ZEMURON® (rocuronium bromide) INJECTION SHOULD BE ADMINISTERED IN CAREFULLY ADJUSTED DOSAGES 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 IMMEDIATELY AVAILABLE. IT IS RECOMMENDED THAT CLINICIANS ADMINISTERING NEUROMUSCULAR BLOCKING AGENTS SUCH AS ZEMURON® EMPLOY A PERIPHERAL NERVE STIMULATOR TO MONITOR DRUG RESPONSE, NEED FOR ADDITIONAL RELAXANT, AND ADEQUACY OF SPONTANEOUS RECOVERY OR ANTAGONISM.

ZEMURON® HAS NO KNOWN EFFECT ON CONSCIOUSNESS, PAIN THRESHOLD, OR CEREBRATION. THEREFORE, ITS ADMINISTRATION MUST BE ACCOMPANIED BY ADEQUATE ANESTHESIA OR SEDATION.

In patients with myasthenia gravis or myasthenic (Eaton-Lambert) syndrome, small doses of nondepolarizing neuromuscular blocking agents may have profound effects. In such patients, a peripheral nerve stimulator and use of a small test dose may be of value in monitoring the response to administration of muscle relaxants.

ZEMURON®, which has an acid pH, should not be mixed with alkaline solutions (e.g., barbiturate solutions) in the same syringe or administered simultaneously during intravenous infusion through the same needle.

Anaphylaxis

Although rare, severe anaphylactic reactions to neuromuscular blocking agents, including ZEMURON® (rocuronium bromide) Injection, have been reported. These reactions have, in some cases, been life threatening. Due to the potential severity of these reactions, the necessary precautions, such as the immediate availability of appropriate emergency treatment, should be taken.

Special precautions should be taken in patients who have had previous anaphylactic reactions to other neuromuscular blocking agents, since allergic cross-reactivity has been reported in this class of drugs.

Long-term Use in ICU

ZEMURON® (rocuronium bromide) Injection has not been studied for long-term use in the ICU. As with other nondepolarizing neuromuscular blocking drugs, apparent tolerance to ZEMURON® may develop rarely during chronic administration in the ICU. While the mechanism for development of this resistance is not known, receptor up-regulation may be a contributing factor. It is STRONGLY RECOMMENDED THAT NEUROMUSCULAR TRANSMISSION BE MONITORED CONTINUOUSLY DURING ADMINISTRATION AND RECOVERY WITH THE HELP OF A NERVE STIMULATOR. ADDITIONAL DOSES OF ZEMURON® OR ANY OTHER NEUROMUSCULAR BLOCKING AGENT SHOULD NOT BE GIVEN UNTIL THERE IS A DEFINITE RESPONSE (ONE TWITCH OF THE TRAIN-OF-FOUR) TO NERVE STIMULATION. Prolonged paralysis and/or skeletal muscle weakness may be noted during initial attempts to wean from the ventilator patients who have chronically received neuromuscular blocking drugs in the ICU. Therefore, ZEMURON® should only be used in this setting if, in the opinion of the prescribing physician, the specific advantages of the drug outweigh the risk.

Labor and Delivery

The use of ZEMURON® (rocuronium bromide) Injection in Cesarean section has been studied in a limited number of patients. ZEMURON® is not recommended for rapid sequence induction in Cesarean section patients (see CLINICAL PHARMACOLOGY - Clinical Trials).

Hepatic Disease

Since ZEMURON® (rocuronium bromide) Injection is primarily excreted by the liver, it should be used with caution in patients with clinically significant hepatic disease. ZEMURON® 0.6 mg/kg has been studied in a limited number of patients (n=9) with clinically significant hepatic disease under steady-state isoflurane anesthesia. After ZEMURON® 0.6 mg/kg, the median (range) clinical duration of 60 (35–166) minutes was moderately prolonged compared to 42 minutes in patients with normal hepatic function. The median recovery time of 53 minutes was also prolonged in patients with cirrhosis compared to 20 minutes in patients with normal hepatic function. Four of eight patients with cirrhosis, who received ZEMURON® 0.6 mg/kg under opioid/nitrous oxide/oxygen anesthesia, did not achieve complete block. These findings are consistent with the increase in volume of distribution at steady state observed in patients with significant hepatic disease (see CLINICAL PHARMACOLOGY - Pharmacokinetics). If used for rapid sequence induction in patients with ascites, an increased initial dosage may be necessary to assure complete block. Duration will be prolonged in these cases. The use of doses higher than 0.6 mg/kg has not been studied.

Renal Failure

Due to the limited role of the kidney in the excretion of ZEMURON® (rocuronium bromide) Injection, usual dosing guidelines should be adequate. ZEMURON® 0.6 mg/kg has been evaluated in three single center trials (n=30, ages 19 to 61 years) in patients undergoing renal transplant surgery, or shunt procedures in preparation for dialysis. After ZEMURON® 0.6 mg/kg, the time to maximum block was about 1 to 2 minutes and was not different from patients without renal dysfunction. The mean (SD) clinical duration of 54 (22) minutes was not considered prolonged compared to 46 (12) minutes in normal patients; however, there was substantial variation (range, 22–90 minutes). The spontaneous recovery rate from 25 to 75% of control in renal dysfunction patients of 27 (11) minutes was similar to 28 (20) minutes in normal patients (see CLINICAL PHARMACOLOGY - Pharmacokinetics).

Anaphylaxis

There have been rare reports of severe anaphylactic reactions to ZEMURON® (rocuronium bromide) Injection, including some that have been life threatening. Clinicians should be prepared for the possibility of these reactions and take the necessary precautions, including the immediate availability of emergency treatment (see WARNINGS).

Malignant Hyperthermia (MH)

In an animal study in MH-susceptible swine, the administration of ZEMURON® (rocuronium bromide) Injection did not appear to trigger malignant hyperthermia. ZEMURON® has not been studied in MH-susceptible patients. Because ZEMURON® is always used with other agents, and the occurrence of malignant hyperthermia during anesthesia is possible even in the absence of known triggering agents, clinicians should be familiar with early signs, confirmatory diagnosis and treatment of malignant hyperthermia prior to the start of any anesthetic.

Altered Circulation Time

Conditions associated with slower circulation time, e.g., cardiovascular disease or advanced age, may be associated with a delay in onset time. Because higher doses of ZEMURON® (rocuronium bromide) Injection produce a longer duration of action, the initial dosage should usually not be increased in these patients to reduce onset time; instead, when feasible, more time should be allowed for the drug to achieve onset of effect.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies in animals have not been performed to evaluate carcinogenic potential or impairment of fertility. Mutagenicity studies (Ames test, analysis of chromosomal aberrations in mammalian cells, and micronucleus test) conducted with ZEMURON® (rocuronium bromide) Injection did not suggest mutagenic potential.

Pregnancy

Pregnancy Category C

Developmental toxicology studies have been performed in pregnant, conscious, nonventilated rabbits and rats. Inhibition of neuromuscular function was the endpoint for high-dose selection. The maximum tolerated dose served as the high-dose and was administered intravenously three times a day to rats (0.3 mg/kg, 15 to 30% of human intubation dose of 0.6 to 1.2 mg/kg based on the body surface unit of mg/m²) from day 6 to 17 and to rabbits (0.02 mg/kg, 25% human dose) from day 6 to 18 of pregnancy. High-dose treatment caused acute symptoms of respiratory dysfunction due to the pharmacological activity of the drug. Teratogenicity was not observed in these animal species. The incidence of late embryonic death was increased at the high-dose in rats most likely due to oxygen deficiency. Therefore, this finding probably has no relevance for humans because immediate mechanical ventilation of the intubated patient will effectively prevent embryo-fetal hypoxia. However, there are no adequate and well-controlled studies in pregnant women. ZEMURON® (rocuronium bromide) Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Pediatric Use

The use of ZEMURON® (rocuronium bromide) Injection in pediatric patients less than 3 months of age and greater than 14 years of age has not been studied. See Pharmacodynamics subsection of CLINICAL PHARMACOLOGY and Use in Pediatrics subsection of DOSAGE AND ADMINISTRATION for clinical experience and recommendations for use in pediatric patients 3 months to 14 years of age.

Geriatric Use

ZEMURON® (rocuronium bromide) Injection was administered to 140 geriatric patients (≥65 years) in US clinical trials and 128 geriatric patients in European clinical trials. The observed pharmacokinetic profile for geriatric patients (n=20) was similar to that for other adult surgical patients (see CLINICAL PHARMACOLOGY). Onset time and duration of action were slightly longer for geriatric patients (n=43) in clinical trials. For clinical experiences and recommendations for use in geriatric patients, see Pharmacodynamics and Clinical Trials subsections of CLINICAL PHARMACOLOGY and Use in Geriatrics subsection of DOSAGE AND ADMINISTRATION.

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