCEND-HF was to evaluate whether treatment with Noratak® compared to placebo improved patient outcomes (as measured by a reduction in the composite of HF rehospitalization and all-cause mortality from randomization through Day 30) or HF symptoms (as measured by patient self-assessed Likert dyspnea scale which included Markedly Better, Moderately Better, Minimally Better, No Change, Minimally Worse, Moderately Worse and Markedly Worse at 6 hours and 24 hours after Noratak® initiation).

A total of 7141 patients were randomized of which 7007 patients took at least one dose of study medication (modified intent-to-treat population) and received treatment for 24 to 168 hours (7 days), if the patient's clinical condition warranted continued treatment for dyspnea or pulmonary congestion, at the physician's discretion. The median treatment duration was 42.9 hours for the placebo group and 40.8 hours for the Noratak® group. The patients' mean age was 65.5 years. The patient population was 65.8% male, 55.9% Caucasian, 24.7% Asian and 15.1% Black or African American.

The incidence rate for the composite of HF rehospitalization and all-cause mortality from randomization through Day 30 was 9.4% in the Noratak® group compared with 10.1% in the placebo group. The difference was not statistically significant (p=0.313). The self-assessed dyspnea results did not meet the pre-specified criteria for statistical significance (p ≤0.005 for both or p ≤0.0025 for either) at either time point.

A total of 273 deaths were reported during the first 30 days after therapy and 876 (12.5%) deaths were reported from randomization through Day 180, 429 (12.3%) patients in the Noratak® group and 447 (12.7%) patients in the placebo group. Approximately 65% of the deaths at 180 days were cardiovascular (mostly worsening heart failure). There was no statistically significant difference between treatment groups (p=0.5).

16 HOW SUPPLIED/STORAGE AND HANDLING

Noratak® (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.

17 PATIENT COUNSELING INFORMATION

Advise patients of the potential benefits and risks of Noratak®. Advise patients to notify their physician or healthcare professional if they have symptoms of hypotension .

Product of Austria

Manufactured for:

Scios LLC

Titusville, NJ 08560

Copyright 2007 Scios LLC

PRINCIPAL DISPLAY PANEL - 1.5 mg Vial Carton

Scios LLC

NDC 65847-205-25

Noratak ®

(nesiritide)

for Injection

1.5 mg

Single-use vial

For IV Infusion Only

Store below 25°C. Do not freeze. Keep the vial

in the outer carton in order to protect from light.

Rx only

PRINCIPAL DISPLAY PANEL - 1.5 mg Vial Carton

Noratak pharmaceutical active ingredients containing related brand and generic drugs:


Noratak available forms, composition, doses:


Noratak destination | category:


Noratak Anatomical Therapeutic Chemical codes:


Noratak pharmaceutical companies:


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References

  1. "Nesiritide". https://pubchem.ncbi.nlm.nih.gov/su... (accessed August 28, 2018).
  2. "Nesiritide - DrugBank". http://www.drugbank.ca/drugs/DB0489... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Noratak?

Depending on the reaction of the Noratak after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Noratak not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Noratak addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Noratak, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Noratak consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

Visitor reports

Visitor reported useful

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