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).

General

NUROMAX has no clinically significant effects on heart rate; therefore, NUROMAX will not counteract the bradycardia produced by many anesthetic agents or by vagal stimulation.

Neuromuscular blocking agents may have a profound effect in patients with neuromuscular diseases (e.g., myasthenia gravis and the myasthenic syndrome). In these and other conditions in which prolonged neuromuscular block is a possibility (e.g., carcinomatosis), the use of a peripheral nerve stimulator and a small test dose of NUROMAX are recommended to assess the level of neuromuscular block and to monitor dosage requirements. Shorter acting muscle relaxants than NUROMAX may be more suitable for these patients.

Resistance to nondepolarizing neuromuscular blocking agents may develop in patients with burns depending upon the time elapsed since the injury and the size of the burn. NUROMAX has not been studied in patients with burns.

Acid- base and/ or serum electrolyte abnormalities may potentiate or antagonize the action of neuromuscular blocking agents. The action of neuromuscular blocking agents may be enhanced by magnesium salts administered for the management of toxemia of pregnancy.

NUROMAX has not been studied in patients with asthma. No data are available to support the use of NUROMAX by intramuscular injection.

Renal and Hepatic Disease

NUROMAX has been studied in patients with end- stage kidney (n = 8) or liver (n = 7) disease undergoing transplantation procedures (see CLINICAL PHARMACOLOGY). The possibility of prolonged neuromuscular block in patients undergoing renal transplantation and the possibility of a variable onset and duration of neuromuscular block in patients undergoing liver transplantation must be considered when NUROMAX is used in such patients.

Obesity

Administration of NUROMAX on the basis of actual body weight is associated with a prolonged duration of action in obese patients (patients weighing ³ 30% more than ideal body weight for height) (see CLINICAL PHARMACOLOGY). Therefore, the dose of NUROMAX should be based upon ideal body weight in obese patients (see CLINICAL PHARMACOLOGY: Individualization of Dosages).

Malignant Hyperthermia (MH)

In a study of MH- susceptible pigs, NUROMAX did not trigger MH. NUROMAX has not been studied in MH-susceptible patients. Since MH can develop in the absence of established triggering agents, the clinician should be prepared to recognize and treat MH in any patient scheduled for general anesthesia.

Long-Term Use in the Intensive Care Unit (ICU)

Information on the use of NUROMAX in the ICU is limited. In a double-blind, randomized study, 17 patients received NUROMAX by intermittent bolus injection for a mean of 2.7 ± 0.5 days (range: 0.8 to 6.8 days) to facilitate mechanical ventilation. No evidence of tachyphylaxis, accumulation, or prolonged recovery was observed. The adverse experiences in patients receiving NUROMAX were consistent in type, severity, and frequency to those expected in a critically ill patient population. Since many ICU patients have hepatic and/ or renal failure, a prolonged duration of block should be anticipated in these patients after administration of NUROMAX.

WHENEVER THE USE OF NUROMAX OR ANY NEUROMUSCULAR BLOCKING AGENT IS CONTEMPLATED IN THE ICU, IT IS RECOMMENDED THAT NEUROMUSCULAR TRANSMISSION BE MONITORED CONTINUOUSLY DURING ADMINISTRATION WITH THE HELP OF A NERVE STIMULATOR. ADDITIONAL DOSES OF NUROMAX OR ANY OTHER NEUROMUSCULAR BLOCKING AGENT SHOULD NOT BE GIVEN BEFORE THERE IS A DEFINITE RESPONSE TO T₁, OR TO THE FIRST TWITCH. IF NO RESPONSE IS ELICITED, BOLUS ADMINISTRATION SHOULD BE DELAYED UNTIL A RESPONSE RETURNS.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis and fertility studies have not been performed. NUROMAX was evaluated in a battery of four short-term mutagenicity tests. It was nonmutagenic in the Ames Salmonella assay, in the mouse lymphoma assay, and in the human lymphocyte assay. In the in vivo rat bone marrow cytogenetic assay, statistically significant increases in the incidence of structural abnormalities, relative to vehicle controls, were observed in male rats dosed with 0.1 mg/ kg (0.625 mg/ m² ) NUROMAX and sacrificed at 6 hours, but not at 24 or 48 hours, and in female rats dosed with 0.2 mg/ kg (1.25 mg/ m² ) NUROMAX and sacrificed at 24 hours, but not at 6 or 48 hours. There was no increase in structural abnormalities in either male or female rats given 0.3 mg/ kg (1.875 mg/ m² ) NUROMAX and sacrificed at 6, 24, or 48 hours. Thus, the incidence of abnormalities in the in vivo rat bone marrow cytogenetic assay was not dose- dependent and, therefore, the likelihood that the observed abnormalities were treatment- related or clinically significant is low.

Pregnancy

Teratogenic Effect: Pregnancy Category C. Teratology testing in nonventilated, pregnant rats and mice treated subcutaneously with maximum subparalyzing doses of NUROMAX revealed no maternal or fetal toxicity or teratogenic effects. There are no adequate and well-controlled studies of NUROMAX in pregnant women. Because animal studies are not always predictive of human response and the doses used were subparalyzing, NUROMAX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Labor and Delivery

The use of NUROMAX during labor, vaginal delivery, or cesarean section has not been studied. It is not known whether NUROMAX administered to the mother has immediate or delayed effects on the fetus. The duration of action of NUROMAX exceeds the usual duration of operative obstetrics (cesarean section). Therefore, NUROMAX is not recommended for use in patients undergoing C-section.

Nursing Mothers

It is not known whether NUROMAX is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised following administration of NUROMAX to a nursing woman.

Pediatric Use

NUROMAX has not been studied in pediatric patients below the age of 2 years. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION for clinical experience and recommendations for use in children 2 to 12 years of age.)

Geriatric Use

Doxacurium has been used in elderly patients, including patients with significant cardiovascular disease. In elderly patients, the onset of maximum block is slower and the duration of neuromuscular block produced by doxacurium is more variable, and in some cases longer, than in young adult patients (see CLINICAL PHARMACOLOGY: Pharmacodynamics). As with other long-acting neuromuscular blocking agents, the possibility of prolonged block must be considered when doxacurium is administered to elderly patients, especially those known to have reduced liver or kidney function.

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