Professional Drug Information > Doxacurium Chloride

Doxacurium (Systemic)

VA CLASSIFICATION
Primary: MS300

Commonly used brand name(s): Nuromax.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Neuromuscular blocking (paralyzing) agent—

Indications

Accepted

Skeletal muscle paralysis—Doxacurium is indicated as an adjunct to anesthesia to facilitate endotracheal intubation and to induce skeletal muscle relaxation in the surgical field ^{{01} {08} {09} {10} {15} {16} {17} {18} {19} {20} {21} {22} {23} {30} {31}}. Doxacurium has a long duration of action in adults ^{57}; use of doses sufficient to facilitate endotracheal intubation should be considered only for procedures expected to last 90 minutes or longer ^{32}.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Doxacurium chloride: 1106.15 ^{58}

Mechanism of action/Effect:

Doxacurium is a nondepolarizing (competitive) neuromuscular blocking agent. Nondepolarizing neuromuscular blocking agents inhibit neuromuscular transmission by competing with acetylcholine for the cholinergic receptors of the motor end plate ^{{01} {34}}, thereby reducing the response of the end plate to acetylcholine ^{34}. This type of neuromuscular block generally is antagonized by anticholinesterase agents ^{{01} {33} {34}}. The paralysis is selective initially and usually appears in the following muscles consecutively: levator muscles of eyelids, muscles of mastication, limb muscles, abdominal muscles, muscles of the glottis, and finally, the intercostal muscles and the diaphragm. Neuromuscular blocking agents have no clinically significant effect on consciousness or the pain threshold ^{{01} {29}}.

Distribution:


Volume of distribution (steady-state):

Normal renal function: About 0.22 (range, 0.11 to 0.43) L per kg of body weight (L/kg), in nongeriatric patients ^{{01} {03} {16} {20}}. Values within this range have also been reported for geriatric patients (about 0.22 [range, 0.14 to 0.40] L/kg) ^{{01} {03} {16}} and for patients with hepatic failure undergoing liver transplantation (about 0.29 [range, 0.17 to 0.35] L/kg) ^{{01} {03} {20}}.

Renal function impairment: About 0.27 (range, 0.17 to 0.55) L/kg, determined in patients with end-stage renal failure undergoing kidney transplantation ^{{01} {03} {20}}.


Protein binding:

Low (about 30%) ^{01}.

Biotransformation:

Metabolites have not been detected in studies performed to date ^{35}.

Half-life:


Elimination:

Normal renal function: About 86 ^{{01} {03} {16}} to 123 (range, 25 to 193) ^{{01} {03} {20} {39}} minutes, with doses ranging between 15 and 80 mcg per kg of body weight (mcg/kg). Values within this range have also been reported for geriatric patients (about 96 [range, 50 to 114] minutes) ^{{01} {03} {16}} and patients undergoing hepatic transplantation (about 115 [range, 69 to 148] minutes) ^{{01} {03} {20}}.

Renal function impairment: About 221 (range, 84 to 592) minutes, determined following administration to patients with end-stage renal failure undergoing kidney transplantation ^{{01} {03} {20}}.


Onset of action:


Time to achieve intubating conditions:

Note: The onset of action of each dose of doxacurium is dependent on dosage and on the age of the patient ^{{01} {15} {16} {17} {18} {19} {20} {22} {23}}. The ED ₉₅ (dose of a neuromuscular blocking agent required to produce 95% suppression of the adductor pollicis muscle twitch response to ulnar nerve stimulation) is lower after establishment of steady-state anesthesia with a potent volatile inhalation agent (e.g., enflurane, halothane, isoflurane) than during other types of anesthesia ^{{01} {15} {17}}. The following values were not obtained during steady-state anesthesia with a volatile agent.


50 mcg/kg: About 5 minutes ^{{01} {19}}.

80 mcg/kg: About 4 minutes ^{{01} {19}}.

Note: Information on the time to achieve intubating conditions with lower doses of doxacurium has not been published; however, when a dose of 25 mcg/kg is administered after succinylcholine-assisted intubation, 90% suppression of the response to peripheral nerve stimulation occurs in about 6 minutes ^{{04} {15} {17} {22}}.



Time to peak concentration:

About 2 minutes following administration of an initial dose of 30 mcg/kg or a supplemental dose of 5 mcg/kg administered after 25% recovery from the initial dose ^{03}.

Peak serum concentration:

30 mcg/kg—About 340 nanograms per mL (0.31 micromole/L) ^{03}.

5 mcg/kg (supplemental dose)—90 to 100 nanograms per mL (0.08 to 0.09 micromole/L); values are consistent for all supplemental doses given at 25% recovery from the previous initial (30 mcg/kg) or supplemental (5 mcg/kg) dose, when the doxacurium concentration has decreased to about 44.75 nanograms per mL (0.04 micromole/L) ^{{03} {40}}.

Time to peak effect:

Note: The time to peak effect is dependent on dosage and the age of the patient. Also, it is shorter during anesthesia with a volatile inhalation agent (specified below when applicable) than during other types of anesthesia. However, the time to peak effect is not altered by prior administration of an intubating dose (1 mg per kg of body weight [mg/kg]) of succinylcholine, provided that doxacurium is administered after recovery of the twitch response to 10% or more of the control value ^{{01} {22}}.
In most patients, recommended doses of doxacurium produce maximal responses of 90 to 95% (or even higher) inhibition of the twitch response to peripheral nerve stimulation. However, patients with hepatic failure may be somewhat resistant to the effects of doxacurium; a maximal response of only 70% inhibition of the twitch response was achieved in these patients by a dose that produced higher maximal responses in patients with normal hepatic function ^{{01} {20}}.



Time to maximal suppression of the twitch response to peripheral nerve stimulation:


Children 2 to 12 years of age (halothane anesthesia)—

30 mcg/kg—About 7 minutes ^{{01} {08}}.

50 mcg/kg—About 4 minutes ^{01}.



Adults up to 50 years of age with normal hepatic and renal function—

25 mcg/kg—About 8 to 10 (range, 5.4 to 16) minutes ^{01}.

50 mcg/kg—About 4 to 5 (range, 2.5 to 13) minutes ^{{01} {04} {15} {17}}.

80 mcg/kg—About 3.5 (range, 2.4 to 5) minutes ^{01}.



Adults up to 55 years of age with end-stage renal failure undergoing renal transplantation—

Tends to be longer than in nongeriatric adults with normal renal function ^{{20} {21}}.



Adults up to 55 years of age with hepatic failure undergoing hepatic transplantation—

Tends to be longer than in nongeriatric adults with normal hepatic function ^{{01} {20}}.



Adults older than 65 years of age with normal hepatic and renal function—

25 mcg/kg (isoflurane anesthesia)—About 11 minutes; slightly more prolonged than in nongeriatric patients with normal hepatic and renal function ^{{03} {16}}.



Duration of action:

Note: Doxacurium's duration of action (for both initial and supplemental doses) is dependent on dosage, the age of the patient, and the clearance rate from plasma (which is at least partially dependent on the patient's renal function), as well as being subject to substantial interpatient variability ^{{01} {41}}. The duration of action is more prolonged during anesthesia with a volatile anesthetic (specified below when applicable) than during other types of anesthesia ^{01}. However, cumulative effects on the duration or depth of neuromuscular blockade do not occur when supplemental doses of doxacurium are given after 25% recovery from an initial dose ^{{01} {03} {04}}. Also, the duration of action is not significantly altered by prior administration of an intubating dose (1 mg/kg) of succinylcholine, provided that doxacurium is administered after the twitch response has returned to 10% or more of the control value ^{22}.



Duration of clinical effect (time for spontaneous recovery of the twitch response to peripheral nerve stimulation to 25% of the control value):


Children 2 to 12 years of age (halothane anesthesia)—

30 mcg/kg—About 25 to 30 minutes ^{{01} {08} {10} {15}}.

50 mcg/kg—About 45 to 50 minutes ^{{01} {08} {10} {15}}.



Adults up to 50 years of age with normal renal and hepatic function—


Initial dose—

25 mcg/kg: About 55 (range, 9 to 145) minutes ^{{01} {15} {22} {42}}.

40 mcg/kg: About 70 to 85 minutes ^{04}.

50 mcg/kg: About 100 (range, 39 to 232) minutes ^{01}.

60 mcg/kg: About 123 minutes ^{04}.

80 mcg/kg: About 160 (range, 110 to 338) minutes ^{01}.



Supplemental dose, administered after 25% recovery from an initial 25 mcg/kg dose—

5 mcg/kg: About 30 (range, 9 to 57) minutes ^{01}.

10 mcg/kg: About 45 (range, 14 to 108) minutes ^{01}.




Adults older than 65 years of age with normal renal and hepatic function—

25 mcg/kg (isoflurane anesthesia)—About 97 (range, 36 to 179) minutes ^{{01} {03} {16}}; more variable ^{{01} {16}} and more prolonged ^{{01} {03} {16}} than in younger adults.



Adults up to 55 years of age with end-stage renal failure undergoing renal transplantation—

Values tend to be more variable ^{20}, as well as more prolonged ^{{03} {20}}, than in patients with normal renal function.


Halothane anesthesia—

25 mcg/kg initial dose: About 120 minutes ^{21}.

5 mcg/kg supplemental dose, administered after 25% recovery from the initial dose: About 27.5 minutes ^{21}.



Isoflurane anesthesia—

15 mcg/kg—About 80 ^{{01} {03} {20}} (range, 29 to 133) ^{{01} {20}} minutes.




Adults up to 55 years of age with hepatic failure undergoing hepatic transplantation—

15 mcg/kg (isoflurane anesthesia)—About 52 ^{{01} {03} {20}} (range, 20 to 91) ^{{01} {20}} minutes; longer than in patients with normal hepatic function ^{01}.




Recovery index (time for the twitch response to peripheral stimulation to increase, spontaneously, from 25% to 75% of the control value):


Children 2 to 12 years of age (halothane anesthesia)—

About 27 to 34 minutes (range, 11.2 to 57.5) minutes, with doxacurium doses ranging from 27.5 to 50 mcg/kg ^{{08} {10}}.



Adults up to 50 years of age with normal renal and hepatic function—

25 mcg/kg—About 51 minutes ^{{17} {22}}.

50 mcg/kg—About 84 (range, 40 to 128) minutes ^{17}.




Time to spontaneous 95% recovery of the twitch response to peripheral stimulation—Determined in adults up to 50 years of age with normal renal and hepatic function:

25 mcg/kg—Average 74 minutes ^{04}, but up to 4 hours in some patients ^{01}.

40 mcg/kg—Average 126 minutes ^{04}.

50 mcg/kg—Average 204 minutes ^{04}.


Elimination:
    Renal and biliary, as unchanged doxacurium ^{{01} {03}}; 24 to 38% of a dose is eliminated in the urine within 6 to 12 hours ^{{01} {43}}. The overall extent of biliary excretion is unknown ^{{01} {03}}.


Plasma clearance rate—


Adults—
        Normal renal function—About 2.2 to 2.6 (range, 1 to 6.6) mL per minute per kg ^{01}. Values determined over a dose range of 15 to 80 mcg/kg in nongeriatric adults ^{{01} {03} {16} {20}}, with 25 mcg/kg in geriatric patients ^{{03} {16}}, and with 15 mcg/kg in patients undergoing hepatic transplantation ^{{03} {20}} are all within this range.
        Renal failure (patients undergoing transplantation)—About 1.23 (range, 0.48 to 2.4) mL per minute per kg ^{01}.




Precautions to Consider

Carcinogenicity

Carcogenicity studies have not been done ^{01}.

Mutagenicity

No mutagenicity was detected in the Ames Salmonella assay, mouse lymphoma assay, and human lymphocyte assay ^{01}. However, statistically significant increases in the incidence of structural abnormalities, relative to vehicle controls, occurred in the in vivo rat bone marrow cytogenic assay in male rats receiving 0.1 mg per kg of body weight (mg/kg) (0.625 mg per square meter of body surface area [mg/m ²]) when the animals were sacrificed 6 hours, but not 24 or 48 hours, after administration. Structural abnormalities also occurred in female rats administered 0.2 mg/kg (1.25 mg/m ²) when the animals were sacrificed 24 hours, but not 6 or 48 hours, after administration. Abnormalities did not occur in male or female rats receiving 0.3 mg/kg (1.875 mg/m ²) at any time after administration. Because of the lack of a dose-dependent effect, the likelihood that the abnormalities found in this study were treatment-related or are clinically significant is low ^{01}.

Pregnancy/Reproduction
Fertility—
Studies have not been done ^{01}.

Pregnancy—
Adequate and well-controlled studies have not been done in pregnant women.

No maternal or fetal toxicity or teratogenicity was found in animal studies performed in nonventilated mice and rats receiving subcutaneous injections of subparalyzing doses.

FDA Pregnancy Category C ^{01}.


Labor and delivery—

Doxacurium has not been studied in obstetrics (labor, vaginal delivery, or cesarean section). Doxacurium is not recommended for cesarean section because its duration of action exceeds the expected duration of the surgical procedure ^{01}.

Breast-feeding

It is not known whether doxacurium is distributed into breast milk ^{01}.

Pediatrics

Neonates—Doxacurium is not approved for use in neonates by drug regulatory agencies in the U.S. and Canada ^{{01} {02}}. Doxacurium injection contains benzyl alcohol, which is not recommended for administration to neonates. A fatal toxic syndrome consisting of metabolic acidosis, central nervous system (CNS) depression, respiratory problems, renal failure, hypotension, and possibly seizures and intracranial hemorrhages has been associated with administration of excessive doses of this preservative to neonates. A doxacurium dose of 0.05 mg per kg of body weight includes 0.45 mg per kg of body weight of benzyl alcohol. This is less than 1% of the benzyl alcohol load associated with toxicity ^{68}.

Infants—Doxacurium is not approved for use in infants and children up to 2 years of age ^{01}. However, doxacurium has been studied in a limited number of infants and children up to 2 years of age. A study that included fifteen infants up to 11 months of age found that the ED ₅₀ and ED ₇₅ of doxacurium in infants are about one half those observed in children 3 to 10 years of age ^{61}.

Children 2 to 12 years of age—Children are less sensitive to the effects of doxacurium than are adults or infants. Higher doses (on a mcg/kg basis) are required to achieve comparable levels of neuromuscular blockade ^{{01} {08} {10} {15}}. Even with higher doses, the onset of action ^{{01} {08}}, the duration of clinical effect (time for the twitch response to peripheral stimulation to return to 25% of the control value) ^{{01} {08} {10}}, and the recovery index (time for the spontaneous recovery from 25% to 75% of the twitch response to peripheral stimulation) are all significantly shorter in children than in adults ^{{01} {08}}.

There may be a high incidence of myopathy in pediatric patients who receive doxacurium to facilitate mechanical ventilation in intensive care units. In a trial in fourteen pediatric patients 6 months to 10 years of age who received doxacurium in intensive care units for 4.7 to 12.3 days, prolonged recovery was observed in over 40% of the patients ^{60}.


Geriatrics


Appropriate studies performed to date have shown that elderly patients may be more sensitive than younger adults to the neuromuscular blocking effect of doxacurium ^{01}. However, the time to maximum block is longer in elderly patients ^{{01} {16} {59}}. The duration of clinical effect tends to be longer and more variable in elderly patients ^{{01} {16} {59}}. Also, elderly patients are more likely to have age-related renal function impairment, which may also increase sensitivity to, and the duration of action of, doxacurium ^{01}. The risk of an undesirably prolonged duration of effect in geriatric patients may be reduced by reducing initial dosage and titrating additional doses to achieve the desired response ^{01}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
Some of the following interactions have not been documented with doxacurium. However, because they have been reported to occur with other nondepolarizing neuromuscular blocking agents, the possibility of a significant interaction with doxacurium must be considered.

» Aminoglycosides^{{01}{36}{63}{64}{65}{67}} , possibly including oral neomycin (if significant quantities are absorbed in patients with renal function impairment) or
Anesthetics, parenteral-local^{01}{36} (large doses leading to significant plasma concentrations) or
Bacitracin or^{01}
» Capreomycin or
» Citrate-anticoagulated blood (massive transfusions) or
» Clindamycin or^{01}
Colistin or^{01}{36}
Colistimethate sodium or^{01}{36}
Lidocaine (intravenous doses > 5 mg/kg) or
» Lincomycin or^{01}{36}
» Polymyxins or^{01}{36}
Procaine (intravenous) or
Tetracyclines or^{01}{36}
Trimethaphan (large doses)    (neuromuscular blocking activity of these medications may be additive to that of neuromuscular blocking agents; increased or prolonged respiratory depression or paralysis [apnea] may occur but is of minor clinical significance while the patient is being mechanically ventilated; however, reversal agents have sometimes been ineffective in reversing neuromuscular blockade potentiated by aminoglycosides, clindamycin, lincomycin, or polymyxins ^{36}; caution and careful monitoring of the patient are recommended during and following concurrent or sequential use, especially if there is a possibility of incomplete reversal of neuromuscular blockade postoperatively)


Analgesics, opioid (narcotic), especially those commonly used as adjuncts to anesthesia    (central respiratory depressant effects of opioid analgesics may be additive to the respiratory depressant effects of neuromuscular blocking agents; increased or prolonged respiratory depression or paralysis [apnea] may occur but is of minor clinical significance while the patient is being mechanically ventilated; however, caution and careful monitoring of the patient are recommended during and following concurrent or sequential use, especially if there is a possibility of incomplete reversal of neuromuscular blockade postoperatively)

    (concurrent use of a neuromuscular blocking agent prevents or reverses muscle rigidity induced by sufficiently high doses of most opioid analgesics, especially alfentanil, fentanyl, or sufentanil)


Anesthetics, hydrocarbon inhalation^{01}{50}    (neuromuscular blocking activity of inhalation hydrocarbon anesthetics, especially enflurane or isoflurane, may be additive to that of nondepolarizing neuromuscular blocking agents; a reduction of doxacurium dosage may be necessary when it is given after steady-state anesthesia with one of these anesthetics has been established; the duration of block may be as much as 25% longer when doxacurium is used concurrently with enflurane, halothane, or isoflurane ^{01})


Antihypertensives or other hypotension-inducing medications or
Bradycardia-inducing medications    (doxacurium does not counteract hypotension or bradycardia induced by other medications or vagal stimulation; the incidence and/or severity of these effects may be increased, especially in patients with compromised cardiac function and in patients receiving two or more medications that may decrease heart rate and/or blood pressure [e.g., benzodiazepines, beta-adrenergic blocking agents, calcium channel blocking agents, opioid analgesics] prior to and/or during surgery ^{12})


Antimyasthenics or
Edrophonium    (these agents antagonize the effects of nondepolarizing neuromuscular blocking agents; parenteral neostigmine or pyridostigmine are indicated to reverse neuromuscular blockade following surgery; edrophonium at a dose of 1 mg/kg is not recommended for reversal of moderate to deep levels of doxacurium-induced blockade because it has been reported to be less effective than neostigmine [dose of 60 or 80 mcg/kg (0.06 or 0.08 mg/kg)] ^{{01} {15} {21}}; use of pyridostigmine for reversal of doxacurium-induced blockade has not been studied ^{01})

    (neuromuscular blocking agents may antagonize the effects of antimyasthenics on skeletal muscle; temporary dosage adjustment may be required to control symptoms of myasthenia gravis following surgery)


Calcium channel blocking agents^{28}{36}{37}    (although an interaction with doxacurium has not been documented, verapamil and nifedipine have been shown to potentiate the effects of several other neuromuscular blocking agents; also, difficulty in reversing verapamil-potentiated neuromuscular blockade with a single dose of neostigmine has been reported)


Calcium salts    (calcium salts may reverse the effects of nondepolarizing neuromuscular blocking agents)


Carbamazepine and/or^{01}{15}{24}
Phenytoin^{{01}{15}{24}{25}}    (resistance to the effects of doxacurium, leading to a lengthening of the time needed to achieve adequate skeletal muscle relaxation and to significantly accelerated recovery from an initial or supplemental dose, may occur in patients receiving chronic carbamazepine and/or phenytoin therapy)


Lithium or^{01}{36}
Magnesium salts, parenteral or^{01}{36}
» Procainamide or^{01}
» Quinidine^{01}{36}    (these medications may enhance the blockade produced by the neuromuscular blocking agents; increased or prolonged respiratory depression or paralysis [apnea] may occur but is of minor clinical significance while the patient is being mechanically ventilated; however, caution and careful monitoring of the patient are recommended during and following concurrent or sequential use, especially if there is a possibility of incomplete reversal of neuromuscular blockade postoperatively)


Neuromuscular blocking agents, other    (prior administration of succinylcholine [for endotracheal intubation] does not potentiate the effects of doxacurium, provided that doxacurium is administered after recovery from the effects of succinylcholine has begun ^{{01} {22}})

    (administration of doxacurium in conjunction with other nondepolarizing neuromuscular blocking agents has not been studied ^{01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
Burns    (doxacurium has not been studied in burn patients; the possibility of resistance, depending on the age and size of the burn, should be considered ^{01})


» Cachexia or debilitation    (prolonged neuromuscular block may occur ^{01})


Carcinoma, bronchogenic    (duration of action of neuromuscular blocking agents may be prolonged)


Dehydration or
Electrolyte or acid-base imbalance^{01} , especially
Hypokalemia    (action of neuromuscular blocking agents may be altered ^{01}; neuromuscular blockade is usually counteracted by alkalosis and enhanced by acidosis, but mixed imbalances may be present, leading to unpredictable responses ^{29})

    (serum potassium determinations may be advisable prior to administration of a nondepolarizing neuromuscular blocking agent, because hypokalemia tends to enhance the blockade produced by these medications; adjustment of dosage of the neuromuscular blocking agent, or correction of potassium concentration prior to administration, may be needed; increased or prolonged respiratory depression or paralysis [apnea] may occur but is of minor clinical significance while the patient is being mechanically ventilated; however, caution and careful monitoring of the patient are recommended during and following concurrent or sequential use, especially if there is a possibility of incomplete reversal of neuromuscular blockade postoperatively ^{44})


Hepatic function impairment    (patients with hepatic failure undergoing hepatic transplantation appear less sensitive to the effects of doxacurium than patients with normal hepatic function; a comparative study [in which the same dose was administered under the same type of anesthesia] indicated a tendency toward a slower onset of action and achievement of less intense neuromuscular blockade [maximum block of only 70% and an unusally high incidence of failure to produce more than 50% block] in the hepatic failure patients; however, there was also a tendency toward a prolonged duration of clinical effect in those patients with hepatic failure in whom more than 50% block was achieved ^{{01} {20}})

    (doxacurium has not been studied in patients with lesser degrees of hepatic function impairment; caution is recommended ^{01})


Hypothermia    (intensity and duration of action of nondepolarizing neuromuscular blocking agents may be increased ^{38})


Myasthenia gravis or
Myasthenic syndrome (Eaton-Lambert syndrome)    (increased risk of severe and prolonged muscle paralysis or weakness; a neuromuscular blocking agent with a shorter duration of action may be preferable ^{01} [although caution is required even with shorter-acting agents])


Pulmonary function impairment or
Respiratory depression    (risk of additive respiratory depression or impairment)


» Renal function impairment    (clearance of doxacurium is decreased, leading to a prolonged elimination half-life and duration of action, in patients with end-stage renal disease undergoing renal transplantation ^{{01} {03} {20}}; clearance continues to be decreased after the transplanted kidney begins functioning ^{20}; these patients may also be more sensitive to the effects of doxacurium than patients with normal renal function ^{01}; use of a neuromuscular blocking agent with a more predictable duration of action in patients with renal function impairment, i.e., atracurium or vecuronium, may be preferred ^{45})


Sensitivity to doxacurium
Caution is also advised if a long-acting neuromuscular blocking agent such as doxacurium is used to assist endotracheal intubation in a patient with a potentially difficult airway; some anesthesiologists recommend that an endotracheal tube be inserted (with the assistance of a short-acting agent) before a long-acting agent is given to such a patient^{46}


Side/Adverse Effects

Note: Unlike gallamine and pancuronium, doxacurium has no vagolytic activity ^{{01} {03} {04} {05} {06} {07} {08} {11} {13} {16} {19}}. Also, histamine release following administration of doxacurium appears minimal ^{{01} {03} {07} {57}}, although isolated cases of increased serum histamine ^{04} or symptoms possibly associated with histamine release (hypotension ^{{01} {11} {26}}, cutaneous flushing ^{{11} {26}}, urticaria ^{01}, bronchospasm ^{01}, or wheezing) have been reported. Therefore, doxacurium causes minimal hemodynamic disturbance ^{{01} {11} {19}}, although bradycardia and/or hypotension may occur because doxacurium does not counteract the bradycardia and/or hypotension induced by other medications (e.g., anesthetics, opioid analgesics) or vagal stimulation ^{01}.
Doxacurium failed to trigger malignant hyperthermia in one study in malignant hyperthermia–susceptible swine (in doses up to four times the ED ₉₅) ^{14}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention ^{01}
Incidence rare (< 0.1–0.3%)
    
Bronchospasm^{01}
    
double vision^{01}
    
fever^{01}
    
flushing^{01}
    
hypotension^{01}
    
injection site reaction^{01}
    
prolonged paralysis^{01}
    
urticaria^{01}
    
wheezing^{01}





Overdose
For specific information on the agents used in the management of doxacurium overdose see:
   • Atropine and/or Glycopyrrolate in Anticholinergics/Antispasmodics (Systemic) monograph;
   • Neostigmine in Antimyasthenics (Systemic) monograph.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance—not necessarily inclusive:
Acute effects
    
Apnea^{01}
    
prolonged paralysis^{01}


For treatment of overdose
Recommended treatment includes maintaining a patent airway and assisting ventilation until adequate recovery has occurred ^{01}.


Specific treatment:
An anticholinesterase agent, e.g., neostigmine (40 to 80 mcg/kg, depending on the dose of doxacurium) ^{48} can be administered to antagonize the action of doxacurium ^{{01} {04} {15} {21}}. It is recommended that reversal of doxacurium-induced neuromuscular blockade be attempted only after some spontaneous recovery, as demonstrated using a peripheral nerve stimulator, has taken place. Recovery will not occur as rapidly if the antagonist is administered earlier ^{{01} {04} {15} {49}}. Also, higher doses of the anticholinesterase may be needed when more profound levels of block are present (three or fewer responses to train-of-four stimulation) at the time of reversal ^{{01} {48}}. Recovery of the single twitch response to 80% of the control value with recommended doses of neostigmine, when administered after 25% spontaneous recovery has occurred, usually occurs in about 5 minutes ^{{04} {19}}; 90 to 95% recovery usually occurs within 20 ^{{01} {04} {19}} (range, 7 to 55) minutes ^{01}. However, recovery of the response to train-of-four stimulation (T ₄:T ₁ ratio) is slower than recovery of the response to single twitch stimulation ^{{08} {15} {19}}. A T ₄:T ₁ ratio of 0.7 generally indicates 90 to 95% recovery ^{51}. Edrophonium (1 mg per kg of body weight) does not antagonize the effects of doxacurium as rapidly as neostigmine does, even when given after > 25% spontaneous recovery has occurred ^{{01} {15}}, and is not recommended for reversing moderate to deep levels of block (< 60% recovery) ^{01}. Use of pyridostigmine for antagonism of doxacurium has not been studied ^{01}. It is recommended that a suitable anticholinergic agent (e.g., atropine, glycopyrrolate) ^{52} be administered prior to or concurrently with the antagonist to counteract its side effects. However, use of an antagonist is merely an adjunct to, and not to be substituted for, the institution of measures to ensure adequate ventilation.



Monitoring:
The degree of the neuromuscular blockade can be monitored using a peripheral nerve stimulator ^{01}. The patient should be monitored following successful antagonism, because the duration of action of doxacurium may exceed that of the antagonist ^{01}.



Supportive care for apnea or prolonged paralysis:
An adequate airway should be maintained and ventilation should be assisted or controlled as needed. Ventilatory assistance should be continued until adequate spontaneous ventilation can be maintained. Ventilatory assistance must be continued until the patient can maintain an adequate ventilatory exchange unassisted. Administration of a sedative or an anxiolytic may be needed if paralysis continues or recurs and/or mechanical ventilation is maintained after the patient is awake ^{{47} {53}}.



General Dosing Information
Neuromuscular blocking agents have no clinically significant ^{30} effect on consciousness or the pain threshold; therefore, when used as an adjunct to surgery, the neuromuscular blocking agent should always be used with adequate anesthesia or sedation ^{{01} {47}}.

Since neuromuscular blocking agents may cause respiratory depression, they should be used only by those individuals experienced in the techniques of tracheal intubation, artificial respiration, and the administration of oxygen under positive pressure; facilities for these procedures should be immediately available ^{01}.

Doxacurium is intended for intravenous administration only ^{01}.

The stated doses are intended as guidelines. Actual dosage must be individualized. It is recommended that a peripheral nerve stimulator be used to monitor response, need for additional doses, and reversal ^{01}.

The ED ₉₅ (dose required to produce maximum [95%] suppression of the adductor pollicis muscle twitch response to ulnar nerve stimulation) is about 25 (range, 20 to 33) mcg per kg of body weight (mcg/kg) ^{01}. The ED ₉₅ may be higher in patients with hepatic failure than in patients with normal hepatic function ^{20}.

When nondepolarizing neuromuscular blocking agents are administered after anesthesia with a volatile inhalation anesthetic has been established, a reduction in dosage, as determined using a peripheral nerve stimulator, may be required ^{{01} {15} {17} {20}}. Halothane may cause less potentiation of doxacurium than either enflurane or isoflurane ^{{01} {17} {20}}. However, in one study, administration of 15 mcg/kg of doxacurium with isoflurane (the dose having been selected as approximating the ED ₉₅ for that anesthetic) produced maximum neuromuscular blockade of only 70% in patients undergoing hepatic transplantation ^{{01} {20}} and only 86% in patients with normal hepatic function ^{20}.

The ED ₉₅ in children 2 to 12 years of age (halothane anesthesia) is about 30 (range, 12 to 52) mcg/kg ^{{01} {15}}.

A reduction of initial dosage may be advisable in geriatric, very ill, or debilitated patients; patients with impaired renal function, neuromuscular disease, severe electrolyte abnormalities, or carcinomatosis; and other patients in whom there is a risk of potentiation of neuromuscular blockade or difficulty with reversal ^{01}. Supplemental doses should be titrated according to patient response ^{01}.

Higher initial doses may be needed in burn patients and in patients with hepatic failure ^{01}. However, clinically effective block, once attained in patients with hepatic failure, may persist somewhat longer than in patients with normal hepatic function ^{01}.

For obese patients (> 30% above ideal body weight for height), dosage of doxacurium should be calculated on the basis of ideal body weight ^{01}.

Experience with use of doxacurium in critically ill patients to facilitate mechanical ventilation is limited. In a trial in 17 adult patients who received doxacurium in intensive care units for a mean of 2.7 ± 0.5 (range, 0.8 to 6.8) days, no evidence of tachyphylaxis, accumulation, or prolonged recovery was observed ^{01}. In a second trial in eight adult patients with head trauma who received doxacurium in an intensive care unit for a mean of 66 ± 12 hours, no evidence of prolonged recovery was observed, and intracranial pressure was not increased ^{62}. However, in a trial in 14 pediatric patients 6 months to 10 years of age who received doxacurium in intensive care units for 4.7 to 12.3 days, prolonged recovery was observed in more than 40% of the patients ^{60}.


Parenteral Dosage Forms

Note: The dosing and the strength of the dosage form available are expressed in terms of doxacurium base.

DOXACURIUM CHLORIDE INJECTION

Usual adult dose
Skeletal muscle paralysis


Initial ^{01}:


For endotracheal intubation and surgical relaxation—
Intravenous, 50 mcg (0.05 mg) (base) per kg of body weight, to provide adequate intubating conditions in about five minutes and about one hundred minutes of relaxation, or

Intravenous, 80 mcg (0.08 mg) (base) per kg of body weight, to provide adequate intubating conditions in about four minutes and an average of one hundred sixty minutes of relaxation ^{01}.

Note: Satisfactory intubating conditions are attained more slowly when initial doses lower than 50 mcg (0.05 mg) are administered ^{01}.




For surgical relaxation only, following succinylcholine-assisted endotracheal intubation—
Intravenous, 25 mcg (0.025 mg) (base) per kg of body weight, to provide an average of sixty minutes of relaxation ^{01}. Higher doses may be used if a longer duration of relaxation is required ^{01}.




Maintenance:


Intravenous, to be administered after the twitch response to an initial dose has returned to about 25% of the control value or after reappearance of the second twitch response to train-of-four stimulation ^{{01} {54}}—
5 mcg (0.005 mg) (base) per kg of body weight, to provide about thirty minutes of relaxation, or

10 mcg (0.01 mg) (base) per kg of body weight, to provide about forty-five minutes of relaxation.

Note: Higher or lower maintenance doses may be given, depending on the desired duration of action.
The interval between maintenance doses is subject to considerable interindividual variability.





Usual pediatric dose
Skeletal muscle paralysis
Children up to 2 years of age: Dosage has not been established ^{01}.

Children 2 to 12 years of age (inhalation [halothane] anesthesia): Intravenous, 30 mcg (0.03 mg) (base) per kg of body weight, to provide maximum block in about seven minutes and about thirty minutes of relaxation ^{01}, or

Intravenous, 50 mcg (0.05 mg) (base) per kg of body weight, to provide maximum block in about four minutes and about forty-five minutes of relaxation.


Note: Maintenance doses are generally required more frequently than in adults.


Strength(s) usually available
U.S.—


1 mg per mL (Rx) [Nuromax (0.9% benzyl alcohol)]

Canada—


1 mg per mL (Rx) [Nuromax (0.9% benzyl alcohol)]

Packaging and storage:
Store between 15 and 25 °C (59 and 77 °F) ^{01}. Protect from freezing ^{01}.

Preparation of dosage form:
If necessary, doxacurium chloride injection may be diluted up to 1 in 10 with 5% dextrose injection or 0.9% sodium chloride injection ^{01}.

Stability:
Doxacurium chloride injection is stable when diluted up to 1 in 10 with 5% dextrose injection or 0.9% sodium chloride injection, when the diluted product is stored in polypropylene syringes and kept at a temperature of 5 to 25 °C (41 to 77 °F) for up to 24 hours ^{01}.

Diluting the injection diminishes the effectiveness of the preservative in the formulation. Careful attention to aseptic technique is required. It is recommended that the injection be administered immediately after dilution, and that any unused portion of the diluted injection be discarded after 8 hours ^{01}.

Doxacurium chloride injection is compatible (for Y-site administration) with 5% dextrose injection, 0.9% sodium chloride injection, 5% dextrose and 0.9% sodium chloride injection, and lactated Ringer's injection, and, when the following are diluted as recommended by the manufacturer, with alfentanil hydrochloride injection, fentanyl citrate injection, and sufentanil citrate injection ^{01}.

Incompatibilities:
Doxacurium chloride injection is acidic and may not be compatible with alkaline solutions having a pH > 8.5 (e.g., barbiturate injections) ^{01}.

Revised: 05/03/1999

References

1. Nuromax package insert (Glaxo Wellcome—US), Rev 12/97, Rec 11/98.
   

2. Nuromax package insert (Glaxo Wellcome—Canada), Rev 12/96, Rec 3/97.
   

3. Savarese JJ, Wastila WB, Rudd GD, et al. Pharmacodynamics and pharmacokinetics of doxacurium chloride (BW A938U): background and overview. J Cardiothorac Anesth 1990; 4 Suppl 4: 14-9.
   

4. Murray DJ, Mehta MP, Choi WW, et al. The neuromuscular blocking and cardiovascular effects of doxacurium chloride in patients receiving nitrous oxide narcotic anesthesia. Anesthesiology 1988; 69: 472-7.
   

5. Stoops CM, Curtis CA, Kovach DA, et al. Hemodynamic effects of doxacurium chloride in patients receiving oxygen–sufentanil anesthesia for coronary artery bypass grafting or valve replacement. Anesthesiology 1988; 69: 365-70.
   

6. Reich DL, Konstadt SN, Thys DM, et al. Effects of doxacurium chloride on biventricular cardiac function in patients with cardiac disease. Br J Anaesth 1989; 63: 675-81.
   

7. Forbes RB, Murray DJ. Review of the hemodynamic profile of doxacurium chloride in healthy patients. J Cardiothorac Anesth 1990; 4 Suppl 4: 24-7.
   

8. Sarner JB, Brandom BW, Cook DR, et al. Clinical pharmacology of doxacurium chloride (BW A938U) in children. Anesth Analg 1988; 67: 303-6.
   

9. Murray DJ, Mehta MP, Sokoll MD, et al. The neuromuscular pharmacology of BW A938U during isoflurane anesthesia [abstract]. Anesth Analg 1987; 66: S191.
   

10. Goudsouzian NG, Alifimoff JK, Liu LM, et al. Neuromuscular and cardiovascular effects of doxacurium in children anesthetized with halothane. Br J Anaesth 1989; 62: 263-8.
    

11. Reich DL, Thys DM, Guffin AV, et al. The hemodynamic effects of doxacurium during abdominal surgery. J Cardiothorac Anesth 1990; 4 Suppl 4: 28-30.
    

12. Estafanous FG. Anesthetics and muscle relaxants in patients with heart disease: historical perspective. J Cardiothorac Anesth 1990; 4 Suppl 4: 3-13.
    

13. Flynn PJ, Goldhill DR. Hemodynamic effects of neuromuscular blocking agents. J Cardiothorac Anesth 1990; 4 Suppl 4: 31-7.
    

14. Sufit RL, Kreul JF, Bellay YM, et al. Doxacurium and mivacurium do not trigger malignant hyperthermia in susceptible swine. Anesth Analg 1990; 71: 285-7.
    

15. Lynam DP. Clinical neuromuscular pharmacology of doxacurium chloride. J Cardiothorac Anesth 1990; 4 Suppl 4: 20-3.
    

16. Dresner DL, Basta SH, Ali HH, et al. Pharmacokinetics and pharmacodynamics of doxacurium in young and elderly patients during isoflurane anesthesia. Anesth Analg 1990; 71: 498-502.
    

17. Katz JA, Fragen RJ, Shanks CA, et al. Dose-response relationships of doxacurium chloride in humans during anesthesia with nitrous oxide and fentanyl, enflurane, isoflurane, or halothane. Anesthesiology 1989; 70: 432-6.
    

18. Lynam DP, Caldwell JE, Miller RD. Doxacurium chloride pharmacology during narcotic, isoflurane, and halothane anesthesia [abstract]. Anesth Analg 1989; 68: S321.
    

19. Lennon RL, Hosking MP, Houck PC, et al. Doxacurium chloride for neuromuscular blockade before tracheal intubation and surgery during nitrous oxide–oxygen–narcotic–enflurane anesthesia. Anesth Analg 1989; 68: 255-60.
    

20. Cook DR, Freeman JA, Lai AA, et al. Pharmacokinetics and pharmacodynamics of doxacurium in normal patients and in those with hepatic or renal failure. Anesth Analg 1991; 72: 145-50.
    

21. Cashman JN, Luke JJ, Jones RM. Neuromuscular block with doxacurium (BW A938U) in patients with normal or absent renal function. Br J Anaesth 1990; 64: 186-92.
    

22. Katz JA, Fragen RJ, Shanks CA, et al. The effects of succinylcholine on doxacurium-induced neuromuscular blockade. Anesthesiology 1988; 69: 604-7.
    

23. Lynam DP, Caldwell JE, Miller RD. Onset time, maximum blockade, spontaneous recovery and clinical duration of action of doxacurium chloride during narcotic anesthesia with and without the prior administration of succinylcholine [abstract]. Anesthesiology 1988; 69: A884.
    

24. Desai P, Hewitt PB, Jones RM. Influence of anticonvulsant therapy on doxacurium & pancuronium-induced paralysis [abstract]. Anesthesiology 1989; 71: A784.
    

25. Ornstein E, Matteo RS, Halevy JD, et al. Accelerated recovery from doxacurium in carbamazepine treated patients [abstract]. Anesthesiology 1989; 71: A785.
    

26. Reich DL. Transient systemic arterial hypotension and cutaneous flushing in response to doxacurium chloride. Anesthesiology 1989; 71: 783-5.
    

27. Ornstein E, Matteo RS, Weinstein HA, et al. Accelerated recovery from doxacurium-induced neuromuscular blockade in patients receiving chronic anticonvulsant therapy. J Clin Anesth 1991; 3: 108-11.
    

28. Jones RM, Cashman JN, Casson WR, et al. Verapamil potentiation of neuromuscular blockade: failure of reversal with neostigmine but prompt reversal with edrophonium. Anesth Analg 1985; 64: 1021-5.
    

29. Panel comment, 1991.
    

30. Panel comment; 7/91.
    

31. Panel comments; 7/91.
    

32. Reviewers' consensus on monograph draft 7/91.
    

33. Miller RD, editor. Anesthesia. 4th ed. New York: Churchill Livingston Inc; 1994. p. 430-1.
    

34. Gilman AG, Rall TW, Nies AS, et al, editors. Goodman and Gilman's The pharmacological basis of therapeutics. 8th Ed. New York: Pergamon Press; 1990. p. 96-178.
    

35. Reviewers' consensus on monograph draft 10/91.
    

36. Ostergaard D, Engbaek J, Viby-Mogensen J. Adverse reactions and interactions of the neuromuscular blocking agents. Med Toxicol Adverse Drug Exp 1989; 4: 351-68.
    

37. Jones RM, Cashman JN, Casson WR, et al. Verapamil potentiation of neuromuscular blockade: failure of reversal with neostigmine but prompt reversal with edrophonium. Anesth Analg 1985; 64: 1021-5.
    

38. Panel comments, 1991.
    

39. Manufacturer comment; draft 7/91.
    

40. Manufacturer comment, 7/91.
    

41. Panel comment, 7/91.
    

42. Manufacturer comment, 7/91.
    

43. Manufacturer comment, 7/91.
    

44. Panel comments, 7/91 and 10/91.
    

45. Panel consensus, 7/91.
    

46. Panel comment, 7/91.
    

47. Panel comments, 1991.
    

48. Panel comment, 7/91.
    

49. Panel comments, 1991.
    

50. Swen J, Rashkovsky OM, Ket JM, et al. Interaction between nondepolarizing neuromuscular blocking agents and inhalational anesthetics. Anesth Analg 1989; 69: 752-5.
    

51. Manufacturer comment, 10/91.
    

52. Panel comment, 7/91.
    

53. Panel comment, 10/91.
    

54. Panel comment, 10/91.
    

55. Manufacturer comment, 7/91.
    

56. Estafanous FG. Clinical experience with a new long-acting neuromuscular blocking agent. Proceedings of a symposium. J Cardiothorac Anesth 1990; 4 Suppl 4: 1-42.
    

57. Basta SJ, Savarese JJ, Ali HH. Clinical pharmacology of doxacurium chloride: a new long-acting nondepolarizing muscle relaxant. Anesthesiology 1988; 69: 478-86.
    

58. Canada JR, editor. USP dictionary of USAN and international drug names 1998. Rockville, MD: The United States Pharmacopeial Convention Inc; 1997. p. 254.
    

59. Martlew RA, Harper NJ. The clinical pharmacology of doxacurium in young adults and in elderly patients. Anaesthesia 1995; 50: 779-82.
    

60. Brandom BW, Yellon RF, Lloyd ME, et al. Recovery from doxacurium infusion administered to produce immobility for more than four days in pediatric patients in the intensive care unit. Anesth Analg 1997; 84: 307-14.
    

61. Taivainen TR, Meretoja OA. Potency of doxacurium in infants, children, and adolescents during N2O-O2-alfentanil anesthesia. J Clin Anesth 1996; 8: 225-8.
    

62. Prielipp RC, Robinson JC, Wilson JA, et al. Dose response, recovery, and cost of doxacurium as a continuous infusion in neurosurgical intensive care unit patients. Crit Care Med 1997; 25: 1236-41.
    

63. Burkett L, Bikhazi GB, Thomas KC Jr, et al. Mutual potentiation of the neuromuscular effects of antibiotics and relaxants. Anesth Analg 1979; 58: 107-15.
    

64. Singh YN, Marshall IG, Harvey AL. Some effects of the aminoglycoside antibiotic amikacin on neuromuscular and autonomic transmission. Br J Anaesth 1978; 50: 109-17.
    

65. Waterman PM, Smith RB. Tobramycin-curare interaction. Anesth Analg 1977; 56: 587-8.
    

66. Viljoen JF. Parenteral neomycin and muscle relaxants: two case reports of interest. S Afr Med J 1966; 40: 963-4.
    

67. Levanen J, Nordman R. Complete respiratory paralysis caused by a large dose of streptomycin and its treatment with calcium chloride. Ann Clin Res 1975; 7: 47-9.
    

68. Panel comment, 3/99.
    

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