Nesipide Chinese Description

description

Natrecor® (Nexitide) is a novel drug, a sterile preparation of human B-type natriuretic peptide (hBNP), prepared from E. coli using recombinant DNA techniques. The molecular weight of nesiceptin is 3464g / mol, and the empirical formula is C143H244N50O42S4. Nesiritide has the same 32 amino acid sequence as the endogenous peptide, which is produced by the ventricular myocardium.

Natrecor is formulated as a citrate salt of rhBNP and is provided in a sterile disposable vial. Each 1.5 mg vial contains a white to off-white lyophilized powder for intravenous (IV) administration after reconstitution. The quantitative composition of each bottle of lyophilized drug was: 1.58 mg of nesiceptin, 20.0 mg of mannitol, 2.1 mg of citric acid monohydrate, and 2.94 mg of sodium citrate dihydrate.

Action mechanism

Human BNP binds to the granulosa guanylate cyclase receptor of vascular smooth muscle and endothelial cells, resulting in increased intracellular concentrations of guanosine 3'5'-cyclic monophosphate (cGMP) and smooth muscle cell relaxation. Circulating GMP acts as a second messenger to dilate veins and arteries. Nesiritide has been shown to relax isolated arterial and venous tissue preparations that pre-contract with endothelin-1 or the alpha-adrenergic agonist phenylephrine.

In human studies, nesiritide produced a dose-dependent reduction in pulmonary capillary wedge pressure (PCWP) and systemic arterial pressure in patients with heart failure.

In animals, nesiritide has no effect on cardiac contractility or cardiac electrophysiological measurements, such as atrial and ventricular effective refractory time or atrioventricular node conduction.

The naturally occurring atrial natriuretic peptide (ANP) is a related peptide that increases vascular permeability in animals and humans and reduces the amount of vascular content. The effect of nesiceptin on vascular permeability has not been studied.

Pharmacokinetics

In patients with congestive heart failure (CHF), Natrecor administered intravenously by infusion or bolus showed biphasic treatment from plasma. Natrecor's average terminal elimination half-life (t1 / 2) is approximately 18 minutes and is associated with approximately 2/3 of the area under the curve (AUC). The average initial elimination phase is estimated to be approximately 2 minutes. In these patients, the average volume of the Natrecor central chamber (Vc) was estimated to be 0.073 L / kg, the mean steady-state volume (Vss) was 0.19 L / kg, and the mean clearance (CL) was about 9.2 ml / min / kilogram. At steady state, plasma BNP levels increased approximately 3- to 6-fold from baseline endogenous levels, and Natrecor infusion doses ranged from 0.01 to 0.03 μg/kg/min.

eliminate

Elimination of human BNP by three independent mechanisms, reduced importance: 1) binding to cell surface clearance receptors, followed by cell internalization and lysosomal proteolysis; 2) by endopeptidase (eg neutral endopeptidase) Peptide proteolytic cleavage, the endopeptidase is present on the surface of the vascular lumen; 3) renal filtration.

Special population

Although the Natrecor fraction was eliminated by renal clearance, clinical data indicate that patients with renal insufficiency do not need to adjust the dose. Natrecor's effects on PCWP, cardiac index (CI), and systolic blood pressure (SBP) were not significantly different in patients with chronic renal insufficiency (baseline serum creatinine range of 2 mg/dL to 4.3 mg/dL) and patients. Renal function is normal. Population pharmacokinetic (PK) analysis was performed to determine the effect of demographic and clinical variables on PK parameters, indicating that Natrecor's clearance is proportional to body weight and supports the weight-adjusted dose of Natrecor (ie, in μg/give Medicine) kg / min (basis). Age, gender, race/ethnicity, baseline endogenous hBNP concentration, CHF severity (as indicated by baseline PCWP, baseline C1 or New York Heart Association [NYHA] classification) or concurrent administration of ACE inhibitors had no significant effect on clearance .

Accompanying drug effects

Co-administration of Natrecor and enalapril had no significant effect on Natrecor's PK. The PK effect of Natrecor in combination with other IV vasodilators such as nitroglycerin, sodium nitroprusside, milrinone or IV ACE inhibitors has not been evaluated. Natrecor is used concurrently with other drugs during clinical studies, including: diuretics, digoxin, oral ACE inhibitors, anticoagulants, oral nitrates, statins, class III antiarrhythmic drugs, beta-receptors Blockers, dobutamine, calcium channel blockers, angiotensin II receptor antagonists, and dopamine. Although there is no specific assessment of PK interactions, there appears to be no evidence of any clinically significant PK interaction.

Pharmacodynamics

Natrecor's recommended dosing regimen is an intravenous bolus of 2 μg/kg followed by an intravenous infusion of 0.01 μg/kg/min. With this dosing regimen, 60% of the 3-hour effect of PCWP reduction was achieved within 15 minutes after the bolus injection, and 95% of the 3-hour effect was achieved within 1 hour. Approximately 70% of the 3-hour impact on SBP reduction was achieved in 15 minutes. The onset of the hemodynamic effects of Natrecor and the offset pharmacodynamic (PD) half-life are predicted to be longer than the 18-minute PK half-life. For example, in patients with symptomatic hypotension in the VMAC (Vascular Relaxation in Acute Congestive Heart Failure Management) trial, SBP recovered to half of the baseline value after stopping or reducing the Natrecor dose within about 60 minutes. When a higher dose of Natrecor is infused, the duration of hypotension is sometimes several hours.

Clinical Trials

Natrecor has been studied in 10 clinical trials, including 941 CHF patients (61% for NYHA II-III, 36% for NYHA IV; mean age 60 years, and women 28%). There were 5 randomized, multicenter, placebo or active controlled trials (comparative medications including nitroglycerin, dobutamine, milrinone, sodium nitroprusside or dopamine), of which 772 patients with decompensated CHF were continuously infused Natrecor, doses range from 0.01 to 0.03 μg/kg/min. (See the Adverse Reactions section for the relative frequency of adverse events from the recommended dose to 0.03 μg/kg / min). Of these patients, the majority (n = 541, 70%) received Natrecor infusion for at least 24 hours; 371 (48%) received Natrecor for 24-48 hours, and 170 (22%) received Natrecor for more than 48 hours.

In a controlled trial, Natrecor was used alone or in combination with other standard therapies, including diuretics (79%), digoxin (62%), oral ACE inhibitors (55%), anticoagulants (38%), Oral nitrate (32%), statins (18%), class III antiarrhythmic drugs (16%), beta blockers (15%), dobutamine (15%), calcium Channel blockers (11%), angiotensin II receptor antagonists (6%) and dopamine (4%). Natrecor has been studied in a wide range of patients, including the elderly (42% > 65 years), women (30%), ethnic minorities (26% black) and patients with a history of major diseases such as hypertension (67%), previous myocardial infarction (50%), diabetes (44%), atrial fibrillation/tremor (34%), non-sustained ventricular tachycardia (25%), ventricular tachycardia/fibrillation (12%), systolic function retention ( 9%) and Natrecor less than 7 days before the onset of acute coronary syndrome (4%).

The VMAC (Vascular Relaxation in Acute Congestive Heart Failure Management) trial is a randomized, double-blind study in which 489 patients (246 patients requiring right heart catheterization and 243 patients without right heart catheterization) require hospitalization due to Acute decompensated CHF leads to rest. This study compared the effects of Natrecor, placebo, and intravenous nitroglycerin in the context of background treatment (IV and oral diuretics, non-IV cardiac drugs, dobutamine, and dopamine). Patients with acute coronary syndrome, retained systolic function, arrhythmia, and renal insufficiency are not excluded. The primary end point of the study was the change in PCWP from baseline and baseline changes in patient dyspnea, assessed after 3 hours. Due to the relatively long half-life of PK and PD of nesiritide (compared to nitroglycerin), the occurrence and persistence of hypotension is also closely monitored.

Natrecor was administered as a 2-μg/kg bolus in approximately 60 seconds and then infused at a continuous fixed dose of 0.01 μg/kg/min. After a 3-hour placebo-controlled period, placebo-treated patients were treated with Natrecor or nitroglycerin for double-blind activity. The dose of nitroglycerin is at the discretion of the doctor.

If PCWP ≥ 20 mm Hg and SBP ≥ 100, some of the VMAC trials (62 of 124 patients) treated with Natrecor allowed an increase in Natrecor dose after the first 3 hours of treatment. Mm Hg. The dose is increased by 1 μg/kg bolus every 3 hours, then the infusion dose is increased by 0.005 μg/kg / min until the maximum dose is 0.03 μg/kg / min. Overall, 23 patients in this subset increased the Natrecor dose in the VMAC trial.

In the second double-blind study, 127 patients requiring hospitalized symptomatic CHF were randomized to placebo or one of two doses of Natrecor (0.015 μg/kg / min, followed by an IV bolus of 0.3 μg/ The IV bolus before kg, 0.03 μg/kg) / min was 0.6 μg/kg). The primary endpoint of the trial was the change in PCWP from baseline to 6 hours, but the effects on symptoms were also examined.

Effect on symptoms

In the VMAC study, patients treated with Natrecor reported a 3-hour improvement in dyspnea greater than those receiving placebo (p = 0.034).

In a dose-response study, patients receiving two doses of Natrecor reported greater improvement in dyspnea at 6 hours than patients receiving placebo.

Impact on hemodynamics

In the VMAC trial, 246 patients were monitored for PCWP, right atrial pressure (RAP), CI, and other hemodynamic variables. The mean PCWP was reduced within 15 minutes of the start of Natrecor infusion and most of the effect was achieved for 3 hours during the first 60 minutes of infusion (see pharmacodynamics).

In some studies, hemodynamic parameters were measured after withdrawal of Natrecor. After discontinuing Natrecor, PCWP returned to within 10% of baseline within 2 hours, but no increase in rebound was observed above baseline. In clinical trials, there is no evidence that Natrecor's hemodynamic effects are rapidly tolerated.

The VMAC study did not allow for a sufficient effectiveness comparison with nitroglycerin. In this trial, the nitroglycerin group provided a rough milestone using familiar therapies and protocols.

Effect on urine output

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

Indications and usage

Natrecor (Nexide) is indicated for intravenous treatment in patients with acute decompensated congestive heart failure who have difficulty breathing during periods of minimal rest or activity. In this population, Natrecor reduces pulmonary capillary wedge pressure and improves breathing difficulties.

Contraindications

Natrecor is contraindicated in patients who are allergic to any of its ingredients. For patients with cardiogenic shock or patients with systolic blood pressure <90 mm Hg, Natrecor should not be used as the primary treatment.

caveat

Patients who are suspected of having or known to have a low heart filling should avoid giving Natrecor.

Precautions

General: Parenteral administration of protein drugs or E. coli derived products should take appropriate precautions to prevent allergies or adverse reactions. Natrecor did not report a severe allergic or allergic reaction.

Natrecor is not recommended for patients who are not suitable for vasodilators, such as those with significant valvular stenosis, restrictive or obstructive cardiomyopathy, constrictive pericarditis, pericardial tamponade or other cardiac output depending on venous return, or suspected The patient's heart is underfilled. (See "Contraindications.")

Kidney: Natrecor may affect renal function in susceptible individuals. In patients with severe heart failure and whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with Natrecor may be associated with azotemia. When Natrecor starts at doses above 0.01 μg/kg / min (0.015 and 0.030 μg/kg / min), serum creatinine rises faster than baseline, despite acute renal failure and rate of need There was no increase in dialysis. During the 30-day follow-up of the VMAC trial, 5 patients (2%) in the nitroglycerin group and 9 patients (3%) in the Natrecor group required first dialysis.

Cardiovascular: Natrecor may cause hypotension. In the VMAC trial, Natrecor's first 24-hour symptomatic hypotension was similar (4%) in patients who received the recommended dose (2μg/kg bolus, then infusion 0.01μg/kg/min) or adjustable dose. And intravenous nitroglycerin (5%). However, when hypotension occurred, Natrecor (average duration of 2.2 hours) of symptomatic hypotension lasted longer than nitroglycerin (average duration of 0.7 hours). In early trials, when Natrecor started with a dose higher than 2-μg/kg bolus and then infused 0.01-μg/kg/min (ie a small bolus before 0.015 and 0.030 μg/kg / min), more The hypotensive events and the intensity and duration of these events are longer. They also have more frequent symptoms and/or may require medical intervention (see Adverse Reactions). Natrecor should be administered only in an environment where blood pressure can be closely monitored, and Natrecor's dose should be lowered or discontinued in patients with hypotension (see instructions for dosing). In patients with baseline blood pressure <100 mm Hg, the incidence of symptomatic hypotension may increase, and Natrecor should be used with caution in these patients. Using Natrecor in combination with other drugs that may cause hypotension may increase the likelihood of hypotension. For example, in patients undergoing VMAC testing with Natrecor or nitroglycerin, the incidence of symptomatic hypotension in patients receiving oral ACE inhibitors was 6%, and the incidence of symptomatic hypotension in patients not receiving oral ACE inhibitors. It is 1%. Oral ACE inhibitors.

Drug Interactions: Although many concomitant drugs are used in clinical trials, there are no tests specifically designed to interact with Natrecor's potential drugs. No drug interactions were detected except for the increase in symptomatic hypotension in patients receiving oral ACE inhibitors (see Preventive Measures, Cardiovascular).

Co-administration of Natrecor with IV vasodilators such as nitroglycerin, sodium nitroprusside, milrinone or IV ACE inhibitors (these drugs have not been co-administered with Natrecor in clinical trials) has not been evaluated.

Carcinogenesis, mutagenesis, impaired fertility: Long-term studies have not been conducted on animals to assess the potential for lethality or the effects on Natrecor's fertility. When used in an in vitro bacterial cell assay (Ames test), Natrecor did not increase the frequency of mutations. No other genotoxicity studies were conducted.

Adverse events not listed in the above table occurred in at least 1% of patients receiving any of the above Natrecor doses: tachycardia, atrial fibrillation, abnormal atrioventricular node conduction, catheter pain, fever, injection site reaction, confusion, paresthesia , lethargy, tremors, increased cough, hemoptysis, apnea, elevated creatinine, sweating, itching, rash, leg cramps, amblyopia, anemia. All reported incidents (at least 1%) are included, except for those events that have been listed, those that are too general to provide information, and those that are not relevant to the use of the drug because they are related to the condition being treated Or very common in the treatment of the population.

In placebo and active controlled clinical trials, Natrecor was not associated with an increase in atrial or ventricular tachyarrhythmias. In a placebo-controlled trial, Natrecor and placebo patients had a VT rate of 2%. Comparison of Natrecor (n = 163) and dobutamine (n = 83) in patients with decompensated CHF in a trial of PRECEDENT (a prospective randomized assessment of cardiac ectopic treatment with dobutamine or Natrecor) The effects of stimulation or deterioration of existing ventricular arrhythmias. Monitored using Holter. Treatment with Natrecor (0.015 and 0.03 μg/kg/min, no initial bolus) for 24 hours did not exacerbate the frequency of pre-existing VT or ventricular premature beats compared to baseline 24-hour Holter tape.

Clinical laboratory

In the PRECEDENT trial, Natrecor's 0.015-μg/kg/min group (17%) and Natrecor 0.03-μg/kg/min had a higher incidence of serum creatinine above > 0.5 mg / dL on day 14. Group (19%) was better than the standard treatment group (11%). In the VMAC trial, by day 30, the incidence of creatinine increased above baseline by > 0.5 mg / dL was 28% and 21% in Natrecor (2μg/kg bolus followed by 0.010 μg/kg / min) and nitric acid Glycerol group, respectively.

Impact on mortality

In the VMAC trial, patients receiving Natrecor and nitroglycerin had a mortality rate of 25.1% (95% confidence interval, 20.0% to 30.5%) and 20.8% (95% confidence interval, 15.5% to 26.5%) at 6 months. ). . In all control trials, Natrecor and active controls (including nitroglycerin, dobutamine, sodium nitroprusside, milrinone, amrinone, and dopamine) had mortality rates of 21.5% and 21.7%, respectively.

Overdose

There is no data on human overuse. The expected response is excessive hypotension, which should be stopped or reduced (see preventive measures) and appropriate measures.

Dosage and administration

Natrecor (Nexide) is used only for intravenous injection. The experience of managing Natrecor over 48 hours is limited. Blood pressure should be closely monitored during Natrecor administration.

If hypotension occurs during Natrecor administration, the dose should be reduced or stopped and other blood pressure-supporting measures (intravenous infusion, postural changes) should be initiated. In the VMAC trial, Natrecor was discontinued when symptomatic hypotension occurred, and once the patient was stable, it could then be restarted with a dose that was reduced by 30% (no bolus administration). Because Natrecor's hypotension may be prolonged (up to several hours), it may take some time to observe before restarting the drug.

preparation

1. Add 5 ml of the dilution and reconstitute a 1.5 ml bottle of Natrecor.

A pre-filled 250 ml plastic IV bag containing the selected diluent. It is recommended to use the following preservative-free diluent for reconstitution: 5% dextrose injection (D5W), USP; 0.9% sodium chloride injection, USP; USP, 5% dextrose and 0.45% sodium chloride injection , USP, or 5% glucose and 0.2% sodium chloride injection.

2. Do not shake the vial. Gently shake the vial so that all surfaces, including the stopper, are in contact with the diluent to ensure complete reconstitution. Use only a clear, substantially colorless solution.

3. Remove the entire contents of the reconstituted Natrecor vial and add to a 250-mL plastic IV bag. This will result in a solution of Natrecor at a concentration of about 6 [mu]g/mL. The IV bag should be inverted several times to ensure complete mixing of the solution.

4. Use the reconstituted solution within 24 hours because Natrecor does not contain an antimicrobial preservative. In the case where the solution and container permit, the particulate matter and discoloration of the parenteral drug product should be visually inspected prior to administration. According to the United States Pharmacopoeia (USP), recombinant Natrecor vials can be kept at controlled room temperature (20-25 ° C; 68-77 ° F) or refrigerated (2-8 ° C; 36-46 ° F) up to 24 hour.

Dosing instructions

Natrecor's recommended dose is an IV bolus of 2 μg/kg followed by continuous infusion at a dose of 0.01 μg/kg / min. Natrecor should not be started at doses above the recommended dose.

The IV tube was perfused with 25 mL of infusion prior to connection to the patient's vascular access port and prior to administration of a bolus or infusion.

Bolus and then infusion: After preparation of the infusion bag, the bolus volume was removed from the Natrecor infusion bag as previously described (see table below) and administered via the IV port in the tube in approximately 60 seconds. Immediately after the bolus administration, Natrecor was injected at a flow rate of 0.1 mL / kg / hr. This will provide a Natrecor infusion dose of 0.01 μg/kg / min.

Calculate the appropriate bolus volume and infusion flow to provide