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Natrecor® (nesiritide) is a sterile, purified preparation of a new drug class, human B-type natriuretic peptide (hBNP), and is manufactured from E. coli using recombinant DNA technology. Nesiritide has a molecular weight of 3464 g/mol and an empirical formula of C 143 H 244 N 50 O 42 S 4 . Nesiritide has the same 32 amino acid sequence as the endogenous peptide, which is produced by the ventricular myocardium.
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Natrecor 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: nesiritide 1.58 mg, mannitol 20.0 mg, citric acid monohydrate 2.1 mg, and sodium citrate dihydrate 2.94 mg.
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. Nesiritide 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 human studies, nesiritide produced dose-dependent reductions in pulmonary capillary wedge pressure (PCWP) and systemic arterial pressure in patients with heart failure.
In animals, nesiritide had no effects on cardiac contractility or on measures of cardiac electrophysiology such as atrial and ventricular effective refractory times or atrioventricular node conduction.
Naturally occurring atrial natriuretic peptide (ANP), a related peptide, increases vascular permeability in animals and humans and may reduce intravascular volume. The effect of nesiritide on vascular permeability has not been studied.
In patients with congestive heart failure (CHF), Natrecor administered intravenously by infusion or bolus exhibits biphasic disposition from the plasma. The mean terminal elimination half-life (t 1/2 ) of Natrecor 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 Natrecor® (nesiritide) for Injection 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 µg/kg/min.
Human BNP is cleared from the circulation via the following three independent mechanisms, in order of decreasing importance: 1) binding to cell surface clearance receptors with subsequent cellular internalization and lysosomal proteolysis; 2) proteolytic cleavage of the peptide by endopeptidases, such as neutral endopeptidase, which are present on the vascular lumenal surface; and 3) renal filtration.
Although Natrecor is eliminated, in part, through renal clearance, clinical data suggest that dose adjustment is not required in patients with renal insufficiency. The effects of Natrecor on PCWP, cardiac index (CI), and systolic blood pressure (SBP) were not significantly different in patients with chronic renal insufficiency (baseline serum creatinine ranging from 2 mg/dL to 4.3 mg/dL), and patients with normal renal function. The population pharmacokinetic (PK) analyses carried out to determine the effects of demographics and clinical variables on PK parameters showed that clearance of Natrecor is proportional to body weight, supporting the administration of weight-adjusted dosing of Natrecor (i.e., administration on a µg/kg/min basis). Clearance was not influenced significantly by age, gender, race/ethnicity, baseline endogenous hBNP concentration, severity of CHF (as indicated by baseline PCWP, baseline Cl, or New York Heart Association [NYHA] classification), or concomitant administration of an ACE inhibitor
The co-administration of Natrecor with enalapril did not have significant effects on the PK of Natrecor. The PK effect of co-administration of Natrecor with other IV vasodilators such as nitroglycerin, nitroprusside, milrinone, or IV ACE inhibitors has not been evaluated. During clinical studies, Natrecor 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.
The recommended dosing regimen of Natrecor is a 2 µg/kg IV bolus followed by an intravenous infusion dose of 0.01 µg/kg/min. 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 seventy percent 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® (nesiritide) for Injection is longer than what the PK half-life of 18 minutes would predict. 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.
Natrecor has been studied in 10 clinical trials including 941 patients with CHF (NYHA class II-III 61%, NYHA class IV 36%; mean age 60 years, women 28%). There were five randomized, multi-center, placebo- or active-controlled studies (comparative agents included nitroglycerin, dobutamine, milrinone, nitroprusside, or dopamine) in which 772 patients with decompensated CHF received continuous infusions of Natrecor at doses ranging from 0.01 to 0.03 µg/kg/min. (See the ADVERSE REACTION section for relative frequency of adverse events at doses ranging from the recommended dose up to 0.03 µg/kg/min). Of these patients, the majority (n = 541, 70%) received the Natrecor infusion for at least 24 hours; 371 (48%) received Natrecor for 24-48 hours, and 170 (22%) received Natrecor for greater than 48 hours.
In controlled trials, Natrecor has been 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%). Natrecor has been studied in a broad range of patients, including the elderly (42% > 65 years of age), women (30%), minorities (26% black), and patients with a history of significant morbidities such as hypertension (67%), previous myocardial infarction (50%), diabetes (44%), atrial fibrillation/flutter (34%), nonsustained ventricular tachycardia (25%), ventricular tachycardia/fibrillation (12%), preserved systolic function (9%), and acute coronary syndromes less than 7 days before the start of Natrecor (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 CHF. The study compared the effects of Natrecor, 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 insufficiency 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.
Natrecor was administered as a 2-µg/kg bolus over approximately 60 seconds, followed by a continuous fixed dose infusion of 0.01 µg/kg/min. After the 3-hour placebo-controlled period, patients receiving placebo crossed over to double-blinded active therapy with either Natrecor® (nesiritide) for Injection or nitroglycerin. The nitroglycerin dose was titrated at the physician' discretion. A subset of patients in the VMAC trial with central hemodynamic monitoring who were treated with Natrecor (62 of 124 patients) were allowed dose increases of Natrecor 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-µg/kg bolus followed by an increase of the infusion dose by 0.005 µg/kg/min were allowed every 3 hours, up to a maximum dose of 0.03 µg/kg/min. Overall, 23 patients in this subset had the dose of Natrecor increased in the VMAC trial.
In a second double-blind study, 127 patients requiring hospitalization for symptomatic CHF were randomized to placebo or to one of two doses of Natrecor (0.015 µg/kg/min preceded by an IV bolus of 0.3 µg/kg, and 0.03 µg/kg/min preceded by an IV bolus of 0.6 µg/kg). The primary endpoint of the trial was the change in PCWP from baseline to 6 hours, but the effect on symptoms also was examined.
In the VMAC study, patients receiving Natrecor 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 Natrecor reported greater improvement in dyspnea at 6 hours than patients receiving placebo.
The PCWP, right atrial pressure (RAP), CI, and other hemodynamic variables were monitored in 246 of the patients in the VMAC trial. There was a reduction in mean PCWP within 15 minutes of starting the Natrecor infusion, with most of the effect seen at 3 hours being achieved within the first 60 minutes of the infusion (see Pharmacodynamics ).
In several studies, hemodynamic parameters were measured after Natrecor withdrawal. Following discontinuation of Natrecor, PCWP returns to within 10% of baseline within 2 hours, but 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.
The following table and graph summarize the changes in the VMAC trial in PCWP and other measures during the first 3 hours.
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The VMAC study does not constitute an adequate effectiveness comparison with nitroglycerin. In this trial, the nitroglycerin group provides a rough landmark using a familiar therapy and regimen.
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.
Natrecor® (nesiritide) for Injection is indicated for the intravenous treatment of patients with acutely decompensated congestive 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 dyspnea.
Natrecor is contraindicated in patients who are hypersensitive to any of its components. Natrecor should not be used as primary therapy for patients with cardiogenic shock or in patients with a systolic blood pressure < 90 mm Hg.
Administration of Natrecor® (nesiritide) for Injection should be avoided in patients suspected of having, or known to have, low cardiac filling pressures.
General: Parenteral administration of protein pharmaceuticals or E. coli-derived products should be attended by appropriate precautions in case of an allergic or untoward reaction. No serious allergic or anaphylactic reactions have been reported with Natrecor.
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 .)
Renal Natrecor may affect renal function in susceptible individuals. 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 µg/kg/min (0.015 and 0.030 µg/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. In the 30-day follow-up period in the VMAC trial, 5 patients in the nitroglycerin group (2%) and 9 patients in the Natrecor group (3%) required first-time dialysis.
Cardiovascular: Natrecor may cause hypotension. In the VMAC trial, in patients given the recommended dose (2 µg/kg bolus followed by a 0.01 µg/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). In earlier trials, when Natrecor was initiated at doses higher than the 2-µg/kg bolus followed by a 0.01-µg/kg/min infusion (i.e., 0.015 and 0.030 µg/kg/min preceded by a small bolus), there were more hypotensive episodes and these episodes were of greater intensity and duration. They were also more often symptomatic and/or more likely to require medical intervention (see ADVERSE REACTIONS ). Natrecor should be administered only in settings where blood pressure can be monitored closely, and the dose of Natrecor should be reduced or the drug discontinued in patients who develop hypotension (see Dosing Instructions ). The rate of symptomatic hypotension may be increased in patients with a blood pressure < 100 mm Hg at baseline, and Natrecor should be used cautiously in these patients. The potential for hypotension may be increased by combining Natrecor with other drugs that may cause hypotension. For example, in the VMAC trial in patients treated with either Natrecor or nitroglycerin therapy, the frequency of symptomatic hypotension in patients who received an oral ACE inhibitor was 6%, compared to a frequency of symptomatic hypotension of 1% in patients who did not receive an oral ACE inhibitor.
Drug Interactions: No trials specifically examining potential drug interactions with Natrecor® (nesiritide) for Injection 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.
Adverse events that occurred with at least a 3% frequency during the first 24 hours of Natrecor infusion are shown in the following table.
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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 µg/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.
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-µg/kg/min group (17%) and the Natrecor 0.03-µg/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 µg/kg bolus followed by 0.010 µg/kg/min) and nitroglycerin groups, respectively.
In the VMAC trial, the mortality rates at six months in the patients receiving Natrecor® (nesiritide) for Injection and nitroglycerin were 25.1% (95% confidence interval, 20.0% to 30.5%) and 20.8% (95% confidence interval, 15.5% to 26.5%), respectively. In all controlled trials combined, the mortality rates for Natrecor and active control (including nitroglycerin, dobutamine, nitroprusside, milrinone, amrinone, and dopamine) patients were 21.5% and 21.7%, respectively.
No data are available with respect to overdosage in humans. The expected reaction would be excessive hypotension, which should be treated with drug discontinuation or reduction (see PRECAUTIONS ) and appropriate measures.
Natrecor is for intravenous use only. There is limited experience with administering Natrecor for longer than 48 hours. Blood pressure should be monitored closely during Natrecor administration.
If hypotension occurs during the administration of Natrecor, the dose should be reduced or discontinued and other measures to support blood pressure should be started (IV fluids, changes in body position). In the VMAC trial, when symptomatic hypotension occurred, Natrecor was discontinued and subsequently could be restarted at a dose that was reduced by 30% (with no bolus administration) once the patient was stabilized. Because hypotension caused by Natrecor may be prolonged (up to hours), a period of observation may be necessary before restarting the drug.
The recommended dose of Natrecor is an IV bolus of 2 µg/kg followed by a continuous infusion at a dose of 0.01 µg/kg/min. Natrecor should not be initiated at a dose that is above the recommended dose.
Prime the IV tubing with an infusion of 25 mL prior to connecting to the patient' vascular access port and prior to administering the bolus or starting the infusion.
Bolus followed by infusion: After preparation of the infusion bag, as described previously, withdraw the bolus volume (see table below) from the Natrecor infusion bag, and administer it over approximately 60 seconds through an IV port in the tubing. 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 µg/kg/min.
To calculate the appropriate bolus volume and infusion flow rate to deliver a 0.01-µg/kg/min dose, use the following formulas (or refer to the following dosing table):
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Dose Adjustments: The dose-limiting side effect of Natrecor is hypotension. Do not initiate Natrecor at a dose that is higher than the recommended dose of a 2 µg/kg bolus followed by an infusion of 0.01 µg/kg/min. In the VMAC trial there was limited experience with increasing the dose of Natrecor above the recommended dose (23 patients, all of whom had central hemodynamic monitoring). In those patients, the infusion dose of Natrecor was increased by 0.005 µg/kg/min (preceded by a bolus of 1 µg/kg), no more frequently than every 3 hours up to a maximum dose of 0.03 µg/kg/min. Natrecor should not be titrated at frequent intervals as is done with other IV agents that have a shorter half-life (see Clinical Trials ).
Natrecor® (nesiritide) for Injection is physically and/or chemically incompatible with injectable formulations of heparin, insulin, ethacrynate sodium, bumetamide, enalaprilat, hydralazine, and furosemide. These drugs should not be co-administered as infusions with Natrecor through the same IV catheter. The preservative sodium metabisulfite is incompatible with Natrecor. Injectable drugs that contain sodium metabisulfite should not be administered in the same infusion line as Natrecor. The catheter must be flushed 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, Natrecor must not be administered through a central heparin-coated catheter. Concomitant administration of a heparin infusion through a separate catheter is acceptable.
Store Natrecor at controlled room temperature (20-25°C; 68-77°F); excursions permitted to 15-30°C (59-86°F; see USP Controlled Room Temperature), or refrigerated (2-8°C; 36-46°F). Keep in carton until time of use.
Natrecor 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)
US patent No. 5,114,923 and 5,674,710.
Distributed by Scios Inc.
820 West Maude Ave
Sunnyvale, CA 94085
Copyright. 2001 Scios Inc.
NA1030
August 2001
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