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NUROMAX (doxacurium chloride) binds competitively to cholinergic receptors on the motor end-plate to antagonize the action of acetylcholine, resulting in a block of neuromuscular transmission. This action is antagonized by acetylcholinesterase inhibitors, such as neostigmine.
NUROMAX (doxacurium chloride) is approximately 2.5 to 3 times more potent than pancuronium and 10 to 12 times more potent than metocurine. NUROMAX (doxacurium chloride) in doses of 1.5 to 2 × ED95 has a clinical duration of action (range and variability) similar to that of equipotent doses of pancuronium and metocurine (historic data and limited comparison). The average ED95 (dose required to produce 95% suppression of the adductor pollicis muscle twitch response to ulnar nerve stimulation) of NUROMAX (doxacurium chloride) is 0.025 mg/kg (range: 0.020 to 0.033) in adults receiving balanced anesthesia.
The onset and clinically effective duration (time from injection to 25% recovery) of NUROMAX (doxacurium chloride) administered alone or after succinylcholine during stable balanced anesthesia are shown in Table 1.
Table 1: Pharmacodynamic Dose Response* Balanced Anesthesia
|Initial Dose of NUROMAX (mg/kg)|
(n = 27)
(n = 9)
|Time to Maximum Block (min)||9.3||5.2||3.5|
|Clinical Duration (min) (Time to 25% Recovery)||55||100||160|
|* Values shown are means (range).
† NUROMAX administered after 10% to 100% recovery from an intubating dose of succinylcholine.
Initial doses of 0.05 mg/kg (2 × ED95) and 0.08 mg/kg (3 × ED95) NUROMAX (doxacurium chloride) administered during the induction of thiopental-narcotic anesthesia produced good-to-excellent conditions for tracheal intubation in 5 minutes (13 of 15 cases studied) and 4 minutes (eight of nine cases studied) (which are before maximum block), respectively.
As with other long-acting agents, the clinical duration of neuromuscular block associated with NUROMAX (doxacurium chloride) shows considerable interpatient variability. An analysis of 390 cases in US clinical trials utilizing a variety of premedications, varying lengths of surgery, and various anesthetic agents, indicates that approximately two thirds of the patients had clinical durations within 30 minutes of the duration predicted by dose (based on mg/kg actual body weight). Patients ≥ 60 years old are approximately twice as likely to experience prolonged clinical duration (30 minutes longer than predicted) than patients < 60 years old; thus, care should be used in older patients when prolonged recovery is undesirable (see PRECAUTIONS -Geriatric Use and CLINICAL PHARMACOLOGY -Individualization of Dosages subsection). In addition, obese patients (patients weighing ≥ 30% more than ideal body weight for height) were almost twice as likely to experience prolonged clinical duration than non-obese patients; therefore, dosing should be based on ideal body weight (IBW) for obese patients (see CLINICAL PHARMACOLOGY - Individualization of Dosages subsection).
The mean time for spontaneous T1 recovery from 25% to 50% of control following initial doses of NUROMAX (doxacurium chloride) is approximately 26 minutes (range: 7 to 104, n = 253) during balanced anesthesia. The mean time for spontaneous T1 recovery from 25% to 75% is 54 minutes (range: 14 to 184, n = 184).
Most patients receiving NUROMAX (doxacurium chloride) in clinical trials required pharmacologic reversal prior to full spontaneous recovery from neuromuscular block (see OVERDOSAGE - Antagonism of Neuromuscular Block); therefore, relatively few data are available on the time from injection to 95% spontaneous recovery of the twitch response. As with other long-acting neuromuscular blocking agents, NUROMAX (doxacurium chloride) may be associated with prolonged times to full spontaneous recovery. Following an initial dose of 0.025 mg/kg NUROMAX (doxacurium chloride) , some patients may require as long as 4 hours to exhibit full spontaneous recovery.
Cumulative neuromuscular blocking effects are not associated with repeated administration of maintenance doses of NUROMAX (doxacurium chloride) at 25% T1 recovery. As with initial doses, however, the duration of action following maintenance doses of NUROMAX (doxacurium chloride) may vary considerably among patients.
The NUROMAX (doxacurium chloride) ED95 for children 2 to 12 years of age receiving halothane anesthesia is approximately 0.03 mg/kg. Children require higher doses of NUROMAX (doxacurium chloride) on a mg/kg basis than adults to achieve comparable levels of block. The onset time and duration of block are shorter in children than adults. During halothane anesthesia, doses of 0.03 mg/kg and 0.05 mg/kg NUROMAX (doxacurium chloride) produce maximum block in approximately 7 and 4 minutes, respectively. The duration of clinically effective block is approximately 30 minutes after an initial dose of 0.03 mg/kg and approximately 45 minutes after 0.05 mg/kg. NUROMAX (doxacurium chloride) has not been studied in pediatric patients below the age of 2 years.
The neuromuscular block produced by NUROMAX (doxacurium chloride) may be antagonized by anticholinesterase agents. As with other nondepolarizing neuromuscular blocking agents, the more profound the neuromuscular block at reversal, the longer the time and the greater the dose of anticholinesterase required for recovery of neuromuscular function.
Administration of doses of NUROMAX (doxacurium chloride) up to and including 0.08 mg/kg (~3 × ED95) over 5 to 15 seconds to healthy adult patients during stable-state balanced anesthesia and to patients with serious cardiovascular disease undergoing coronary artery bypass grafting, cardiac valvular repair, or vascular repair produced no dose-related effects on mean arterial blood pressure (MAP) or heart rate (HR).
No dose-related changes in MAP and HR were observed following administration of up to 0.05 mg/kg NUROMAX (doxacurium chloride) over 5 to 15 seconds in 2- to 12-year-old children receiving halothane anesthesia.
Doses of 0.03 to 0.08 mg/kg (1.2 to 3 × ED95) were not associated with dose-dependent changes in mean plasma histamine concentration. Clinical experience with more than 1000 patients indicates that adverse experiences typically associated with histamine release (e.g., bronchospasm, hypotension, tachycardia, cutaneous flushing, urticaria, etc.) are very rare following the administration of NUROMAX (see ADVERSE REACTIONS).
Pharmacokinetic and pharmacodynamic results from a study of 24 healthy young adult patients and eight healthy elderly patients are summarized in Table 2. The pharmacokinetics are linear over the dosage range tested (i.e., plasma concentrations are approximately proportional to dose).
Table 2: Pharmacokinetic and Pharmacodynamic Parameters*
of NUROMAX (doxacurium chloride) in Young Adult and Elderly Patients (Isoflurane Anesthesia)
|Healthy Young Adult Patients (22 to 49 yrs)||Healthy Elderly Patients (67 to 72 yrs)|
(n = 8)
(n = 8)
(n = 8)
(n = 8)
|Volume of Distribution at Steady State (L/kg)||0.15||0.24||0.22||0.22|
|Plasma Clearance (mL/min per kg)||2.22||2.62||2.53||2.47|
|Maximum Block (%)||97||100||100||96|
|Clinically Effective Duration of Block† (min)||68||91||177||97|
|* Values shown are means (range).
† Time from injection to 25% recovery of the control twitch height.
This study showed that the pharmacokinetics of NUROMAX (doxacurium chloride) were similar in healthy young adult and elderly patients. Some healthy elderly patients tended to be more sensitive to the neuromuscular blocking effects of NUROMAX (doxacurium chloride) than healthy young adult patients receiving the same dose. The time to maximum block was longer in elderly patients than in young adult patients (11.2 minutes versus 7.7 minutes at 0.025 mg/kg NUROMAX (doxacurium chloride) ). In addition, the clinically effective duration of block was more variable and tended to be longer in healthy elderly patients than in healthy young adult patients receiving the same dose. In contrast, a second study evaluated the pharmacokinetics and pharmacodynamics of doxacurium and showed that the plasma clearance was lower (1.75 ± 0.16 vs. 2.54 ± 0.24, respectively) and the half-life was longer (120 ± 10 vs. 75.9 ± 4.4 minutes, respectively) in 9 elderly patients (70 to 83 years of age) than in 9 younger patients (19 to 39 years of age) receiving a single intravenous dose of NUROMAX (doxacurium chloride) 0.03 mg/kg. In addition, the time to maximum block was slower (12.9 versus 8.9 minutes, respectively) and the time to 25% T1 recovery was longer (113.4 ± 17.0 vs. 48.1 ± 5.2 minutes, respectively) in elderly patients than in younger patients. Overall, these studies showed that there may be differences in the pharmacokinetics of doxacurium in individual elderly patients and that the onset is slower and the duration of action is likely to be more variable and may be longer in elderly patients.
Table 3 summarizes the pharmacokinetic and pharmacodynamic results from a study of nine healthy young adult patients, eight patients with end-stage kidney disease undergoing kidney transplantation, and seven patients with end-stage liver disease undergoing liver transplantation. The results suggest that a longer t½ can be expected in patients with end-stage kidney disease; in addition, these patients may be more sensitive to the neuromuscular blocking effects of NUROMAX (doxacurium chloride) . The time to maximum block was slightly longer and the clinically effective duration of block was prolonged in patients with end-stage kidney disease.
Table 3: Pharmacokinetic and Pharmacodynamic Parameters*
of NUROMAX (doxacurium chloride) in Healthy Patients and in Patients Undergoing Kidney or Liver Transplantation
|Parameter||Healthy Young Adult Patients||Kidney Transplant Patients||Liver Transplant Patients|
( n = 9)
(n = 8)
(n = 7)
|t½ elimination (min)||99||221||115|
|Volume of Distribution at Steady State (L/kg)||0.22||0.27||0.29|
|Plasma Clearance (mL/min per kg)||2.66||1.23||2.30|
|Maximum Block (%)||86||98||70|
|Clinically Effective Duration of Block (min)||36||80||52|
|* Values shown are means (range).|
No data are available from patients with liver disease not requiring transplantation. There are no significant alterations in the pharmacokinetics of NUROMAX (doxacurium chloride) in liver transplant patients. Sensitivity to the neuromuscular blocking effects of NUROMAX (doxacurium chloride) was highly variable in patients undergoing liver transplantation. Three of seven patients developed ≤ 50% block, indicating that a reduced sensitivity to NUROMAX (doxacurium chloride) may occur in such patients. In those patients who developed > 50% neuromuscular block, the time to maximum block and the clinically effective duration tended to be longer than in healthy young adult patients (see CLINICAL PHARMACOLOGY - Individualization of Dosages subsection).
Consecutively administered maintenance doses of 0.005 mg/kg NUROMAX (doxacurium chloride) , each given at 25% T1 recovery following the preceding dose, do not result in a progressive increase in the plasma concentration of doxacurium or a progressive increase in the depth or duration of block produced by each dose.
NUROMAX (doxacurium chloride) is not metabolized in vitro in fresh human plasma. Plasma protein binding of NUROMAX (doxacurium chloride) is approximately 30% in human plasma.
In vivo data from humans suggest that NUROMAX (doxacurium chloride) is not metabolized and that the major elimination pathway is excretion of unchanged drug in urine and bile. In studies of healthy adult patients, 24% to 38% of an administered dose was recovered as parent drug in urine over 6 to 12 hours after dosing. High bile concentrations of NUROMAX (doxacurium chloride) (relative to plasma) have been found 35 to 90 minutes after administration. The overall extent of biliary excretion is unknown. The data derived from analysis of human urine and bile are consistent with data from in vivo studies in the rat, cat, and dog, which indicate that all of an administered dose of NUROMAX (doxacurium chloride) is recovered as parent drug in the urine and bile of these species.
Individualization of Dosages
In elderly patients or patients who have impaired renal function, the potential for a prolongation of block may be reduced by decreasing the initial dose of NUROMAX (doxacurium chloride) and by titrating the dose to achieve the desired depth of block. In obese patients (patients weighing ≥ 30% more than ideal body weight for height), the dose of NUROMAX (doxacurium chloride) should be determined using the patient's ideal body weight (IBW), according to the following formulae:
Men: IBW in kg = [106 + (6 × inches in height above 5 feet)]/2.2
Women: IBW in kg = [100 + (5 × inches in height above 5 feet)]/2.2
Dosage requirements for patients with severe liver disease are variable; some patients may require a higher than normal initial dose of NUROMAX (doxacurium chloride) to achieve clinically effective block. Once adequate block is established, the clinical duration of block may be prolonged in such patients relative to patients with normal liver function.
As with pancuronium, metocurine, and vecuronium, resistance to NUROMAX (doxacurium chloride) , manifested by a reduced intensity and/or shortened duration of block, must be considered when NUROMAX (doxacurium chloride) is selected for use in patients receiving phenytoin or carbamazepine (see PRECAUTIONS - DRUG INTERACTIONS).
As with other nondepolarizing neuromuscular blocking agents, a reduction in dosage of NUROMAX (doxacurium chloride) must be considered in cachectic or debilitated patients; in patients with neuromuscular diseases, severe electrolyte abnormalities, or carcinomatosis; and in other patients in whom potentiation of neuromuscular block or difficulty with reversal is anticipated. Increased doses of NUROMAX (doxacurium chloride) may be required in burn patients (see PRECAUTIONS).
Last reviewed on RxList: 1/4/2011
This monograph has been modified to include the generic and brand name in many instances.
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