Nuromax

Nuromax (doxacurium chloride) is a long-acting, nondepolarizing skeletal muscle relaxant for intravenous administration. Doxacurium chloride is [1α,2β(1'S*,2'R*)]-2,2'-[(1,4-dioxo-1,4-butanediyl)bis(oxy-3,1-propanediyl)]bis[1,2,3,4-tetrahydro-6,7,8-trimethoxy-2- methyl-1-[(3,4,5-trimethoxyphenyl)methyl]isoquinolinium] dichloride (meso form). The molecular formula is C56H78CI2N2O16 and the molecular weight is 1106.14. The compound does not partition into the 1-octanol phase of a distilled water/ 1-octanol system, i.e., the n-octanol:water partition coefficient is 0.

Doxacurium chloride is a mixture of three trans, trans stereoisomers, a dl pair [(1R,1'R,2S,2'S) and (1S,1'S,2R,2'R)] and a meso form (1R,1'S,2S,2'R). The meso form is illustrated below:

Nuromax Injection is a sterile, nonpyrogenic aqueous solution (pH 3.9 to 5.0) containing doxacurium chloride equivalent to 1 mg/mL doxacurium in Water for Injection. Hydrochloric acid may have been added to adjust pH. Nuromax Injection contains 0.9% w/v benzyl alcohol.

Nuromax SHOULD BE ADMINISTERED IN CAREFULLY ADJUSTED DOSAGE BY OR UNDER THE SUPERVISION OF EXPERIENCED CLINICIANS WHO ARE FAMILIAR WITH THE DRUG'S ACTIONS AND THE POSSIBLE COMPLICATIONS OF ITS USE. THE DRUG SHOULD NOT BE ADMINISTERED UNLESS FACILITIES FOR INTUBATION, ARTIFICIAL RESPIRATION, OXYGEN THERAPY, AND AN ANTAGONIST ARE WITHIN IMMEDIATE REACH. IT IS RECOMMENDED THAT CLINICIANS ADMINISTERING LONG-ACTING NEUROMUSCULAR BLOCKING AGENTS SUCH AS Nuromax EMPLOY A PERIPHERAL NERVE STIMULATOR TO MONITOR DRUG RESPONSE, NEED FOR ADDITIONAL RELAXANTS, AND ADEQUACY OF SPONTANEOUS RECOVERY OR ANTAGONISM.

Nuromax HAS NO KNOWN EFFECT ON CONSCIOUSNESS, PAIN THRESHOLD, OR CEREBRATION. TO AVOID DISTRESS TO THE PATIENT, NEUROMUSCULAR BLOCK SHOULD NOT BE INDUCED BEFORE UNCONSCIOUSNESS.

Nuromax Injection is acidic (pH 3.9 to 5.0) and may not be compatible with alkaline solutions having a pH greater than 8.5 (e.g., barbiturate solutions).

Nuromax Injection contains benzyl alcohol. In newborn infants, benzyl alcohol has been associated with an increased incidence of neurological and other complications which are sometimes fatal (see PRECAUTIONS - Pediatric Use).

Overdosage with neuromuscular blocking agents may result in neuromuscular block beyond the time needed for surgery and anesthesia. The primary treatment is maintenance of a patent airway and controlled ventilation until recovery of normal neuromuscular function is assured. Once evidence of recovery from neuromuscular block is observed, further recovery may be facilitated by administration of an anticholinesterase agent (e.g., neostigmine, edrophonium) in conjunction with an appropriate anticholinergic agent (see Antagonism of Neuromuscular Block below).

Antagonism of Neuromuscular Block

ANTAGONISTS (SUCH AS NEOSTIGMINE) SHOULD NOT BE ADMINISTERED PRIOR TO THE DEMONSTRATION OF SOME SPONTANEOUS RECOVERY FROM NEUROMUSCULAR BLOCK. THE USE OF A NERVE STIMULATOR TO DOCUMENT RECOVERY AND ANTAGONISM OF NEUROMUSCULAR BLOCK IS RECOMMENDED. T4/T1 SHOULD BE > ZERO BEFORE ANTAGONISM IS ATTEMPTED.

In an analysis of patients in whom antagonism of neuromuscular block was evaluated following administration of single doses of neostigmine averaging 0.06 mg/kg (range:  0.05 to 0.075) administered at approximately 25% T1 spontaneous recovery during balanced anesthesia, 71% of patients exhibited T4/T1≥ 0.7 before monitoring was discontinued. For these patients, the mean time to T4/T1≥ 0.7 was 19 minutes (range:  7 to 55). As with other long-acting nondepolarizing neuromuscular blocking agents, the time for recovery of neuromuscular function following administration of neostigmine is dependent upon the level of residual neuromuscular block at the time of attempted reversal; longer recovery times than those cited above may be anticipated when neostigmine is administered at more profound levels of block (i.e., at < 25% T1 recovery).

Patients should be evaluated for adequate clinical evidence of antagonism, e.g., 5-second head lift, and grip strength. Ventilation must be supported until no longer required. As with other neuromuscular blocking agents, physicians should be alert to the possibility that the action of the drugs used to antagonize neuromuscular block may wear off before the effects of Nuromax on the neuromuscular junction have declined sufficiently.

Antagonism may be delayed in the presence of debilitation, carcinomatosis, and the concomitant use of certain broad-spectrum antibiotics or anesthetic agents and other drugs which enhance neuromuscular block or separately cause respiratory depression (see PRECAUTIONS - Drug Interactions). Under such circumstances the management is the same as that of prolonged neuromuscular block.

In clinical trials, a dose of 1 mg/kg edrophonium was not as effective as a dose of 0.06 mg/kg neostigmine in antagonizing moderate to deep levels of neuromuscular block (i.e., < 60% T1 recovery). Therefore, the use of 1 mg/kg edrophonium is not recommended for reversal from moderate to deep levels of block. The use of pyridostigmine has not been studied.

Nuromax SHOULD ONLY BE ADMINISTERED INTRAVENOUSLY.

Nuromax, like other long-acting neuromuscular blocking agents, displays variability in the duration of its effect. The potential for a prolonged clinical duration of neuromuscular block must be considered when Nuromax is selected for administration. The dosage information provided below is intended as a guide only. Doses should be individualized (see CLINICAL PHARMACOLOGY -Individualization of Dosages). Factors that may warrant dosage adjustment include: advancing age, the presence of kidney or liver disease, or obesity (patients weighing ≥ 30% more than ideal body weight for height). The use of a peripheral nerve stimulator will permit the most advantageous use of Nuromax, minimize the possibility of overdosage or underdosage, and assist in the evaluation of recovery.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Adults

When administered as a component of a thiopental/narcotic induction-intubation paradigm as well as for production of long-duration neuromuscular block during surgery, 0.05 mg/kg (2 × ED95) Nuromax produces good-to-excellent conditions for tracheal intubation in 5 minutes in approximately 90% of patients. Lower doses of Nuromax may result in a longer time for development of satisfactory intubation conditions. Clinically effective neuromuscular block may be expected to last approximately 100 minutes on average (range: 39 to 232) following 0.05 mg/kg Nuromax administered to patients receiving balanced anesthesia.

An initial Nuromax dose of 0.08 mg/kg (3 × ED95) should be reserved for instances in which a need for very prolonged neuromuscular block is anticipated. In approximately 90% of patients, good-to-excellent intubation conditions may be expected in 4 minutes after this dose; however, clinically effective block may be expected to persist for as long as 160 minutes or more (range: 110 to 338) (see CLINICAL PHARMACOLOGY).

If Nuromax is administered during steady-state isoflurane, enflurane, or halothane anesthesia, reduction of the dose of Nuromax by one third should be considered.

When succinylcholine is administered to facilitate tracheal intubation in patients receiving balanced anesthesia, an initial dose of 0.025 mg/kg (ED95) Nuromax provides about 60 minutes (range: 9 to 145) of clinically effective neuromuscular block for surgery. For a longer duration of action, a larger initial dose may be administered.

Maintenance dosing will generally be required about 60 minutes after an initial dose of 0.025 mg/kg Nuromax or 100 minutes after an initial dose of 0.05 mg/kg Nuromax during balanced anesthesia. Repeated maintenance doses administered at 25% T1 recovery may be expected to be required at relatively regular intervals in each patient. The interval may vary considerably between patients. Maintenance doses of 0.005 and 0.01 mg/kg Nuromax each provide an average 30 minutes (range: 9 to 57) and 45 minutes (range: 14 to 108), respectively, of additional clinically effective neuromuscular block. For shorter or longer desired durations, smaller or larger maintenance doses may be administered.

Children

When administered during halothane anesthesia, an initial dose of 0.03 mg/kg (ED95) produces maximum neuromuscular block in about 7 minutes (range: 5 to 11) and clinically effective block for an average of 30 minutes (range: 12 to 54). Under halothane anesthesia, 0.05 mg/kg produces maximum block in about 4 minutes (range:  2 to 10) and clinically effective block for 45 minutes (range:  30 to 80). Maintenance doses are generally required more frequently in children than in adults. Because of the potentiating effect of halothane seen in adults, a higher dose of Nuromax may be required in children receiving balanced anesthesia than in children receiving halothane anesthesia to achieve a comparable onset and duration of neuromuscular block. Nuromax has not been studied in pediatric patients below the age of 2 years.

Compatibility

Nuromax Injection may not be compatible with alkaline solutions with a pH greater than 8.5 (e.g., barbiturate solutions).

Nuromax is compatible with:

• 5% Dextrose Injection, USP
• 0.9% Sodium Chloride Injection, USP
• 5% Dextrose and 0.9% Sodium Chloride Injection, USP
• Lactated Ringer's Injection, USP
• 5% Dextrose and Lactated Ringer's Injection
• Sufenta® (sufentanil citrate) Injection, diluted as directed
• Alfenta® (alfentanil hydrochloride) Injection, diluted as directed
• Sublimaze® (fentanyl citrate) Injection, diluted as directed

Nuromax diluted up to 1:10 in 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP has been shown to be physically and chemically stable when stored in polypropylene syringes at 5° to 25°C (41° to 77°F), for up to 24 hours. Since dilution diminishes the preservative effectiveness of benzyl alcohol, aseptic techniques should be used to prepare the diluted product. Immediate use of the diluted product is preferred, and any unused portion of diluted Nuromax should be discarded after 8 hours.

Nuromax Injection, 1 mg doxacurium in each mL.

5-mL Multiple-dose vials containing 0.9% w/v benzyl alcohol as a preservative (see WARNINGS). Tray of 10 (List No. 4437).

Storage

Store Nuromax Injection at room temperature of 15° to 25°C (59° to 77°F). DO NOT FREEZE.

US Patent No. 4,701,460

Nuromax is a registered trademark of GlaxoSmithKline, licensed for use by Abbott Laboratories.

Manufactured for Abbott Laboratories, North Chicago, IL 60064, USA

©Abbott 2003