This Product Monograph is the exclusive property of Janssen-Ortho Inc. It may not be copied in whole or in part without the written permission of Janssen-Ortho Inc. Janssen-Ortho Inc. 19 Green Belt Drive Toronto, Ontario M3C 1L9 www.janssen-ortho.com Date of Preparation: November 8, 2007 Date of Revision: May 13, 2008 Submission Control No: 119843-1 All trademark rights used under license (c) 2008 JANSSEN-ORTHO Inc.
This product has been approved under the Notice of Compliance with Conditions (NOC/c) policy for one or all of its indicated uses.
An NOC/c is a form of market approval granted to a product on the basis of promising evidence of clinical effectiveness following review of the submission by Health Canada. Products approved under Health Canada's NOC/c policy are intended for the treatment, prevention or diagnosis of a serious, life-threatening or severely debilitating illness. They have demonstrated promising benefit, are of high quality and possess an acceptable safety profile based on a benefit/risk assessment. In addition, they either respond to a serious unmet medical need in Canada or have demonstrated a significant improvement in the benefit/risk profile over existing therapies. Health Canada has provided access to this product on the condition that sponsors carry out additional clinical trials to verify the anticipated benefit within an agreed upon time frame.
The following Product Monograph will contain boxed text at the beginning of each major section clearly stating the nature of the market authorization. Sections for which NOC/c status holds particular significance will be identified in the left margin by the symbol NOC/c. These sections may include, but are not limited to, the following: Indications and Clinical Use; Actions and Clinical Pharmacology; Warnings and Precautions; Adverse Reactions; Dosage and Administration; and Clinical Trials.
Health care providers are encouraged to report Adverse Drug Reactions associated with normal use of these and all drug products to Health Canada's Health Product Safety Information Division at 1-866-234-2345. The Product Monograph will be re-issued in the event of serious safety concerns previously unidentified or at such time as the sponsor provides the additional data in support of the product's clinical benefit. Once the latter has occurred, and in accordance with the NOC/c policy, the conditions associated with market authorization will be removed.
Table of Contents
PART I: HEALTH PROFESSIONAL INFORMATION 4
SUMMARY PRODUCT INFORMATION 4 DESCRIPTION. 4 INDICATIONS AND CLINICAL USE 5 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5 ADVERSE REACTIONS 7 DRUG INTERACTIONS 11 DOSAGE AND ADMINISTRATION 11 OVERDOSAGE 15 ACTION AND CLINICAL PHARMACOLOGY 15 STORAGE AND STABILITY 17 DOSAGE FORMS, COMPOSITION AND PACKAGING 17
PART II: SCIENTIFIC INFORMATION 18
PHARMACEUTICAL INFORMATION 18 CLINICAL TRIALS 19 DETAILED PHARMACOLOGY 23 TOXICOLOGY 26 REFERENCES 30
PART III: CONSUMER INFORMATION. 31
Pr *
NATRECOR
nesiritide for Injection lyophilized powder for solution 1.5 mg vial recombinant human B-type natriuretic peptide (rhBNP)
PART I: HEALTH PROFESSIONAL INFORMATION
Conditional market authorization has been issued for NATRECOR for the treatment of hospitalized symptomatic Acute Decompensated Heart Failure (ADHF) patients, presenting with moderate to severe dyspnea. These are patients who present with signs and symptoms of persistent heart failure despite 2 hours of treatment with intravenous loop diuretics. This authorization is conditional upon further confirmation of clinical benefit. Patients should be advised of the conditional nature of the authorization.
SUMMARY PRODUCT INFORMATION
| Route of Administration | Dosage Form / Strength | Clinically Relevant Nonmedicinal Ingredients |
| Intravenous infusion only | Lyophilized powder for injection 1.5 mg in a 5 mL vial | None. For a complete listing see DOSAGE FORMS, COMPOSITION AND PACKAGING section. |
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 C143H244N50O42S4. Nesiritide has the same 32 amino acid sequence as the endogenous peptide, which is produced by the ventricular myocardium. NATRECOR is formulated as the citrate salt of recombinant hBNP 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.
NOC/c
NOC/c
NOC/c
NATRECOR is indicated for the treatment of hospitalized symptomatic Acute Decompensated Heart Failure (ADHF) patients, presenting with moderate to severe dyspnea. These are patients who present with signs and symptoms of persistent heart failure despite 2 hours of treatment with intravenous loop diuretics. For clinical data in support of this indication, see Product Monograph Part II: CLINICAL TRIALS section. Additional clinical efficacy parameters are being further assessed in a confirmatory phase III multinational study.
Geriatrics (> 65 years of age):
No dose adjustment is required in the elderly. Evidence from clinical studies suggests that when using NATRECOR in the geriatric population, no overall differences in effectiveness were observed between these subjects and younger subjects (see
).
The safety and effectiveness of NATRECOR in pediatric patients have not been established.
NATRECOR should not be used as primary therapy for patients with cardiogenic shock or in patients with a systolic blood pressure < 90 mm Hg. NATRECOR should not be used in patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING.
Administration of NATRECOR 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 of having low cardiac filling pressures.
Carcinogenesis and Mutagenesis
See Product Monograph Part II: TOXICOLOGY, Carcinogenesis, Mutagenesis, Impairment of Fertility for discussions on animal data.
Cardiovascular
As expected with an agent having potent vasodilator properties, NATRECOR may cause hypotension which is dose-dependent. In the VMAC (Vasodilation in the Management of Acute Congestive Heart Failure) trial, in patients given the recommended dose (2 mg/kg bolus followed by a 0.01 mg/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, 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 recommended 2 mg/kg bolus followed by a 0.01 mg/kg/min infusion (i.e. 0.015 and 0.03 mg/kg/min preceded by a small bolus), there were more hypotensive episodes and these were of greater intensity and duration. They were also more often symptomatic and/or more likely to require medical intervention (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests, and ADVERSE REACTIONS). 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 those patients. The potential for hypotension may be increased by combining NATRECOR with other drugs that cause hypotension (see DRUG INTERACTIONS).
Renal
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 pulmonary capillary wedge pressure (PCWP), cardiac index (CI), and systolic blood pressure (SBP) were not significantly different in patients with chronic renal insufficiency and patients with normal renal function (see
.
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. 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 using the recommended dose (3%) required first-time dialysis. When NATRECOR was initiated at doses higher than the recommended dose of 0.01 mg/kg/min (0.015 and 0.03 mg/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.
Special Populations
Animal developmental and reproductive toxicity studies have not been conducted with nesiritide. It is 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.
It is not known whether NATRECOR is excreted in human milk. Therefore, caution should be exercised when NATRECOR is administered to a nursing woman.
The safety and effectiveness of NATRECOR in pediatric patients have not been established.
NATRECOR has been shown to be well tolerated in patients with a safety profile broadly similar across a wide age range, including those 75 years or older. 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 clinical experience has not identified differences in responses between the elderly and younger patients. Some older individuals may experience a higher frequency of hypotension.
Monitoring and Laboratory Tests
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 DOSAGE AND ADMINISTRATION). Monitoring of renal function is recommended. (See WARNINGS AND PRECAUTIONS, Renal).
NOC/c
Adverse Drug Reaction Overview
The overall safety database consists of 941 HF patients that enrolled in IV bolus, short infusion and long infusion studies. The nature and incidence of adverse events (AEs) that occurred during the NATRECOR clinical trial program have been well characterized and are consistent with the expected AE profile for the acutely decompensated HF population. Patients in these studies had typical comorbidity such as diabetes, hypertension, renal insufficiency, arrhythmia and coronary artery disease. Therefore, NATRECOR has been evaluated in patients who are highly susceptible to adverse events and in whom a high reporting rate would be expected. For the purposes of assessing the safety profile of NATRECOR, data have been reported at 24 hours and 14 days post-initiation of study medication. Data from the first 24-hour period is considered important since this is the period when treatment is aimed at producing rapid improvements in hemodynamic status and symptoms. Also, this is the time during which NATRECOR is actually being infused. Therefore, AEs during this period provide the clearest profile of drug treatment effect.
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. Adverse drug reactions that occurred with at least a 1% frequency during the first 24 hours of NATRECOR infusion are shown in the following table (Table 1.1).
Table 1.1: Adverse drug reactions that occurred with >= 1% frequency during the first 24 hours of NATRECOR infusion
| Undesirable Effect | VMAC Trial | Other Long Infusion Trials * * | |||
| IV Nitroglycerin (n = 216) | NATRECOR Recommended Dose 0.010 : g/kg/min (n = 273) | Control * (n = 256) | NATRECOR : g /kg/min | ||
| 0.015 (n = 253) | 0.03 (n = 246) | ||||
| Cardiovascular | |||||
| Hypotension | 12% | 11% | 8% | 22% | 35% |
| Symptomatic Hypotension | 5% | 4% | 3% | 11% | 17% |
| Asymptomatic Hypotension | 8% | 8% | 5% | 12% | 20% |
| Bradycardia | < 1% | 1% | < 1% | 3% | 5% |
| Body as a Whole | |||||
| Headache | 20% | 8% | 9% | 9% | 7% |
| Nervous | |||||
| Dizziness | 2% | 3% | 3% | 6% | 5% |
| Digestive | |||||
| Nausea | 6% | 4% | 5% | 9% | 13% |
| Vomiting | 2% | 1% | 1% | 2% | 4% |
| Urogenital | |||||
| Creatinine Increased | 0% | 0% | <1% | 2% | 2% |
| Skin and Appendages | |||||
| Sweating | 0% | <1% | <1% | 2% | 3% |
| Pruritus | <1% | 0% | <1% | 2% | 1% |
| Rash | <1% | 1% | 1% | 0% | <1% |
* Includes dobutamine, milrinone, nitroglycerin, placebo, dopamine, nitroprusside, or amrinone.
* * Trials in which NATRECOR was administered as a continuous infusion for >= 24 hours.
In placebo and active-controlled clinical trials, NATRECOR has not been associated with an increase in atrial or ventricular tachyarrhythmias (VT). 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 mg/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.
Effect on Mortality
NATRECOR has not been studied in a trial designed or powered to assess mortality as a primary or key secondary endpoint. A large double-blind controlled trial (VMAC) included 273 patients receiving NATRECOR and 216 patients receiving IV nitroglycerin. The mortality rates at thirty days from any cause were 8.1% in the NATRECOR arm and 5.1% in the nitroglycerin arm (hazard ratio of 1.56 [95% CI: 0.75-3.24]). The mortality rates at six months in patients receiving NATRECOR or nitroglycerin were 25.1% and 20.8% respectively (hazard ratio of 1.22 [95% CI: 0.83-1.79]). In a pooled analysis of adequate and well-controlled clinical trials (Studies 311, 325, 326, 329 [PRECEDENT], 339 [VMAC], 341 [PROACTION], and 348 [FUSION I]), mortality with NATRECOR was compared with control treatment (30 day hazard ratio of 1.34 [95% CI: 0.85- 2.11]). Of the 1059 patients treated with NATRECOR in these 7 trials, 58 died at 30 days of any cause (Kaplan-Meier estimate, 5.5%), whereas 28 of the 658 control patients died (Kaplan-Meier estimate, 4.3%). All-cause mortality from 5 trials (Studies 325, 326, 329 [PRECEDENT], 339 [VMAC] and 341 [PROACTION] where 180-day mortality data were collected showed a 180-day hazard ratio of 1.08 [95% CI: 0.85-1.37]. In this analysis, 178/844 patients treated with NATRECOR (Kaplan-Meier estimate, 21.5%) and 114/560 control patients (Kaplan-Meier estimate, 20.7%) died of any cause. There were few deaths in these studies, so the confidence limits around the hazard ratios were wide. The studies were small and some potentially important baseline imbalances existed among the treatment groups, the effects of which could not be ascertained.
Abnormal Hematologic and Clinical Chemistry Findings
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 mg/kg bolus followed by 0.01 mg/kg/min) and nitroglycerin groups, respectively. 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 mg/kg/min group (17%) and the NATRECOR 0.03 mg/kg/min group (19%) than with standard therapy (11%).
Post-Market Adverse Drug Reactions
In addition to the previously mentioned clinical trials safety data, spontaneous adverse drug reactions (ADRs) from the worldwide post-marketing experience with NATRECOR are listed below. The frequency provided is a reflection of reporting rates for spontaneous adverse drug reactions and does not represent true incidence or frequency as seen with clinical trials or epidemiologic studies. ADRs reported in the post-marketing period by System Organ Class include: Immune System Disorders: very rare - hypersensitivity reactions
Overview
No trials specifically examining potential drug interactions with NATRECOR were conducted, although many concomitant drugs were used in clinical trials.
Drug-Drug Interactions
During clinical studies, NATRECOR was administered concomitantly with other medications, including: diuretics, digoxin, oral ACE inhibitors, anticoagulants, oral nitrates, 3-hydroxy-3- methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, class III antiarrhythmics, beta- blockers, dobutamine, calcium channel blockers, angiotensin II receptor antagonists, and dopamine. Although pharmacokinetic (PK) interactions were not specifically assessed, there did not appear to be evidence suggesting any clinically significant PK interaction, except for an increase in symptomatic hypotension in patients receiving oral ACE inhibitors (see WARNINGS AND PRECAUTIONS, Cardiovascular). 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.
Drug-Food Interactions
Interactions with food have not been established.
Drug-Herb Interactions
Interactions with herbal products have not been established.
Drug-Laboratory Interactions
Interactions with laboratory tests have not been established.
Chemical/Physical Interactions
NATRECOR is physically and/or chemically incompatible with injectable formulations of heparin, insulin, ethacrynate sodium, bumetanide, 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 (see DOSAGE AND ADMINISTRATION, Dosing Instructions, Chemical/Physical Interactions).
NOC/c
NATRECOR (nesiritide) is for intravenous use only.
Dosing Considerations
The dose-limiting side effect of NATRECOR is hypotension. NATRECOR should not be titrated at frequent intervals as is done with other IV agents that have a shorter half-life (see Product Monograph Part II: CLINICAL TRIALS).
Recommended Dose and Dosage Adjustment
The NATRECOR bolus must be drawn from the prepared infusion bag.
The recommended dose of NATRECOR is an IV bolus of 2 mg/kg followed by a continuous infusion of 0.01 mg/kg/min. NATRECOR should not be initiated at a dose that is above the recommended dose. The use of NATRECOR at doses higher than recommended is not encouraged. However, in the few cases where, following physician assessment further optimization of clinical status may be required, the NATRECOR infusion dose may be increased or decreased according to hemodynamic and clinical response. If an increase in dose is required, the infusion dose may be increased by 0.005 mg/kg/min (preceded by a bolus of 1 mg/kg) no more frequently than every 3 hours up to a maximum dose of 0.03 mg/kg/min. Blood pressure should be monitored closely during NATRECOR administration. There is limited experience with administering NATRECOR for longer than 48 hours. 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.
Administration
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. Aseptic technique must be used in the reconstitution procedure.
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 colourless solution.
Reconstituted single use vials of NATRECOR should be added to the 250 mL plastic IV bag and used immediately (within 3 hours). If the reconstituted vial is not used right away, store under refrigeration (2-8degC). Do not freeze. Protect from light. As NATRECOR contains no antimicrobial preservative, the storage of the reconstituted vial is not recommended. However, when prepared under aseptic conditions, the chemical and physical stability of the reconstituted vial has been demonstrated for 24 hours at 25degC.
and add to the 250 mL plastic IV bag. This will yield a solution with a concentration of NATRECOR of approximately 6 mg/mL. The IV bag should be inverted several times to ensure complete mixing of the solution.
Use the reconstituted and diluted solution, to start dosing, immediately (within 3 hours). As NATRECOR contains no antimicrobial preservative, storage of the reconstituted solution is not recommended. However, when prepared under aseptic conditions, the chemical and physical stability of the reconstituted and diluted solution has been demonstrated for 24 hours at 25degC. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Table 1.2 Reconstitution and Dilution of NATRECOR
| Vial Size | Volume of Diluent to be Added to Vial | Approximate Available Volume | Nominal Concentration per mL | Concentration per 250 mL Bag |
| 5 mL | 5 mL | 5 mL | 0.32 mg of nesiritide | 6 ug/mL |
Dosing Instructions
Prime the IV tubing with an infusion of 5 mL prior to connecting to the patient's vascular access port and prior to administering the bolus or starting the infusion. The administration of the recommended dose of NATRECOR is a two-step process:
Step 1. Administration of the IV Bolus
, as described previously, withdraw the bolus volume (see Table 1.3 Weight-Adjusted Bolus Volume) from the NATRECOR infusion bag, and administer it over approximately 60 seconds through an IV port in the tubing.
Table 1.3 Weight-Adjusted Bolus Volume
Bolus Volume (mL) = Patient Weight (kg) / 3 | |
|---|---|
| NATRECOR Weight-Adjusted Bolus Volume Administered Over 60 Seconds (Final Concentration = 6 mg/mL) | |
| Patient Weight (kg) | Volume of Bolus (mL = kg/3) |
| 60 | 20 |
| 70 | 23.3 |
| 80 | 26.7 |
| 90 | 30 |
| 100 | 33.3 |
| 110 | 36.7 |
Step 2. Administration of the Continuous Infusion
Immediately following the administration of the bolus, infuse NATRECOR at a flow rate of mL/kg/hr. This will deliver a NATRECOR infusion dose of 0.01 mg/kg/min. To calculate the infusion flow rate to deliver a 0.01 mg/kg/min dose, use the following formula (see Table 1.4 Weight-Adjusted Infusion Flow Rate for Dosing):
Table 1.4 Weight-Adjusted Infusion Flow Rate for Dosing
Infusion Flow Rate (mL/hr) = Patient Weight (kg) x 0.1 | |
|---|---|
| NATRECOR Weight-Adjusted Infusion Flow Rate for a 0.01 mg/kg/min Dose following Bolus (Final Concentration = 6 mg/mL) | |
| Patient Weight (kg) | Infusion Flow Rate (mL/hr) |
| 60 | 6 |
| 70 | 7 |
| 80 | 8 |
| 90 | 9 |
| 100 | 10 |
| 110 | 11 |
Chemical/Physical Interactions
NATRECOR is physically and/or chemically incompatible with injectable formulations of heparin, insulin, ethacrynate sodium, bumetanide, 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.
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 WARNINGS AND PRECAUTIONS) and appropriate measures.
NOC/c
Mechanism of Action
Human BNP (hBNP) acts on the cardio-renal axis by exerting effects on the vasculature, the heart and the kidneys. 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. hBNP also suppresses the renin- angiotensin-aldosterone system (RAAS) and has natriuretic and diuretic effects. 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.
Pharmacodynamics
The recommended dosing regimen of NATRECOR is a 2 mg/kg IV bolus followed by an intravenous infusion dose of 0.01 mg/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 70% of the 3-hour effect on SBP reduction is reached within 15 minutes. The pharmacodynamic half-life of the onset and offset of the hemodynamic effect of NATRECOR is longer than the pharmacokinetic half-life of 18 minutes. In patients who developed symptomatic hypotension in the VMAC 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.
Pharmacokinetics
In patients with congestive heart failure (CHF), NATRECOR administered intravenously by infusion or bolus exhibits biphasic disposition from the plasma. 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 mg/kg/min. The mean terminal elimination half-life (t1/2) of nesiritide is approximately 18 minutes. The mean initial elimination phase was estimated to be approximately 2 minutes. Steady-state volume of distribution, plasma clearance, and terminal elimination half-life were not dose dependent. Distribution: The mean volume of distribution of the central compartment (Vc) of nesiritide was estimated to be 0.073 (range 0.034 to 0.59) L/kg and the mean steady-state volume of distribution (Vss) was 0.19 (range 0.005 to 0.177) L/kg.
Human BNP is cleared from the circulation via the following three independent mechanisms, in order of decreasing importance:
binding to cell surface clearance receptors with subsequent cellular internalization and lysosomal proteolysis;
proteolytic cleavage of the peptide by endopeptidases, such as neutral endopeptidase, which are present on the vascular lumenal surface;
renal filtration.
Nesiritide has a mean terminal elimination half-life of 18 minutes and a mean clearance of 9.2 (range 2.4 to 44.6) mL/min/kg.
Special Populations and Conditions
There are no pharmacokinetic data in pediatric patients.
Clearance of nesiritide is not influenced significantly by age. The safety profile in the elderly is consistent with that in the general population, further supporting no requirement for dosage adjustment in the elderly.
The effects of gender and race on the pharmacokinetics of nesiritide have not been evaluated.
While hepatically impaired patients were not excluded from the clinical program, the effects of hepatic impairment on pharmacokinetic parameters of nesiritide have not been specifically assessed.
Although nesiritide is eliminated, in part, through renal clearance, clinical data suggest that dose adjustment is not required in patients with renal insufficiency. The effects of nesiritide 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 nesiritide is proportional to body weight, supporting the administration of weight-adjusted dosing of nesiritide (i.e., administration on a mg/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 CI, or New York Heart Association [NYHA] classification), or concomitant administration of an ACE inhibitor.
Store NATRECOR at 2-25degC. Do not freeze. Keep in carton until time of use, to protect from light. For storage of reconstituted vial and reconstituted and diluted solution, see Preparation, Reconstitution and Special Handling Instructions in DOSAGE AND ADMINISTRATION.
NATRECOR (nesiritide) contains the active ingredient nesiritide and the following inactive ingredients: mannitol, citric acid monohydrate and sodium citrate dihydrate NATRECOR (nesiritide) is provided as a sterile lyophilized powder in 1.5 mg, single-use 5 mL vials. Each carton contains one vial and is available in the following package: 1 vial/carton Product Monograph available upon request. Janssen-Ortho Inc. Toronto, Ontario M3C 1L9 Last revised: May 2008 (Component #) (c) 2008 JANSSEN-ORTHO Inc. All trademark rights used under license Ortho Biotech Logo Scios Logo