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Zemuron

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Zemuron

Zemuron

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Appropriate Administration and Monitoring

ZEMURON 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, mechanical ventilation, 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 effect, need for additional doses, adequacy of spontaneous recovery or antagonism, and to decrease the complications of overdosage if additional doses are administered.

Anaphylaxis

Severe anaphylactic reactions to neuromuscular blocking agents, including ZEMURON, have been reported. These reactions have, in some cases (including cases with ZEMURON), been life threatening and fatal. Due to the potential severity of these reactions, the necessary precautions, such as the immediate availability of appropriate emergency treatment, should be taken. Precautions should also be taken in those patients who have had previous anaphylactic reactions to other neuromuscular blocking agents, since cross-reactivity between neuromuscular blocking agents, both depolarizing and nondepolarizing, has been reported.

Need for Adequate Anesthesia

ZEMURON has no known effect on consciousness, pain threshold, or cerebration. Therefore, its administration must be accompanied by adequate anesthesia or sedation.

Residual Paralysis

In order to prevent complications resulting from residual paralysis, it is recommended to extubate only after the patient has recovered sufficiently from neuromuscular block. Other factors which could cause residual paralysis after extubation in the post-operative phase (such as drug interactions or patient condition) should also be considered. If not used as part of standard clinical practice the use of a reversal agent should be considered, especially in those cases where residual paralysis is more likely to occur.

Long-Term Use in an Intensive Care Unit

ZEMURON has not been studied for long-term use in the intensive care unit (ICU). As with other nondepolarizing neuromuscular blocking drugs, apparent tolerance to ZEMURON may develop 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.

Myopathy after long-term administration of other nondepolarizing neuromuscular blocking agents in the ICU alone or in combination with corticosteroid therapy has been reported. Therefore, for patients receiving both neuromuscular blocking agents and corticosteroids, the period of use of the neuromuscular blocking agent should be limited as much as possible and only used in the setting where in the opinion of the prescribing physician, the specific advantages of the drug outweigh the risk.

Malignant Hyperthermia (MH)

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.

In an animal study in MH-susceptible swine, the administration of ZEMURON Injection did not appear to trigger malignant hyperthermia.

Prolonged Circulation Time

Conditions associated with an increased circulatory delayed time, e.g., cardiovascular disease or advanced age, may be associated with a delay in onset time [see DOSAGE AND ADMINISTRATION].

QT Interval Prolongation

The overall analysis of ECG data in pediatric patients indicates that the concomitant use of ZEMURON with general anesthetic agents can prolong the QTc interval [see Clinical Studies].

Conditions/Drugs Causing Potentiation of, or Resistance to, Neuromuscular Block

Potentiation

Nondepolarizing neuromuscular blocking agents have been found to exhibit profound neuromuscular blocking effects in cachectic or debilitated patients, patients with neuromuscular diseases, and patients with carcinomatosis.

Certain inhalation anesthetics, particularly enflurane and isoflurane, antibiotics, magnesium salts, lithium, local anesthetics, procainamide, and quinidine have been shown to increase the duration of neuromuscular block and decrease infusion requirements of neuromuscular blocking agents [see DRUG INTERACTIONS].

In these or other patients in whom potentiation of neuromuscular block or difficulty with reversal may be anticipated, a decrease from the recommended initial dose of ZEMURON should be considered [see DOSAGE AND ADMINISTRATION].

Resistance

Resistance to nondepolarizing agents, consistent with up-regulation of skeletal muscle acetylcholine receptors, is associated with burns, disuse atrophy, denervation, and direct muscle trauma. Receptor up-regulation may also contribute to the resistance to nondepolarizing muscle relaxants which sometimes develops in patients with cerebral palsy, patients chronically receiving anticonvulsant agents such as carbamazepine or phenytoin, or with chronic exposure to nondepolarizing agents. When ZEMURON is administered to these patients, shorter durations of neuromuscular block may occur, and infusion rates may be higher due to the development of resistance to nondepolarizing muscle relaxants.

Potentiation or Resistance

Severe acid-base and/or electrolyte abnormalities may potentiate or cause resistance to the neuromuscular blocking action of ZEMURON. No data are available in such patients and no dosing recommendations can be made.

ZEMURON-induced neuromuscular blockade was modified by alkalosis and acidosis in experimental pigs. Both respiratory and metabolic acidosis prolonged the recovery time. The potency of ZEMURON was significantly enhanced in metabolic acidosis and alkalosis, but was reduced in respiratory alkalosis. In addition, experience with other drugs has suggested that acute (e.g., diarrhea) or chronic (e.g., adrenocortical insufficiency) electrolyte imbalance may alter neuromuscular blockade. Since electrolyte imbalance and acid-base imbalance are usually mixed, either enhancement or inhibition may occur.

Incompatibility with Alkaline Solutions

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.

Increase in Pulmonary Vascular Resistance

ZEMURON may be associated with increased pulmonary vascular resistance, so caution is appropriate in patients with pulmonary hypertension or valvular heart disease [see Clinical Studies].

Use In Patients with Myasthenia

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.

Extravasation

If extravasation occurs, it may be associated with signs or symptoms of local irritation. The injection or infusion should be terminated immediately and restarted in another vein.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

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

Use In Specific Populations

Pregnancy

Pregnancy Category C

Developmental toxicology studies have been performed with rocuronium bromide 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 3 times a day to rats (0.3 mg/kg, 15%-30% of human intubation dose of 0.6-1.2 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 should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Labor and Delivery

The use of ZEMURON in Cesarean section has been studied in a limited number of patients [see Clinical Studies]. ZEMURON is not recommended for rapid sequence induction in Cesarean section patients.

Pediatric Use

The use of ZEMURON has been studied in pediatric patients 3 months to 14 years of age under halothane anesthesia. Of the pediatric patients anesthetized with halothane who did not receive atropine for induction, about 80% experienced a transient increase (30% or greater) in heart rate after intubation. One of the 19 infants anesthetized with halothane and fentanyl who received atropine for induction experienced this magnitude of change [see DOSAGE AND ADMINISTRATION and Clinical Studies].

ZEMURON was also studied in pediatric patients up to 17 years of age, including neonates, under sevoflurane (induction) and isoflurane/nitrous oxide (maintenance) anesthesia. Onset time and clinical duration varied with dose, the age of the patient, and anesthetic technique. The overall analysis of ECG data in pediatric patients indicates that the concomitant use of ZEMURON with general anesthetic agents can prolong the QTc interval. The data also suggest that ZEMURON may increase heart rate. However, it was not possible to conclusively identify an effect of ZEMURON independent of that of anesthesia and other factors. Additionally, when examining plasma levels of ZEMURON in correlation to QTc interval prolongation, no relationship was observed [see DOSAGE AND ADMINISTRATION, and Clinical Studies].

ZEMURON is not recommended for rapid sequence intubation in pediatric patients. Recommendations for use in pediatric patients are discussed in other sections [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

Geriatric Use

ZEMURON was administered to 140 geriatric patients (65 years or greater) 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. Clinical experiences and recommendations for use in geriatric patients are discussed in other sections [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY, and Clinical Studies].

Patients with Hepatic Impairment

Since ZEMURON is primarily excreted by the liver, it should be used with caution in patients with clinically significant hepatic impairment. ZEMURON 0.6 mg/kg has been studied in a limited number of patients (n=9) with clinically significant hepatic impairment 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 8 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 impairment [see CLINICAL PHARMACOLOGY]. 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 [see DOSAGE AND ADMINISTRATION].

Patients with Renal Impairment

Due to the limited role of the kidney in the excretion of ZEMURON, usual dosing guidelines should be followed. In patients with renal dysfunction, the duration of neuromuscular blockade was not prolonged; however, there was substantial individual variability (range: 22-90 minutes) [see CLINICAL PHARMACOLOGY].

Last reviewed on RxList: 6/7/2013
This monograph has been modified to include the generic and brand name in many instances.

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